Anti-mesothelin Chimeric Antigen Receptor (CAR) constructs and uses thereof

文档序号：788881 发布日期：2021-04-09 浏览：28次中文

阅读说明：本技术 抗间皮素嵌合抗原受体(car)构建体及其用途 (Anti-mesothelin Chimeric Antigen Receptor (CAR) constructs and uses thereof ) 是由戴晴刘健杨帅蒋坤彭园园呼晨武术于 2019-08-29 设计创作，主要内容包括：本文描述了经工程改造以表达单独的嵌合抗原受体(CAR)诸如抗间皮素CAR或其与滤泡刺激素受体(FSHR)结合结构域和/或显性负性转化生长因子-β受体II(dnTGFβRII)的组合的T细胞,所述T细胞用于治疗与间皮素表达相关的疾病。还描述了经工程改造以表达修饰的T细胞受体(TCR)的T细胞。(Described herein are T cells engineered to express Chimeric Antigen Receptors (CARs) such as anti-mesothelin CARs alone or in combination with Follicle Stimulating Hormone Receptor (FSHR) binding domain and/or dominant negative transforming growth factor-beta receptor II (dnTGF β RII) for the treatment of diseases associated with mesothelin expression. T cells engineered to express a modified T Cell Receptor (TCR) are also described.)

1. An isolated polynucleotide comprising a first nucleotide sequence encoding a fusion protein, wherein the fusion protein comprises, from N-terminus to C-terminus, a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR), and an extracellular domain, a transmembrane domain, and an intracellular domain of a CD3 polypeptide selected from the group consisting of CD 3-gamma chain, CD 3-delta chain, and CD 3-epsilon chain.

2. The isolated polynucleotide of claim 1, said extracellular domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 433 through 435, respectively; the transmembrane domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs 436 to 438; and the intracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOS 439 to 441, respectively.

3. The isolated polynucleotide of claim 1 or 2, further comprising a second nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises: (a) an extracellular domain comprising an antigen-binding fragment that specifically binds to a tumor antigen; (b) a transmembrane domain; and (c) an intracellular signaling domain.

4. An isolated polynucleotide comprising a nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises:

(a) an extracellular domain comprising a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR) and an antigen-binding fragment that specifically binds to a tumor antigen;

(b) a transmembrane domain; and

5. The isolated polynucleotide of any one of claims 1 to 4, further comprising a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response of an immune cell, preferably a dominant negative form of a transforming growth factor beta (TGF- β) receptor.

6. The isolated polynucleotide of any one of claims 1 to 5, wherein said first, said second and/or said third nucleotide sequence are linked to each other via a 2A peptide coding sequence.

7. The isolated polynucleotide of any one of claims 1 to 6, wherein said first polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO 319-331, preferably said fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO 442-444.

8. The isolated polynucleotide of any one of claims 1 to 7, wherein said first polypeptide is linked to the amino-terminus or the carboxy-terminus of the extracellular domain of said CD3 polypeptide or of said antigen-binding fragment via a linker.

9. The isolated polynucleotide of any one of claims 3 to 8, wherein said tumor antigen is selected from the group consisting of mesothelin, folate receptor alpha, mucin 16(MUC16), Prostate Specific Membrane Antigen (PSMA), human epidermal growth factor receptor 2(HER2), Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR).

10. The isolated polynucleotide of claim 9, wherein the tumor antigen is mesothelin, preferably human mesothelin.

11. The isolated polynucleotide of any one of claims 3 to 10, wherein the antigen-binding fragment is Fab, Fab ', F (ab')₂Fv, single chain variable fragment (scFv), minibody, diabody, single domain antibody (sdAb), light chain variable domain (VL), or variable domain of camelid antibody (V)_HH)。

12. The isolated polynucleotide of claim 11, wherein the antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

A single chain variable fragment (scFv) comprising a heavy chain complementarity determining region 1(HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1(LCDR1), LCDR2 and LCDR3, said complementarity determining regions having the polypeptide sequences:

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively.

13. The isolated polynucleotide of claim 12, wherein the antigen-binding fragment comprises:

i. the single domain antibody comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428; or

The single-stranded variable fragment comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 205-220.

14. The isolated polynucleotide of any of claims 4 to 13, wherein said extracellular domain of said CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NO 348-357, or said CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NO 370-379 and SEQ ID NO 448-450.

15. An isolated polynucleotide comprising a nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises:

(a) an extracellular domain comprising an antigen-binding fragment that specifically binds to mesothelin, preferably human mesothelin;

(b) a transmembrane domain; and

wherein the CAR optionally further comprises a signal peptide at the amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain, and wherein the antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively.

16. The isolated polynucleotide of claim 15, wherein the antigen-binding fragment comprises:

i. said single domain antibody comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428, or

The single-stranded variable fragment comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 205-220,

preferably, the CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NO 358-367 and SEQ ID NO 445-447.

17. The isolated polynucleotide of claim 15 or 16, wherein the polynucleotide further comprises a second nucleotide sequence encoding a fusion protein, and the fusion protein comprises, from N-terminus to C-terminus, a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR), and an extracellular domain, a transmembrane domain, and an intracellular domain of a CD3 polypeptide selected from the group consisting of the CD3- γ chain, CD3- δ chain, or CD 3-epsilon chain, preferably the nucleotide sequence encoding the CAR is linked to the second nucleotide sequence via a 2A peptide coding sequence.

18. The isolated polynucleotide of claim 17, wherein said extracellular domain of said CD3 polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs 433 through 435; the transmembrane domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs 436 to 438; and the intracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOS 439 to 441, respectively.

19. The isolated polynucleotide of claim 15 or 16, wherein the polynucleotide further comprises a second nucleotide sequence encoding a second Chimeric Antigen Receptor (CAR), wherein the second CAR comprises:

(a) an extracellular domain comprising a polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR);

(b) a transmembrane domain; and

wherein the second CAR optionally further comprises a signal peptide at the amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain,

preferably, the nucleotide sequence encoding the CAR is linked to the second nucleotide sequence via a 2A peptide coding sequence.

20. The isolated polynucleotide of any of claims 17-19, wherein the polypeptide that specifically binds to FSHR comprises an amino acid sequence selected from the group consisting of SEQ ID NOs 319-331, preferably the fusion protein of claim 17 comprises an amino acid sequence selected from the group consisting of SEQ ID NOs 442-444, or the isolated polynucleotide of claim 17 encodes a protein having an amino acid sequence selected from the group consisting of SEQ ID NOs 454-456; and the isolated polynucleotide of claim 19 comprising an amino acid sequence selected from the group consisting of SEQ ID NO 380-389 and SEQ ID NO 451-453.

21. The isolated polynucleotide of any of claims 3-20, wherein the transmembrane domain in the CAR or the second CAR is independently selected from the group consisting of: a CD8 a transmembrane domain, a CD28 transmembrane domain, a CD4 transmembrane domain, a CD3 zeta transmembrane domain, a CD2 transmembrane domain, a 4-1BB transmembrane domain, an OX40 transmembrane domain, an ICOS transmembrane domain, a CTLA-4 transmembrane domain, a PD-1 transmembrane domain, a LAG-3 transmembrane domain, a 2B4 transmembrane domain, a BTLA transmembrane domain, and a GMCSFR transmembrane domain.

22. The isolated polynucleotide of any of claims 2-21, wherein said intracellular signaling domain in said CAR or said second CAR is independently selected from the group consisting of the signaling domains of: CD3 ζ, FcR γ, FcR β, CD3 γ, CD3 δ, CD3 ε, CD5, CD22, CD79a, CD79b, and CD66 d.

23. The isolated polynucleotide of claim 22, wherein the CAR or the second CAR independently comprises a costimulatory domain selected from the group consisting of costimulatory domains of one or more of: CD28, 4-1BB (CD137), CD27, OX40, CD27, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, TNFRSF9, TNFRSF4, TNFRSF8, CD40LG, ITGB2, KLRC2, TNFRSF18, TNFRSF14, HAVR 1, LGALS9, CD83, and a ligand that specifically binds to CD 83.

24. The isolated polynucleotide of any of claims 4-8, wherein said CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NO 370 and 379 and SEQ ID NO 448 and 450.

25. The isolated polynucleotide of any of claims 3 and 15-24, wherein the CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NOs 358 and 367 and 445.

26. The isolated polynucleotide of any of claims 1-25, further comprising a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response of said immune cell, preferably said nucleotide sequence encoding said CAR or said second CAR is linked to said third nucleotide sequence via a 2A peptide coding sequence.

27. The isolated polynucleotide of claim 26, wherein said inhibitor of the cell-mediated immune response of said immune cell is a transforming growth factor beta (TGF- β) receptor.

28. The isolated polynucleotide of claim 27, wherein said dominant negative form of said inhibitor comprises the amino acid sequence of SEQ ID NO: 347.

29. The isolated polynucleotide of claim 27, wherein the isolated polynucleotide encodes a protein having an amino acid sequence selected from the group consisting of seq id no:390-419 SEQ ID NO, 460-468 SEQ ID NO, 457-459 SEQ ID NO and 469-471 SEQ ID NO.

30. An isolated antibody or antigen-binding fragment, wherein the isolated antibody or antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158,

wherein the isolated antibody or antigen-binding fragment thereof specifically binds mesothelin, preferably human mesothelin.

31. The isolated antibody or antigen-binding fragment of claim 30, wherein the antibody or antigen-binding fragment comprises:

The single-stranded variable fragment comprising an amino acid sequence at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 205-220.

32. An isolated nucleic acid encoding the isolated antibody or antigen-binding fragment thereof of claim 30 or 31.

33. A vector comprising the polynucleotide of any one of claims 1-29 and 32.

34. A host cell comprising the polynucleotide of any one of claims 1-29 and 32 or the vector of claim 33, preferably the cell is a T cell.

35. A method of treating cancer, preferably ovarian cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the host cell of claim 34.

36. An engineered immune cell expressing a CAR or TCR complex encoded by the polynucleotide of any one of claims 1-29.

37. The engineered immune cell of claim 36, wherein the engineered immune cell is selected from the group consisting of a cytotoxic T cell, a helper T cell, a natural killer T cell, a γ δ T cell, and an NK cell.

38. A pharmaceutical composition comprising the engineered immune cell of claim 36 or 37 and a pharmaceutically acceptable carrier.

39. A pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of claim 30 or 31, and a pharmaceutically acceptable carrier.

40. A method of treating cancer in a subject in need thereof, preferably the following cancers: ovarian cancer, primary peritoneal cancer, Pancreatic Ductal Adenocarcinoma (PDA), Malignant Pleural Mesothelioma (MPM), lung adenocarcinoma, triple negative breast cancer, endometrial cancer, cholangiocarcinoma, gastric cancer, or pediatric acute myelogenous leukemia, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 38 or 39.

41. A method of engineering an immune cell, the method comprising introducing into the immune cell the polynucleotide of any one of claims 1-29 operably linked to a promoter.

42. A method of producing a pharmaceutical composition, the method comprising combining the engineered immune cell of claim 36 or 37 with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition.

Technical Field

The present invention relates generally to the use of T cells engineered to express a Chimeric Antigen Receptor (CAR), such as an anti-mesothelin CAR, alone or in combination with a Follicle Stimulating Hormone Receptor (FSHR) binding domain and/or a dominant negative transforming growth factor-beta receptor II (dnTGF β RII), for the treatment of diseases associated with mesothelin expression.

Background

Adoptive T cell immunotherapy, in which patient's own T lymphocytes are engineered to express Chimeric Antigen Receptors (CARs), has shown great promise in the treatment of hematologic malignancies. Gill S et al, Blood Rev.2016; 30(3):157-167. CARs generally contain 3 modules: an extracellular target-binding moiety, a transmembrane domain (TM domain) that anchors the CAR in the cell membrane, and an intracellular signaling domain (ICD) that transmits activation signals. Once bound to the target tumor antigen, the CAR can activate T cells to mount a specific anti-tumor response in a Major Histocompatibility Complex (MHC) -independent manner.

Mesothelin (MSLN) was originally identified as a tumor-associated antigen by Ira Pastan and Mark Willingham in 1992 at the national cancer institute. Chang K et al, Cancer Res.1992; 52(1) 181-; 93(1):136-140. Mesothelin is a Glycosylated Phosphatidylinositol (GPI) -anchored glycoprotein with normal expression confined to mesothelial cells lining the pleura, peritoneum and pericardium, but overexpressed in many malignancies, including: malignant Pleural Mesothelioma (MPM), Pancreatic Ductal Adenocarcinoma (PDA), ovarian cancer, lung adenocarcinoma, triple negative breast cancer, endometrial cancer, cholangiocarcinoma, gastric cancer, and pediatric acute myelogenous leukemia.

Mesothelin is synthesized as a 71-kD precursor protein and cleaved by endoprotease furin to release the secreted N-terminal region, known as megakaryocyte enhancing factor (MPF), while the 41-kD mature mesothelin remains attached to the membrane. Yamaguchi N et al, Biol chem.1994; 269:805-808. The remaining GPI-linked mature mesothelin can also be shed from the cell by the action of tumor necrosis factor alpha-converting enzyme protease. Zhang Y et al, Cancer res.2011; 71:5915-5922.

The correlation between serum levels of shed mesothelin and disease suggests a potential role for mesothelin protein in cancer progression. However, the biological function of mesothelin is not well understood. Mesothelin is known to bind to the ovarian cancer antigen MUC16 (cancer antigen 125), which has been shown to induce cell-to-cell adhesion and may promote peritoneal seeding and metastatic spread. Gubbels JA et al, Mol cancer.2006; 5:50. Furthermore, mesothelin knockout mice typically grow and multiply and have no detectable phenotype. Bera TK et al, Mol Cell biol.2000; 20:2902-2906.

Follicle Stimulating Hormone Receptors (FSHRs) are G protein-linked receptors found in ovarian surface epithelium as well as in some ovarian cancer cell lines and tissues, the distribution of which may be limited to the reproductive system. Zhang W et al, Am J Pathol. 1996; 148:47-53. Follicle Stimulating Hormone (FSH) is a glycoprotein hormone consisting of an α chain and a β chain, and it has been identified that amino acids 33 to 53 of the FSH β chain bind to FSHR with high affinity. Agris PF et al, J Protein chem.1992; 11:495-507. In particular, the FSH β 33-53 peptide, when covalently linked to a nanoparticle, exhibits a function providing highly selective nanoparticle delivery to FSHR-expressing ovarian tumors. Zhang XY et al, Cancer res.2009; 69(16):6506-6514. FSHR expression in 50-70% of ovarian cancer tissues and its selective expression on the vascular surface of a wide range of tumors has been reported: such as renal cell carcinoma, prostate Cancer, breast Cancer, colon Cancer, pancreatic Cancer, bladder Cancer, kidney Cancer, lung Cancer, liver Cancer, stomach Cancer, testicular Cancer, and ovarian Cancer (primary tumors and/or metastases) (Radu et al, N Engl J Med 363:1621,2010; Siraj et al, BMC Cancer 13:246,2013; and Renner et al, Histopathology 63:29,2013). The relative specific expression of FSHR on the cell surface of malignant tissues makes it an attractive target for FSHR tumor immunotherapy.

Transforming growth factor-beta 1(TGF β 1) is a multifunctional secreted protein that regulates cell proliferation, differentiation, and movement and affects the production of extracellular matrix, neovascularization, and immune function. Derynck R et al, Nature.2003; 425:577-584. Expression of TGF β 1 and its receptors (TGF β receptor type I and TGF β receptor type II) has been shown to play a key role in the proliferation and progression of epithelial ovarian cancer. TGF β may also adversely affect the tumor cells themselves by promoting terminal differentiation and apoptosis. Tumors can avoid this activity by mutations in their TGF β receptors (TGF β RI and TGF β RII). Ebner R et al, science.1993; 260:1344-1348. The immunosuppressive environment in many cancers, due in part to TGF signaling, can be blocked by the use of dominant negative TGF β RII that is truncated and lacks the intracellular domains necessary for downstream signaling. Wieser R et al, Molecular and cellular biology.1993; 13:7239-7247. A clinical trial (NCT00368082) has recently been reported that tests the safety and efficacy of dnTGF β RII receptors in EBV-specific T cells of lymphoma. Bollard CM et al, J Clin Oncol.2018; 36:1128-1139. More recently, another clinical trial was initiated to evaluate CAR-T cells involved in Prostate Specific Membrane Antigen (PSMA) co-expressed with dnTGF β RII as a method for patients with relapsed and refractory metastatic prostate cancer (NCT 03089203). Christopher C et al, Molecular therapy.2018; 26:1855-1866.

T Cell Receptors (TCRs) are transmembrane heterodimers containing an alpha chain and a beta chain or a delta chain and a gamma chain linked by a disulfide bond. TCRs typically contain highly variable alpha and beta chains, expressed as part of a complex with an invariant CD3 chain molecule. Complementarity Determining Regions (CDRs) within the α and β chains determine the antigen to which the TCR will bind, thereby activating T cells, resulting in an overabundance of immune responses. For example, Antigen Presenting Cells (APCs) digest pathogens and display fragments thereof on Major Histocompatibility Complex (MHC) molecules. This MHC/antigen complex binds to the TCR, while other costimulatory molecules (e.g., CD28) are activated, resulting in T cell activation, proliferation, differentiation, apoptosis, or cytokine release (see, e.g., Samelson,2011, Cold Spring Harb Perspectrum biol.,3(12): a 011510). The TCR may also interact with other molecules including non-peptide antigens such as lipids (Mori and De Libero,2012, immunological Res,53,191-199), metabolic intermediates that bind to the MHC-like molecule MR1 (Reantragoon et al 2012, J Exp Med,209: 761-774), and the like. Initiation of TCR signaling requires co-receptors such as CD4 for helper T cells and CD8 for cytotoxic T cells. These co-receptors act as cell adhesion molecules that bind to their respective MHC molecules and stabilize the interaction of T cells with antigen presenting cells. The TCR is also located in close proximity to a complex of signaling molecules, which helps to mediate T cell activation. They include the CD3 protein family (CD 3. delta., CD 3. epsilon. and CD 3. gamma.) and the TCR zeta (. zeta.) chain (FIG. 1) (Wucherpfennig et al, 2010, Cold Spring Harb Perspect Biol,2: a 005140).

There is a need for a more targeted antigen-specific immunotherapy for the treatment of certain cancers, such as ovarian cancer.

Disclosure of Invention

In one general aspect, the invention relates to T cells engineered to express a Chimeric Antigen Receptor (CAR) and their use for treating certain cancers. In another general aspect, the invention relates to T cells engineered to express a modified T Cell Receptor (TCR) complex containing a Follicle Stimulating Hormone Receptor (FSHR) binding domain. In certain aspects, the invention relates to T cells engineered to express an anti-mesothelin CAR in combination with a modified TCR complex containing an FSHR binding domain and/or dnTGF β RII for use in the treatment of a disease associated with mesothelin and/or FSHR expression. In certain aspects, the invention relates to T cells engineered to express a CAR comprising a FSHR binding domain and an antigen binding fragment that specifically binds to a tumor antigen, and uses thereof. In certain aspects, the invention relates to T cells engineered to express a CAR targeting mesothelin and/or FSHR and/or dominant negative transforming growth factor-beta receptor II (dnTGF β RII), for use in the treatment of a disease associated with mesothelin expression.

Provided herein is an isolated polynucleotide comprising a nucleotide sequence encoding a modified T Cell Receptor (TCR) complex protein. The protein comprises, from N-terminus to C-terminus, a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR), and the extracellular, transmembrane and intracellular domains of a CD3 polypeptide selected from the group consisting of CD 3-gamma chain, CD 3-delta chain and CD 3-epsilon chain.

In certain embodiments, the first polypeptide that specifically binds to FSHR may, for example, comprise an amino acid sequence selected from the group consisting of SEQ ID NO 319-331 and the protein further comprises an extracellular domain comprising an amino acid sequence selected from the group consisting of SEQ ID NO 433 to 435, respectively; a transmembrane domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 436 to 438; and intracellular domains comprising amino acid sequences selected from the group consisting of SEQ ID NOS 439 to 441, respectively. In certain embodiments, the protein further comprises a signal peptide. In certain embodiments, the signal peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 430 to 432.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a modified TCR complex protein comprising an amino acid sequence selected from the group consisting of SEQ ID NO 442-444.

In certain embodiments, the isolated polynucleotide further comprises a second nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises: (a) an extracellular domain comprising an antigen-binding fragment that specifically binds to a tumor antigen; (b) a transmembrane domain; and (c) an intracellular signaling domain. The second nucleotide sequence may encode any suitable CAR. Preferably, the second nucleotide sequence encodes a CAR of the invention, such as a CAR that specifically binds to mesothelin. Examples of CARs include, but are not limited to, the CARs exemplified herein. Preferably, the nucleotide sequence encoding the modified TCR complex protein is linked to the nucleotide sequence encoding the CAR via a 2A peptide coding sequence.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a protein having an amino acid sequence selected from the group consisting of SEQ ID NO 454-456.

In certain embodiments, the nucleotide sequence encoding the modified TCR complex protein further comprises a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response of an immune cell. The inhibitor of the cell-mediated immune response of the immune cell may be, for example, a transforming growth factor beta (TGF- β) receptor. The dominant negative form of the inhibitor may, for example, comprise the amino acid sequence of SEQ ID NO: 347. In certain embodiments, the nucleotide sequence encoding the modified TCR complex protein is linked to the third nucleotide sequence via a 2A peptide coding sequence.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a protein having an amino acid sequence selected from the group consisting of SEQ ID NO 457-.

In certain embodiments, the isolated polynucleotide comprises: a first nucleotide sequence encoding a modified TCR complex protein; a second nucleotide sequence encoding a CAR; and a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response of the immune cell. In certain embodiments, the first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence are linked via a 2A peptide coding sequence. The first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence may be arranged in any order in the isolated polynucleotide.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a protein having an amino acid sequence selected from the group consisting of SEQ ID NO 469-471.

Also provided herein are isolated polynucleotides comprising a nucleotide sequence encoding a Chimeric Antigen Receptor (CAR). The CAR may, for example, comprise: (a) an extracellular domain comprising a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR) and an antigen-binding fragment that specifically binds to a tumor antigen; (b) a transmembrane domain; and (c) an intracellular signaling domain. The CAR may optionally further comprise a signal peptide at its amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain.

In certain embodiments, the first polypeptide that specifically binds to FSHR comprises an amino acid sequence selected from the group consisting of SEQ ID NO 319-331.

In certain embodiments, the first polypeptide is linked to the amino terminus or the carboxy terminus of the antigen-binding fragment via a linker. The linker may for example be selected from the group consisting of: g₄S joint, (G)₄S)₂Linker, (G)₄S)₃Linker, (G)₄S)₄A joint and (G)₄S)₅And (4) a joint.

In certain embodiments, the tumor antigen is selected from the group consisting of: mesothelin, folate receptor alpha, mucin 16(MUC16), Prostate Specific Membrane Antigen (PSMA), human epidermal growth factor receptor 2(HER2), Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR). The tumor antigen may be, for example, mesothelin, preferably human mesothelin.

In certain embodiments, the antigen binding fragment comprises Fab, Fab ', F (ab')₂Fv, single chain variable fragment (scFv), minibody, diabody, single domain antibody (sdAb), light chain variable domain (VL), or variable domain of camelid antibody (V)_HH) In that respect The antigen-binding fragment may, for example, comprise:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158,

or variants thereof comprising up to about 3 (such as any of about 1, 2, or 3) amino acid substitutions in the CDR regions.

In certain embodiments, the antigen-binding fragment comprises:

i. a single domain antibody comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions; or

A single-stranded variable fragment comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 205-220 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

In certain embodiments, the extracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO 348-357, or a variant thereof, preferably the variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

Also provided are isolated polynucleotides comprising a nucleotide sequence encoding a Chimeric Antigen Receptor (CAR). The CAR can, for example, comprise (a) an extracellular domain comprising an antigen-binding fragment that specifically binds to mesothelin, preferably human mesothelin; (b) a transmembrane domain; and (c) an intracellular signaling domain. The CAR can optionally further comprise a signal peptide at the amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain. The antigen binding fragment may, for example, comprise

i. A single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs: 45. 113 and 181;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs: 58. 126 and 194;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs: 60. 128 and 196;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158,

or variants thereof comprising up to about 3 (such as any of about 1, 2, or 3) amino acid substitutions in the CDR regions.

In certain embodiments, the antigen-binding fragment comprises:

i. single domain antibody comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and 420-428 or a variant thereof, preferably said variant comprises one, two or three amino acid substitutions, deletions or insertions, or

A single-stranded variable fragment comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 205-220 or a variant thereof, preferably said variant comprises one, two or three amino acid substitutions, deletions or insertions.

In certain embodiments, the polynucleotide further comprises a second nucleotide sequence encoding a second Chimeric Antigen Receptor (CAR), wherein the second CAR comprises:

(a) an extracellular domain comprising a polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR);

(b) A transmembrane domain; and

wherein the second CAR optionally further comprises a signal peptide at the amino terminus and a hinge region connecting the extracellular domain with the transmembrane domain.

Preferably, the nucleotide sequence encoding the CAR is linked to the second nucleotide sequence via a 2A peptide coding sequence.

The polypeptide that specifically binds to FSHR may for example comprise an amino acid sequence selected from the group consisting of SEQ ID NO 319-331.

In certain embodiments, the CAR comprises a signal peptide having an amino acid sequence at least 90% identical to SEQ ID NO: 340. In certain embodiments, the CAR comprises a hinge region having an amino acid sequence at least 90% identical to SEQ ID NO 341.

In certain embodiments, the CAR comprises a transmembrane domain selected from the group consisting of: a CD8 a transmembrane domain, a CD28 transmembrane domain, a CD4 transmembrane domain, a CD3 zeta transmembrane domain, a CD2 transmembrane domain, a 4-1BB transmembrane domain, an OX40 transmembrane domain, an ICOS transmembrane domain, a CTLA-4 transmembrane domain, a PD-1 transmembrane domain, a LAG-3 transmembrane domain, a 2B4 transmembrane domain, a BTLA transmembrane domain, and a GMCSFR transmembrane domain.

In certain embodiments, the CAR comprises an intracellular signaling domain selected from the group consisting of: signaling domains of CD3 ζ, FcR γ, FcR β, CD3 γ, CD3 δ, CD3 ε, CD5, CD22, CD79 α, CD79 β, and CD66 δ.

In certain embodiments, the CAR comprises a co-stimulatory domain selected from the group consisting of a co-stimulatory domain of one or more of: CD28, 4-1BB (CD137), CD27, OX40, CD27, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, TNFRSF9, TNFRSF4, TNFRSF8, CD40LG, ITGB2, KLRC2, TNFRSF18, TNFRSF14, HAVR 1, LGALS9, CD83, and a ligand that specifically binds to CD 83.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a CAR comprising an amino acid sequence selected from the group consisting of SEQ ID NO:370-379 and SEQ ID NO: 448-450.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO 380-389 and SEQ ID NO 451-453.

In certain embodiments, the nucleotide sequence encoding the CAR further comprises a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response of the immune cell. The inhibitor of the cell-mediated immune response of the immune cell may be, for example, a transforming growth factor beta (TGF- β) receptor. The dominant negative form of the inhibitor may, for example, comprise the amino acid sequence of SEQ ID NO: 347. In certain embodiments, the nucleotide sequence encoding the CAR is linked to the third nucleotide sequence via a 2A peptide coding sequence.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding an amino acid sequence selected from the group consisting of SEQ ID NO:390-419 and SEQ ID NO: 460-468.

Vectors comprising the polynucleotides of the invention are also provided.

Also provided is a host cell comprising a polynucleotide of the invention or a vector of the invention.

Also provided are engineered immune cells that express a CAR encoded by a polynucleotide of the invention. The engineered immune cell may, for example, be selected from the group consisting of: cytotoxic T cells, helper T cells, natural killer T cells, γ δ T cells, and NK cells.

Pharmaceutical compositions are also provided. The pharmaceutical composition may comprise a polynucleotide of the invention, a vector of the invention, a host cell of the invention, and/or an engineered immune cell of the invention, and a pharmaceutically acceptable carrier.

Also provided are methods of treating cancer in a subject in need thereof. The method can, for example, comprise administering to the subject a therapeutically effective amount of a host cell of the invention. The method can, for example, comprise administering to the subject a therapeutically effective amount of a pharmaceutical composition of the invention. In certain embodiments, the cancer is selected from the group consisting of: ovarian cancer, primary peritoneal cancer, Pancreatic Ductal Adenocarcinoma (PDA), Malignant Pleural Mesothelioma (MPM), lung adenocarcinoma, triple negative breast cancer, endometrial cancer, cholangiocarcinoma, gastric cancer, and pediatric acute myelogenous leukemia.

Methods of engineering immune cells are also provided. The method comprises introducing a polynucleotide of the invention into an immune cell, wherein the polynucleotide is operably linked to a promoter.

Methods of producing the pharmaceutical compositions are also provided. The method comprises combining a polynucleotide of the invention, a vector of the invention, a host cell of the invention, and/or an engineered immune cell of the invention with a pharmaceutically acceptable carrier to obtain a pharmaceutical composition.

Also provided are systems for inducing the activity of immune cells and/or target cells. The system can, for example, comprise a Chimeric Antigen Receptor (CAR) of the invention.

Also provided are isolated antibodies or antigen-binding fragments that specifically bind mesothelin, preferably human mesothelin. The isolated antibody or antigen-binding fragment may, for example, be selected from the group consisting of: fab, Fab ', F (ab')₂Fv, single chain variable fragment (scFv), minibody, diabody, single domain antibody (sdAb), light chain variable domain (VL), and variable domain of camelid antibody (V)_HH)。

In certain embodiments, an isolated antibody or antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NOs: 40. 108 and 176;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs: 45. 113 and 181;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

x. SEQ ID NOs: 51. 119 and 187;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. are SEQ ID NOs: 62. 130 and 198;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. Are respectively SEQ ID NO: 7. 75, 143, 8, 76 and 144;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

21, 89, 157, 22, 90 and 158, respectively; or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR regions;

wherein the isolated antibody or antigen-binding fragment thereof specifically binds mesothelin, preferably human mesothelin.

In certain embodiments, the antibody or antigen-binding fragment comprises:

i. a single domain antibody comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and 420-428 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions; or

A single-chain variable fragment comprising a sequence identical to a sequence selected from the group consisting of seq id NOs: 205-220 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

In certain embodiments, the antibody or antigen-binding fragment thereof is chimeric. In certain embodiments, the antibody or antigen-binding fragment thereof is human or humanized.

Also provided are isolated nucleic acids encoding the isolated antibodies or antigen-binding fragments thereof of the invention. Vectors comprising the isolated nucleic acids of the invention are also provided. Also provided are host cells comprising the isolated nucleic acids and/or vectors of the invention.

Also provided are pharmaceutical compositions comprising an isolated antibody or antigen-binding fragment thereof of the invention and a pharmaceutically acceptable carrier.

Also provided are methods of treating cancer in a subject in need thereof. The method comprises administering to the subject a pharmaceutical composition comprising an isolated antibody or antigen-binding fragment thereof of the invention and a pharmaceutically acceptable carrier.

Also provided are methods of producing the antibodies of the invention or antigen-binding fragments thereof. The method comprises culturing a cell comprising a nucleic acid encoding the antibody or antigen-binding fragment thereof under conditions in which the antibody or antigen-binding fragment thereof is produced, and recovering the antibody or antigen-binding fragment thereof from the cell or culture.

Also provided are methods of producing a pharmaceutical composition comprising an antibody or antigen-binding fragment thereof of the invention. The method comprises combining the antibody or antigen-binding fragment thereof with a pharmaceutically acceptable carrier to obtain a pharmaceutical composition.

Drawings

The foregoing summary, as well as the following detailed description of preferred embodiments of the present application, will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the present application is not limited to the precise embodiments shown in the drawings.

Figure 1A is a schematic of an anti-mesothelin CAR construct; and figure 1B shows the CAR construct anchored in the T cell membrane.

FIG. 2A is a schematic representation of the FSHR TCR construct; and figure 2B shows the TCR construct anchored in the T cell membrane.

Figures 3A-3D show schematic diagrams of embodiments of FSHR/mesothelin tandem CAR constructs and illustrations of the constructs anchored in the T cell membrane.

Figures 4A-4B show a schematic of the mesothelin/FSHR dual CAR construct and a diagram of the construct anchored in the T cell membrane.

Figures 5A-5B show a schematic of the mesothelin/FSHR CAR/TCR construct and a schematic of the construct anchored in the T cell membrane.

Fig. 6A-6L show schematic diagrams of dnTGF β RII armored CAR and/or TCR constructs and illustrations of constructs anchored in T cell membranes, according to embodiments of the application.

Figures 7-8 are graphs demonstrating that anti-mesothelin CAR-T induces killing against OVCAR-8 cells according to embodiments of the present invention. In each figure, the results of CAR are depicted in the order shown in the right-hand legend.

Figures 9-10 are graphs showing the levels of IFN γ in the supernatant of T cells transduced with various CAR constructs according to embodiments of the present application. In each figure, the results of CAR are depicted in the order shown in the right-hand legend.

Figure 11 shows a graph demonstrating long-term expansion of anti-mesothelin CAR-T by repeated stimulation, according to embodiments of the present application.

Figure 12 shows a graph demonstrating anti-tumor efficacy of anti-mesothelin CAR-T according to embodiments of the present application in an OVCAR-8 xenograft model.

Figure 13 shows FSHR expression on ovarian cancer cell lines as determined by flow cytometry.

Figure 14 shows a graph demonstrating that FSHR/mesothelin tandem CAR-T induces killing against OVCAR-8 cells according to an embodiment of the invention. In the figure, the results of CAR are depicted in the order shown in the right-hand legend.

Figure 15 shows a graph demonstrating that mesothelin/FSHR dual CAR-T and mesothelin/FSHR CAR/TCR-T induce killing against OVCAR-8 cells according to embodiments of the present application. In the figure, the results of CAR are depicted in the order shown in the right-hand legend.

Figures 16-17 show graphs demonstrating that dnTGF β RII armored CAR-T and naked CAR-T induce killing against OVCAR-8 cells according to embodiments of the present application. In each figure, the results of CAR are depicted in the order shown in the right-hand legend.

Figures 18-19 show graphs demonstrating levels of IFNg and TNFa release detected after administration of CARs and/or TCR constructs according to embodiments of the present application. In each figure, the results of CAR are depicted in the order shown in the right-hand legend.

Figures 20-21 show graphs demonstrating anti-tumor efficacy of anti-mesothelin CAR-T and mesothelin/FSHR dual CAR-T according to embodiments of the present application in an OVCAR-8 xenograft model.

Figure 22 shows a graph demonstrating the anti-tumor efficacy of dnTGF β RII armored CAR-T and naked CAR-T according to embodiments of the present application in an OVCAR-8 xenograft model.

Detailed Description

Various publications, articles and patents are cited or described in the background and throughout this specification; each of these references is incorporated herein by reference in its entirety. The discussion of documents, acts, materials, devices, articles or the like included in this specification is solely for the purpose of providing a context for the present invention. The discussion is not an admission that any or all of these matters form part of the prior art with respect to any of the disclosed or claimed inventions.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, certain terms used herein have the meanings as set forth in the specification.

Unless the context clearly dictates otherwise, it must be noted that, as used herein and in the appended claims, the singular forms "a", "an" and "the" include plural references.

Unless otherwise indicated, any numerical value, such as concentration or concentration range described herein, is to be understood as being modified in all instances by the term "about". Accordingly, numerical values typically include the enumerated values. + -. 10%. For example, a concentration of 1mg/mL includes 0.9mg/mL to 1.1 mg/mL. Also, a concentration range of 1% to 10% (w/v) includes 0.9% (w/v) to 11% (w/v). The use of numerical ranges as used herein expressly includes all possible subranges, all individual numerical values within the range, including integers within the range and fractions of these values, unless the context clearly dictates otherwise.

The term "at least" preceding a series of elements is to be understood as referring to each element in the series, unless otherwise indicated. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the present invention.

As used herein, the terms "comprising," "comprises," "including," "includes," "having," "has," "having," "contains" or "containing" or any other variation thereof, are to be construed as including the stated integer or group of integers but not to exclude any other integer or group of integers and are intended to be non-exclusive or open-ended. For example, a composition, mixture, process, method, article, or apparatus that comprises a list of elements is not necessarily limited to only those elements but may include other elements not expressly listed or inherent to such composition, mixture, process, method, article, or apparatus. Further, unless expressly stated to the contrary, "or" means an inclusive or and not an exclusive or. For example, condition a or B is satisfied by either: a is true (or present) and B is false (or not present), a is false (or not present) and B is true (or present), and both a and B are true (or present).

As used herein, the connecting term "and/or" between a plurality of listed elements is understood to encompass both individual options and combination options. For example, when two elements are connected by "and/or," a first option refers to applying the first element without the second element. The second option refers to applying the second element without the first element. The third option refers to applying the first element and the second element together. Any of these options should be understood to fall within the meaning described and thus meet the requirements of the term "and/or" as used herein. Simultaneous application of more than one option should also be understood to fall within the meaning and thus fulfil the requirements of the term "and/or".

As used herein, the term "consists of" or variations such as "consists of" or "consisting of" as used throughout the specification and claims, is intended to include any listed integer or group of integers without adding additional integers or groups of integers to a specified method, structure or composition.

As used herein, the term "consisting essentially of" or variations such as "consisting essentially of" or "consisting essentially of" as used throughout the specification and claims indicates that any listed integer or group of integers, and optionally any listed integer or group of integers, is included that does not substantially alter the basic or novel properties of the illustrated method, structure or composition. See m.p.e.p. § 2111.03.

As used herein, "subject" means any animal, preferably a mammal, most preferably a human. As used herein, the term "mammal" encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, more preferably humans.

It will also be understood that the terms "about," "approximately," "generally," "substantially," and the like as used herein, when referring to a dimension or characteristic of a component of the preferred invention, indicate that the dimension/characteristic is not a strict boundary or parameter and does not preclude minor variations thereof that are functionally identical or similar, as would be understood by one of ordinary skill in the art. At the very least, such references, including numerical parameters, are to include variations that do not change the least significant digit using accepted mathematical and industrial principles in the art (e.g., rounding, measurement or other systematic errors, manufacturing tolerances, etc.).

The term "identical" or percent "identity," in the context of two or more nucleic acid or polypeptide sequences (e.g., CAR polypeptides and CAR polynucleotides encoding same; anti-mesothelin antibodies and antigen-binding fragments thereof and polynucleotides encoding same; FSHR peptides and polynucleotides encoding same; dntgfbetarii peptides and polynucleotides encoding same), means that the two or more sequences or subsequences are the same or have the indicated percentage of amino acid residues or nucleotides that are the same when compared and aligned for maximum correspondence as measured using one of the following sequence comparison algorithms or by visual inspection.

For sequence comparison, typically one sequence is used as a reference sequence and the test sequence is compared to the reference sequence. When using a sequence comparison algorithm, both the test sequence and the reference sequence are entered into the computer, subsequence coordinates are set, if necessary, and then sequence algorithm program parameters are set. The sequence comparison algorithm then calculates the percent sequence identity of one or more test sequences relative to the reference sequence based on the set program parameters.

Optimal sequence alignments for comparison can be made by: local homology algorithms such as Smith & Waterman, adv.Appl.Math.2:482 (1981); homology alignment algorithms of Needleman and Wunsch, J.mol.biol.48:443 (1970); search similarity methods of Pearson & Lipman, Proc.Nat' l.Acad.Sci.USA 85:2444 (1988); computerized implementation of these algorithms (GAP, BESTFIT, FASTA and TFASTA in Wisconsin Genetics Software Package, Genetics Computer Group,575Science Dr., Madison, Wis.); or visual inspection (see generally, Current Protocols in Molecular Biology, ed. F.M. Ausubel et al, Current Protocols, Greene Publishing Associates, Inc., and commissions between John Wiley & Sons, Inc. (1995 suppl.) (Ausubel)).

Examples of algorithms suitable for determining percent sequence identity and sequence similarity are the BLAST and BLAST 2.0 algorithms described in Altschul et al (1990) J.Mol.biol.215: 403-. Software for performing BLAST analysis is publicly available via the National Center for Biotechnology Information. This algorithm involves first identifying high scoring sequence pairs (HSPs) by identifying short words of length W in the query sequence that match or meet some positive-valued threshold score T when aligned with a word of the same length in a database sequence. T is referred to as the neighborhood word score threshold (Altschul et al, supra). These original neighborhood word hits act as seeds for initiating searches to find longer HSPs containing them. The word hits then extend in both directions along each sequence until the cumulative alignment score can be increased.

Cumulative scores were calculated for nucleotide sequences using the parameters M (reward score for a pair of matching residues; always >0) and N (penalty score for mismatching residues; always < 0). For amino acid sequences, a scoring matrix is used to calculate the cumulative score. The extension of word hits in each direction stops when the following conditions are met: the cumulative alignment score decreases by an amount X from its maximum obtained value; the cumulative score goes to zero or lower due to the accumulation of one or more negative-scoring residue alignments; or to the end of either sequence. The BLAST algorithm parameters W, T and X determine the sensitivity and speed of the alignment. The BLASTN program (for nucleotide sequences) uses the following defaults: word length (W) is 11, expectation (E) is 10, M-5, N-4 and a comparison of the two chains. For amino acid sequences, the BLASTP program uses the following defaults: word length (W) is 3, expectation (E) is 10, and BLOSUM62 scoring matrix (see Henikoff & Henikoff, Proc. Natl. Acad. Sci. USA 89:10915 (1989)).

In addition to calculating percent sequence identity, the BLAST algorithm also performs statistical analysis of the similarity between two sequences (see, e.g., Karlin & Altschul, Proc. nat' l. Acad. Sci. USA 90: 5873-. One measure of similarity provided by the BLAST algorithm is the smallest sum probability (P (N)), which provides an indication of the probability by which a match will occur by chance between two nucleotide or amino acid sequences. For example, a nucleic acid is considered similar to a reference sequence if the smallest sum probability in comparing the test nucleic acid to the reference nucleic acid is found to be less than about 0.1, more preferably less than about 0.01, and most preferably less than about 0.001.

Another indication that two nucleic acid sequences or polypeptides are substantially identical is that the polypeptide encoded by the first nucleic acid is immunologically cross-reactive with the polypeptide encoded by the second nucleic acid, as described below. Thus, a polypeptide is typically substantially identical to a second polypeptide, e.g., where the two peptides differ only by conservative substitutions. Another indication that two nucleic acid sequences are substantially identical is that the two molecules hybridize to each other under stringent conditions.

As used herein, the term "isolated" means a biological component (such as a nucleic acid, peptide, or protein) that has been substantially isolated, produced from, or purified from other biological components of an organism in which it is naturally found, i.e., other chromosomal and extra-chromosomal DNA and RNA, and proteins. Nucleic acids, peptides and proteins that have been "isolated" thus include nucleic acids and proteins purified by standard purification methods. "isolated" nucleic acids, peptides, and proteins can be part of a composition and still be isolated if the composition is not part of the natural environment of the nucleic acid, peptide, or protein. The term also includes nucleic acids, peptides and proteins prepared by recombinant expression in a host cell, as well as chemically synthesized nucleic acids.

As used herein, the term "polynucleotide," synonymously referred to as a "nucleic acid molecule," "nucleotide," or "nucleic acid," refers to any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. "Polynucleotide" includes, but is not limited to, single-and double-stranded DNA, DNA that is a mixture of single-and double-stranded regions, single-and double-stranded RNA, and RNA that is a mixture of single-and double-stranded regions, hybrid molecules comprising DNA and RNA, which may be single-stranded or, more typically, double-stranded or a mixture of single-and double-stranded regions. In addition, "polynucleotide" refers to a triple-stranded region comprising RNA or DNA or both RNA and DNA. The term polynucleotide also includes DNA or RNA containing one or more modified bases and DNA or RNA having a backbone modified for stability or other reasons. "modified" bases include, for example, triacylated bases and unusual bases such as inosine. Various modifications can be made to DNA and RNA; thus, "polynucleotide" includes chemically, enzymatically or metabolically modified forms of polynucleotides as are commonly found in nature, as well as chemical forms of DNA and RNA that are characteristic of viruses and cells. "Polynucleotide" also includes relatively short nucleic acid strands, often referred to as oligonucleotides.

As used herein, the term "vector" is a replicon in which another nucleic acid segment may be operably inserted in order to effectuate replication or expression of the segment.

The term "host cell" as used herein refers to a cell comprising a nucleic acid molecule of the invention. The "host cell" may be any type of cell, e.g., a primary cell, a cultured cell, or a cell from a cell line. In one embodiment, a "host cell" is a cell transfected with a nucleic acid molecule of the invention. In another embodiment, a "host cell" is a progeny or potential progeny of such a transfected cell. Progeny of a cell may be the same as or different from the parent cell, e.g., due to mutations or environmental effects that may occur in the subsequent production of the nucleic acid molecule or integration into the host cell genome.

The term "expression" as used herein refers to the biosynthesis of a gene product. The term encompasses transcription of a gene into RNA. The term also encompasses translation of RNA into one or more polypeptides, and also encompasses all naturally occurring post-transcriptional and post-translational modifications. The expressed CAR may be within the cytoplasm of the host cell, in an extracellular environment such as the growth medium of a cell culture, or anchored to the cell membrane.

As used herein, the term "immune cell" or "immune effector cell" refers to a cell that participates in, e.g., promotes, an immune response. Examples of immune cells include T cells, B cells, Natural Killer (NK) cells, mast cells, and bone marrow-derived phagocytic cells. According to a particular embodiment, the engineered immune cells are T cells, and are referred to as CAR-T cells, as they are engineered to express the CARs of the invention.

As used herein, the term "engineered immune cell" refers to an immune cell, also known as an immune effector cell, that has been genetically modified by the addition of additional genetic material in the form of DNA or RNA to the total genetic material of the cell. According to embodiments herein, the engineered immune cell has been genetically modified to express a CAR construct according to the invention.

As used herein, the term "signal peptide" refers to a leader sequence at the amino terminus (N-terminus) of a nascent protein that co-or post-translationally directs the nascent protein to the endoplasmic reticulum and subsequent surface expression.

As used herein, the term "extracellular antigen-binding domain", "extracellular domain" or "extracellular ligand-binding domain" refers to the portion of a protein that is located outside of the cell membrane and is capable of binding to an antigen, target or ligand.

As used herein, the term "hinge region" refers to the portion of a protein that connects two adjacent domains (e.g., the extracellular domain and the transmembrane domain) of the protein.

As used herein, the term "transmembrane domain" refers to the portion of a protein that extends across a cell membrane and anchors the protein to the cell membrane.

T Cell Receptor (TCR) complexes and Chimeric Antigen Receptors (CAR)

TCRs are disulfide-linked, membrane-anchored heterodimeric proteins, typically comprising highly variable alpha (α) and beta (β) chains, expressed as a complex with an invariant CD3 chain molecule. T cells expressing these types of TCRs are referred to as α: β (or α β) T cells. A small number of T cells express alternative TCRs comprising variable gamma (γ) and delta (δ) chains and are called γ δ T cells. TCRs cannot mediate signaling themselves because of their short cytoplasmic tail, and therefore TCRs still require CD3 and ξ for signaling in their place. The TCR receptor complex is an octameric complex of variable TCR receptors alpha and beta chains with three dimerization signaling modules CD3 δ/epsilon, CD3 γ/epsilon, and CD247 ζ/ζ or ζ/η.

According to embodiments of the present application, a suitable TCR specifically binds to the Major Histocompatibility Complex (MHC) on the surface of a cancer cell, which MHC displays peptide fragments of a tumor antigen. MHC is a group of cell surface proteins that allow the acquired immune system to recognize "foreign" molecules. Proteins are degraded inside the cell and presented on the cell surface by MHC. MHC displaying "foreign" peptides such as viral or cancer-associated peptides are recognized by T cells with appropriate TCRs, promoting cell destruction pathways. MHC on the surface of cancer cells can display peptide fragments of tumor antigens, i.e. antigens present on cancer cells but not on corresponding non-cancer cells. T cells recognizing these peptide fragments can exert cytotoxic effects on cancer cells.

For example, T cells can be modified to express a xenogeneic TCR that specifically binds to MHC displaying peptide fragments of a tumor antigen expressed by cancer cells in a particular cancer patient. Tumor antigens expressed by cancer cells in cancer patients can be identified using standard techniques. According to one embodiment of the invention, the heterologous TCR specifically binds to FSHR. For example, a polypeptide that specifically binds to FSHR, such as a FSH fragment, is fused to the CD3 epsilon chain, CD3 gamma chain, or CD3 delta chain. The fusion protein forms a TCR complex on T cells via the interaction of CD3 with the TCR α/β chain. The TCR complex specifically binds to FSHR on the tumor cells via the FSH fragment, and said binding initiates TCR signalling towards the tumor cells. According to yet another embodiment of the invention, the heterologous TCR is expressed with a CAR that specifically binds to mesothelin. The heterologous TCR may comprise an α β TCR heterodimer.

The TCR may be engineered to increase its affinity or avidity for the tumor antigen (i.e., an affinity-enhanced TCR). The affinity-enhanced TCR may comprise one or more mutations relative to a naturally-occurring TCR, for example, one or more mutations in the hypervariable Complementarity Determining Regions (CDRs) of the variable regions of the TCR a and β chains. These mutations increase the affinity of the TCR for MHC displaying peptide fragments of tumor antigens expressed by cancer cells. Suitable methods for generating affinity-enhanced TCRs include screening libraries of TCR mutants using phage or yeast display and are well known in the art (see, e.g., Robbins et al, J Immunol (2008)180 (9): 6116; San Miguel et al (2015) Cancer Cell 28(3) 281-.

Expression of heterologous antigen receptors such as heterologous TCRs or CARs may alter the immunogenic specificity of T cells such that they recognize or display improved recognition for one or more tumor antigens present on the surface of cancer cells in an individual having cancer.

In some embodiments, the T cells may exhibit reduced or no binding to cancer cells in the absence of xenoantigen receptors. For example, expression of a heterologous antigen receptor (such as an engineered CAR and/or TCR) can increase the affinity and/or specificity of a cancer cell to bind to a modified T cell relative to an unmodified T cell.

In some embodiments, the coding sequences of the individual components of the CAR and/or TCR (e.g., scFv or sdAb, FSH fragment, CD3 epsilon chain, CD3 gamma chain or CD3 delta chain, or TCR alpha chain and TCR beta chain) can be isolated by sequences encoding cleavage recognition sequences. This allows the components of the construct to be expressed as a single fusion, which undergoes intracellular cleavage to produce two or more separate proteins. Suitable cleavage recognition sequences are well known in the art and include, but are not limited to, 2A-furin sequences, such as P2A.

The term "heterologous" refers to a polypeptide or nucleic acid that is foreign to a particular biological system, such as a host cell, and not naturally occurring in the system. Heterologous polypeptides or nucleic acids can be introduced into biological systems by artificial means, for example using recombinant techniques. For example, a heterologous nucleic acid encoding a polypeptide can be inserted into a suitable expression construct, which in turn is used to transform a host cell to produce the polypeptide. The heterologous polypeptide or nucleic acid may be synthetic or artificial or may be present in different biological systems, such as different species or cell types. Endogenous polypeptides or nucleic acids are native to a particular biological system, such as a host cell, and are naturally present in the system. Recombinant polypeptides are expressed from heterologous nucleic acids that have been introduced into cells by artificial means, for example, using recombinant techniques. The recombinant polypeptide may be the same as or different from a polypeptide naturally occurring in a cell.

In one general aspect, an isolated polynucleotide is provided that comprises a nucleotide sequence encoding a modified T Cell Receptor (TCR) complex protein. The protein comprises, from N-terminus to C-terminus, an optional signal peptide, a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR), and an extracellular domain, a transmembrane domain, and an intracellular domain of a CD3 polypeptide selected from the group consisting of CD 3-gamma chain, CD 3-delta chain, and CD 3-epsilon chain.

In certain embodiments, the protein comprises: a signal peptide comprising a sequence selected from the group consisting of SEQ ID NOs: an amino acid sequence in the group consisting of amino acid sequences that are at least 90% identical between 430 and 432; a first polypeptide that specifically binds to FSHR comprising an amino acid sequence selected from the group consisting of amino acid sequences at least 90% identical to SEQ ID NO 319-331, respectively; an extracellular domain comprising an amino acid sequence selected from the group consisting of amino acid sequences at least 90% identical to SEQ ID NOs 433 to 435, respectively; a transmembrane domain comprising an amino acid sequence selected from the group consisting of amino acid sequences at least 90% identical to SEQ ID NOs 436 to 438, respectively; and an intracellular domain comprising an amino acid sequence selected from the group consisting of amino acid sequences at least 90% identical to SEQ ID NOs 439 to 441, respectively.

In certain embodiments, the protein comprises: a signal peptide comprising a sequence selected from the group consisting of SEQ ID NOs: 430 to 432; a first polypeptide that specifically binds to FSHR comprising an amino acid sequence selected from the group consisting of SEQ ID NO 319-331; an extracellular domain comprising a sequence selected from the group consisting of SEQ ID NOs: 433 to 435; a transmembrane domain comprising an amino acid sequence selected from the group consisting of SEQ ID NOs 436 to 438; and an intracellular domain comprising a sequence selected from the group consisting of SEQ ID NOs: 439 to 441.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a modified TCR complex protein comprising the amino acid sequence of SEQ ID NO 442-444 or a variant thereof. Preferably, the variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

In certain embodiments, the isolated polynucleotide comprising a nucleotide sequence encoding a modified TCR protein further comprises a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response of an immune cell. An inhibitor of the cell-mediated immune response of the immune cell may be, for example, a transforming growth factor beta (TGF- β) receptor (e.g., TGF β RII). In certain embodiments, the dominant negative form of the inhibitor comprises the amino acid sequence of SEQ ID NO: 347. In certain embodiments, the nucleotide sequence encoding the modified TCR complex protein is linked to the third nucleotide sequence via a 2A peptide coding sequence.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a protein that is subsequently cleaved to produce a modified TCR protein and a dominant negative form of an inhibitor of a cell-mediated immune response of an immune cell. Preferably, the protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 457-.

In certain embodiments, the isolated polynucleotide encoding the modified TCR protein further comprises a second nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises: (a) an extracellular domain comprising an antigen-binding fragment that specifically binds to a tumor antigen; (b) a transmembrane domain; and (c) an intracellular signaling domain. Preferably, the nucleotide sequence encoding the modified TCR complex protein is linked to the nucleotide sequence encoding the CAR via a 2A peptide coding sequence.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a protein that is subsequently cleaved to produce a modified TCR protein and a CAR protein. Preferably, the protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO 454-456.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a protein that is subsequently cleaved to produce a modified TCR protein, a CAR protein, and a dominant negative form of an inhibitor of a cell-mediated immune response of an immune cell. Preferably, the protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO 469-471.

As used herein, the term "chimeric antigen receptor" (CAR) refers to an artificial receptor that is recombinantly engineered to comprise at least one extracellular domain that specifically binds to an antigen or target, a transmembrane domain, and an intracellular T cell receptor activation signaling domain. Engagement of the extracellular domain of the CAR with a target antigen on the surface of a target cell causes the CAR to cluster and deliver an activation stimulus to the CAR-containing cell. The CARs redirect the specificity of immune effector cells and trigger the production of molecules that proliferate, cytokine production, phagocytosis, and/or can mediate cell death of cells expressing a target antigen in a Major Histocompatibility Complex (MHC) -independent manner.

The CAR may, for example, comprise a scFv or peptide ligand fused to the transmembrane and endodomain of TCR CD 3. scFv is a heavy chain of immunoglobulins linked via a short linker peptide of about 10 to 25 amino acids (V)_H) And light chain (V)_L) Fusion proteins of the variable regions of (Huston j.s. et al, Proc Natl Acad Sci USA 1988; 85(16): 5879-5883). The linker may be glycine-rich to facilitate flexibility, and serine-or threonine-rich to facilitate flexibilityAnd (4) solubility. The linker peptide may be a peptide of formula V_HIs connected to V_LOr vice versa. The peptide ligand may be any peptide that specifically binds to a target receptor. The scFv or peptide ligands can be placed before the signal peptide to direct the protein to the endoplasmic reticulum and then to the T cell surface. In a CAR, the scFv or peptide ligand can be fused to the TCR transmembrane and internal domains. A flexible spacer may be included between the scFv and the TCR transmembrane domain to allow variable orientation and antigen binding. The endodomain is a functional signaling domain of the receptor. The endodomain of the CAR may comprise, for example, an intracellular signaling domain from the CD3 zeta-chain or from a receptor such as CD28, 41BB or ICOS. The CAR may comprise multiple signaling domains, such as, but not limited to, CD3z-CD28-41BB or CD3z-CD28-OX 40.

The CAR can specifically bind to a tumor-specific antigen expressed by a cancer cell. For example, T cells can be modified to express a CAR that specifically binds to a tumor antigen expressed by cancer cells in a particular cancer patient. Tumor antigens expressed by cancer cells in cancer patients can be identified using standard techniques. According to one embodiment of the invention, the CAR specifically binds to mesothelin. According to another embodiment of the invention, the CAR specifically binds to FSHR. According to yet another embodiment of the invention, the CAR specifically binds to mesothelin and FSHR.

In certain general aspects, the invention relates to an isolated polynucleotide comprising a nucleotide sequence encoding a Chimeric Antigen Receptor (CAR). The CAR comprises:

(b) a transmembrane domain; and

wherein the CAR optionally further comprises a signal peptide at its amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain.

In certain embodiments, the first polypeptide that specifically binds to FSHR comprises an amino acid sequence selected from the group consisting of SEQ ID NO 319-331. In certain embodiments, the first polypeptide comprises SEQ ID NO:319 to seq id no.

In certain embodiments, the antigen binding fragment is Fab, Fab ', F (ab')₂Fv, single chain variable fragment (scFv), minibody, diabody, single domain antibody (sdAb), light chain variable domain (VL), or variable domain of camelid antibody (V)_HH)。

In other general aspects, the CAR comprises:

(a) an extracellular domain comprising an antigen-binding fragment that specifically binds to mesothelin, preferably human mesothelin;

(b) a transmembrane domain; and

wherein the CAR optionally further comprises a signal peptide at the amino-terminus and a hinge region connecting the extracellular domain and the transmembrane domain, and wherein the antigen-binding fragment is (i) a single domain antibody (sdAb) or (ii) a single chain variable fragment (scFv). In certain embodiments, the CAR further comprises a polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR). The polypeptide that specifically binds to FSHR may for example comprise a polypeptide selected from the group consisting of SEQ ID NOs: 319-331 amino acid sequence from the group consisting of amino acid sequences which are at least 90% identical. In certain embodiments, the polypeptide that specifically binds to FSHR may comprise the amino acid sequence of SEQ ID NO: 319.

In certain embodiments, the extracellular domain of the CAR is placed before the signal peptide at the amino terminus. Any suitable signal peptide may be used in the present invention. The signal peptide may, for example, be derived from natural, synthetic, semi-synthetic or recombinant sources. According to one embodiment, the signal peptide is a human CD8 α signal peptide, a human CD3 δ signal peptide, a human CD3 ζ signal peptide, a human GMCSFR signal peptide, a human 4-1BB signal peptide, or a derivative thereof. According to a specific embodiment, the signal peptide is human CD8 a signal peptide. The human CD8 a signal peptide comprises an amino acid sequence at least 90% identical to SEQ ID NO:340, preferably comprising SEQ ID NO: 340. The signal peptide can be cleaved by a signal peptidase during or after completion of the CAR translocation to generate a mature CAR that is free of the signal peptide.

In certain embodiments, the CAR can further comprise a hinge region connecting the extracellular domain and the transmembrane domain. The hinge region serves to move the extracellular domain away from the surface of the engineered immune cell to enable proper cell/cell contact, binding to a target or antigen, and activation (Patel et al, Gene Therapy 6: 412-9 (1999)). Any suitable hinge region can be used in the CARs of the invention. The hinge region may be derived from natural, synthetic, semi-synthetic or recombinant sources. According to a particular embodiment, the hinge region of the CAR is the hinge region from the CD8 a peptide. In a specific embodiment, the hinge region comprises a sequence identical to SEQ ID NO:341 at least 90% identical, preferably comprising the amino acid sequence of SEQ ID NO: 341.

The CAR of the invention comprises a transmembrane domain. Any suitable transmembrane domain may be used in the CARs of the invention. The transmembrane domain may be derived from natural, synthetic, semi-synthetic or recombinant sources. According to some embodiments, the transmembrane domain is a transmembrane domain from a peptide selected from the group consisting of: CD8 alpha peptide, CD28 peptide, CD4 peptide, CD3 zeta peptide, CD2 peptide, 4-1BB peptide, OX40 peptide, ICOS peptide, CTLA-4 peptide, PD-1 peptide, LAG-3 peptide, 2B4 peptide, BTLA peptide, GMCSFR peptide, and analogs thereof. In a specific embodiment, the transmembrane domain is a CD8 a transmembrane domain. The CD8 a transmembrane domain may comprise an amino acid sequence which is at least 90% identical to SEQ ID NO:342, preferably comprises the amino acid sequence of SEQ ID NO: 342.

The CAR of the invention comprises an intracellular signaling domain. Any suitable intracellular domain may be used in the CARs of the invention. In particular embodiments, the entire intracellular signaling domain is used. In other embodiments, truncated portions of the signaling domain that transduce an effector or signal are used. According to an embodiment of the invention, the intracellular signaling domain produces a signal that promotes an immune effector function of the CAR-containing cell (e.g., CAR-T cell), including but not limited to proliferation, activation, and/or differentiation. In particular embodiments, the signal promotes, e.g., cytolytic activity, helper activity, and/or cytokine secretion of the CAR-T cell. According to some embodiments, the intracellular signaling domain of the CAR comprises the signaling domains of: fc γ receptor (Fc γ R), Fc ∈ receptor (Fc ∈ R), Fc α receptor (Fc α R), neonatal Fc receptor (FcRn), CD3, CD3 ζ, CD3 γ, CD3 δ, CD3 ε, CD4, CD5, CD8, CD21, CD22, CD28, CD32, CD40L (CD154), CD45, CD66 δ, CD79 α, CD79 β, CD80, CD86, CD278 (also known as ICOS), CD247 ζ, CD247 η DAP, 10, DAP12, FYN, LAT, Lck, MAPK, MHC complex, NFAT, NF- κ B, PLC- γ, iC3b, C3dg, C3d, and Zap 70. According to some embodiments, the intracellular signaling domain is selected from the group consisting of signaling domains of: CD3 ζ, FcR γ, FcR β, CD3 γ, CD3 δ, CD3 ε, CD5, CD22, CD79 α, CD79 β, and CD66 δ.

According to a specific embodiment, the intracellular signaling domain further comprises one or more co-stimulatory signaling domains. The co-stimulatory domain may, for example, comprise a signaling domain of a peptide selected from the group consisting of: 2B/CD 244/SLAMF, 4-1 BB/TNFSF/CD 137, B-1/CD, B-2/CD, B-H/PD-L, B-H, BAFF-R/TNFRSF13, BAFF/BLyS/TNFSF13, BLAME/SLAMF, BTLA/CD272, CD100(SEMA 4), CD103, CD11, CD150, CD160 (BY), CD200, CD229/SLAMF, CD ligand/TNFSF, CD/TNFRSF, CD 2-10/SLAMF, CD ligand/TNFRSF, CD 300/TNFRSF, CD ligand/TNFRSF, CD 49/LFAMF, CD 49/LFSF, CD3, CD-A, CD-I, Ka-R/TNFRSF, CD1, CD-L, CD84/SLAMF 84, CD 84/Thy 84, CD84, CDS, CEACAM 84, CRACC/SLAMF 84, CRTAM, CTLA-4, DAP 84, Dectin-1/CLEC7 84, DNAM 84 (CD226), DPPIV/CD 84, DR 84/TNFRSF 84, EphB 84, GADS, Gi 84/VISTA/B84-H84, GITR ligand/TNFSF 84, GITR/TNFRSF 84, HLA class I, HLA-DR, HVEM/TNFRSF 84, IA 84, ICAM-1, ICOS/CD278, Ikaros, IL2 84 beta, IL2 84 gamma, IL7 84 alpha, Lyintegrin alpha 4/CD49, integrin alpha 4 beta 1, integrin alpha 4 beta 7/7, IPAM-1, IPO-3, GAITGB, GAITGA 72, GAITGB-84, GAITGB, GAITGA 84, GAITGB-84, GAITGB 3, GAITGB-84, GAITGB, GAITGA 84, GAITGB 3-84, GAITGB, GAITX 84, GAITGB, NKG2C, NKG2D, NKp30, NKp44, NKp46, NKp80(KLRF1), NTB-A/SLAMF6, OX40 ligand/TNFSF 4, OX40/TNFRSF4, PAG/Cbp, PD-1, PDCD6, PD-L2/B7-DC, PSGL1, RELT/TNFRSF19 1, SELPLG (CD162), SLAM (SLAMF1), SLAM/CD150, SLAMF 1(CD 244), SLAMF1 (NTB-A), SLAMF1, SLSF-76, TACI/TNFRSF13 1, TCL 11, TIM-1/KIM-1/CR, TIM-4, TIM 1/TNFRSF 1, TNFRSF 1/TNFRSF 1, VLRSF 1/TSLP 72, TSLP-LSA, TNFRSF-6, TNFR-L1, TNFRSF 72, TSLP-LSA, TNFRSF 72, TNFRSF5, TSLP-LSA, TNFRSF. In certain embodiments, the co-stimulatory domain is selected from the group consisting of co-stimulatory domains of one or more of: CD28, 4-1BB (CD137), CD27, OX40, CD27, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, TNFRSF9, TNFRSF4, TNFRSF8, CD40LG, ITGB2, KLRC2, TNFRSF18, TNFRSF14, HAVR 1, LGALS9, CD83, and a ligand that specifically binds to CD 83.

In certain embodiments, the CAR is a tandem CAR that specifically binds to FSHR and mesothelin. Preferably, the CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NO:370-379 and SEQ ID NO: 448-450.

In certain embodiments, the CAR specifically binds to mesothelin. Preferably, the CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NO 358-367 and SEQ ID NO 445-447.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a protein that is subsequently cleaved to produce a dual CAR containing a first CAR that specifically binds to FSHR and a second CAR that specifically binds to mesothelin. Preferably, the protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO 380-389 and SEQ ID NO 451-453.

According to a particular aspect, the isolated polynucleotide comprising a nucleotide sequence encoding a CAR further comprises a third nucleotide sequence. The third nucleotide sequence may, for example, encode a dominant negative form of an inhibitor of a cell-mediated immune response of the immune cell. The inhibitor of the cell-mediated immune response of the immune cell can be, for example, a transforming growth factor beta (TGF- β) receptor (e.g., TGF β RII). In certain embodiments, the dominant negative form of the inhibitor comprises the amino acid sequence of SEQ ID NO: 347.

The nucleotide sequence encoding the CAR can be linked, e.g., via a 2A peptide coding sequence, to a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response.

In certain embodiments, the isolated polynucleotide comprises a nucleotide sequence encoding a protein that is subsequently cleaved to produce one or more CARs and a dominant negative form of an inhibitor of a cell-mediated immune response of an immune cell. Preferably, the protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO:390-419 and SEQ ID NO: 460-468.

Immune cell

According to a particular aspect, the invention provides a cell, which is an immune cell, comprising an isolated polynucleotide comprising a nucleotide sequence encoding a CAR provided herein, or a vector comprising an isolated polynucleotide. An immune cell comprising an isolated polynucleotide and/or vector of the invention may be referred to as an "engineered immune cell". Preferably, the engineered immune cells are of human origin (of human origin prior to undergoing recombination).

The engineered immune cells can be, for example, cells of lymphoid lineage. Non-limiting examples of cells of lymphoid lineage can include T cells and Natural Killer (NK) cells. T cells express a T Cell Receptor (TCR), with the majority of cells expressing an alpha chain and Beta chains and a smaller population expresses gamma and delta chains. A T cell useful as an engineered immune cell of the invention can be CD4⁺Or CD8⁺And may include, but is not limited to, T helper cells (CD 4)⁺) Cytotoxic T cells (also known as cytotoxic T lymphocytes, CTLs; CD8⁺Cells) and memory T cells, including central, stem-like and effector memory T cells, natural killer T cells, mucosa-associated invariant T cells, and γ δ T cells. Other exemplary immune cells include, but are not limited to, macrophages, Antigen Presenting Cells (APCs), or any immune cell expressing an inhibitor of a cell-mediated immune response, such as an immune checkpoint inhibitor pathway receptor (e.g., PD-1). Precursor cells of immune cells that can be used according to the invention include hematopoietic stem cells and/or progenitor cells. Hematopoietic stem and/or progenitor cells can be derived from bone marrow, cord blood, adult peripheral blood following cytokine mobilization, and the like by methods known in the art. The immune cells are engineered to recombinantly express the CARs of the invention.

Immune cells and their precursors can be isolated by methods known in the art, including commercially available methods (see, e.g., Rowland Jones et al, lymphocells: A Practical Approach, Oxford University Press, NY (1999)). Sources of immune cells or precursors thereof include, but are not limited to, peripheral blood, cord blood, bone marrow, or other sources of hematopoietic cells. Various techniques can be used to isolate cells into isolated or enriched desired immune cells. For example, negative selection methods can be used to remove cells that are not desired immune cells. In addition, positive selection methods can be used to isolate or enrich for desired immune cells or their precursors, or a combination of negative and positive selection methods can be employed. If a particular type of cell, e.g., a particular T cell, is to be isolated, various cell surface markers or combinations of markers (e.g., CD3, CD4, CD8, CD34) can be used to isolate the cell.

The immune cells or their precursors may be autologous or non-autologous to the subject to whom the cells are administered in the treatment methods of the invention. Isolating autologous cells from a subject to be administered engineered immune cells that recombinantly express the CAR. Optionally, the cells may be obtained by leukapheresis, in which leukocytes are selectively removed from the withdrawn blood, recombined, and then returned to the donor. Alternatively, allogeneic cells from non-autologous donors other than the subject may be used. In the case of non-autologous donors, cells are typed and matched with Human Leukocyte Antigens (HLA) to determine the appropriate level of compatibility. For both autologous and non-autologous cells, the cells may optionally be cryopreserved until ready for use.

Various methods for isolating immune cells useful for recombinant expression of the CAR of the invention have been previously described and may be used, including, but not limited to, the use of peripheral donor lymphocytes (Sadelain et al, nat. Rev. Cancer 3: 35-45 (2003); Morgan et al, Science 314: 126-9(2006)), the use of lymphocyte cultures derived from Tumor Infiltrating Lymphocytes (TILs) in tumor biopsies (Panelli et al, J.Immunol.164:495-504 (2000); Panelli et al, J.Immunol.164:4382-92(2000)), and the use of antigen-specific peripheral Blood leukocytes selectively expanded in vitro using Artificial Antigen Presenting Cells (AAPC) or dendritic cells (Dupont et al, Cancer Res.65:5417- (427); Papanicola et al, Blood 102: 98-. In the case of Stem Cells, the Cells can be isolated by methods well known in the art (see, e.g., Klug et al, Hematopic Stem Cell Protocols, Humana Press, NJ (2002); Freshney et al, Culture of Human Stem Cells, John Wiley & Sons (2007)).

According to particular embodiments, a method of making an engineered immune cell comprises transfecting or transducing an immune effector cell isolated from an individual such that the immune effector cell expresses one or more CARs according to embodiments of the invention. Methods of preparing immune cells for immunotherapy are described, for example, in WO2014/130635, WO2013/176916, and WO2013/176915, which are incorporated herein by reference. Individual steps useful for preparing engineered immune cells are disclosed in, for example, WO2014/039523, WO2014/184741, WO2014/191128, WO2014/184744, and WO2014/184143, which are incorporated herein by reference.

In a specific embodiment, immune effector cells such as T cells are genetically modified (e.g., transduced with a viral vector comprising a nucleic acid encoding a CAR) with the CARs of the invention, then activated and amplified in vitro. In various embodiments, T cells can be activated and expanded to express a CAR, either before or after genetic modification, using methods as described in, for example, US6352694, US6534055, US6905680, US6692964, US5858358, US6887466, US6905681, US7144575, US7067318, US7172869, US7232566, US7175843, US5883223, US6905874, US6797514, US6867041, US2006/121005, which are incorporated herein by reference. T cells can be expanded in vitro or in vivo. In general, the T cells of the invention can be expanded by contacting the surface with an agent that stimulates a signal associated with the CD3/TCR complex and a ligand that stimulates a co-stimulatory molecule on the surface of the T cell. As non-limiting examples, the population of T cells can be stimulated as described herein, such as by contact with an anti-CD 3 antibody or antigen-binding fragment thereof, or an anti-CD 2 antibody immobilized on a surface; or by contact with a protein kinase C agonist (e.g. bryodin) together with a calcium ionophore; or by activating the CAR itself. For co-stimulation of helper molecules on the surface of T cells, ligands that bind helper molecules are used. For example, a population of T cells can be contacted with an anti-CD 3 antibody and an anti-CD 28 antibody under conditions suitable to stimulate T cell proliferation. Suitable conditions for T cell culture include, for example, suitable media (e.g., minimal essential medium or RPMI medium 1640 or X-vivo 15(Lonza)) which may contain factors necessary for proliferation and survival, including serum (e.g., fetal bovine or human serum), cytokines such as IL-2, IL-7, IL-15 and/or IL-21, insulin, IFN-g, GM-CSF, TGF β and/or any other additive known to the skilled artisan for cell growth. In other embodiments, T cells can be activated and stimulated to proliferate with feeder cells and appropriate antibodies and cytokines using methods such as those described in US6040177, US5827642, and WO2012129514, which are incorporated herein by reference.

Antigen binding fragments

Antibodies

The present invention relates generally to CAR constructs comprising an antigen-binding fragment. The antigen-binding fragment can be, for example, an antibody or antigen-binding fragment thereof that specifically binds to a tumor antigen. In certain aspects, the invention relates to an isolated antibody or antigen-binding fragment that specifically binds to a tumor antigen. The invention also relates generally to isolated anti-mesothelin antibodies, nucleic acids and expression vectors encoding the antibodies, recombinant cells containing the vectors, compositions comprising the antibodies, methods of making the antibodies, and methods of using the antibodies to treat diseases including cancer. The antibodies of the invention have one or more desired functional properties, including, but not limited to, high affinity binding to a tumor antigen (e.g., mesothelin), high specificity for a tumor antigen (e.g., mesothelin), the ability to stimulate complement-dependent cytotoxicity (CDC), antibody-dependent phagocytosis (ADPC) and/or antibody-dependent cell-mediated cytotoxicity (ADCC) against cells expressing a tumor antigen (e.g., mesothelin), and the ability to inhibit tumor growth in a subject in need thereof and in an animal model when administered alone or in combination with other anti-cancer therapies.

The antigen-binding fragment can be, for example, an antibody or antigen-binding fragment thereof that specifically binds to a tumor antigen. Any suitable tumor antigen bound by the antibody or antigen-binding fragment may be selected based on the type of tumor and/or cancer exhibited by the subject to be treated. Suitable antigens include, but are not limited to, Mesothelin (MSLN), Prostate Specific Membrane Antigen (PSMA), prostate stem cell antigen (PCSA), Carbonic Anhydrase IX (CAIX), carcinoembryonic antigen (CEA), CD5, CD7, CD10, CD19, CD20, CD22, CD30, CD33, CD34, CD38, CD41, CD44, CD49f, CD56, CD74, CD123, CD133, CD138, epithelial glycoprotein-2 (EGP 2), epithelial glycoprotein-40 (EGP-40), epithelial adhesion molecule (EpCAM), Folate Binding Protein (FBP), fetal acetylcholine receptor (AChR), folate receptor alpha and beta (FR alpha and beta), ganglioside G2(GD2), ganglioside G3(GD3), human epidermal growth factor receptor 2(HER-2/ERB 5), Epidermal Growth Factor Receptor (EGFR), epidermal growth factor III receptor (EGFR III), epidermal growth factor III receptor 24, R584623, human telomerase (hTERT-40), hTERT-40 (EGP-40), human EGFR-40), hTERT-40, hTCA-40, and hTCA-40, Interleukin-13 receptor subunit alpha-2 (IL-13R alpha 2), k-light chain, kinase insert domain receptor (KDR), Lewis A (CA19.9), Lewis Y (LeY), L1 cell adhesion molecule (LICAM), melanoma binding antigen 1 (melanoma antigen family A1, MAGE-A1), mucin-16 (Muc-16), mucin 1(Muc carcinoma), NKG2D ligand, cancer-testis antigen NY-ESO-1, carcinoembryonic antigen (H5T4), tumor associated glycoprotein 72(TAG-72), Vascular Endothelial Growth Factor Receptor (VEGFR), vascular endothelial growth factor R2(VEGF-R2), Wilms' tumor protein (WT-1), tyrosine protein kinase type 1 receptor (ROR1), B7-H3 (CD), B7-H6 (CS Nkp30), chondroitin sulfate proteoglycan-4 (PG 4), DNAX accessory molecules (DNAM-1), ephrin A type receptor 2(EpHA2), fibroblast-associated protein (FAP), Gp100/HLA-A2, glypican 3(GPC3), HA-1H, HERK-V, IL-11 Ra, latent membrane protein (LMP1), neural cell adhesion molecules (N-CAM/CD56) and TRAIL receptor (TRAIL R). Suitable antigens are preferably selected from the group consisting of: mesothelin, folate receptor alpha, mucin 16, Prostate Specific Membrane Antigen (PSMA), human epidermal growth factor receptor 2(HER2), Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR).

In one general aspect, the invention relates to a CAR construct comprising and/or an antibody or antigen-binding fragment thereof that binds mesothelin.

As used herein, the term "antibody" is used in a broad sense and includes immunoglobulins or antibody molecules, including human, humanized, composite and chimeric antibodies and antibody fragments, which are monoclonal or polyclonal. In general, an antibody is a protein or peptide chain that exhibits binding specificity to a particular antigen. Antibody structures are well known. Depending on the heavy chain constant domain amino acid sequence, immunoglobulins can be assigned to 5 major classes (i.e., IgA, IgD, IgE, IgG, and IgM). IgA and IgG are further subdivided into isotypes IgA1, IgA2, IgG1, IgG2, IgG3 and IgG 4. Thus, the antibodies of the invention can be in any of the 5 main classes or corresponding subclasses. Preferably, the antibody of the invention is IgG1, IgG2, IgG3 or IgG 4. Antibody light chains of vertebrate species can be classified into one of two distinctly different types, κ and λ, based on the amino acid sequences of their constant domains. Thus, an antibody of the invention may contain a kappa or lambda light chain constant domain. According to a specific embodiment, the antibody of the invention comprises a heavy chain constant region and/or a light chain constant region from a rat or human antibody. In addition to the heavy and light chain constant domains, antibodies contain antigen-binding regions composed of a light chain variable region and a heavy chain variable region, each of which contains three domains (i.e., complementarity determining regions 1-3; CDR1, CDR2, and CDR 3). The light chain variable region domains are alternatively referred to as LCDR1, LCDR2 and LCDR3, and the heavy chain variable region domains are alternatively referred to as HCDR1, HCDR2 and HCDR 3.

As used herein, the term "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to mesothelin is substantially free of antibodies that do not bind to mesothelin). In addition, the isolated antibody is substantially free of other cellular material and/or chemicals.

As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., individual antibodies that are identical in the population except for possible naturally occurring mutations that may be present in minor amounts. The monoclonal antibody of the present invention can be produced by a hybridoma method, a phage display technique, a single lymphocyte gene cloning technique, or by a recombinant DNA method. For example, a monoclonal antibody can be produced by a hybridoma that includes a B cell obtained from a transgenic non-human animal, such as a transgenic mouse or rat, having a genome that includes a human heavy chain transgene and a light chain transgene.

As used herein, the term "antigen-binding fragment" refers to antibody fragments, such as diabodies, Fab ', F (ab')2, Fv fragments, disulfide stabilized Fv fragments (dsFv), (dsFv)₂Bispecific dsFvs (dsFvs-dsFvs'), disulfide stabilized diabodies (ds diabodies), single chain antibody molecules (scFv), single domain antibodies (sdabs), scFv dimers (diabodies), multispecific antibodies formed from a portion of an antibody comprising one or more CDRs, camelized single domain antibodies Minibody, nanobody, domain antibody, bivalent domain antibody, light chain variable domain (VL), variable domain of camelid antibody (V)_HH) Or any other antibody fragment that binds to an antigen but does not comprise the entire antibody structure. The antigen binding fragment is capable of binding to the same antigen to which the parent antibody or parent antibody fragment binds.

As used herein, the term "single chain antibody" refers to a conventional single chain antibody in the art comprising a heavy chain variable region and a light chain variable region linked via a short peptide of about 15 to about 20 amino acids (e.g., a linker peptide).

The term "single domain antibody" as used herein refers to a conventional single domain antibody in the art comprising a heavy chain variable region and a heavy chain constant region or which comprises only a heavy chain variable region.

As used herein, the term "human antibody" refers to an antibody produced by a human or an antibody having an amino acid sequence corresponding to an antibody produced by a human using any technique known in the art. This definition of human antibody includes whole or full-length antibodies, fragments thereof, and/or antibodies comprising at least one human heavy and/or light chain polypeptide.

As used herein, the term "humanized antibody" refers to a non-human antibody that has been modified to increase sequence homology to a human antibody such that the antigen-binding properties of the antibody are retained but its antigenicity in humans is reduced.

As used herein, the term "chimeric antibody" refers to an antibody in which the amino acid sequences of immunoglobulin molecules are derived from two or more species. The variable regions of both the light and heavy chains often correspond to the variable regions of antibodies derived from one species of mammal (e.g., mouse, rat, rabbit, etc.) with the desired specificity, affinity, and capacity, while the constant regions correspond to the sequences of antibodies derived from another species of mammal (e.g., human) to avoid eliciting an immune response in those species.

The term "multispecific antibody" as used herein refers to an antibody comprising a plurality of immunoglobulin variable domain sequences, wherein a first immunoglobulin variable domain sequence of the plurality of sequences has binding specificity for a first epitope and a second immunoglobulin variable domain sequence of the plurality of sequences has binding specificity for a second epitope. In one embodiment, the first epitope and the second epitope are on the same antigen, e.g., the same protein (or subunit of a polyprotein). In one embodiment, the first epitope overlaps or substantially overlaps with the second epitope. In one embodiment, the first epitope does not overlap or substantially does not overlap with the second epitope. In one embodiment, the first epitope and the second epitope are on different antigens, e.g., different proteins (or different subunits of a polyprotein). In one embodiment, the multispecific antibody comprises a third immunoglobulin variable domain, a fourth immunoglobulin variable domain, or a fifth immunoglobulin variable domain. In one embodiment, the multispecific antibody is a bispecific antibody molecule, a trispecific antibody molecule, or a tetraspecific antibody molecule.

As used herein, the term "bispecific antibody" refers to a multispecific antibody that binds no more than two epitopes or two antigens. Bispecific antibodies are characterized by a first immunoglobulin variable domain sequence having binding specificity for a first epitope and a second immunoglobulin variable domain sequence having binding specificity for a second epitope. In one embodiment, the first epitope and the second epitope are on the same antigen, e.g., on the same protein (or subunit of a polyprotein). In one embodiment, the first epitope overlaps or substantially overlaps with the second epitope. In one embodiment, the first epitope and the second epitope are on different antigens, e.g., different proteins (or different subunits of a polyprotein). In one embodiment, the bispecific antibody comprises a heavy chain variable domain sequence and a light chain variable domain sequence having binding specificity for a first epitope and a heavy chain variable domain sequence and a light chain variable domain sequence having binding specificity for a second epitope. In one embodiment, the bispecific antibody comprises a half-antibody or fragment thereof having binding specificity for a first epitope and a half-antibody or fragment thereof having binding specificity for a second epitope. In one embodiment, the bispecific antibody comprises a scFv or fragment thereof having binding specificity for a first epitope and a scFv or fragment thereof having binding specificity for a second epitope. In one embodiment, the first epitope is on mesothelin and the second epitope is on PD-1, PD-L1, CTLA-4, EGFR, HER-2, CD19, CD20, CD33, CD3, and/or other tumor-associated immunosuppressive factors or surface antigens.

As used herein, the term "mesothelin" refers to a 71-kD precursor protein that is cleaved by endoprotease furin to release a secreted N-terminal region, known as megakaryocyte enhancer factor (MPF). The 41-kD mature mesothelin (i.e., MPF) remains attached to the membrane (Yamaguchi N et al, Biol chem.1994; 269: 805-. The remaining GPI-linked mature mesothelin can also be shed from the cell by the action of tumor necrosis factor alpha-converting enzyme protease (Zhang Y et al, Cancer Res.2011; 71: 5915-5922). The correlation between serum levels of shed mesothelin and disease suggests a potential role for mesothelin protein in cancer progression. However, the biological function of mesothelin is not well understood. Mesothelin is known to bind to the ovarian cancer antigen MUC16 (cancer antigen 125), which has been shown to induce cell-to-cell adhesion and possibly promote peritoneal seeding and metastatic spread (Gubbels JA et al, Mol cancer.2006; 5: 50). Furthermore, mesothelin knockout mice typically grow and multiply and have no detectable phenotype. Bera TK et al, Mol Cell biol.2000; 20:2902-2906. The full length sequence of human mesothelin is provided by SEQ ID NO 315 and the sequence of human 41-kD mature mesothelin is provided by SEQ ID NO: 318.

As used herein, an antibody that "specifically binds to mesothelin" refers to an antibody that binds to mesothelin, preferably human mesothelin, with a KD as follows: 1X 10^-7M or less, preferably 1X 10^-8M or less, more preferably 5X 10^-9M or less, 1X 10^-9M or less, 5X 10^-10M or less, or 1X 10^-10M or less. The term "KD" refers to the dissociation constant, which is obtained from the ratio of KD to Ka (i.e., KD/Ka) and is expressed as molar concentration (M). In view of the present disclosure, KD values of antibodies can be determined using methods in the art. For example, the KD of an antibody can be determined by using surface plasmon resonance, such as by using a biosensor system,for exampleA system; or by using a bio-layer interferometric technique such as the Octet RED96 system.

The smaller the KD value of the antibody, the higher the affinity of the antibody for binding to the target antigen.

According to a particular aspect, the invention relates to a CAR construct comprising an antigen-binding fragment, wherein the antigen-binding fragment is an antibody or antigen-binding fragment that specifically binds to a tumor antigen and/or an isolated antibody or antigen-binding fragment that specifically binds to a tumor antigen. The antibody or antigen binding fragment can be, for example, Fab ', F (ab')₂Fv, single chain variable fragment (scFv), minibody, diabody, single domain antibody (sdAb), light chain variable domain (VL), or variable domain of camelid antibody (V) _HH)。

In certain embodiments, the antibody or antigen-binding fragment is a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, said complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. are respectively SEQ ID NO: 32. 100 and 168;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NOs: 40. 108 and 176;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs: 45. 113 and 181;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively;

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR regions;

wherein the single domain antibody specifically binds to mesothelin, preferably human mesothelin. In certain embodiments, the single domain antibody comprises an amino acid sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428. In certain embodiments, the single domain antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428 or a variant thereof. Preferably, the variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 31, 99 and 167, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 221. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 221.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 32, 100 and 168, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 222. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 222.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NO:33, 101 and 169, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 223. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 223.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 34, 102 and 170, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 224, 420, 421 or 422. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 224, 420, 421 or 422.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 35, 103 and 171, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 225. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 225.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs: 36, 104 and 172, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 226. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 226.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 37, 105 and 173, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 227. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises SEQ ID NO: 227.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 38, 106 and 174, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 228. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 228.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 39, 107 and 175, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 229. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 229.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 40, 108 and 176, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 230. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises SEQ ID NO: 230.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs: 41, 109 and 177, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a heavy chain variable region comprising a heavy chain variable region sequence identical to SEQ ID NO: 231, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises SEQ ID NO: 231.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 42, 110 and 178, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 232. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 232.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 43, 111 and 179, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 233. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises SEQ ID NO: 233.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the amino acid sequences of SEQ ID NOs: 44. 112 and 180. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 234. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 234.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the amino acid sequences of SEQ ID NOs: 45. 113 and 181. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 235. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 235.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 46, 114 and 182, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 236. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises SEQ ID NO: 236.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the amino acid sequences of SEQ ID NOs: 47. 115 and 183. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a heavy chain variable region comprising a heavy chain variable region sequence identical to SEQ ID NO:237 polypeptide sequences which are at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 237.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the amino acid sequences of SEQ ID NOs: 48. 116 and 184. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 238. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 238.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 49, 117 and 185, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 239. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 239.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 50, 118 and 186, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 240. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 240.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 51, 119 and 187, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 241. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 241.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 52, 120 and 188, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 242. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO: 242.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 53, 121 and 189, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 243. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 243.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 54, 122 and 190, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 244. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 244.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the amino acid sequences of SEQ ID NOs: 55. 123 and 191. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a heavy chain variable region comprising a heavy chain variable region sequence identical to SEQ ID NO:245, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 245.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 56, 124 and 192, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a heavy chain variable region comprising a heavy chain variable region sequence identical to SEQ ID NO: 246, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises SEQ ID NO: 246.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the amino acid sequences of SEQ ID NOs: 57. 125 and 193. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a heavy chain variable region comprising a heavy chain variable region sequence identical to SEQ ID NO:247 at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 247.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 58, 126 and 194, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 248. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO: 248.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 59, 127 and 195, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a heavy chain variable region comprising a heavy chain variable region sequence identical to SEQ ID NO:249, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO: 249.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 60, 128 and 196, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 250. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 250.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 61, 129 and 197, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 251. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 251.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 62, 130 and 198, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 252. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 252.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 63, 131 and 199, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 253. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises SEQ ID NO: 253.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 64, 132 and 200, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 254. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 254.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 65, 133 and 201, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 255. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 255.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 66, 134 and 202, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:256, 426, 427 or 428. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 256, 426, 427, or 428.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 67, 135 and 203, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:257, 423, 424 or 425. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO 257, 423, 424 or 425.

In one embodiment, the invention relates to a CAR construct comprising a single domain antibody or an isolated single domain antibody, said single domain antibody comprising CDR1, CDR2 and CDR3 having the polypeptide sequences of SEQ ID NOs 68, 136 and 204, respectively. In another embodiment, a CAR construct comprising a single domain antibody (sdAb) or an isolated sdAb comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 258. Preferably, the CAR construct comprising the sdAb or the isolated sdAb comprises the polypeptide sequence of SEQ ID NO: 258.

In certain embodiments, the antibody or antigen-binding fragment thereof is a single chain variable fragment (scFv) comprising heavy chain complementarity determining region 1(HCDR1), HCDR2, HCDR3, light chain complementarity determining region 1(LCDR1), LCDR2, and LCDR3, said complementarity determining regions having the polypeptide sequences:

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively;

21, 89, 157, 22, 90 and 158, respectively; or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR regions;

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively, or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR region,

wherein the scFv specifically binds to mesothelin, preferably human mesothelin. In certain embodiments, the scFv comprises an amino acid sequence which is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to the amino acid sequence selected from the group consisting of SEQ ID NO 205-220. In certain embodiments, the single domain antibody comprises an amino acid sequence selected from the group consisting of SEQ ID NO 205-220 or a variant thereof. Preferably, the variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 1, 69, 137, 2, 70 and 138, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO 205 or 206. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 205 or 206.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 3, 71, 139, 4, 72 and 140, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 207. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 207.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 5, 73, 141, 6, 74 and 142, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 208. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 208.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 7, 75, 143, 8, 76 and 144, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 209. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 209.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 9, 77, 145, 10, 78 and 146, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 210. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 210.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 11, 79, 147, 12, 80 and 148, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 211. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 211.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 13, 81, 149, 14, 82 and 150, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 212. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 212.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 15, 83, 151, 16, 84 and 152, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO:213. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 213.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 17, 85, 153, 18, 86 and 154, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 214. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO: 214.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 19, 87, 155, 20, 88 and 156, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 215. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 215.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 21, 89, 157, 22, 90 and 158, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 216. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 216.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 23, 91, 159, 24, 92 and 160, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID No. 217. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 217.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 25, 93, 161, 26, 94 and 162, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 218. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 218.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 27, 95, 163, 28, 96 and 164, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 219. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO: 219.

In one embodiment, the invention relates to a CAR construct comprising a single chain variable fragment (scFv) or an isolated scFv, comprising HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 having the polypeptide sequences of SEQ ID NOs 29, 97, 165, 30, 98 and 166, respectively. In another embodiment, the CAR construct comprising the scFv and/or the isolated scFv comprises a polypeptide sequence that is at least 85%, preferably 90%, more preferably 95% or more, such as 95%, 96%, 97%, 98% or 99% identical to SEQ ID NO: 220. Preferably, the CAR construct comprising the scFv and/or the isolated scFv comprises the polypeptide sequence of SEQ ID NO 220.

In another general aspect, the invention relates to a method of producing a modified TCR complex, CAR construct, or antibody, or antigen-binding fragment thereof, of the invention, comprising culturing a cell comprising a nucleic acid encoding a protein of the invention under conditions to produce a modified TCR complex, CAR construct, or antibody, or antigen-binding fragment thereof: a modified TCR complex, CAR construct or antibody or antigen-binding fragment thereof. Optionally, the method further comprises recovering the modified TCR complex, CAR construct, or antibody or antigen-binding fragment thereof from the cell or cell culture (e.g., from the supernatant). The expressed antibody or antigen-binding fragment thereof can be harvested from the cells and purified according to conventional techniques known in the art and as described herein.

Follicle Stimulating Hormone Receptor (FSHR) binding peptides

As used herein, the term "FSHR binding domain" or "FSHR binding peptide" refers to a peptide domain or polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR). In certain embodiments, the FSHR binding domain may comprise Follicle Stimulating Hormone (FSH) or a fragment thereof, a FSHR antagonist or a fragment thereof, an antigen binding fragment that specifically binds to FSHR, and/or an anti-FSHR agonist or a fragment thereof.

As used herein, the term "FSHR agonist" refers to a molecule or fragment thereof having affinity for FSHR. FSHR antagonists have affinity for the active site of FSHR (i.e. a binding site similar or identical to FSH). The binding affinity of the FSHR antagonist to FSHR may be reversible or irreversible.

In certain aspects, provided herein are CARs, wherein the CARs comprise an extracellular domain comprising a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR). The first polypeptide may be, for example, an FSHR-binding peptide. The FSHR binding peptide may be, for example, FSH or a fragment thereof, a FSHR antagonist or a fragment thereof, an anti-FSHR antibody or a fragment thereof or an anti-FSHR agonist or a fragment thereof.

In certain embodiments, the FSHR-binding peptide may comprise an amino acid sequence derived from a FSH molecule. FSHR binding peptides include fragments, peptides or polypeptide sequences derived from FSH molecules. In one embodiment, the FSHR-binding peptide comprises the FSH β 33-53 peptide. In another embodiment, the FSHR-binding peptide comprises the FSH β 51-65 peptide. In another embodiment, the FSHR-binding peptide comprises the FSH β 81-95 peptide.

The FSHR binding peptide may comprise any fragment or FSH molecule. In certain embodiments, the FSHR-binding peptide comprises at least 10 amino acids of a FSH molecule. The FSHR-binding peptide may comprise at least about 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 or more amino acids of the FSHR molecule. In certain embodiments, the FSHR-binding peptide may be from about 6 to about 50 amino acids, from about 10 to about 45 amino acids, from about 15 to about 40 amino acids, from about 20 to about 35 amino acids, or from about 25 to about 30 amino acids of the FSH molecule. The FSHR-binding peptide retains the ability to bind to FSHR.

In certain embodiments, the FSHR-binding peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO 319-331. In certain embodiments, the FSHR-binding peptide has 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to an amino acid sequence selected from the group consisting of SEQ ID NO 319-331. In certain embodiments, the FSHR-binding peptide has an amino acid sequence selected from the group consisting of SEQ ID NO 319-331 or a variant thereof comprising up to about 5 (such as, for example, about any one of 1, 2, 3, 4, or 5) amino acid substitutions.

Dominant negative forms of inhibitors of cell-mediated immune responses

An inhibitor of a cell-mediated immune response of an immune cell or its precursor cell refers to a molecule that serves to suppress or suppress the immune response effected by the immune cell or its precursor cell. In certain embodiments, the inhibitor of a cell-mediated immune response may be, for example, an immune checkpoint inhibitor.

In certain aspects, provided herein are engineered immune cells expressing a CAR comprising a dominant negative form of an inhibitor of a cell-mediated immune response of the immune cell. As a non-limiting example, a dominant negative form of an inhibitor may be a receptor that functions in the immune checkpoint inhibitor pathway. The immune checkpoint pathway may halt the immune response of immune cells. The pathway can transmit negative signals to immune cells and attenuate TCR-mediated signals, which can result in decreased cell proliferation, decreased cytokine production, and slowed cell cycle progression (pardol, nat. rev.12:252-64 (2012); Wu et al, int.j.biol.sci.8:1420-30 (2012)). Examples of immune checkpoint inhibitor pathway receptors may include, but are not limited to, PD-1, CTLA-4, BTLA, TIM-3, LAG-3, CD160, TIGIT, LAIR1, 2B4, and analogs thereof (Chen et al, nat. Rev. Immunol.13(4):227-42 (2013)). Corresponding ligands for these receptors include, for example, PD-L1 (for PD-1); PD-L2 (for PD-1); CD80, CD86 (for CTLA-4); HVEM (for BTLA); galectin-9, HMGB1 (for TIM-3); MHCII (for LAG-3); HVEM (for CD 160); CD155, CD112, CD113 (for TIGIT); c1q, collagen (for LAIR 1); CD48 (for 2B4) and its analogs (Chen et al, nat. Rev. Immunol.13(4):227-42 (2013)). Expression of the dominant negative form in an immune cell provides suppression of the checkpoint inhibitor pathway inherent to the cell.

In certain embodiments, the dominant negative form of the inhibitor of a cell-mediated immune response of the immune cell is a dominant negative transforming growth factor-beta receptor type II (dnTGF β RII). TGF- β receptor type II may have an amino acid sequence corresponding to GenBank No. NP _001020018.1 or a fragment thereof. The domains of TGF-. beta.RII include the signal peptide (amino acids 1-22), the extracellular domain (amino acids 23-191), the transmembrane domain (amino acids 192-212) and the intracellular domain (amino acids 213-592) (see, e.g., GenBank, NP-001020018.1).

In certain embodiments, the CAR comprises a dominant negative form of TGF β RII (dnTGF β RII). In one embodiment, dnTGF β RII comprises an extracellular ligand binding domain of TGF β RII. In one embodiment, the dnTGF β RII comprises an extracellular ligand binding domain and a transmembrane domain. In another embodiment, dnTGF β RII comprises an extracellular ligand binding domain, a transmembrane domain, and a signal peptide of TGF β RII.

The dnTGF β RII form has been described previously (see, e.g., Bottinger et al, EMBO J16: 2621-33 (1997); Foster et al, J.Immunother.31:500-5 (2008); Bollard et al, Blood 99:3179-87 (2002); Wieser et al, mol.cell.biol.13:7239-47 (1993)). In certain embodiments, the dnTGF β RII comprises the amino acid sequence of SEQ ID NO: 347.

An isolated polynucleotide comprising a first nucleotide sequence encoding a CAR and a third nucleotide sequence encoding dnTGF β RII can, for example, have the first nucleotide sequence linked to the third nucleotide sequence via the third nucleotide sequence encoding the 2A peptide. The 2A peptide is typically 16-20 amino acids in sequence, for example P2A. When the 2A peptide is encoded between two open reading frames in a polycistronic mRNA, it causes the ribosome to stop at the carboxy terminus of the 2A peptide when translating the polypeptide, thereby resulting in the separation of the polypeptides derived from each open reading frame. The separation point is at the carboxy-terminus of the 2A peptide, where the first amino acid of the downstream open reading frame is proline. 2A peptides are described, for example, in International patent publication No. WO 2017/040815.

Polynucleotides, vectors and host cells

In another general aspect, the invention relates to an isolated nucleic acid encoding a Chimeric Antigen Receptor (CAR) and/or an antibody or antigen-binding fragment thereof of the invention. It will be understood by those skilled in the art that the coding sequence for a protein may be varied (e.g., substituted, deleted, inserted, etc.) without altering the amino acid sequence of the protein. Thus, it will be understood by those skilled in the art that the nucleic acid sequences encoding the CARs and/or antibodies or antigen-binding fragments thereof of the invention can be altered without altering the amino acid sequence of the protein.

In another general aspect, the invention relates to a vector comprising a CAR and/or an isolated nucleic acid encoding an antibody or antigen-binding fragment thereof of the invention. Any vector known to those of skill in the art in view of this disclosure may be used, such as a plasmid, cosmid, phage vector, or viral vector. In some embodiments, the vector is a recombinant expression vector, such as a plasmid. The vector may include any elements that establish the conventional function of an expression vector, for example, a promoter, ribosome binding elements, a terminator, an enhancer, a selection marker and an origin of replication. The promoter may be a constitutive, inducible or repressible promoter. Many expression vectors capable of delivering a nucleic acid to a cell are known in the art and can be used herein to produce a CAR and/or an antibody or antigen-binding fragment thereof in a cell. Conventional cloning techniques or artificial gene synthesis may be used to generate recombinant expression vectors according to embodiments of the present invention.

In another general aspect, the invention relates to a host cell comprising a vector of the invention and/or an isolated nucleic acid encoding a CAR of the invention and/or an antibody or antigen binding fragment thereof. Any host cell known to those of skill in the art in view of this disclosure can be used for recombinant expression of the CARs and/or antibodies or antigen-binding fragments thereof of the invention. Suitable host cells include prokaryotes, yeast, mammalian cells, or bacterial cells. In some embodiments, the host cell is an E.coli TG1 or BL21 cell (for expression of, e.g., CAR, scFv or sdAb), CHO-DG44 or CHO-K1 cell or HEK293 cell (for expression of, e.g., a full-length IgG antibody). According to a specific embodiment, the recombinant expression vector is transformed into the host cell by conventional methods such as chemical transfection, heat shock or electroporation, wherein the recombinant expression vector is stably integrated into the host cell genome for efficient expression of the recombinant nucleic acid.

Pharmaceutical composition

In another general aspect, the invention relates to a pharmaceutical composition comprising an isolated polynucleotide of the invention, an isolated polypeptide of the invention, a host cell of the invention, an engineered immune cell of the invention, and/or an antibody or antigen-binding fragment thereof of the invention, and a pharmaceutically acceptable carrier. The term "pharmaceutical composition" as used herein means a product comprising an isolated polynucleotide of the invention, an isolated polypeptide of the invention, a host cell of the invention and/or an engineered immune cell of the invention, and a pharmaceutically acceptable carrier. The polynucleotides, polypeptides, host cells, engineered immune cells and/or antibodies or antigen-binding fragments of the invention, and compositions comprising the same, may also be used in the manufacture of medicaments for the therapeutic applications mentioned herein.

As used herein, the term "carrier" refers to any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, oil, lipid-containing vesicle, microsphere, liposome encapsulation, or other material well known in the art for use in pharmaceutical formulations. It will be appreciated that the characteristics of the carrier, excipient or diluent will depend on the route of administration for a particular application. The term "pharmaceutically acceptable carrier" as used herein refers to a non-toxic material that does not interfere with the effect of the composition according to the invention or the biological activity of the composition according to the invention. According to particular embodiments, any pharmaceutically acceptable carrier suitable for use in a polynucleotide, polypeptide, host cell, engineered immune cell, and/or antibody pharmaceutical composition can be used in the present invention in view of the present disclosure.

The formulation of pharmaceutically active ingredients with pharmaceutically acceptable carriers is known in The art, e.g., Remington: The Science and Practice of Pharmacy (e.g., 21 st edition (2005) and any subsequent editions). Non-limiting examples of additional ingredients include: buffers, diluents, solvents, tonicity adjusting agents, preservatives, stabilizers and chelating agents. One or more pharmaceutically acceptable carriers may be used to formulate the pharmaceutical compositions of the present invention.

Application method

In another general aspect, the present invention relates to a method of treating cancer in a subject in need thereof. The methods comprise administering to a subject in need thereof a therapeutically effective amount of an isolated polynucleotide, an isolated polypeptide, a host cell, an engineered immune cell, an antibody or antigen binding fragment thereof, and/or a pharmaceutical composition of the invention. The cancer may for example be selected from ovarian cancer, primary peritoneal cancer, Pancreatic Ductal Adenocarcinoma (PDA), Malignant Pleural Mesothelioma (MPM), lung adenocarcinoma, triple negative breast cancer, endometrial cancer, cholangiocarcinoma, gastric cancer or pediatric acute myeloid leukemia.

According to an embodiment of the invention, the pharmaceutical composition comprises a therapeutically effective amount of an isolated polynucleotide, an isolated polypeptide, a host cell, an engineered immune cell and/or an antibody or antigen binding fragment. As used herein, the term "pharmaceutically effective amount" refers to an amount of an active ingredient or component that elicits a desired biological or pharmaceutical response in a subject. A therapeutically effective amount may be determined empirically and in a routine manner and is relevant to the stated purpose.

As used herein, with respect to an isolated polynucleotide, an isolated polypeptide, a host cell, an engineered immune cell, an antibody or antigen-binding fragment, and/or a pharmaceutical composition of the invention, a therapeutically effective amount means an amount of the isolated polynucleotide, the isolated polypeptide, the host cell, the engineered immune cell, the antibody or antigen-binding fragment, and/or the pharmaceutical composition that modulates an immune response in a subject in need thereof.

According to a specific embodiment, a therapeutically effective amount refers to an amount of therapy sufficient to achieve one, two, three, four or more of the following effects: (i) reducing or ameliorating the severity of the disease, disorder or condition to be treated or symptoms associated therewith; (ii) reducing the duration of the disease, disorder or condition to be treated or symptoms associated therewith; (iii) preventing the progression of the disease, disorder or condition to be treated or symptoms associated therewith; (iv) causing regression of the disease, disorder or condition to be treated or symptoms associated therewith; (v) preventing the development or onset of the disease, disorder or condition to be treated or symptoms associated therewith; (vi) preventing recurrence of the disease, disorder or condition to be treated or symptoms associated therewith; (vii) reducing hospitalization of a subject having the disease, disorder or condition to be treated or symptoms associated therewith; (viii) reducing the length of hospitalization of a subject having a disease, disorder or condition to be treated or symptoms associated therewith; (ix) extending the survival of a subject having a disease, disorder, or condition to be treated, or symptoms associated therewith; (x) Inhibiting or alleviating the disease, disorder or condition to be treated or symptoms associated therewith; and/or (xi) enhances or improves one or more prophylactic or therapeutic effects of another therapy.

A therapeutically effective amount or dose may vary depending on various factors such as the disease, disorder or condition to be treated, the mode of administration, the target site, the physiological state of the subject (including, for example, age, weight, health), whether the subject is human or animal, other drugs administered, and whether the treatment is prophylactic or therapeutic. Therapeutic doses are optimally titrated to optimize safety and efficacy.

According to a specific embodiment, the compositions described herein are formulated to be suitable for a predetermined route of administration to a subject. For example, the compositions described herein may be formulated to be suitable for intravenous, subcutaneous, or intramuscular administration.

The cells of the invention may be administered in any convenient manner known to those skilled in the art. For example, the cells of the invention can be administered to a subject by aerosol inhalation, injection, ingestion, infusion, implantation, and/or transplantation. Compositions comprising cells of the invention may be administered intra-arterially, subcutaneously, intradermally, intratumorally, intratubercularly, intramedullary, intramuscularly, intrapleurally, by intravenous (i.v.) injection, or intraperitoneally. In certain embodiments, the cells of the invention may be administered with or without lymphocyte depletion from the subject.

The pharmaceutical compositions comprising the cells of the invention expressing the CARs of the invention can be provided in a sterile liquid formulation, typically an isotonic aqueous solution with a suspension of the cells, or optionally in an emulsion, dispersion, or the like, which is typically buffered to a selected pH. The composition may comprise a carrier, such as water, saline, phosphate buffered saline, and the like, suitable for the integrity and viability of the cells, and for administration of the cell composition.

Sterile injectable solutions can be prepared by incorporating the cells of the invention in an appropriate amount of an appropriate solvent with various other ingredients as required. Such compositions may include a pharmaceutically acceptable carrier, diluent, or excipient, such as sterile water, physiological saline, glucose, dextrose, or the like, suitable for use with the cell composition and suitable for administration to a subject, such as a human. Suitable buffers for providing the cell composition are well known in the art. Any vehicle, diluent or additive used is compatible with maintaining the integrity and viability of the cells of the invention.

The cells of the invention may be administered in any physiologically acceptable vehicle. A cell population comprising cells of the invention may comprise a purified cell population. One skilled in the art can readily determine the cells in a cell population using a variety of well known methods. Purity in a population of cells comprising the genetically modified cells of the invention can range from about 50% to about 55%, about 55% to about 60%, about 60% to about 65%, about 65% to about 70%, about 70% to about 75%, about 75% to about 80%, about 80% to about 85%, about 85% to about 90%, about 90% to about 95%, or about 95% to about 100%. The dosage can be readily adjusted by one skilled in the art, for example, a decrease in purity may require an increase in dosage.

The cells of the invention are typically administered at a dose based on the number of cells per kilogram of body weight of the subject to which the cells are administered (cells/kilogram). Generally, the cell dose is about 10⁴One cell per kilogram body weight to about 10¹⁰Individual cells per kilogram body weight, e.g. about 10⁵One cell per kilogram body weight to about 10⁹About 10 cells/kg body weight⁵One cell per kilogram body weight to about 10⁸About 10 cells/kg body weight⁵One cell per kilogram body weight to about 10⁷Individual cells per kilogram body weight, or about 10⁵One cell per kilogram body weight to about 10⁶Within a range of individual cells per kilogram body weight, depending on the mode and location of administration. In general, for systemic administration, the immune cells of the invention are administered at the region of the tumor and/or cancer upon local administration using a higher dose than local administration. In addition, the dosage can be adjusted to account for whether a single dose is being administered or whether multiple doses are being administered. The precise determination of the dosage to be considered effective may depend on factors specific to each subject.

As used herein, the terms "treatment", "treating" and "treatment" are all intended to mean ameliorating or reversing at least one measurable physical parameter associated with cancer, which is not necessarily discernible in a subject, but may be discernible in a subject. The terms "treat", "treating" and "treatment" may also refer to causing regression, preventing progression or at least slowing the progression of a disease, disorder or condition. In a particular embodiment, "treating" and "treatment" refer to alleviating, preventing the development or onset of, or shortening the duration of one or more symptoms associated with a disease, disorder or condition, such as a tumor or more preferably a cancer. In a particular embodiment, "treating" (therapy), "treating" (therapy), and "treatment" refer to preventing the recurrence of a disease, disorder, or condition. In a particular embodiment, "treating" (therapy), "treating" (therapy), and "treatment" refer to prolonging the survival of a subject having a disease, disorder, or condition. In a particular embodiment, "treating" (therapy), "treating" (therapy), and "treatment" (therapy) refer to the elimination of a disease, disorder, or condition in a subject.

Detailed description of the preferred embodiments

The present invention provides the following non-limiting embodiments.

Embodiment 1 an isolated polynucleotide comprising a nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises:

(b) a transmembrane domain; and

wherein the CAR optionally further comprises a signal peptide at its amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain.

Embodiment 1a is the isolated polynucleotide of embodiment 1, wherein said first polypeptide is an antigen-binding fragment that specifically binds to FSHR, preferably human FSHR.

Embodiment 1b is the isolated polynucleotide of embodiment 1a, wherein said first polypeptide that specifically binds to FSHR comprises Fab, Fab ', F (ab')₂Fv, single chain variable fragment (scFv), minibody, diabody, single domain antibody (sdAb), light chain variable domain (VL), heavy chain-only antibody or variable domain of a camelid antibody (V)_HH)。

Embodiment 2 is the isolated polynucleotide of embodiment 1, wherein the first polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO 319-331.

Embodiment 3 is the isolated polynucleotide of any one of embodiments 1 to 2, wherein said first polypeptide is linked to the amino terminus of said antigen-binding fragment via a linker.

Embodiment 3a is the isolated polynucleotide of embodiment 1 or 2, wherein said first polypeptide is linked to the carboxy-terminus of said antigen-binding fragment via a linker.

Embodiment 4 is the isolated polynucleotide of any one of embodiments 1 to 3a, wherein the tumor antigen is selected from the group consisting of: mesothelin, folate receptor alpha, mucin 16(MUC16), Prostate Specific Membrane Antigen (PSMA), human epidermal growth factor receptor 2(HER2), Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR).

Embodiment 5 is the isolated polynucleotide of embodiment 4, wherein the tumor antigen is mesothelin, preferably human mesothelin.

Embodiment 5a is the isolated polynucleotide of embodiment 4, wherein the tumor antigen is MUC16, preferably human MUC 16.

Embodiment 5b is the isolated polynucleotide of embodiment 4, wherein the tumor antigen is PSMA, preferably human PSMA.

Embodiment 5c is the isolated polynucleotide of embodiment 4, wherein the tumor antigen is HER2, preferably human HER 2.

Embodiment 5d is the isolated polynucleotide of embodiment 4, wherein the tumor antigen is EGFR, preferably human EGFR.

Embodiment 5e is the isolated polynucleotide of embodiment 4, wherein said tumor antigen is VEGFR, preferably human VEGFR.

Embodiment 6 is the isolated polynucleotide of any one of embodiments 5 to 5e, wherein the antigen binding fragment is Fab, Fab ', F (ab')₂Fv, single chain variable fragment (scFv), minibody, diabody, single domain antibody (sdAb), light chain variable domain (VL), heavy chain-only antibody or variable domain of a camelid antibody (V)_HH)。

Embodiment 6a is the isolated polynucleotide of embodiment 6, wherein the antigen binding fragment is a Fab.

Embodiment 6b is the isolated polynucleotide of embodiment 6, wherein the antigen binding fragment is a Fab'.

Embodiment 6c is the isolated polynucleotide of embodiment 6, wherein the antigenBinding fragment is F (ab')₂。

Embodiment 6d is the isolated polynucleotide of embodiment 6, wherein the antigen binding fragment is an Fv.

Embodiment 6e is the isolated polynucleotide of embodiment 6, wherein the antigen-binding fragment is an scFv.

Embodiment 6f is the isolated polynucleotide of embodiment 6, wherein the antigen binding fragment is a miniantibody.

Embodiment 6g is the isolated polynucleotide of embodiment 6, wherein the antigen binding fragment is a diabody.

Embodiment 6h is the isolated polynucleotide of embodiment 6, wherein the antigen binding fragment is an sdAb.

Embodiment 6i is the isolated polynucleotide of embodiment 6, wherein the antigen-binding fragment is a VL.

Embodiment 6j is the isolated polynucleotide of embodiment 6, wherein the antigen binding fragment is a heavy chain-only antibody.

Embodiment 6k is the isolated polynucleotide of embodiment 6, wherein the antigen binding fragment is a V of a camelid antibody_HH。

Embodiment 7 is the isolated polynucleotide of any one of embodiments 6 to 6k, wherein the antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively;

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively, or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR regions.

Embodiment 7a is the isolated polynucleotide of any one of embodiments 6 to 6k, wherein the antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively.

Embodiment 8 is the isolated polynucleotide of embodiment 7 or 7a, wherein the antigen-binding fragment comprises:

Embodiment 8a is the isolated polynucleotide of embodiment 7 or 7a, wherein the antigen-binding fragment comprises:

i. a single domain antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428 or a variant thereof comprising one, two, three or more amino acid substitutions, deletions and/or insertions; or

A single-stranded variable fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NO 205-220 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

Embodiment 8b is the isolated polynucleotide of embodiment 7 or 7a, wherein the antigen-binding fragment comprises:

i. a single domain antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428; or

A single-stranded variable fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NO 205-220.

Embodiment 9 is the isolated polynucleotide of any one of embodiments 1 to 8b, wherein the extracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 348-.

Embodiment 10 is an isolated polynucleotide comprising a nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises:

(a) an extracellular domain comprising an antigen-binding fragment that specifically binds to mesothelin, preferably human mesothelin;

(b) a transmembrane domain; and

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively;

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively, or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR regions.

Embodiment 10a is an isolated polynucleotide comprising a nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises:

(a) an extracellular domain comprising an antigen-binding fragment that specifically binds to mesothelin, preferably human mesothelin;

(b) a transmembrane domain; and

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively.

Embodiment 11 is the isolated polynucleotide of embodiment 10 or 10a, wherein the antigen binding fragment is

i. Single domain antibody comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions, or

Embodiment 11a is the isolated polynucleotide of embodiment 10 or 10a, wherein the antigen-binding fragment comprises:

Embodiment 11b is the isolated polynucleotide of embodiment 10 or 10a, wherein the antigen-binding fragment comprises:

i. a single domain antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428; or

A single-stranded variable fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NO 205-220.

Embodiment 12 is the isolated polynucleotide of any one of embodiments 10 to 11b, wherein the polynucleotide further comprises a second nucleotide sequence encoding a second Chimeric Antigen Receptor (CAR), wherein the second CAR comprises:

(a) an extracellular domain comprising a polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR);

(b) a transmembrane domain; and

wherein the second CAR optionally further comprises a signal peptide at the amino terminus and a hinge region connecting the extracellular domain with the transmembrane domain.

Embodiment 12A is the isolated polynucleotide of embodiment 12, wherein the nucleotide sequence encoding the CAR is linked to the second nucleotide sequence via a 2A peptide coding sequence.

Embodiment 12b is the isolated polynucleotide of embodiment 12 or 12a, wherein the 3 '-end of the nucleotide sequence encoding the CAR is linked to the 5' -end of the second nucleotide sequence.

Embodiment 12c is the isolated polynucleotide of embodiment 12 or 12a, wherein the 3 '-end of the second nucleotide sequence is linked to the 5' -end of the nucleotide sequence encoding the CAR.

Embodiment 12d is the isolated polynucleotide of any one of embodiments 12 to 12c wherein the polypeptide that specifically binds to FSHR is an antigen binding fragment that specifically binds to FSHR, preferably human FSHR.

Embodiment 12e is the isolated polynucleotide of embodiment 12d, wherein the antigen binding fragment that specifically binds to FSHR is Fab, Fab ', F (ab')₂Fv, single-chain variable fragment (scFv), minibody, diabody, single-domain antibody (sdAb), lightChain variable domain (VL), heavy chain-only antibody or variable domain of camelid antibody (V)_HH)。

Embodiment 13 is the isolated polynucleotide of any one of embodiments 12 to 12d, wherein the polypeptide that specifically binds to FSHR comprises a sequence selected from the group consisting of SEQ ID NOs: 319-331.

Embodiment 14 is the isolated polynucleotide of any of embodiments 1-13, wherein the CAR comprises a signal peptide having an amino acid sequence at least 90% identical to SEQ ID NO: 340.

Embodiment 14a is the isolated polynucleotide of any of embodiments 12-14, wherein the second CAR comprises a signal peptide having an amino acid sequence at least 90% identical to SEQ ID NO: 340.

Embodiment 14b is the isolated polynucleotide of embodiment 14 or 14a, wherein the CAR and the second CAR comprise the same signal sequence.

Embodiment 14c is the isolated polynucleotide of embodiment 14 or 14a, wherein the CAR and the second CAR comprise different signal sequences.

Embodiment 15 is the isolated polynucleotide of any of embodiments 1-14c, wherein the CAR comprises a polynucleotide having a sequence identical to SEQ ID NO: 341 at least 90% identical in amino acid sequence.

Embodiment 15a is the isolated polynucleotide of any of embodiments 12-15, wherein the second CAR comprises a polynucleotide having a sequence identical to SEQ ID NO: 341 at least 90% identical in amino acid sequence.

Embodiment 15b is the isolated polynucleotide of embodiment 15 or 15a, wherein the CAR and the second CAR comprise the same hinge region.

Embodiment 15c is the isolated polynucleotide of embodiment 15 or 15a, wherein the CAR and the second CAR comprise different hinge regions.

Embodiment 16 is the isolated polynucleotide of any of embodiments 1-15c, wherein the CAR comprises a transmembrane domain selected from the group consisting of: a CD8 a transmembrane domain, a CD28 transmembrane domain, a CD4 transmembrane domain, a CD3 zeta transmembrane domain, a CD2 transmembrane domain, a 4-1BB transmembrane domain, an OX40 transmembrane domain, an ICOS transmembrane domain, a CTLA-4 transmembrane domain, a PD-1 transmembrane domain, a LAG-3 transmembrane domain, a 2B4 transmembrane domain, a BTLA transmembrane domain, and a GMCSFR transmembrane domain.

Embodiment 16a is the isolated polynucleotide of any of embodiments 12-16, wherein the second CAR comprises a transmembrane domain selected from the group consisting of: a CD8 a transmembrane domain, a CD28 transmembrane domain, a CD4 transmembrane domain, a CD3 zeta transmembrane domain, a CD2 transmembrane domain, a 4-1BB transmembrane domain, an OX40 transmembrane domain, an ICOS transmembrane domain, a CTLA-4 transmembrane domain, a PD-1 transmembrane domain, a LAG-3 transmembrane domain, a 2B4 transmembrane domain, a BTLA transmembrane domain, and a GMCSFR transmembrane domain.

Embodiment 16b is the isolated polynucleotide of embodiment 16 or 16a, wherein the CAR and the second CAR comprise the same transmembrane domain.

Embodiment 16c is the isolated polynucleotide of embodiment 16 or 16a, wherein the CAR and the second CAR comprise different transmembrane domains.

Embodiment 17 is the isolated polynucleotide of any of embodiments 1-16c, wherein the CAR comprises an intracellular signaling domain selected from the group consisting of: signaling domains of CD3 ζ, FcR γ, FcR β, CD3 γ, CD3 δ, CD3 ε, CD5, CD22, CD79 α, CD79 β, and CD66 δ.

Embodiment 17a is the isolated polynucleotide of any of embodiments 12-17, wherein the second CAR comprises an intracellular signaling domain selected from the group consisting of: signaling domains of CD3 ζ, FcR γ, FcR β, CD3 γ, CD3 δ, CD3 ε, CD5, CD22, CD79 α, CD79 β, and CD66 δ.

Embodiment 17b is the isolated polynucleotide of embodiment 17 or 17a, wherein the CAR and the second CAR comprise the same intracellular signaling domain.

Embodiment 17c is the isolated polynucleotide of embodiment 17 or 17a, wherein the CAR and the second CAR comprise different intracellular signaling domains.

Embodiment 18 is the isolated polynucleotide of embodiment 17, wherein the CAR comprises a costimulatory domain selected from the group consisting of the costimulatory domains of one or more of: CD28, 4-1BB (CD137), CD27, OX40, CD27, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, TNFRSF9, TNFRSF4, TNFRSF8, CD40LG, ITGB2, KLRC2, TNFRSF18, TNFRSF14, HAVR 1, LGALS9, CD83, and a ligand that specifically binds to CD 83.

Embodiment 18a is the isolated polynucleotide of any of embodiments 12-17, wherein the second CAR comprises a costimulatory domain selected from the group consisting of costimulatory domains of one or more of: CD28, 4-1BB (CD137), CD27, OX40, CD27, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, TNFRSF9, TNFRSF4, TNFRSF8, CD40LG, ITGB2, KLRC2, TNFRSF18, TNFRSF14, HAVR 1, LGALS9, CD83, and a ligand that specifically binds to CD 83.

Embodiment 18b is the isolated polynucleotide of embodiment 18 or 18a, wherein the CAR and the second CAR comprise the same co-stimulatory domain.

Embodiment 18c is the isolated polynucleotide of embodiment 18 or 18a, wherein the CAR and the second CAR comprise different co-stimulatory domains.

Embodiment 19 is the isolated polynucleotide of embodiment 1, wherein the CAR comprises a sequence selected from the group consisting of SEQ ID NOs: 370-379 and SEQ ID NO: 448-450.

Embodiment 20 is the isolated polynucleotide of embodiment 10, wherein the CAR comprises a polynucleotide sequence selected from the group consisting of SEQ ID NO 358-367 and SEQ ID NO: 445, 447.

Embodiment 20 is the isolated polynucleotide of embodiment 10 encoding a protein having an amino acid sequence selected from the group consisting of SEQ ID NO:380-389 and SEQ ID NO: 451-453.

Embodiment 21 is the isolated polynucleotide of any one of embodiments 1-20, further comprising a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response of an immune cell.

Embodiment 22 is the isolated polynucleotide of embodiment 21, wherein the inhibitor of the cell-mediated immune response of the immune cell is a transforming growth factor beta (TGF- β) receptor.

Embodiment 23 is the isolated polynucleotide of embodiment 22, wherein the dominant negative form of the inhibitor comprises SEQ ID NO: 347, or a pharmaceutically acceptable salt thereof.

Embodiment 24 is the isolated polynucleotide of any one of embodiments 21-23, wherein the nucleotide sequence encoding the CAR is linked to the third nucleotide sequence via a 2A peptide coding sequence.

Embodiment 24a is the isolated polynucleotide of embodiment 24, wherein the 3 'end of the nucleotide sequence encoding the CAR is linked to the 5' end of the third nucleotide sequence.

Embodiment 24b is the isolated polynucleotide of embodiment 24, wherein the 3 'end of the third nucleotide sequence is linked to the 5' end of the nucleotide sequence encoding the CAR.

Embodiment 24c is the isolated polynucleotide of embodiment 24, wherein the 3 'end of the second nucleotide sequence is linked to the 5' end of the third nucleotide sequence.

Embodiment 24d is the isolated polynucleotide of embodiment 24, wherein the 3 'end of the third nucleotide sequence is linked to the 5' end of the second nucleotide sequence.

Embodiment 25 is the isolated polynucleotide of any one of embodiments 24 to 24d wherein the CAR comprises an amino acid sequence selected from the group consisting of SEQ ID NO:390-419 and SEQ ID NO: 460-468.

Embodiment 26 is a vector comprising the polynucleotide of any one of embodiments 1-25 and 72-80.

Embodiment 27 is a host cell comprising the polynucleotide of any one of embodiments 1-25 and 72-80 or the vector of embodiment 26.

Embodiment 28 is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the host cell of embodiment 27.

Embodiment 29 is an engineered immune cell expressing a CAR encoded by the polynucleotide of any one of embodiments 1-25 or a modified TCR comprising a fusion protein encoded by the polypeptide of any one of embodiments 72-80.

Embodiment 30 is the engineered immune cell of embodiment 29, wherein the engineered immune cell is selected from the group consisting of: cytotoxic T cells, helper T cells, natural killer cells, γ δ T cells, and NKT cells.

Embodiment 31 is a pharmaceutical composition comprising the engineered immune cell of embodiment 29 or 30 and a pharmaceutically acceptable carrier.

Embodiment 32 is a method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of embodiment 31.

Embodiment 32a is the method of embodiment 32, wherein the engineered immune cells are autologous.

Embodiment 32b is the method of embodiment 32, wherein the engineered immune cells are allogeneic.

Embodiment 32c is the method of embodiment 32, wherein the engineered immune cells are syngeneic.

Embodiment 33 is the method of any one of embodiments 28 and 32-32c, wherein the cancer is selected from ovarian cancer, primary peritoneal cancer, Pancreatic Ductal Adenocarcinoma (PDA), Malignant Pleural Mesothelioma (MPM), lung adenocarcinoma, triple negative breast cancer, endometrial cancer, cholangiocarcinoma, gastric cancer, or pediatric acute myelogenous leukemia, preferably ovarian cancer.

Embodiment 34 is a method of engineering an immune cell, the method comprising introducing into the immune cell the polynucleotide of any one of embodiments 1-25 and 72-80 operably linked to a promoter.

Embodiment 35 is a method of producing a pharmaceutical composition, the method comprising combining the engineered immune cell of embodiment 29 or 30 with a pharmaceutically acceptable carrier to obtain the pharmaceutical composition.

Embodiment 36 is a system for inducing activity of an immune cell and/or a target cell, the system comprising an engineered cell comprising a Chimeric Antigen Receptor (CAR), wherein the CAR comprises:

(a) An extracellular domain comprising a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR) and an antigen-binding fragment that specifically binds to a tumor antigen;

(b) a transmembrane domain; and

wherein the CAR optionally further comprises a signal peptide at its amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain.

Embodiment 37 is the system of embodiment 36, wherein the first polypeptide comprises a polypeptide selected from the group consisting of SEQ ID NOs: 319-331.

Embodiment 38 is the system of embodiment 36 or 37, wherein the first polypeptide is linked to the amino terminus or the carboxy terminus of the antigen-binding fragment via a linker.

Embodiment 39 is the system of any one of embodiments 36 to 38, wherein the tumor antigen is selected from the group consisting of: mesothelin, folate receptor alpha, mucin 16(MUC16), Prostate Specific Membrane Antigen (PSMA), human epidermal growth factor receptor 2(HER2), Epidermal Growth Factor Receptor (EGFR), and Vascular Endothelial Growth Factor Receptor (VEGFR).

Embodiment 40 is the system of any one of embodiments 36 to 39, wherein the tumor antigen is mesothelin, preferably human mesothelin.

Embodiment 41 is the system of embodiment 40, wherein the antigen binding fragment is Fab, Fab ', F (ab')₂Fv, single chain variable fragment (scFv), minibody, diabody, single domain antibody (sdAb), light chain variable domain (VL), or variable domain of camelid antibody (V)_HH)。

Embodiment 42 is the system of embodiment 41, wherein the antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. are respectively SEQ ID NO: 32. 100 and 168;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively;

21, 89, 157, 22, 90 and 158, respectively; or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR regions.

Embodiment 42a is the system of embodiment 41, wherein the antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. are respectively SEQ ID NO: 32. 100 and 168;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

SEQ ID NOs: 39. 107 and 175;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs: 45. 113 and 181;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NOs: 49. 117 and 185;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively.

Embodiment 43 is the system of embodiment 42 or 42a, wherein the antigen-binding fragment comprises:

i. single domain antibody comprising an amino acid sequence which is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions, or

Embodiment 43a is the system of embodiment 42 or 42a, wherein the antigen-binding fragment comprises:

i. A single domain antibody comprising a sequence selected from the group consisting of SEQ ID NOs: 221-258 and SEQ ID NO 420-428 or a variant thereof comprising one, two, three or more amino acid substitutions, deletions and/or insertions; or

Embodiment 43b is the system of embodiment 42 or 42a, wherein the antigen-binding fragment comprises:

i. a single domain antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428; or

A single-stranded variable fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NO 205-220.

Embodiment 44 is the system of any one of embodiments 36 to 43b, wherein the extracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NO 348-357.

Embodiment 45 is a system for inducing activity of an immune cell and/or a target cell, the system comprising an engineered cell comprising a Chimeric Antigen Receptor (CAR), wherein the CAR comprises:

(a) An extracellular domain comprising an antigen-binding fragment that specifically binds to mesothelin, preferably human mesothelin;

(b) a transmembrane domain; and

wherein the CAR optionally further comprises a signal peptide at the amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain, and

wherein the antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively;

21, 89, 157, 22, 90 and 158, respectively; or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR regions.

Embodiment 45a is a system for inducing the activity of an immune cell and/or a target cell, the system comprising an engineered cell comprising a Chimeric Antigen Receptor (CAR), wherein the CAR comprises:

(a) An extracellular domain comprising an antigen-binding fragment that specifically binds to mesothelin, preferably human mesothelin;

(b) a transmembrane domain; and

wherein the CAR optionally further comprises a signal peptide at the amino terminus and a hinge region connecting the extracellular domain and the transmembrane domain, and

wherein the antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. are respectively SEQ ID NO: 32. 100 and 168;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. are respectively SEQ ID NO: 37. 105 and 173;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NOs: 40. 108 and 176;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs: 45. 113 and 181;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

ii, SEQ ID NOs: 65. 133 and 201;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. Are respectively SEQ ID NO: 1. 69, 137, 2, 70 and 138;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

SEQ ID NOs: 13. 81, 149, 14, 82 and 150;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158, respectively.

Embodiment 46 is the system of embodiment 45 or 45a, wherein the antigen-binding fragment comprises:

A single-chain variable fragment comprising a sequence identical to a sequence selected from the group consisting of SEQ ID NOs: 205-220 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

Embodiment 46a is the system of embodiment 45 or 45a, wherein the antigen-binding fragment comprises:

Embodiment 46b is the system of embodiment 45 or 45a, wherein the antigen-binding fragment comprises:

i. a single domain antibody comprising a light chain variable region selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO: 420-428; or

A single-chain variable fragment comprising a sequence selected from the group consisting of SEQ ID NOs: 205-220.

Embodiment 47 is the system of any one of embodiments 45 to 46b, wherein the CAR further comprises a polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR).

Embodiment 48 is the system of embodiment 47, wherein the polypeptide that specifically binds to FSHR comprises a polypeptide selected from the group consisting of SEQ ID NOs: 319-331.

Embodiment 49 is the system of any one of embodiments 36-47, wherein the CAR comprises a signal peptide having an amino acid sequence at least 90% identical to SEQ ID NO: 340.

Embodiment 50 is the system of any one of embodiments 36-49, wherein the CAR comprises a polypeptide having an amino acid sequence identical to SEQ ID NO: 341 at least 90% identical in amino acid sequence.

Embodiment 51 is the system of any one of embodiments 36-50, wherein the CAR comprises a transmembrane domain selected from the group consisting of: a CD8 a transmembrane domain, a CD28 transmembrane domain, a CD4 transmembrane domain, a CD3 zeta transmembrane domain, a CD2 transmembrane domain, a 4-1BB transmembrane domain, an OX40 transmembrane domain, an ICOS transmembrane domain, a CTLA-4 transmembrane domain, a PD-1 transmembrane domain, a LAG-3 transmembrane domain, a 2B4 transmembrane domain, a BTLA transmembrane domain, and a GMCSFR transmembrane domain.

Embodiment 52 is the system of any one of embodiments 36-51, wherein the CAR comprises an intracellular signaling domain selected from the group consisting of: signaling domains of CD3 ζ, FcR γ, FcR β, CD3 γ, CD3 δ, CD3 ε, CD5, CD22, CD79 α, CD79 β, and CD66 δ.

Embodiment 53 is the system of embodiment 52, wherein the CAR comprises a costimulatory domain selected from the group consisting of costimulatory domains of one or more of: CD28, 4-1BB (CD137), CD27, OX40, CD27, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, TNFRSF9, TNFRSF4, TNFRSF8, CD40LG, ITGB2, KLRC2, TNFRSF18, TNFRSF14, HAVR 1, LGALS9, CD83, and a ligand that specifically binds to CD 83.

Embodiment 54 is the system of embodiment 36, wherein the CAR comprises a polypeptide selected from the group consisting of SEQ ID NO:370-379 and SEQ ID NO: 448-450.

Embodiment 55 is the system of embodiment 45, wherein the CAR comprises a sequence selected from the group consisting of SEQ ID NO 358-367 and SEQ ID NO: 445, 447.

Embodiment 56 is the system of any of embodiments 36-55, wherein the CAR further comprises a dominant negative form of an inhibitor of a cell-mediated immune response of the immune cell.

Embodiment 57 is the system of embodiment 56, wherein the inhibitor of a cell-mediated immune response of the immune cell is a transforming growth factor beta (TGF- β) receptor.

Embodiment 58 is the system of embodiment 57, wherein the dominant negative form of the inhibitor comprises the amino acid sequence of SEQ ID NO: 347.

Embodiment 59 is the system of any one of embodiments 56 to 58, wherein the CAR is linked to the dominant negative form of the inhibitor via a 2A peptide coding sequence.

Embodiment 60 is the system of embodiment 59, wherein the CAR comprises a sequence selected from the group consisting of SEQ ID NO:390-419 and SEQ ID NO: 460-468.

Embodiment 61 is an isolated antibody or antigen-binding fragment, wherein the isolated antibody or antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. 32, 100 and 168, respectively;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively;

21, 89, 157, 22, 90 and 158, respectively; or

Variants thereof comprising up to about 3 (such as any of about 1, 2 or 3) amino acid substitutions in the CDR region,

wherein the isolated antibody or antigen-binding fragment thereof specifically binds mesothelin, preferably human mesothelin.

Embodiment 61a is an isolated antibody or antigen-binding fragment, wherein the isolated antibody or antigen-binding fragment comprises:

i. a single domain antibody (sdAb) comprising complementarity determining region 1(CDR1), CDR2, and CDR3, the complementarity determining regions having the polypeptide sequences:

a. 34, 102 and 170, respectively;

b. 54, 122 and 190, respectively;

c. 55, 123 and 191, respectively;

d. 61, 129 and 197, respectively;

e. 31, 99 and 167, respectively;

f. are respectively SEQ ID NO: 32. 100 and 168;

g. 33, 101 and 169, respectively;

h. 35, 103 and 171, respectively;

i. 36, 104 and 172, respectively;

j. 37, 105 and 173, respectively;

k. 38, 106 and 174, respectively;

39, 107 and 175, respectively;

m. SEQ ID NO 40, 108 and 176, respectively;

n. SEQ ID NO 41, 109 and 177, respectively;

42, 110 and 178, respectively;

p. SEQ ID NO 43, 111 and 179, respectively;

q. SEQ ID NO 44, 112 and 180, respectively;

r. SEQ ID NOs 45, 113 and 181, respectively;

s. SEQ ID NO 46, 114 and 182, respectively;

t. SEQ ID NO 47, 115 and 183, respectively;

u. SEQ ID NOs 48, 116 and 184, respectively;

v. SEQ ID NO 49, 117 and 185, respectively;

w. SEQ ID NO 50, 118 and 186, respectively;

51, 119 and 187, respectively;

y. are SEQ ID NOs 52, 120 and 188, respectively;

z. are SEQ ID NOs 53, 121 and 189, respectively;

aa, SEQ ID NO 56, 124 and 192, respectively;

bb, SEQ ID NO:57, 125 and 193, respectively;

cc. are SEQ ID NOs 58, 126 and 194, respectively;

dd. are SEQ ID NOs 59, 127 and 195, respectively;

ee. are SEQ ID NOs 60, 128 and 196, respectively;

ff. SEQ ID NOs 62, 130 and 198, respectively;

gg. are SEQ ID NOs 63, 131 and 199, respectively;

hh. are SEQ ID NOs 64, 132 and 200, respectively;

65, 133 and 201, respectively;

jj. SEQ ID NOs 66, 134 and 202, respectively;

kk. are SEQ ID NOs 67, 135 and 203, respectively; or

ll. are SEQ ID NOs 68, 136 and 204, respectively; or

a. 1, 69, 137, 2, 70 and 138, respectively;

b. 19, 87, 155, 20, 88 and 156, respectively;

c. 23, 91, 159, 24, 92 and 160, respectively;

d. SEQ ID NOs 25, 93, 161, 26, 94 and 162;

e. 27, 95, 163, 28, 96 and 164, respectively;

f. 29, 97, 165, 30, 98 and 166, respectively;

g. 3, 71, 139, 4, 72 and 140, respectively;

h. 5, 73, 141, 6, 74 and 142, respectively;

i. 7, 75, 143, 8, 76 and 144, respectively;

j. 9, 77, 145, 10, 78 and 146, respectively;

k. 11, 79, 147, 12, 80 and 148, respectively;

13, 81, 149, 14, 82 and 150, respectively;

15, 83, 151, 16, 84 and 152, respectively, SEQ ID NO;

n. SEQ ID NO 17, 85, 153, 18, 86 and 154, respectively; or

o. SEQ ID NO 21, 89, 157, 22, 90 and 158,

Wherein the isolated antibody or antigen-binding fragment thereof specifically binds mesothelin, preferably human mesothelin.

Embodiment 62 is the isolated antibody or antigen-binding fragment of embodiment 61 or 61a, wherein the antibody or antigen-binding fragment comprises:

Embodiment 62a is the isolated antibody or antigen-binding fragment of embodiment 61 or 61a, wherein the antigen-binding fragment comprises:

A single-chain variable fragment comprising a sequence selected from the group consisting of SEQ ID NOs: 205-220 or a variant thereof, preferably said variant comprises one, two, three or more amino acid substitutions, deletions and/or insertions.

Embodiment 62b is the isolated antibody or antigen-binding fragment of embodiment 61 or 61a, wherein the antigen-binding fragment comprises:

i. a single domain antibody comprising an amino acid sequence selected from the group consisting of SEQ ID NO 221-258 and SEQ ID NO 420-428; or

A single-stranded variable fragment comprising an amino acid sequence selected from the group consisting of SEQ ID NO 205-220.

Embodiment 63 is the isolated antibody or antigen-binding fragment of any one of embodiments 61 to 62b, wherein the antibody or antigen-binding fragment thereof is chimeric.

Embodiment 64 is the isolated antibody or antigen-binding fragment of any one of embodiments 61 to 62b, wherein the antibody or antigen-binding fragment thereof is human or humanized.

Embodiment 65 is an isolated nucleic acid encoding the isolated antibody or antigen-binding fragment thereof of any one of embodiments 61 to 64.

Embodiment 66 is a vector comprising the isolated nucleic acid of embodiment 65.

Embodiment 67 is a host cell comprising the vector of embodiment 66.

Embodiment 68 is a pharmaceutical composition comprising the isolated antibody or antigen-binding fragment thereof of any one of embodiments 61-64 and a pharmaceutically acceptable carrier.

Embodiment 69 is a method of treating cancer in a subject in need thereof comprising administering to the subject the pharmaceutical composition of embodiment 68.

Embodiment 70 is a method of producing the antibody or antigen-binding fragment thereof of any one of embodiments 61 to 64, comprising culturing a cell comprising a nucleic acid encoding the antibody or antigen-binding fragment thereof under conditions wherein the antibody or antigen-binding fragment thereof is produced, and recovering the antibody or antigen-binding fragment thereof from the cell or culture.

Embodiment 71 is a method of producing a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of any one of embodiments 61 to 64, the method comprising combining the antibody or antigen-binding fragment thereof with a pharmaceutically acceptable carrier to obtain a pharmaceutical composition.

Embodiment 72 is an isolated polynucleotide comprising a first nucleotide sequence encoding a fusion protein, wherein the fusion protein comprises, from N-terminus to C-terminus, a first polypeptide that specifically binds to Follicle Stimulating Hormone Receptor (FSHR), and the extracellular, transmembrane, and intracellular domains of a CD3 polypeptide selected from the group consisting of CD 3-gamma chain, CD 3-delta chain, and CD 3-epsilon chain.

Embodiment 73 is the isolated polynucleotide of embodiment 72, wherein the extracellular domain of the CD3 polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs 433 through 435, respectively; the transmembrane domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs 436 to 438; and the intracellular domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOS 439 to 441, respectively.

Embodiment 74 is the isolated polynucleotide of embodiment 72 or 73, wherein the first polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO 319-331.

Embodiment 74a is the isolated polynucleotide of embodiment 74, wherein the fusion protein comprises an amino acid sequence selected from the group consisting of SEQ ID NO 442-444.

Embodiment 75 is the isolated polynucleotide of any one of embodiments 72 to 74a, further comprising a second nucleotide sequence encoding a Chimeric Antigen Receptor (CAR), wherein the CAR comprises: (a) an extracellular domain comprising an antigen-binding fragment that specifically binds to a tumor antigen; (b) a transmembrane domain; and (c) an intracellular signaling domain.

Embodiment 76 is the isolated polynucleotide of embodiment 75, wherein the CAR is the CAR of any one of embodiments 10-11a and 20.

Embodiment 76a is the isolated polynucleotide of embodiment 76, wherein the CAR comprises a transmembrane domain selected from the group consisting of: a CD8 a transmembrane domain, a CD28 transmembrane domain, a CD4 transmembrane domain, a CD3 zeta transmembrane domain, a CD2 transmembrane domain, a 4-1BB transmembrane domain, an OX40 transmembrane domain, an ICOS transmembrane domain, a CTLA-4 transmembrane domain, a PD-1 transmembrane domain, a LAG-3 transmembrane domain, a 2B4 transmembrane domain, a BTLA transmembrane domain, and a GMCSFR transmembrane domain.

Embodiment 76b is the isolated polynucleotide of embodiment 76, wherein the CAR comprises an intracellular signaling domain selected from the group consisting of: signaling domains of CD3 ζ, FcR γ, FcR β, CD3 γ, CD3 δ, CD3 ε, CD5, CD22, CD79 α, CD79 β, and CD66 δ.

Embodiment 76c is the isolated polynucleotide of embodiment 76, wherein the CAR comprises a costimulatory domain selected from the group consisting of the costimulatory domains of one or more of: CD28, 4-1BB (CD137), CD27, OX40, CD27, CD40, PD-1, ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, TNFRSF9, TNFRSF4, TNFRSF8, CD40LG, ITGB2, KLRC2, TNFRSF18, TNFRSF14, HAVR 1, LGALS9, CD83, and a ligand that specifically binds to CD 83.

Embodiment 77 is the isolated polynucleotide of embodiment 76 encoding a protein having an amino acid sequence selected from the group consisting of SEQ ID NO 454-456.

Embodiment 78 is the isolated polynucleotide of any one of embodiments 72 to 77, further comprising a third nucleotide sequence encoding a dominant negative form of an inhibitor of a cell-mediated immune response of an immune cell, preferably a dominant negative form of a transforming growth factor beta (TGF- β) receptor.

Embodiment 78a is the isolated polynucleotide of embodiment 78, wherein the dominant negative form of the inhibitor comprises the amino acid sequence of SEQ ID NO: 347.

Embodiment 79 is the isolated polynucleotide of embodiment 78 or 78a, wherein the first, second and/or third nucleotide sequences are linked to each other via a 2A peptide coding sequence.

Embodiment 79a is the isolated polynucleotide of embodiment 79, wherein the first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence are linked in the order of the first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence from the N-terminus to the C-terminus.

Embodiment 79b is the isolated polynucleotide of embodiment 79, wherein the first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence are linked in the order of the second nucleotide sequence, the first nucleotide sequence, and the third nucleotide sequence from the N-terminus to the C-terminus.

Embodiment 79C is the isolated polynucleotide of embodiment 79, wherein the first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence are linked in the order of the third nucleotide sequence, the first nucleotide sequence, and the second nucleotide sequence from the N-terminus to the C-terminus.

Embodiment 79d is the isolated polynucleotide of embodiment 79, wherein the first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence are linked in the order of the third nucleotide sequence, the second nucleotide sequence, and the first nucleotide sequence from the N-terminus to the C-terminus.

Embodiment 79e is the isolated polynucleotide of embodiment 79, wherein the first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence are linked in the order of the second nucleotide sequence, the third nucleotide sequence, and the first nucleotide sequence from the N-terminus to the C-terminus.

Embodiment 79f is the isolated polynucleotide of embodiment 79, wherein the first nucleotide sequence, the second nucleotide sequence, and the third nucleotide sequence are linked in the order of the first nucleotide sequence, the third nucleotide sequence, and the second nucleotide sequence from the N-terminus to the C-terminus.

Embodiment 80 is the isolated polynucleotide of embodiment 79 encoding a protein comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 469-471.

Embodiment 81 is a system for inducing the activity of an immune cell and/or a target cell, the system comprising an engineered cell comprising a modified TCR complex comprising a fusion protein encoded by a polynucleotide of embodiment 72-80.

Examples

The examples provided below are for illustrative purposes only and are not intended to be limiting unless otherwise specified. Thus, the present invention should in no way be construed as limited to the following examples, but rather should be construed to cover any and all modifications that would become apparent from the teachings provided herein.

Example 1: selection of anti-mesothelin antibodies

The mesothelin binding domain to be used in the CAR construct is derived from panning of a phage library. The mesothelin binding domain used in the CAR construct may encompass an scFv or sdAb.

Animal immunization

Immunogens comprising recombinant human mesothelin protein (R & D Systems, cat # 3265-MS; Minneapolis, MN) with a C-terminal 6-His tag were mixed with adjuvant or PBS and injected into mice or camels. Typically, the animals are immunized 2-4 times at intervals of 1 to 2 weeks. After multiple rounds of immunization, the immune response to the target antigen was assessed by serotitration via both enzyme-linked immunosorbent assay (ELISA) and flow cytometry.

Phage display library construction

According to the manufacturer's protocol, usingReagent for extracting total RNA from lymphocytes of immunized mice or immunized camels. PRIMESCRIPT was used according to the manufacturer's protocol^TMFirst Strand cDNA Synthesis kit based on cDNA having oligo (dT)₂₀cDNA was synthesized from the RNA template of the primers. VH and VL were amplified from mouse cDNA to generate scFv phage libraries. Amplification of self-camelid cDNA V_HH to generate V_HH phage library.

Biopanning and isolation of anti-mesothelin antibodies

The constructed scFv phage library and V_HThe H phage library was panned against human mesothelin protein and mesothelin expressing tumor cells, respectively. The exported phage particles obtained via panning were used to infect exponentially growing E.coli TG1 cells to generate single clones for screening. Individual clones were randomly picked and screened for binding to mesothelin. Specific binders were selected and sequenced to identify unique anti-mesothelin scFv or sdAb clones.

Example 2: humanization of anti-mesothelin antibodies

3 anti-mesothelin camelid sdAb clones were selected: AS65233, AS80444 and AS80533 were used for humanization. Briefly, a CDR grafting method was applied: the 3 CDRs of the sdAb are inserted into the human framework, followed by several back mutations in the framework regions to maintain the structural and binding properties of the antibody. 3 humanized sdAb variants (VH4, VH5, VH6) were designed for AS65233, AS80444 and AS80533(SEQ ID NO:420-428), respectively. To confirm the binding affinity of sdabs, camelid sdabs with human IgG1Fc were expressed and fused to humanized sdabs and purified using a eukaryotic expression system. Surface Plasmon Resonance (SPR) was performed to determine the affinity of purified camelid and humanized sdabs for human mesothelin. As shown in table 1, the difference in affinity between camelid and humanized sdabs is less than 3-fold.

Table 1: affinity against mesothelin sdAb as determined by SPR

Example 3: preparation of anti-mesothelin CAR constructs

The amino acid sequences of the Complementarity Determining Regions (CDRs) of the anti-mesothelin scFv and sdAb fragments are provided in table 2, and the full-length anti-mesothelin scFv and sdAb amino acid sequences are provided in table 3. Generating a full CAR construct using the scFv or sdAb fragment of table 2 with additional sequences for generating a full CAR construct. SS1 scFv (SEQ ID NO:313) is a mouse anti-mesothelin scFv used to generate the CAR construct as a reference (SS1 CAR). M5 scFv (SEQ ID NO:314) was a human anti-mesothelin scFv used to generate the CAR construct as a reference (M5 CAR). TC-210 is a previously described unconventional CAR construct comprising a humanized anti-mesothelin sdAb fused to the epsilon chain of CD3 (SEQ ID:429), TC-210 also serving as a reference. The full-length anti-mesothelin CAR construct contains, from N-terminus to C-terminus: CD8 a signal peptide (SEQ ID NO:340), the mesothelin binding domain scFv or sdAb (SEQ ID NO:205-258 and SEQ ID NO:420-428), the CD8 a hinge domain (SEQ ID NO:341), the CD8 a transmembrane domain (SEQ ID NO:342), the CD137 endodomain (SEQ ID NO:343) and the CD3 ζ endodomain (SEQ ID NO: 345). Schematic diagrams of anti-mesothelin CAR constructs are shown in figures 1A-1B. The CAR fragment was then cloned into a lentiviral vector using the human EF1 alpha promoter (SEQ ID NO:339) for expression to generate a full-length anti-mesothelin CAR construct in a single coding frame. The resulting CAR backbone vector was named "PLLV-hEF 1 a-mesothelin CAR".

Table 2: anti-mesothelin scFV and sdAb CDR amino acid sequences

Table 3: anti-mesothelin scFV and sdAb amino acid sequences

Example 4: production of anti-mesothelin CAR-T

Preparation of lentiviruses

The lentiviral packaging plasmid mixture comprising pCMV- Δ R-8.47 and pMD2.G (Addgene, Cat. No. 12259; Cambridge, Mass.) was premixed with the vector PLLV-hEF1 α -mesothelin in a pre-optimized ratio with polyethyleneimine, followed by addition of HEK293 cells. After overnight incubation the supernatant was collected. The virus-containing supernatant was filtered through a 0.45 μm PES filter and then ultracentrifuged to concentrate the lentivirus. The viral pellet was washed with pre-cooled DPBS. The virus was aliquoted appropriately and immediately stored at-80 ℃. Viral titers were determined by measuring transduction efficiency of the supT1 cell line via flow cytometry assays.

T lymphocyte Collection and transduction

White blood cells were collected from healthy donors by apheresis. According to manufacturer's protocol, FICOLL-PAQUE is used^TMThe PLUS medium isolates Peripheral Blood Mononuclear Cells (PBMCs). Human T cells were purified from PBMCs using the Pan T cell isolation kit (Miltenyi, catalog number 130-096-535; Bergisch Gladbach, Germany) according to the manufacturer's protocol. Purified T cells were then pre-activated for 48 hours using the human T cell activation/amplification kit (Miltenyi, catalog No. 130-091-441) according to the manufacturer's protocol, with anti-CD 3/CD28 MACSiBead particles added at a bead-to-cell ratio of 1: 2. Preactivated T cells were transduced with lentiviral stocks in the presence of 7. mu.g/ml of coaguloamine. The transduced cells are then transferred to a cell culture incubator for transgene expression under appropriate conditions.

Example 5: evaluation of in vitro Activity against mesothelin CAR-T

In vitro cytotoxicity assay

OVCAR-8 cells are human ovarian cancer cell lines expressing both mesothelin and FSHR, which are used as target cells in the following studies to evaluate CAR-T activity. At day 5 or 9 post-transduction, transduced T cells were harvested and incubated with effector cells (CAR-T) and target cells (OVCAR-8) at a ratio of 7.5:1 for 20 hours. SS1 CAR-T, M5CAR-T and TC-210 were used as controls. Controls SS1 CAR-T and M5CAR-T were used to compare assay variations and/or serve as controls in all assays. Untransduced T cells (UnT) were used as negative controls.

Cytotoxicity was determined by Lactate Dehydrogenase (LDH) assay. The results show that M5CAR-T, AS51674 CAR-T, AS60676 CAR-T, TC-210, AS65233CAR-T, AS65691 CAR-T, AS80444 CAR-T and AS80533 CAR-T exhibit strong anti-tumor activity against OVCAR-8 cells in vitro, whereas SS1 CAR-T exhibits sub-equal in vitro activity and UnT has no killing effect (fig. 7 and 8).

IFN gamma release assay

In addition, supernatants were collected from in vitro cytotoxicity assays to assess CAR-induced cytokine release, such as interferon gamma (IFN γ) release. AS shown in fig. 9 and fig. 10, M5CAR-T, AS51674 CAR-T, AS60702 CAR-T, AS91156 CAR-T, AS91189 CAR-T, AS92110 CAR-T, AS65233CAR-T, AS65271 CAR-T and AS80533 CAR-T were stimulated by OVCAR-8 to produce IFN γ, whereas SS1 CAR-T produced less IFN γ, UnT produced little IFN γ.

Long-term amplification assay by repeated stimulation

Day 0 (4 days after transduction), 2X 10⁵Individual OVCAR-8 cells were plated in 6-well plates to establish a monolayer. On day 1, T cells were counted and 1X 10 cells were plated⁶Personal Activity CAR⁺T cells were plated on top of OVCAR-8 cells in fresh medium in the absence of cytokines. On day 3, new 2X 10 was added⁵Individual OVCAR-8 cell monolayers were plated as in day 0. On day 4, live CAR-T cells were counted. On day 4, 1X 10 wells from expanded (with at least this number of cells) will be harvested⁶A CAR⁺T cells were replated on a new monolayer as in day 1. The process is repeated for 3-4 repeated stimulations. Fold expansion after each stimulation was calculated as [ day 4 live CAR⁺T is thinCell]/1×10⁶I.e., the amount of CAR-T cells plated on day 1 of each stimulation. To normalize for cells discarded at each new stimulation, they were normalized by [ (fold expansion) × (fold expansion +1) … …]Cumulative fold amplification was determined. AS shown in figure 11, AS51674 CAR-T, AS80444CAR-T, AS80533 CAR-T, AS80533VH 4CAR-T and AS60702 CAR-T exhibited better expansion ability than M5 CAR-T and TC-210 after 3 rounds of co-culture with target cells.

Example 6: evaluation of anti-mesothelin CAR-T in an in vivo mouse model

Anti-mesothelin CAR-T was evaluated for anti-tumor activity in vivo in an OVCAR-8 xenograft model. On day 0, 10X 10⁶One OVCAR-8 cell was implanted subcutaneously in NOD Scid Gamma (NSG) mice. Once the tumor reaches 150-³Mice were randomized into treatment groups. 0.33X 10 was administered intravenously at a dose of 200. mu.l⁶Individual CAR positive T cells (M5CAR-T, TC-210, anti-mesothelin CAR-T, UnT). Mice and tumors were monitored for about 60 days after tumor cell implantation.

AS shown in figure 12, AS80533VH4CAR-T effectively eradicated tumors in mice and resulted in tumor-free. AS80444 CAR-T also significantly regressed tumors in vivo. However, M5CAR-T inhibited tumor growth by about 50%, while TC-210 hardly inhibited tumor growth. No tumor suppression effect was observed by infusion of UnT. 10X 10 days 65 after CAR-T infusion⁶Individual OVCAR-8 cells were re-challenged subcutaneously in AS80533VH4CAR-T cured mice. Tumors remained growing in the initially treated mice, while re-challenged tumors were eradicated in AS80533VH4 cured mice. These results indicate that AS80533VH4CAR-T was administered at a relatively low dose (0.33X 10)⁶Individual CAR positive T cells) eradicate the tumor and provide long-term protection in vivo (greater than 100 days).

Example 7: detection of expression of Follicle Stimulating Hormone Receptor (FSHR) on ovarian tumor cell lines

The FSH β 33-53 peptide (SEQ ID NO:319) was fused to the Fc region of human IgG at the C-terminus, followed by transient generation and purification from HEK293F cells. Transient expression and purification in HEK293F cells was performed using standard methods. Briefly, 100. mu.g of plasmid and 300. mu.g of poly100ml of ethyleneimine transfection 3X 10⁶HEK293F cells per ml. Cells were incubated at 37 ℃ with 8% CO₂Incubate and spin at 80 rpm. After 6 days, cells were harvested by centrifugation at 3500 × g for 20 minutes. The supernatant was purified by binding the Fc fusion FSH β 33-53 peptide to protein a sepharose beads. The proteins were eluted with citrate buffer and dialyzed against Phosphate Buffered Saline (PBS).

To confirm FSHR expression on ovarian tumor cell lines, Fc fusion FSH β 33-53 peptide (SEQ ID NO:332) was tested for binding to OVCAR-3 cells, OVCAR-8 cells and HEK293F cells (negative control) via flow cytometry. Fluorescence Activated Cell Sorting (FACS) data (fig. 13) show that Fc fusion FSH β 33-53 peptide specifically binds to OVCAR-3 and OVCAR-8 cells and does not bind to HEK293 control cells, indicating FSHR expression on ovarian tumor cell lines.

Example 8: preparation of the FSHR TCR Complex

The FSH β 33-53 peptide was fused to the CD3 epsilon chain, gamma chain or delta chain for TCR/CD3 complex signaling in a FSHR-dependent and MHC-independent manner. This TCR complex was designated as the FSHR TCR complex. Thus, the FSHR TCR complex comprises a fusion protein comprising, from N-terminus to C-terminus, a CD3 epsilon, CD3 gamma or CD3 delta signal peptide (SEQ ID NO: 430-432); FSH β 33-53 peptide (SEQ ID NO: 319); a joint; CD3 epsilon, CD3 gamma or CD3 delta extracellular domain (SEQ ID NO: 433-435); CD3 epsilon, CD3 gamma or CD3 delta transmembrane domain (SEQ ID NO: 436-438); and CD3 epsilon, CD3 gamma or CD3 delta intracellular domain (SEQ ID NO: 439-441). Schematic representations of FSHR TCR complexes comprising a fusion construct having the FSH β 33-53 peptide fused to the extracellular domain of CD3 s are shown in fig. 2A-2B. Similar FSHR TCR complexes may also be prepared having the FSH β 33-53 peptide fused to the CD3 γ or CD3 δ extracellular domains. The coding sequence of the fusion protein was then cloned into a lentiviral vector to generate the FSHR TCR construct in a single coding frame, using the human EF1 a promoter for expression. The resulting CAR backbone vector was named "PLLV-hEF 1 α -FSHR TCR".

Example 9: preparation of FSHR/mesothelin tandem CAR constructs

The FSH β 33-53 peptide was fused between the CD8 α signal peptide of the anti-mesothelin CAR and the anti-mesothelin scFv or sdAb fragment to generate a tandem CAR construct containing mesothelin and FSHR binding domains. A linker sequence (selected from SEQ ID NO: 334-338) was used to link the C-terminus of the FSH β 33-53 peptide to the N-terminus of the anti-mesothelin scFv or sdAb fragment. Thus, the full-length FSHR/mesothelin tandem CAR contains, from N-terminus to C-terminus: a CD8 a signal peptide, a FSH β 33-53 peptide, a linker, a mesothelin binding domain scFv or sdAb, a CD8 a hinge domain, a CD8 a transmembrane domain, a CD137 endodomain, and a CD3 ζ endodomain. Schematic diagrams of tandem CAR constructs are shown in figures 3A-3D. The CAR fragment was then cloned into a lentiviral vector to generate a tandem CAR construct in a single coding frame, using the human EF1 a promoter for expression. The resulting CAR backbone vector was named "PLLV-hEF 1 α -tandem".

Example 10: preparation of mesothelin/FSHR dual CAR constructs

The FSH β 33-53 peptide was used to generate a second generation CAR construct comprising a CD28 intracellular domain and a CD3 ζ intracellular domain. The FSHR-targeted CAR was then C-terminally linked to an anti-mesothelin CAR via the 2A element (SEQ ID NO: 346). Thus, the full-length mesothelin/FSHR dual CAR contains from N-terminus to C-terminus: CD8 a signal peptide (SEQ ID NO:340), the mesothelin binding domain scFv or sdAb (SEQ ID NO:205-258 and SEQ ID NO:420-428), the CD8 a hinge domain (SEQ ID NO:341), the CD8 a transmembrane domain (SEQ ID NO:342), the CD137 intracellular domain (SEQ ID NO:343), the CD3 ζ intracellular domain (SEQ ID NO:345), the 2A element (SEQ ID NO:346), the CD8 a signal peptide (SEQ ID NO:340), the FSH β 33-53 peptide (SEQ ID NO:319), the CD8 a hinge domain (SEQ ID NO:341), the CD8 a transmembrane domain (SEQ ID NO:342), the CD28 intracellular domain (SEQ ID NO:344) and the CD3 ζ intracellular domain (SEQ ID NO: 345). Schematic diagrams of the dual CAR constructs are shown in figures 4A-4B. The CAR fragment was then cloned into a lentiviral vector to generate a dual CAR construct in a single coding frame, using the human EF1 a promoter for expression. The resulting CAR backbone vector was named "PLLV-hEF 1 α -duplex".

Example 11: preparation of mesothelin/FSHR CAR/TCR construct

The FSHR TCR was then C-terminally linked to the anti-mesothelin CAR via the 2A element (SEQ ID NO: 346). Thus, the full-length mesothelin/FSHR CAR/TCR contains from N-terminus to C-terminus: CD8 a signal peptide (SEQ ID NO:340), the mesothelin binding domain scFv or sdAb (SEQ ID NO:205-258 and SEQ ID NO:420-428), the CD8 a hinge domain (SEQ ID NO:341), the CD8 a transmembrane domain (SEQ ID NO:342), the CD137 intracellular domain (SEQ ID NO:343), the CD3 ζ intracellular domain (SEQ ID NO:345), the 2A element (SEQ ID NO:346), the CD3 ε signal peptide (SEQ ID NO:430), the FSH β 33-53 peptide (SEQ ID NO:319), a linker, the CD3 ε extracellular domain (SEQ ID NO:433), the CD3 ε transmembrane domain (SEQ ID NO:436) and the CD3 ε intracellular domain (SEQ ID NO: 439). Schematic diagrams of the CAR/TCR constructs are shown in figures 5A-5B. The CAR fragment was then cloned into a lentiviral vector to generate the CAR/TCR construct in a single coding frame, using the human EF1 a promoter for expression. The resulting CAR backbone vector was named "PLLV-hEF 1 α -CAR/TCR".

Using similar methods, mesothelin/FSHR CAR/TCR constructs containing the FSHR TCR complex having the FSH β 33-53 peptide fused to the CD3 γ or CD3 δ extracellular domains may also be prepared.

Example 12: preparation of CAR constructs armored with dnTGF-. beta.RII

Dominant negative TGF-. beta.RII (dnTGF-. beta.RII) was constructed by truncating human TGF-. beta.RII to remove the intracellular kinase domain at residue 199 as originally reported (Wieser R et al, Molecular and cellular biology.1993; 13: 7239-. dnTGF β RII is linked to a component of the CAR or TCR complex at the N-terminus or C-terminus via the P2A element. A dnTGF-beta RII-armored anti-mesothelial CAR, a dnTGF-beta RII-armored FSHR TCR, a dnTGF-beta RII-armored FSHR/mesothelial tandem CAR, a dnTGF-beta RII-armored mesothelial/FSHR dual CAR, and a dnTGF-beta RII-armored mesothelial/FSHR CAR/TCR were prepared, respectively. Schematic diagrams of dnTGF β RII armored CAR and/or TCR constructs are shown in figures 6A-6L. The nucleic acid encoding the CAR and/or TCR construct is then cloned into a lentiviral vector to generate a CAR construct with dnTGF β RII in a single coding frame, using the human EF1 a promoter for expression. The resulting CAR backbone vector was named "PLLV-hEF 1 α -dnTGF β RII armored CAR".

Example 13: evaluation of in vitro Activity of different CAR/TCR constructs

Transgenic lentiviruses containing different CAR/TCR constructs were prepared as described above. CAR-T cells with different patterns (anti-mesothelin CAR, FSHR TCR, FSHR/mesothelin tandem CAR, mesothelin/FSHR dual CAR, mesothelin/FSHR CAR/TCR, dnTGF β RII armored CAR) were generated by transduction of lentiviruses into primary T cells, respectively.

In vitro Activity of anti-mesothelin CAR and FSHR/mesothelin tandem CAR

In vitro cytotoxicity of AS51674 CAR-T and FSHR/mesothelin tandem CAR-T based on AS51674 was assessed by LDH assay. The FSH β 33-53 peptide was linked to AS51674 via a short or long linker at the N-or C-terminus, and then combined with second generation CAR constructs corresponding to: FSH33-53+ AS51674-SL, AS51674+ FSH33-53-SL, FSH33-53+ AS51674-LL, 51674+ FSH 33-53-LL. The results indicated that FSHR/mesothelin tandem CAR had comparable killing efficacy against OVCAR-8 cells as the anti-mesothelin CAR, whereas UnT had no killing effect (figure 14).

Anti-mesothelin CAR, mesothelin/FSHR dual CAR, and mesothelin/FSHR In vitro Activity of CAR/TCR

In vitro cytotoxicity of AS51674 CAR-T, AS51674 based mesothelin/FSHR dual CAR-T, AS80533VH4CAR-T, AS80533VH4 based mesothelin/FSHR dual CAR-T and AS80533VH4 based mesothelin/FSHR CAR/TCR-T was evaluated by LDH assay. The results indicated that AS 51674-based mesothelin/FSHR duplex CAR-T had comparable killing efficacy against OVCAR-8 cells AS51674 CAR-T, AS80533VH 4-based mesothelin/FSHR CAR/TCR-T, AS80533VH 4-based mesothelin/FSHR CAR/TCR-T had comparable killing efficacy against OVCAR-8 cells AS80533VH4CAR-T, and UnT had no killing effect (fig. 15).

In vitro Activity of naked (non-dnTGFbetaRII-armored) CAR and dnTGFbetaRII-armored CAR

As previously described, dnTGF β RII is linked to the CAR construct at the N-terminus (dnTGF β RII + CAR) or the C-terminus (CAR + dnTGF β RII). In vitro cytotoxicity of AS51674CAR-T and dnTGF β RII armored AS51674CAR-T was assessed by LDH assay. The results indicate that dnTGF β RII armored AS51674CAR-T had better killing efficacy against OVCAR-8 cells than AS51674CAR-T, whereas UnT had no killing effect (fig. 16).

In addition, in vitro cytotoxicity of AS80533VH 4-based mesothelin/FSHR dual CAR-T, AS 80533-based mesothelin/FSHR CAR/TCR-T and the corresponding dnTGF β RII-armored CAR-T was evaluated by LDH assay. The results indicate that dnTGF β RII armored CAR-T has comparable killing efficacy against OVCAR-8 cells as naked CAR-T, whereas UnT has no killing effect (fig. 17).

In addition, supernatants were collected from in vitro cytotoxicity assays to assess CAR-induced cytokine release, e.g., interferon gamma (IFN γ) and tumor necrosis factor alpha (TNF α) release. AS shown in fig. 18 and fig. 19, AS80533VH 4-based mesothelin/FSHR dual CAR-T, AS 80533-based mesothelin/FSHR CAR/TCR-T and the corresponding dnTGF β RII armored CAR-T were stimulated by OVCAR-8 to produce comparable IFN γ and TNF α levels, while UnT produced little IFN γ and TNF α.

Example 14: comparison of in vivo efficacy of anti-mesothelin CAR with mesothelin/FSHR Dual CAR

The antitumor activity of AS51674CAR-T and the mesothelin/FSHR dual CAR-T based on AS51674 were evaluated in vivo in an OVCAR-8 xenograft model. On day 0, 10X 10⁶Individual OVCAR-8 cells were implanted subcutaneously in NSG mice. Once the tumor reaches 150-³Mice were randomized into treatment groups. 0.33X 10 was administered intravenously at a dose of 200. mu.l⁶Individual CAR-positive T cells. AS shown in figure 20, mesothelin/FSHR dual CAR-T based on AS51674 effectively eradicated tumors in mice, while AS51674CAR-T hardly inhibited tumor growth. No tumor suppression effect was observed by infusion of UnT.

In addition, the antitumor activity of AS80533VH4CAR-T and the mesothelin/FSHR dual CAR-T based on AS80533VH4 were also evaluated in vivo in an OVCAR-8 xenograft model. Similarly, when the tumor reaches 150-³At a dose of 200. mu.l, 0.11X 10⁶Intravenous administration of individual CAR-positive T cells to tumor-bearingNSG mice. As shown in figure 21, mesothelin/FHSR dual CAR-T effectively eradicated tumors in all 4 mice and resulted in tumor-free, whereas anti-mesothelin CAR-T regressed tumors in only 3 out of 4 mice. No tumor suppression effect was observed by infusion of UnT. These results indicate that the mesothelin/FSHR dual CAR-T has more potent anti-tumor efficacy in vivo than anti-mesothelin CAR-T.

Example 15: in vivo efficacy comparison of naked CAR and dnTGF β RII armored CAR

mesothelin/FSHR dual CAR-T based on AS80533VH4, mesothelin/FSHR CAR/TCR-T based on AS80533 and the corresponding dnTGF β RII armored CAR-T were evaluated in vivo in an OVCAR-8 xenograft model. Similarly, when the tumor reaches 150-³At a dose of 200. mu.l, 0.1X 10⁶Individual CAR-positive T cells were administered intravenously into tumor-bearing NSG mice. As shown in figure 22, dnTGF β RII-armored CAR-T inhibited tumor growth more effectively than the corresponding naked CAR-T, for both mesothelin/FSHR dual CAR and mesothelin/FSHR CAR/TCR. Furthermore, mesothelin/FSHR CAR/TCR was a little more effective in vivo than mesothelin/FSHR dual CAR. No tumor suppression effect was observed by infusion of UnT. These results indicate that dnTGF β RII armoring can enhance the in vivo efficacy of CAR-T.

It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications within the spirit and scope of the present invention as defined in the present specification.

Sequences of exemplary constructs according to embodiments of the invention:

SEQ ID NO: 205(AD58126 scFv amino acid sequence; CDR underlined)

QVQLKQSGAELAKPGASVEMSCKASGYTFTSYWMHWVKQRPGQGLEWIGYINPSTGHTDYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSNWAWFPYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGKPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGSGTRLEIK

SEQ ID NO:206(AD58126VH3VL1 scFv amino acid sequence; CDR underlined)

QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVKQAPGQGLEWIGYINPSTGHTDYNQKFKDRATLTADTSTSTVYMELSSLRSEDTAVYYCARSNWAWFPYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGGGTKLEIK

207(AD58116 scFv amino acid sequence; CDR underlined)

QVQLKESGPELVKPGASVKISCKTSGYTFTEYTMNWVRQSHGKSLEWIGGIIPNNGDTSYNQKFKGKATLTVDKSSSTAYMELRSLTSEDSAVYYCAGRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQAPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWFLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQ GTHFPFTFGSGTKLEIK

SEQ ID NO:208(AD58117 scFv amino acid sequence; CDR underlined)

QVQLQQSGPELKKPGETVKISCKASFYTFTAYSMHWVKQAPGKGLKWMGWINTETGEPTYADDFKGRFAFSLETSATTAYLQINNLKNEDTATFFCARGLRRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPTSLAVSLGQRATISCRASESVDSYGNSFMNWYQQKPGQPPKLLIYLASYLESGVPARFSGSGSRTDFTLTIDPVEADDAATYYCQQNNEDPYTFGGGTRLEIK

SEQ ID NO: 209(AD58127 scFv amino acid sequence; CDR underlined)

QVQLQQSGAELVRPGASVTLSCKASGYTFTDYEIHWVKQTPVHGLEWIGGIDPETGGAAYTQKFKGKATLTADKSSSTAYMELRSLTSEDSAVYYCTTYGNYPLDSWGQGTTLTVSSGGGGSGGGGSGGGGSGIVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYFCSQSTHVPLTFGAGTRLEIK

210(AD58143 scFv amino acid sequence; CDR underlined)

QVQLKQSGAELVRPGASVTLSCKASGYTFTDYEMHWVKQTPVHGLEWIGGIDPETGGAAYTQKFKGKATPTADKSSSTAYMELRSLTSEDSAVYYCTTYGNYPLDSWGQGTTVTVSSGGGGSGGGGSGGGGSDIQMTQTPLSLPVSLGDQASISCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISGVEAEDLGVYFCSQSTHVPLTFGAGTKLELK

SEQ ID NO: 211(AD58159 scFv amino acid sequence; CDR underlined)

QVQLKQSGAELVRPGTSVKISCKASGYTITNYWLGWVKQRPGHGLEWIGDIYPGGGYTNYNEKFKGKATLTADTSSITAYMQLSSLTSEDSAVYFCARGGSSYWYFDVWGAGTSVTVSSGGGGSGGGGSGGGGSDIQMTQTTSSLSASLGDRVTISCSASQDISNYLNWYQQKPDGTVKLLIYYTSSLHSGVPSRFSGSGSGTDYSLTISNLEPEDIATYYCQ QYSKVPYTFGGGTKLELK

212(AD58115 scFv amino acid sequence; CDR underlined)

QVQLKQSGPELVKPGASVKISCKTSGYTFTEYTMNWVKQSHGKSLEWIGGIIPNNGDTSYKQEFKGKATLTVDKSSSTAYMELRSLTSDDSAVYYCAGRFAYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWFLQRPGQSPKRLIYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQ GTHFPFTFGSGTKLEIK

213(AD58123 scFv amino acid sequence; CDR underlined)

EVQLQQSGPGLVAPSQSLSITCTVSGFSLSRYSVHWVRQPPGKGLEWLGMIWGGGNTDYNSALKSRLSISKDNSKSQVFLKMNSLQTDDTAMYYCARSLGWYFDIWGAGTTVTVSSGGGGSGGGGSGGGGSDIVMTQSPSSLAVSAGEKVTMSCKSSQSVLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCHQYLSSWTFGGGTKLEIK

SEQ ID NO: 214(AD58145 scFv amino acid sequence; CDR underlined)

EVQLQQSGAELAKPGASVKMSCKASGYTFTSYWMHWVKQRPGQGLEWIGYINPSTGYTDYNQKFKDKATLTADKSSSTAYMQLSSLTSEDSAVYYCARSNWAWFPYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDYSYPLTFGAGTKLELK

215(AS51489 scFv amino acid sequence; CDR underlined)

EVQLVESGGGLVQPGGSLRLSCAASGFNLYYYSIHWVRQAPGKGLEWVAYISSSSSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYPYYGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQ GFSYYPITFGQGTKVEIK

216(AS51491 scFv amino acid sequence; CDR underlined)

EVQLVESGGGLVQPGGSLRLSCAASGFNLYSYSMHWVRQAPGKGLEWVAYIYPYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQSYY WLFTFGQGTKVEIK

SEQ ID NO: 217(AS92110 scFv amino acid sequence; CDR underlined)

EVQLVESGGGLVQPGGSLRLSCAASGFNIYYSSMHWVRQAPGKGLEWVAYIYPYYSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYALDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASS GYHYLITFGQGTKVEIK

218(AS91156 scFv amino acid sequence; CDR underlined)

EVQLVESGGGLVQPGGSLRLSCAASGFNIYSSSIHWVRQAPGKGLEWVASISSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGPY YHPITFGQGTKVEIK

SEQ ID NO:219(AS91189 scFv amino acid sequence; CDR underlined)

EVQLVESGGGLVQPGGSLRLSCAASGFNLSYSSIHWVRQAPGKGLEWVASIYSYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYWGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYW YYPITFGQGTKVEIK

SEQ ID NO:220(AS51674 scFv amino acid sequence; CDR underlined)

EVQLVESGGGLVQPGGSLRLSCAASGFNLYSYYMHWVRQAPGKGLEWVASIYSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARPFGWGYAGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGYAPITFGQGTKVEIK

221(AS66073 sdAb amino acid sequence; CDR underlined)

QVQLVESGGDSVQAGGSLTLACTGRKYSSLYCMAWFRQAPGKAREGVAVISSGGFTNYADSVKGRFTISRDNSKNTLYLAMNGLKPEDTAMYYCAAGLSYCHSSTATATYRGQGTQVTVSS

222(AS66439 sdAb amino acid sequence; CDR underlined)

QMQLVESGGGSVQAGGSLRLSCTAPGFTSSDCDMDWYRQAAGNQREWVSSLLSTDGSTSYADSVRGRFTISKDPAKDTVYLQMNSLKPEDTAMYFCRCVVAEWGGMDYWGKGTLVTVSS

SEQ ID NO:223(AS65955 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQAGGSLRLSCAASGDRVSTGCMGWFRQGPGEEREGLAQIHNYNIAKYADSVKGRFTISKDNAKNILYLQMNSLKPEDTGLYICTAPVDCSWSMFLQDPLALSPPRGQGTQVTVSS

SEQ ID NO: 224(AS65233 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQAGGSLRLSCAASEFTYSMGWFRQAPGKEREGVAHIYTRGGTTVYADSVKGRFVLSRYNAKSIMYLQMNSVKLEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTQVTVSS

225(AS65926 sdAb amino acid sequence; CDR underlined)

QVQLVESGGGSVQAGGSLRLSCAASGNLYNNMCMGWFRQAPGKEREGVASIYIGGGYTNYADSVKGRFTISPISRDNAKSTLYLQMNSLKPEDTAMYYCAAVSIALTREFCAPIVSRYNYWGQGTQVTVSS

226(AS66159 sdAb amino acid sequence; CDR underlined)

QVRLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASIYVGGGYTNYADSVRGRFTISQDNAKNTLYLQMNSLKPEDTAMYYCAAITVALTRAFCAPIPSRYTNWGQGTQVTVSS

SEQ ID NO:227(AS66416 sdAb amino acid sequence; CDR underlined)

QVQLAESGGGSVQAGGSLRLSCAASGNLYNNMCMGWFRQAPGKEREGVGSIYIGGGYTNYSESVRGRFTISLDNAKKTLNLQMNSLKPEDTAMYYCAAIPIALTRAFCAPIVSRYTYWGQGTQVTVSS

228(AS65850 sdAb amino acid sequence; CDR underlined)

EVQLMESGGGSVQAGGSLRLSCAASGFSYSNICMGWFRQAPGKEREGVAAIYSNGSTIYADSVKGRFTVSKEFAKNTQYLQMNSLKPEDTAMYYCAAGRCGGPNYWGQGTQVTVSS

229(AS65183 sdAb amino acid sequence; CDR underlined)

EVQLAESGGGSAQAGGSLRLSCASNGYYNRRYCMAWFRQAPGKEREGVATMTTTSGRTYYADAVKGRFTVSQDNAKSTLYLQMSSLKPEDTAMYYCAAHLPSSWVTSTDYCDNLQAGFYNSWGQGTQVTVSS

SEQ ID NO: 230(AS65062 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQAGGSLRLSCAASGVSVVNFAMRWYRQAPGNEREFVSAMYRSGSTSYADSVRGRFTISRDSALNTVFLQMSGLKPEDTATYYCQATSPMGDTYWGQGTQVTVSS

231(AS65065 sdAb amino acid sequence; CDR underlined)

EVQLAESGGGSVQAGGSLRLSCAASGYSYCRSTMRWYRQAPGNVREFVSAIYSDGTTSYTDSVKGRFTISQDNAKNTVYLQMNSLQPEDTAMYYCRIDLVGCNVAGGSPYWGQGTQVTVSS

232(AS65556 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQVGGSLRLSCAASGYNASICRMSWYRQAPGTEREFVSSSYRDGSQSYADSVKGRFTTSRDSAKNTVFLQMNSLKPSDTAMYYCNAACPWRAYWGQGTQVTVSS

SEQ ID NO: 233(AS65069 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQAGGSLRLSCVASGDTGYQPTMRWYRQAPGKEREFVSAIYSDQTTSYADSVKGRFTISQDNARKTVYLQMASLKPEDTAMYYCKLTTRRGSEYWGQGTQVTVSS

234(AS65691 sdAb amino acid sequence; CDR underlined)

QMQLVESGGGSVQAGGSLRLSCTVSGYTDYRLVLRWYRQALGKEREFISAIYSDGVTSYSDSVKGRFTISRDNAKNTAYLQMNSLKSEDTAMYYCKATGSGGVAYWGQGTQVTVSS

235(AS65064 sdAb amino acid sequence; CDR underlined)

QVQLVESGGGSVQAGGSLKLSCAVSGDTVQTNCMAWFRQAPGKEREAVASILSLYSSGGKTVYADSVKGRFTISPDNAQNTVSLQMNNLKPEDTAMYYCATVRVTVTWAEKLRRCTGFSGMDYWGKGTLVTVSS

SEQ ID NO: 236(AS65081 sdAb amino acid sequence; CDR underlined)

QVHLMESGGGSVQAGGSLRLSCAASGVPASSYCMGWFRQAPGKEREGVAGIVSDTTTTYADSVKGRFTISKDNAKNTLYLQMNSLKPEDTATYYCAASHFLLCARKPRWDDLIKYEYWGQGTQVTVSS

237(AS65115 sdAb amino acid sequence; CDR underlined)

QVQLVESGGGSVQAGGSLRLSCAASGYIYGCMGWFRRAPGKAREEVATIYRDGTAYYANSVEGRFTASRNNAENTLSLEMNSLNAEDTAMYYCAARTTGCNWDISGVYWGQGTQVTVSS

238(AS65271 sdAb amino acid sequence; CDR underlined)

QMQLVESGGGSVQAGGSLTLSCAASGKTYGRCMAWFRQAPGKERELVAATYISGGRPYVADSVKGRFTISRDNAKSTMSLQMNSLRPDDSAMYYCAAGSAGRGPCDRFDQNQYTFWGQGTQVTVSS

SEQ ID NO: 239(AS65166 sdAb amino acid sequence; CDR underlined)

QVQLVESGGGSVQAGGSLRLSCTASEDLSIYGYNCMGWFRQAPGKEREAVAAIYTGRGTTYYADSVKGRFTISQDNAKNTVYLQMNSLKPEDTAMYYCASKYCAVVADFGNSRLVRYWGQGTQVTVSS

240(AS65450 sdAb amino acid sequence; CDR underlined)

QVRLVESGGGSVQAGGSLRLSCAASGDMNGYKCMGWFRQAPGKEREAVAGIYTGRGTTYYADSVKDRFTISQDNAKNTVYLQMNSLKPEDTAMYYCAAKYCAVVAEFGGPRLVRYWGQGTQVTVSS

241(AS65454 sdAb amino acid sequence; CDR underlined)

QVRLVESGGGSVQAGGSLRLSCAASGDMNGYKCMGWFRQAPGKEREAVAGIYTGRNTTYYADSVKDLFTISQDNAQNTVFLQMNSLKPEDTAMYYCASYCAVVAEFRGPRLDRYWGYGTQVTVTS

SEQ ID NO:242(AS65131 sdAb amino acid sequence; CDR underlined)

EVQLAESGGGSVQAGGSLTLSCTASEYVTHLGWFRQAPGKEREGVAIESFRIGYTYYADSVKGRFTISHDNAKNTLYLQMNSLKPEDTAIYYCAARQDRSGASMVNRDSYNYWGKGTQVTVSS

SEQ ID NO:243(AS65182 sdAb amino acid sequence; CDR underlined)

QVKLVESGGGSVQAGGSLRLSCAASGYTYSYGYMGWFRQAPGKEREGVAKIYNGDGSTYYADSVKGRFTISQDRRNNTLYLQMNSLAPEDTGMYYCATNRLPNSDVDLVLPRFGRFGYWGQGTQVTVSS

244(AS60685 sdAb amino acid sequence; CDR underlined)

QVQLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASMYVGGGYTYYDDSVKGRFTISRDNAKNTLYLQMNSLKPEDTAMYYCAAISIALTREFCAPIVSRYNYWGQGTQVTVSS

SEQ ID NO:245(AS60702 sdAb amino acid sequence; CDR underlined)

QVKLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASIYVGGGYTNYADSVRGRFTISQDNAKNTLYLQMNSLKPEDTAMYYCAAITVALTRAFCAPIPSRYTNWGQGTQVTVSS

SEQ ID NO:246(AS60705 sdAb amino acid sequence; CDR underlined)

QVQLVESGGGSVQSGGSLRLSCAASGYAYSGSCMMAWFRQAPGKEREGVAVSVRRTGSAFYADSVKARFTISRDNAKNTLYLQMNNLKVEDTAMYYCAADFTCRTWTLNKNYNHWGQGTQVTVSS

SEQ ID NO: 247(AS60660 sdAb amino acid sequence; CDR underlined)

QVHLMESGGGSVQAGGSLRLSCVASGDTGYQPTMRWYRQAPGKEREFVSAIYSDQTTSYADSVKGRFTISQDNARKTVYLQMASLKPEDTAMYYCKLTTRRGSEYWGQGTQVTVSS

SEQ ID NO:248(AS60662 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQAGGSLRLSCVASGYRNCRSTMRWYRQGPGQVRDWVSSIYTDGTTSYTDSVKGRFTIAQDKGKNTVYLQMNSLQPEDTAMYYCRIDLVGCNVAGGSPYWGHGTQVTVSS

SEQ ID NO:249(AS60664 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQAGGSLTLSCAASGKTYGRCMAWFRQAPGKERELVAATYISGGRPYVADSVKGRFTISRDNAKSTMSLQMNSLRPDDSAMYYCAAGSAGRGPCDRFDQNQYTFWGQGTQVTVSS

SEQ ID NO: 250(AS60668 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQAGGSLRLSCAASGDMNGYKCMGWFRQAPGKEREAVAGIYTGRNTTYYADSVKDRFTISQDNAKNTVFLQMNSLKPEDTAMYYCASKYCAVVAEFGGPRLVRYWGQGTQVTVSS

251(AS60676 sdAb amino acid sequence; CDR underlined)

QVQLVESGGGSVQAGGSLRLSCAASGYTVSSGCMGWFRQAPGKERERVAQIGRDATTTYADSVKGRFTIARDDAENTLYLQMNSLKPEDTAMYSCTAYWGVYCLSPGRYWGQGTQVTVSS

252(AS60678 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQAGGSLRLSCAVSGYTSSRGCMSWFRQAPGKERERVAYINMRVLTTIYAASVKDRFAISRDNAKNTVDLQMNNLKPEDTAMYYCAAGYNGQWCEHASDVTAWGQGTQVTVSS

SEQ ID NO: 253(AS60679 sdAb amino acid sequence; CDR underlined)

QVHLMESGGGSVQAGGSLRLSCARSGVTYCRLTMRWYRQAPGSEREFVSAIYSDGSTAYADSVKGRFTMSQDDAKNTVYLQMNSVKPEDTAMYYCKLNCASGLTAWGQGTQVTVSS

SEQ ID NO:254(AS81326 sdAb amino acid sequence; CDR underlined)

EVQLVESGGGSVQAGGSLTLSCAASESRDCMAWFRQAPGKAREGVASIYAPDGSTTYADTVKGRFTISQDNAKNTLYLQMNSLQPEDAAMYHCAIGGLSRNTCGYLRGGYFAYFGRGTQVTVSS

255(AS81187 sdAb amino acid sequence; CDR underlined)

QVRLVESGGGSVQAGGSLRLSCAASGYTYSSYSSNCLGWFRQAPGKEREAVARIYPNSGSTYYADSVKGRFTISQDNAKNTVYLQMNSLKPEDTAMYYCAVAVGVGDNWCASGAAYFGYWGQGTQVTVSS

SEQ ID NO: 256(AS80533 sdAb amino acid sequence; CDR underlined)

QVHLVESGGGSVQTGGSLRLSCTASGLSFSTYTVAWFRQAPGKEREGVAAIPYTSQHMVYTDSVKGRFTISRDNTKNMVYLQMNSLKPEDTAMYYCATDRRPGTSMLAINGYNRWGQGTQVTVSS

257(AS80444 sdAb amino acid sequence; CDR underlined)

EVQLAESGGGSVQAGGSLRLSCAASGFTFSRNTMGWFRQAPGKEREGVAAIPYTSTGIVYSDSVGGRFTISRDNTKNMVYLQMNNLEPEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTQVTVSS

SEQ ID NO:258(AS81487 sdAb amino acid sequence; CDR underlined)

QVRLVESGGGSVQAGGSLRVSCLVSKLTAWRSCVGWFRQAPGKEREGVAAIYSGTGSTYYADSVKGRFTIAQDYAKNMVYLQMNSLKPEDTAMYYCAGTSIRSSCGLVRDEYAYWGQGTQVTVSS

259(AD58126 scFv nucleic acid sequence)

CAGGTGCAGCTGAAGCAGTCTGGGGCTGAACTGGCAAAACCTGGGGCCTCAGTGGAGATGTCCTGCAAGGCTTCTGGCTACACCTTTACTAGCTACTGGATGCACTGGGTAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGATACATTAATCCTAGTACTGGTCATACTGACTACAATCAGAAGTTCAAGGACAAGGCCACATTGACTGCAGACAAATCCTCCAGCACAGCCTACATGCAACTGAGCAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGATCCAACTGGGCCTGGTTTCCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCGAGCggtggaggcggttcaggcggaggtggctctggcggtggcgggtcgGACATTGTGATGACTCAGTCTCCATCCTCCCTGACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAAACAGTGGAAATCAAAAGAACTACTTGACCTGGTACCAGCAGAAACCAGGGAAGCCTCCTAAACTGTTGATCTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGAACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGAATGATTATAGTTATCCGCTCACGTTCGGTTCTGGGACCAGACTGGAAATAAAA

260(AD58126VH3VL1 scFv nucleic acid sequence)

CAGGTGCAGCTGGTGCAGTCCGGAGCAGAGGTGAAGAAGCCAGGAGCCAGCGTGAAGGTGTCCTGCAAGGCCTCTGGCTACACCTTCACAAGCTATTGGATGCACTGGGTGAAGCAGGCACCAGGACAGGGACTGGAGTGGATCGGCTACATCAATCCCTCCACAGGCCACACCGACTATAACCAGAAGTTTAAGGATCGGGCCACCCTGACAGCCGACACCTCTACAAGCACCGTGTACATGGAGCTGAGCTCCCTGAGGTCCGAGGATACAGCCGTGTACTATTGCGCCCGCTCTAATTGGGCCTGGTTCCCCTATTGGGGCCAGGGCACACTGGTGACCGTGTCTAGCGGAGGAGGAGGATCCGGAGGAGGAGGATCTGGCGGCGGCGGCAGCGATATCGTGATGACACAGTCCCCTGACTCTCTGGCCGTGTCTCTGGGAGAGAGGGCAACCATCAACTGTAAGTCCTCTCAGAGCCTGCTGAACTCCGGCAATCAGAAGAACTACCTGACCTGGTATCAGCAGAAGCCTGGCCAGCCCCCTAAGCTGCTGATCTACTGGGCATCTACAAGGGAGAGCGGAGTGCCAGATAGATTCTCCGGCTCTGGCAGCGGCACCGACTTTACACTGACCATCAGCTCCCTGCAGGCCGAGGATGTGGCCGTGTACTATTGTCAGAATGACTACAGCTATCCCCTGACATTTGGCGGCGGCACCAAGCTGGAGATCAAG

261(AD58116 scFv nucleic acid sequence)

CAGGTGCAGCTGAAGGAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGACTTCTGGATACACATTCACTGAATACACCATGAACTGGGTGAGGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAGGTATTATTCCTAACAATGGTGATACTAGCTACAACCAGAAGTTCAAGGGCAAGGCCACATTGACTGTAGACAAGTCCTCCAGCACAGCCTACATGGAACTCCGCAGCCTGACATCTGAGGATTCTGCAGTCTATTACTGTGCAGGGCGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCGAGCggtggaggcggttcaggcggaggtggctctggcggtggcgggtcgGATATTGTGATGACCCAGGCTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTCTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGTACACATTTTCCATTCACGTTCGGCTCGGGCACAAAGTTGGAAATAAAA

262(AD58-1-17scFv nucleic acid sequence)

CAGGTCCAGCTGCAGCAGTCTGGACCTGAGCTGAAGAAGCCTGGAGAGACCGTCAAGATCTCCTGCAAGGCTTCTTTTTATACCTTCACAGCCTATTCAATGCACTGGGTGAAGCAGGCTCCAGGAAAGGGTTTAAAGTGGATGGGCTGGATAAACACTGAGACTGGTGAGCCAACATATGCAGATGACTTCAAGGGACGGTTTGCCTTCTCTTTGGAAACCTCTGCCACCACTGCCTATTTGCAGATCAACAACCTCAAAAATGAGGACACGGCTACATTTTTCTGTGCTAGGGGACTACGGCGGTTTGCTTACTGGGGCCAGGGGACTCTGGTCACTGTCTCGAGCggtggaggcggttcaggcggaggtggctctggcggtggcgggtcgGACATTGTGATGACACAGTCTCCAACTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCACCATATCCTGCAGAGCCAGTGAAAGTGTTGATAGTTATGGCAATAGTTTTATGAATTGGTACCAGCAGAAACCAGGACAGCCACCCAAACTCCTCATCTATCTTGCATCCTACCTAGAATCTGGGGTCCCTGCCAGGTTCAGTGGCAGTGGGTCTAGGACAGACTTCACCCTCACCATTGATCCTGTGGAGGCTGATGATGCTGCAACCTATTACTGTCAGCAAAATAATGAGGATCCGTACACGTTCGGAGGGGGGACCAGACTGGAAATAAAA

263(AD58127 scFv nucleic acid sequence)

CAGGTTCAGCTGCAGCAGTCTGGGGCTGAACTGGTGAGGCCTGGGGCTTCAGTGACGCTGTCCTGCAAGGCTTCGGGCTACACATTTACTGACTATGAAATTCACTGGGTGAAGCAGACACCTGTGCATGGCCTGGAATGGATTGGAGGTATTGATCCTGAAACTGGTGGTGCTGCCTACACTCAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACAAATCCTCCAGCACAGCCTACATGGAGCTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTATTACTGTACAACTTATGGTAACTACCCCCTTGACTCCTGGGGCCAAGGCACCACTCTCACAGTCTCGAGCggtggaggcggttcaggcggaggtggctctggcggtggcgggtcgGGTATTGTGATGACCCAGACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCAGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGCTCACGTTCGGTGCTGGGACCAGACTGGAAATAAAA

264(AD58143 scFv nucleic acid sequence)

CAGGTGCAACTGAAGCAGTCTGGGGCTGAACTGGTGAGGCCTGGGGCTTCAGTGACGCTGTCCTGCAAGGCTTCGGGCTACACATTTACTGACTATGAAATGCACTGGGTGAAGCAGACACCTGTGCATGGCCTGGAATGGATCGGAGGTATTGATCCTGAAACTGGTGGTGCTGCCTACACTCAGAAGTTCAAGGGCAAGGCCACACCGACTGCAGACAAATCCTCCAGCACAGCCTACATGGAGCTCCGCAGCCTGACATCTGAGGACTCTGCCGTCTATTACTGTACAACTTATGGTAACTACCCCCTTGACTCCTGGGGCCAAGGCACCACGGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGATATCCAGATGACACAGACTCCACTCTCCCTGCCTGTCAGTCTTGGAGATCAAGCCTCCATCTCTTGCAGATCTAGTCAGAGCCTTGTACACAGTAATGGAAACACCTATTTACATTGGTACCTGCAGAAGCCAGGCCAGTCTCCAAAGCTCCTGATCTACAAAGTTTCCAACCGATTTTCTGGGGTCCCAGACAGGTTCAGTGGCAGTGGATCAGGGACAGATTTCACACTCAAGATCAGCGGAGTGGAGGCTGAGGATCTGGGAGTTTATTTCTGCTCTCAAAGTACACATGTTCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA

SEQ ID NO: 265(AD58159 scFv nucleic acid sequence)

CAGGTGCAACTGAAGCAGTCTGGAGCTGAGCTGGTAAGGCCTGGGACTTCAGTGAAGATATCCTGCAAGGCTTCTGGCTACACCATCACTAACTACTGGCTAGGTTGGGTAAAGCAGAGGCCAGGACATGGACTTGAGTGGATTGGAGATATTTACCCTGGAGGTGGTTATACTAACTACAATGAGAAGTTCAAGGGCAAGGCCACACTGACTGCAGACACATCCTCCATCACTGCCTACATGCAGCTCAGTAGCCTGACATCTGAGGACTCTGCTGTCTATTTCTGTGCAAGAGGCGGTAGTAGCTACTGGTACTTCGATGTCTGGGGCGCAGGGACCTCAGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGATATCCAGATGACACAGACTACATCCTCCCTGTCTGCCTCTCTGGGAGACAGAGTCACCATCAGTTGCAGTGCAAGTCAGGACATTAGCAATTATTTAAACTGGTATCAGCAGAAACCAGATGGAACTGTTAAACTCCTGATCTATTACACATCAAGTTTACACTCAGGAGTCCCATCAAGGTTCAGTGGCAGTGGGTCTGGGACAGATTATTCTCTCACCATCAGCAACCTGGAACCTGAAGATATTGCCACTTACTATTGTCAGCAGTATAGTAAGGTTCCGTACACGTTCGGAGGGGGGACCAAGCTGGAGCTGAAA

SEQ ID NO: 266(AD58115 scFv nucleic acid sequence)

CAGGTGCAGCTGAAGCAGTCTGGACCTGAGCTGGTGAAGCCTGGGGCTTCAGTGAAGATATCCTGCAAGACTTCTGGATACACATTCACTGAATACACCATGAACTGGGTGAAGCAGAGCCATGGAAAGAGCCTTGAGTGGATTGGAGGAATTATTCCTAACAATGGTGATACTAGCTACAAACAGGAGTTCAAGGGCAAGGCCACATTGACTGTAGACAAGTCCTCCAGCACAGCCTACATGGAGCTCCGCAGCCTGACATCTGACGATTCTGCAGTCTATTACTGTGCAGGGCGGTTTGCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGATATTGTGATGACCCAGACTCCACTCACTTTGTCGGTTACCATTGGACAACCAGCCTCCATCTCTTGCAAGTCAAGTCAGAGCCTCTTAGATAGTGATGGAAAGACATATTTGAATTGGTTCTTACAGAGGCCAGGCCAGTCTCCAAAGCGCCTAATCTATCTGGTGTCTAAACTGGACTCTGGAGTCCCTGACAGGTTCACTGGCAGTGGATCAGGGACAGATTTCACACTGAAAATCAGCAGAGTGGAGGCTGAGGATTTGGGAGTTTATTATTGCTGGCAAGGTACACATTTTCCATTCACGTTCGGCTCGGGCACAAAGTTGGAAATAAAA

267(AD58123 scFv nucleic acid sequence)

GAGGTCCAGCTGCAGCAGTCAGGACCTGGCCTGGTGGCACCCTCACAGAGCCTGTCCATCACATGCACTGTCTCTGGGTTCTCATTATCCAGATATAGTGTACACTGGGTTCGCCAGCCTCCAGGAAAGGGTCTGGAGTGGCTGGGAATGATATGGGGTGGTGGAAACACAGACTATAATTCAGCTCTCAAATCCAGACTGAGCATCAGCAAGGACAACTCCAAGAGCCAAGTTTTCTTAAAAATGAACAGTCTGCAAACTGATGACACAGCCATGTACTACTGTGCCAGAAGCCTGGGCTGGTACTTCGATATCTGGGGCGCAGGGACCACGGTCACCGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGACATTGTGATGACACAGTCGCCATCATCTCTGGCTGTGTCTGCAGGAGAAAAGGTCACTATGAGCTGTAAGTCCAGTCAAAGTGTTTTATACAGTTCAAATCAGAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTCTCCTAAACTGCTGATCTACTGGGCATCCACTAGGGAATCTGGTGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTTACTCTTACCATCAGCAGTGTACAAGCTGAAGACCTGGCAGTTTATTACTGTCATCAATACCTCTCCTCGTGGACGTTCGGTGGAGGCACAAAGCTGGAAATCAAA

SEQ ID NO: 268(AD58145 scFv nucleic acid sequence)

GAGGTTCAGCTGCAACAGTCTGGGGCTGAACTGGCAAAACCTGGGGCCTCAGTGAAGATGTCCTGCAAGGCTTCTGGCTACACCTTTACTAGCTACTGGATGCACTGGGTAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGATACATTAATCCTAGCACTGGTTATACTGACTACAATCAGAAGTTCAAGGACAAGGCCACATTGACTGCAGACAAATCCTCCAGCACAGCCTACATGCAACTGAGCAGCCTGACATCTGAGGACTCTGCAGTCTATTACTGTGCAAGATCCAACTGGGCCTGGTTTCCTTACTGGGGCCAAGGGACTCTGGTCACTGTCTCGAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGACATCCAGATGACACAGTCTCCATCCTCCCTGACTGTGACAGCAGGAGAGAAGGTCACTATGAGCTGCAAGTCCAGTCAGAGTCTGTTAAACAGTGGAAATCAAAAGAACTACTTGACCTGGTACCAGCAGAAACCAGGGCAGCCTCCTAAACTGTTGATCTACTGGGCATCCACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGAACAGATTTCACTCTCACCATCAGCAGTGTGCAGGCTGAAGACCTGGCAGTTTATTACTGTCAGAATGATTATAGTTATCCGCTCACGTTCGGTGCTGGGACCAAGCTGGAGCTGAAA

269(AS51489 scFv nucleic acid sequence)

GAGGTTCAACTGGTGGAGAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGCGCAGCTTCTGGCTTCAACCTCTATTATTATTCTATCCACTGGGTGCGTCAGGCGCCGGGTAAAGGCCTGGAATGGGTTGCATATATTTCTTCTTCTTCTAGCTATACTTATTATGCCGATAGCGTCAAGGGCCGTTTCACCATCAGCGCGGATACCAGCAAAAACACCGCATACCTGCAAATGAACAGCCTGCGTGCGGAAGATACCGCCGTCTATTATTGTGCTCGCTACTACCCGTACTACGGTATGGACTACTGGGGTCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGACATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTTGGTGACCGTGTTACCATTACCTGCCGTGCGAGCCAGAGCGTTAGCAGCGCGGTGGCGTGGTACCAGCAAAAGCCGGGTAAAGCGCCGAAGCTGCTGATCTATAGCGCGAGCAGCCTGTATAGCGGCGTTCCGAGCCGTTTCAGCGGTAGCCGTAGCGGCACCGACTTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTCGCAACTTATTACTGTCAGCAAGGTTTCTCTTACTACCCGATCACGTTCGGACAGGGCACCAAAGTTGAGATTAAA

SEQ ID NO: 270(AS51491 scFv nucleic acid sequence)

GAGGTTCAACTGGTGGAGAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGCGCAGCTTCTGGCTTCAACCTCTATTCTTATTCTATGCACTGGGTGCGTCAGGCGCCGGGTAAAGGCCTGGAATGGGTTGCATATATTTATCCTTATTCTGGCTCTACTTATTATGCCGATAGCGTCAAGGGCCGTTTCACCATCAGCGCGGATACCAGCAAAAACACCGCATACCTGCAAATGAACAGCCTGCGTGCGGAAGATACCGCCGTCTATTATTGTGCTCGCGGTTACGGTATGGACTACTGGGGTCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGACATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTTGGTGACCGTGTTACCATTACCTGCCGTGCGAGCCAGAGCGTTAGCAGCGCGGTGGCGTGGTACCAGCAAAAGCCGGGTAAAGCGCCGAAGCTGCTGATCTATAGCGCGAGCAGCCTGTATAGCGGCGTTCCGAGCCGTTTCAGCGGTAGCCGTAGCGGCACCGACTTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTCGCAACTTATTACTGTCAGCAATCTTACTACTGGCTGTTCACGTTCGGACAGGGCACCAAAGTTGAGATTAAA

271(AS92110 scFv nucleic acid sequence)

GAGGTTCAACTGGTGGAGAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGCGCAGCTTCTGGCTTCAACATCTATTATTCTTCTATGCACTGGGTGCGTCAGGCGCCGGGTAAAGGCCTGGAATGGGTTGCATATATTTATCCTTATTATAGCTATACTTATTATGCCGATAGCGTCAAGGGCCGTTTCACCATCAGCGCGGATACCAGCAAAAACACCGCATACCTGCAAATGAACAGCCTGCGTGCGGAAGATACCGCCGTCTATTATTGTGCTCGCGGTTACGCTTTGGACTACTGGGGTCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGACATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTTGGTGACCGTGTTACCATTACCTGCCGTGCGAGCCAGAGCGTTAGCAGCGCGGTGGCGTGGTACCAGCAAAAGCCGGGTAAAGCGCCGAAGCTGCTGATCTATAGCGCGAGCAGCCTGTATAGCGGCGTTCCGAGCCGTTTCAGCGGTAGCCGTAGCGGCACCGACTTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTCGCAACTTATTACTGTCAGCAAGCTTCTTCTGGTTACCATTACCTGATCACGTTCGGACAGGGCACCAAAGTTGAGATTAAA

SEQ ID NO: 272(AS91156 scFv nucleic acid sequence)

GAGGTTCAACTGGTGGAGAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGCGCAGCTTCTGGCTTCAACATCTATTCTTCTTCTATCCACTGGGTGCGTCAGGCGCCGGGTAAAGGCCTGGAATGGGTTGCATCTATTTCTTCTTATTCTAGCTATACTTCTTATGCCGATAGCGTCAAGGGCCGTTTCACCATCAGCGCGGATACCAGCAAAAACACCGCATACCTGCAAATGAACAGCCTGCGTGCGGAAGATACCGCCGTCTATTATTGTGCTCGCTACTACGCTATGGACTACTGGGGTCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGACATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTTGGTGACCGTGTTACCATTACCTGCCGTGCGAGCCAGAGCGTTAGCAGCGCGGTGGCGTGGTACCAGCAAAAGCCGGGTAAAGCGCCGAAGCTGCTGATCTATAGCGCGAGCAGCCTGTATAGCGGCGTTCCGAGCCGTTTCAGCGGTAGCCGTAGCGGCACCGACTTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTCGCAACTTATTACTGTCAGCAAGGTCCGTACTACCATCCGATCACGTTCGGACAGGGCACCAAAGTTGAGATTAAA

273(AS91189 scFv nucleic acid sequence)

GAGGTTCAACTGGTGGAGAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGCGCAGCTTCTGGCTTCAACCTCTCTTATTCTTCTATCCACTGGGTGCGTCAGGCGCCGGGTAAAGGCCTGGAATGGGTTGCATCTATTTATTCTTATTCTGGCTCTACTTATTATGCCGATAGCGTCAAGGGCCGTTTCACCATCAGCGCGGATACCAGCAAAAACACCGCATACCTGCAAATGAACAGCCTGCGTGCGGAAGATACCGCCGTCTATTATTGTGCTCGCTACTGGGGTATGGACTACTGGGGTCAAGGCACCCTGGTTACCGTGAGCAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGACATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTTGGTGACCGTGTTACCATTACCTGCCGTGCGAGCCAGAGCGTTAGCAGCGCGGTGGCGTGGTACCAGCAAAAGCCGGGTAAAGCGCCGAAGCTGCTGATCTATAGCGCGAGCAGCCTGTATAGCGGCGTTCCGAGCCGTTTCAGCGGTAGCCGTAGCGGCACCGACTTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTCGCAACTTATTACTGTCAGCAATACTACTGGTACTACCCGATCACGTTCGGACAGGGCACCAAAGTTGAGATTAAA

SEQ ID NO: 274(AS51674 scFv nucleic acid sequence)

GAGGTTCAACTGGTGGAGAGCGGTGGTGGTCTGGTTCAGCCGGGTGGTAGCCTGCGTCTGAGCTGCGCAGCTTCTGGCTTCAACCTCTATTCTTATTATATGCACTGGGTGCGTCAGGCGCCGGGTAAAGGCCTGGAATGGGTTGCATCTATTTATTCTTATTCTAGCTATACTTCTTATGCCGATAGCGTCAAGGGCCGTTTCACCATCAGCGCGGATACCAGCAAAAACACCGCATACCTGCAAATGAACAGCCTGCGTGCGGAAGATACCGCCGTCTATTATTGTGCTCGCCCGTTCGGTTGGGGTTACGCTGGTATGGACTACTGGGGTCAAGGCACCCTGGTTACTGTGAGCAGCGGTGGAGGCGGTTCAGGCGGAGGTGGCTCTGGCGGTGGCGGGTCGGACATCCAGATGACCCAGAGCCCGAGCAGCCTGAGCGCGAGCGTTGGTGACCGTGTTACCATTACCTGCCGTGCGAGCCAGAGCGTTAGCAGCGCGGTGGCGTGGTACCAGCAAAAGCCGGGTAAAGCGCCGAAGCTGCTGATCTATAGCGCGAGCAGCCTGTATAGCGGCGTTCCGAGCCGTTTCAGCGGTAGCCGTAGCGGCACCGACTTTACCCTGACCATTAGCAGCCTGCAGCCGGAAGATTTCGCAACTTATTACTGTCAGCAAGGTTACGCTCCGATCACGTTCGGACAGGGCACCAAAGTTGAGATTAAA

275(AS66073 sdAb nucleic acid sequence)

CAGGTTCAGCTGGTGGAGTCTGGGGGAGACTCGGTGCAGGCTGGGGGGTCTCTGACACTCGCCTGTACAGGGCGTAAATACAGCAGTCTATACTGCATGGCCTGGTTCCGCCAGGCTCCAGGGAAGGCGCGCGAGGGGGTCGCAGTTATTAGCAGTGGCGGCTTCACAAATTACGCTGACTCCGTAAAGGGCCGATTCACCATCTCCAGAGACAACTCCAAGAACACGCTGTATCTGGCAATGAACGGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGGCAGGCCTATCCTATTGCCATTCAAGCACAGCAACCGCCACGTACCGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

276(AS66439 sdAb nucleic acid sequence)

CAGATGCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGGGGGTCTCTGAGACTCTCCTGCACAGCCCCTGGATTCACCTCCAGTGACTGCGACATGGACTGGTACCGCCAGGCTGCAGGGAATCAGCGCGAATGGGTCTCATCTCTTCTTAGTACTGACGGTAGCACAAGCTATGCGGACTCCGTGAGGGGCCGATTCACCATCTCCAAAGACCCAGCCAAGGACACGGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACGGCCATGTATTTCTGTAGGTGTGTCGTGGCTGAGTGGGGCGGCATGGACTACTGGGGCAAAGGAACCCTGGTCACCGTCTCCTCA

SEQ ID NO: 277(AS65955 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGCGACCGCGTCAGTACTGGCTGTATGGGCTGGTTCCGCCAGGGTCCAGGCGAGGAGCGCGAGGGGCTCGCACAAATTCACAATTATAATATCGCAAAGTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAAAGACAACGCCAAGAACATTCTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGGCTTGTACATCTGTACGGCTCCTGTAGATTGTAGCTGGAGCATGTTTCTGCAAGACCCACTTGCGTTGTCTCCACCTAGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

278(AS65233 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGAATTCACGTACAGTATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGCGTCGCACATATTTACACTCGTGGTGGTACCACGGTCTATGCCGACTCCGTGAAGGGCCGATTCGTCCTCTCCCGATACAACGCCAAGAGCATAATGTATCTACAAATGAACAGCGTGAAACTTGAGGACACTGCCATGTATTACTGTGCGGCCCGGACCATATTCGAAGGTAGCTGGTCGTCCCCATCCTCGTTTGACTTCTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

279(AS65926 sdAb nucleic acid sequence)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGAAACCTCTACAATAACATGTGCATGGGCTGGTTCCGGCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAAGTATTTATATTGGTGGTGGTTACACCAACTATGCCGACTCCGTGAAGGGCCGATTCACCATCTCCCCCATCTCCCGAGACAACGCCAAGAGCACGCTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGGCAGTCTCCATCGCGCTTACGAGGGAATTCTGCGCCCCGATCGTTTCTCGGTATAATTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

280(AS66159 sdAb nucleic acid sequence)

CAGGTGAGGTTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCATGTGCAGCCTCTGGAAACGTCTACAATAACATGTGCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAAGTATCTATGTTGGTGGTGGTTACACCAACTATGCCGACTCCGTGAGGGGCCGATTCACCATCTCCCAAGACAACGCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGGCAATTACCGTCGCGCTTACGAGGGCTTTCTGCGCCCCGATCCCTTCTCGGTATACCAACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 281(AS66416 sdAb nucleic acid sequence)

CAGGTGCAGCTGGCGGAGTCTGGGGGAGGTTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGAAACCTCTACAATAACATGTGCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGGAAGTATTTATATTGGTGGTGGTTACACCAACTATTCCGAATCCGTGAGGGGCCGATTCACCATCTCCCTAGACAACGCCAAGAAGACGCTGAATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGGCAATCCCCATCGCGCTTACGAGGGCTTTCTGCGCCCCGATCGTTTCTCGGTATACGTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

282(AS65850 sdAb nucleic acid sequence)

GAGGTGCAGCTGATGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGATTCTCCTACAGTAACATCTGTATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCGGCTATTTATAGTAATGGTAGCACAATCTACGCAGACTCCGTGAAGGGCCGATTCACCGTCTCCAAAGAATTCGCCAAGAACACTCAGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGGCAGGCCGGTGTGGGGGCCCTAACTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

283(AS65183 sdAb nucleic acid sequence)

GAGGTGCAACTGGCGGAGTCTGGGGGAGGCTCGGCGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAAGCAATGGGTACTACAACCGTCGCTATTGTATGGCCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCGACTATGACTACTACTAGTGGTCGCACATACTATGCCGACGCCGTGAAGGGCCGATTCACCGTCTCCCAAGACAACGCCAAGTCCACGCTGTATCTGCAAATGAGCAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGGCGCACCTTCCCAGTTCTTGGGTGACGTCGACTGATTACTGCGACAACTTGCAAGCCGGCTTTTATAACTCCTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

284(AS65062 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGAGTCAGCGTGGTTAACTTCGCCATGAGGTGGTACCGCCAGGCTCCAGGGAACGAGCGCGAGTTCGTCTCAGCGATGTACCGTTCTGGTAGCACGTCTTACGCTGACTCCGTGAGGGGCCGATTCACCATCTCCCGAGACAGCGCCTTGAACACGGTGTTTCTTCAAATGAGCGGCCTGAAACCTGAGGACACGGCCACGTATTACTGTCAAGCGACATCACCTATGGGCGACACCTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

285(AS65065 sdAb nucleic acid sequence)

GAGGTGCAACTGGCGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGATACAGCTACTGTAGGTCCACCATGCGCTGGTACCGCCAGGCTCCAGGGAACGTGCGCGAATTTGTCTCAGCTATCTATAGTGATGGTACCACAAGCTACACAGACTCCGTGAAGGGCCGATTCACCATCTCCCAAGACAACGCCAAGAACACTGTGTATCTACAAATGAACAGCCTGCAACCTGAAGACACGGCCATGTATTACTGTCGGATAGATCTTGTCGGATGCAACGTAGCTGGTGGCAGTCCTTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 286(AS65556 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGTTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGATACAACGCCTCTATCTGCCGCATGAGCTGGTACCGCCAGGCTCCCGGGACTGAGCGCGAGTTCGTCTCATCGTCTTACAGGGATGGTAGCCAAAGCTACGCAGACTCCGTGAAGGGGCGATTCACCACATCCCGAGACTCCGCCAAGAACACGGTGTTTCTGCAAATGAACAGCCTGAAACCTTCGGACACGGCCATGTATTACTGTAACGCAGCTTGCCCCTGGCGGGCCTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 287(AS65069 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGTAGCCTCTGGAGACACCGGCTACCAACCTACGATGAGGTGGTACCGCCAGGCTCCAGGGAAGGAGCGCGAGTTCGTCTCCGCTATTTATAGTGATCAGACCACAAGCTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCAAGACAACGCCAGAAAAACGGTGTATCTGCAAATGGCTAGCCTGAAACCTGAGGACACGGCCATGTATTACTGTAAACTCACTACTCGCAGGGGGTCTGAGTACTGGGGCCAGGGGACACAGGTCACCGTCTCCTCA

SEQ ID NO: 288(AS65691 sdAb nucleic acid sequence)

CAGATGCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTACAGTCTCTGGATACACCGACTATAGGCTCGTACTGAGGTGGTACCGCCAGGCTCTAGGGAAGGAGCGCGAGTTCATCTCAGCTATTTATAGTGATGGAGTCACAAGCTACTCAGACTCCGTGAAGGGCCGATTCACCATCTCCCGAGACAACGCCAAGAACACGGCGTATCTGCAAATGAACAGCCTGAAATCTGAGGACACGGCCATGTATTACTGTAAAGCAACCGGGTCCGGTGGCGTTGCCTACTGGGGCCAGGGAACCCAGGTCACCGTCTCCTCA

SEQ ID NO:289(AS65064 sdAb nucleic acid sequence)

CAGGTTCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAAACTCTCCTGTGCAGTCTCTGGAGACACCGTCCAGACTAACTGTATGGCCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGCGGTCGCCAGCATTTTGAGTCTTTATTCTAGTGGAGGTAAGACAGTCTATGCCGACTCCGTGAAGGGCCGATTCACCATCTCCCCAGACAACGCCCAGAACACGGTGTCGCTGCAAATGAACAATTTGAAACCTGAGGACACTGCCATGTACTACTGTGCGACTGTCCGCGTGACCGTCACTTGGGCCGAAAAGTTGAGGCGTTGTACCGGATTCAGCGGCATGGACTACTGGGGCAAAGGAACCCTGGTCACCGTCTCCTCA

SEQ ID NO: 290(AS65081 sdAb nucleic acid sequence)

CAGGTGCACCTGATGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGAGTCCCCGCTAGTAGCTACTGCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAGGTATTGTCAGTGATACTACCACAACCTACGCAGACTCCGTGAAGGGCCGATTCACCATCTCCAAAGACAACGCCAAGAACACTCTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCACGTACTACTGTGCGGCCTCCCATTTTCTATTGTGCGCCAGAAAACCCCGCTGGGATGACCTCATTAAATATGAGTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

291 SEQ ID NO (AS65115 sdAb nucleic acid sequence)

CAGGTTCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGCGACTCTCCTGTGCAGCCTCTGGATACATTTACGGCTGCATGGGCTGGTTCCGCCGGGCTCCAGGGAAGGCGCGCGAGGAGGTTGCGACTATTTACCGCGATGGTACAGCATACTACGCAAACTCCGTAGAGGGCCGATTCACCGCCTCCAGAAACAACGCCGAGAACACTCTGTCTCTGGAGATGAACAGTCTGAACGCTGAGGACACTGCCATGTACTACTGTGCGGCAAGAACAACTGGTTGTAACTGGGACATATCTGGGGTTTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 292(AS65271 sdAb nucleic acid sequence)

CAGATGCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGACACTCTCCTGTGCAGCCTCTGGAAAAACCTACGGACGCTGCATGGCCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGTTAGTCGCTGCTACTTATATTAGTGGTGGGCGACCCTACGTTGCCGACTCCGTGAAGGGCCGATTCACCATTTCCCGGGACAACGCCAAGAGTACGATGTCTCTGCAAATGAACAGCCTGAGACCTGACGACAGCGCCATGTACTACTGTGCGGCGGGTTCGGCGGGTCGGGGACCTTGTGATCGCTTCGACCAAAATCAATATACCTTCTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO 293(AS65166 sdAb nucleic acid sequence)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTACAGCCTCTGAAGACTTATCTATTTACGGTTACAATTGCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGCGGTCGCAGCTATTTATACTGGCCGTGGTACCACATACTATGCCGACTCCGTGAAGGGCCGATTCACCATCTCCCAAGACAACGCCAAGAACACTGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGTCAAAATACTGTGCGGTGGTAGCTGATTTCGGGAATTCTCGACTCGTTCGTTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 294(AS65450 sdAb nucleic acid sequence)

CAGGTGAGGTTAGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGAGACATGAACGGTTACAAGTGCATGGGGTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGCGGTCGCAGGTATTTATACTGGCCGTGGGACCACATACTATGCCGACTCCGTGAAGGACCGATTCACCATCTCCCAAGACAACGCCAAGAACACTGTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCAGCAAAATACTGTGCGGTGGTAGCTGAATTCGGGGGTCCTCGACTCGTTCGTTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

295(AS65454 sdAb nucleic acid sequence)

CAGGTGAGGTTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTGTCCTGTGCAGCCTCTGGAGACATGAACGGTTACAAGTGCATGGGGTGGTTCCGCCAGGCTCCAGGGAAGGAGCGAGAGGCGGTCGCAGGTATTTATACTGGCCGTAATACTACATACTATGCCGACTCCGTGAAGGACCTATTCACCATCTCCCAAGACAACGCCTAGAACACTGTGTTTCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGTCATAATACTGTGCGGTGGTAGCTGAATTCCGGGGTCCTCGACTCGATCGTTACTGGGGCTATGGGACCCAGGTCACCGTCACCTCA

SEQ ID NO: 296(AS65131 sdAb nucleic acid sequence)

GAGGTGCAGCTGGCGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGACACTCTCCTGTACAGCCTCTGAATACGTCACACACTTGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAATCGAAAGTTTTCGTATTGGTTATACATACTATGCCGACTCCGTGAAGGGTCGATTCACCATCTCCCACGACAACGCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATATACTACTGTGCGGCTCGGCAGGACCGATCGGGGGCTTCCATGGTAAATCGAGATTCATATAATTACTGGGGCAAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO:297(AS65182 sdAb nucleic acid sequence)

CAGGTGAAGTTAGTGGAGTCAGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCGTCTGGATACACGTACAGTTACGGCTACATGGGCTGGTTCCGGCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAAAGATTTATAATGGTGACGGTAGTACATACTATGCCGACTCCGTGAAGGGCCGATTCACCATCTCCCAAGACCGCCGCAACAACACGCTGTATCTGCAAATGAACAGTCTGGCACCTGAGGACACTGGCATGTACTACTGTGCGACAAACCGACTCCCAAATAGCGACGTTGACTTGGTCCTTCCCCGGTTCGGCCGTTTTGGTTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 298(AS60685 sdAb nucleic acid sequence)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGTAATGTCTACAATAACATGTGCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAAGTATGTATGTTGGTGGTGGTTACACCTACTATGACGACTCCGTGAAGGGCCGATTCACCATCTCCCGAGACAACGCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAAACCTGAAGACACTGCCATGTACTACTGTGCGGCAATCTCCATCGCGCTTACGAGGGAATTCTGCGCCCCGATCGTTTCTCGGTATAATTATTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

299(AS60702 sdAb nucleic acid sequence)

CAGGTGAAGTTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCATGTGCAGCCTCTGGAAACGTCTACAATAACATGTGCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAAGTATCTATGTTGGTGGTGGTTACACCAACTATGCCGACTCCGTGAGGGGCCGATTCACCATCTCCCAAGACAACGCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGGCAATTACCGTCGCGCTTACGAGGGCTTTCTGCGCCCCGATCCCTTCTCGGTATACCAACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 300(AS60705 sdAb nucleic acid sequence)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGTCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGATACGCCTACAGTGGGTCTTGCATGATGGCCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAGTTAGCGTTCGTCGTACGGGAAGCGCATTCTATGCCGACTCCGTGAAGGCCCGATTCACCATCTCCCGCGACAATGCCAAGAACACGCTGTATCTGCAAATGAATAACCTGAAAGTTGAGGACACTGCCATGTACTACTGTGCGGCAGATTTTACTTGTCGTACGTGGACTCTCAATAAAAATTACAACCACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

301(AS60660 sdAb nucleic acid sequence)

CAGGTGCACCTGATGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGTAGCCTCTGGAGACACCGGCTACCAACCTACGATGAGGTGGTACCGCCAGGCTCCAGGGAAGGAGCGCGAGTTCGTCTCCGCTATTTATAGTGATCAGACCACAAGCTATGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCCAAGACAACGCCAGAAAAACGGTGTATCTGCAAATGGCTAGCCTGAAACCTGAGGACACGGCCATGTATTACTGTAAACTCACTACTCGCAGGGGGTCTGAGTACTGGGGCCAGGGGACACAGGTCACCGTCTCCTCA

302(AS60662 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGTAGCCTCTGGATACAGGAACTGTAGGTCCACCATGCGCTGGTACCGCCAGGGTCCAGGACAGGTGCGAGACTGGGTCTCAAGTATCTATACTGATGGTACCACAAGCTACACAGACTCCGTGAAGGGCCGATTCACCATCGCCCAAGACAAAGGCAAGAACACGGTGTATCTACAAATGAACAGCCTGCAACCTGAAGACACGGCCATGTATTACTGTCGGATAGATCTTGTCGGATGCAATGTAGCTGGTGGCAGTCCTTACTGGGGCCATGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 303(AS60664 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGACACTCTCCTGTGCAGCCTCTGGAAAAACCTACGGACGCTGCATGGCCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGTTAGTCGCTGCTACTTATATTAGTGGTGGGCGACCCTACGTTGCCGACTCCGTGAAGGGCCGATTCACCATTTCCCGGGACAACGCCAAGAGTACGATGTCTCTGCAAATGAACAGCCTGAGACCTGACGACAGCGCCATGTACTACTGTGCGGCGGGTTCGGCGGGTCGGGGACCTTGTGATCGCTTCGACCAAAATCAATATACCTTCTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

304(AS60668 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTGTCCTGTGCAGCCTCTGGAGACATGAACGGTTACAAGTGCATGGGGTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGCGGTCGCAGGTATTTATACTGGCCGTAATACTACATACTATGCCGACTCCGTGAAGGACCGATTCACCATCTCCCAAGACAACGCCAAGAACACTGTGTTTCTGCAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGTCAAAATACTGTGCGGTGGTAGCTGAATTCGGGGGTCCTCGACTCGTTCGTTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

305(AS60676 sdAb nucleic acid sequence)

CAGGTGCAGCTGGTGGAGTCTGGGGGAGGGTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGCGCAGCCTCTGGATACACCGTCAGTAGCGGCTGCATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGCGGGTCGCACAGATTGGTCGTGATGCTACCACGACCTACGCAGACTCCGTGAAGGGCCGATTCACCATCGCCAGAGACGACGCCGAGAACACTCTGTATCTGCAAATGAACAGCCTGAAACCTGAAGACACTGCCATGTACAGCTGTACGGCCTATTGGGGTGTATACTGTTTATCTCCAGGACGCTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

306(AS60678 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGTCTCTGGATACACCTCCAGTCGCGGTTGCATGAGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGAGGGTCGCATACATTAATATGCGTGTCCTAACCACAATCTATGCCGCCTCCGTGAAGGACCGATTCGCCATCTCCAGAGACAACGCCAAGAACACGGTGGATCTGCAAATGAACAACCTGAAACCTGAGGACACTGCCATGTACTACTGCGCGGCGGGGTACAATGGACAATGGTGCGAACATGCTAGTGACGTTACTGCCTGGGGTCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 307(AS60679 sdAb nucleic acid sequence)

CAGGTGCACCTGATGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCACGCTCTGGAGTCACCTATTGTAGGTTGACCATGAGGTGGTACCGCCAGGCTCCAGGGAGCGAGCGCGAGTTCGTCTCCGCTATTTATAGTGATGGTAGCACAGCCTACGCAGACTCCGTGAAGGGTCGATTCACCATGTCCCAAGACGACGCCAAGAACACGGTGTATCTGCAAATGAACAGCGTGAAACCTGAGGACACGGCCATGTATTATTGTAAATTGAATTGTGCGTCCGGCTTGACTGCCTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 308(AS81326 sdAb nucleic acid sequence)

GAGGTGCAGCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGACACTCTCCTGTGCAGCCTCCGAGAGTAGGGATTGTATGGCCTGGTTCCGCCAGGCTCCAGGGAAGGCGCGCGAGGGGGTCGCATCTATTTATGCTCCGGATGGTAGCACAACCTATGCCGACACCGTGAAGGGCCGATTCACCATCTCCCAAGACAACGCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGCAACCTGAGGACGCTGCCATGTACCACTGTGCGATCGGGGGGCTGTCACGCAATACTTGTGGTTACCTCAGAGGCGGATACTTTGCTTACTTTGGCCGGGGGACCCAGGTCACCGTCTCCTCA

309(AS81187 sdAb nucleic acid sequence)

CAGGTGAGGTTGGTGGAGTCTGGGGGCGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGATACACCTACAGCAGCTACAGTAGCAACTGCCTGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGCAGTCGCACGTATCTATCCTAACAGTGGTAGCACATACTATGCCGACTCCGTGAAGGGCCGCTTCACCATCTCCCAAGACAACGCCAAGAACACGGTGTATCTACAAATGAACAGCCTGAAACCTGAGGACACTGCCATGTACTACTGTGCGGTAGCAGTGGGAGTCGGTGATAATTGGTGTGCGTCAGGGGCCGCATACTTTGGTTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

310(AS80533 sdAb nucleic acid sequence)

CAGGTGCACCTGGTGGAGTCTGGGGGAGGCTCGGTGCAGACTGGAGGGTCTCTAAGACTCTCCTGTACAGCCTCTGGACTCAGCTTCAGTACCTACACGGTGGCCTGGTTCCGCCAGGCTCCAGGAAAGGAGCGCGAGGGGGTCGCGGCTATTCCATATACTAGTCAACACATGGTCTATACCGACTCCGTGAAGGGCCGATTCACCATCTCCCGAGACAACACAAAGAACATGGTGTATCTGCAAATGAACAGCCTGAAACCGGAGGACACCGCCATGTACTACTGTGCGACAGATCGGCGCCCTGGAACGAGTATGTTGGCTATAAATGGGTATAACCGCTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

311(AS80444 sdAb nucleic acid sequence)

GAGGTGCAGCTGGCGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTCAGTCGCAACACGATGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCGGCTATTCCATATACTAGTACTGGCATAGTCTATTCCGACTCCGTGGGCGGCCGATTCACCATCTCCCGAGACAACACAAAGAACATGGTGTATCTGCAAATGAACAACCTGGAACCGGAGGACACTGCCATGTACTACTGTGCGACAGATCGGCGCCCTGGAACGACTATGTTGGCGGTAAATGGGTATAACCACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

SEQ ID NO: 312(AS81487 sdAb nucleic acid sequence)

CAGGTGAGGTTGGTGGAGTCTGGGGGAGGCTCGGTGCAGGCTGGAGGGTCTCTGAGAGTCTCCTGTTTAGTCTCTAAACTCACCGCATGGCGCAGCTGCGTGGGCTGGTTCCGCCAGGCTCCAGGGAAGGAGCGCGAGGGGGTCGCAGCTATATATTCTGGTACTGGTAGTACATACTATGCCGACTCCGTGAAGGGCCGATTCACCATCGCCCAAGACTACGCCAAGAACATGGTGTACTTGCAAATGAACAGCCTGAAACCTGAAGACACTGCCATGTACTACTGTGCGGGCACGTCGATACGCAGCAGTTGTGGCTTAGTGCGCGATGAATACGCCTACTGGGGCCAGGGGACCCAGGTCACCGTCTCCTCA

313(SS1 scFv amino acid sequence; CDR underlined)

QVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASSYNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGNSYSLTISSVEAEDDATYYCQQ WSGYPLTFGAGTKLEI

SEQ ID NO: 314(M5 scFv amino acid sequence; CDR underlined)

QVQLVQSGAEVEKPGASVKVSCKASGYTFTDYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCASGWDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPSSLSASVGDRVTITCRASQSIRYYLSWYQQKPGKAPKLLIYTASILQNGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQTYTTPDFGPGTKVEIK

SEQ ID NO 315 (human mesothelin amino acid sequence)

MALPTARPLLGSCGTPALGSLLFLLFSLGWVQPSRTLAGETGQEAAPLDGVLANPPNISSLSPRQLLGFPCAEVSGLSTERVRELAVALAQKNVKLSTEQLRCLAHRLSEPPEDLDALPLDLLLFLNPDAFSGPQACTRFFSRITKANVDLLPRGAPERQRLLPAALACWGVRGSLLSEADVRALGGLACDLPGRFVAESAEVLLPRLVSCPGPLDQDQQEAARAALQGGGPPYGPPSTWSVSTMDALRGLLPVLGQPIIRSIPQGIVAAWRQRSSRDPSWRQPERTILRPRFRREVEKTACPSGKKAREIDESLIFYKKWELEACVDAALLATQMDRVNAIPFTYEQLDVLKHKLDELYPQGYPESVIQHLGYLFLKMSPEDIRKWNVTSLETLKALLEVNKGHEMSPQVATLIDRFVKGRGQLDKDTLDTLTAFYPGYLCSLSPEELSSVPPSSIWAVRPQDLDTCDPRQLDVLYPKARLAFQNMNGSEYFVKIQSFLGGAPTEDLKALSQQNVSMDLATFMKLRTDAVLPLTVAEVQKLLGPHVEGLKAEERHRPVRDWILRQRQDDLDTLGLGLQGGIPNGYLVLDLSMQEALSGTPCLLGPGPVLTVLALLLASTLA

SEQ ID NO:316 (Macaca fascicularis mesothelin amino acid sequence)

MALPMARPLSGSCGTPALGSLLFLLFSLGWVQPSRVLAGETRQVRSPLGKPGRVFSLSPRQLLGFTCVEVSGLSTELVQELAVALGQKNVKLSAEQLRCLAHQLSEPPEDLDALPLDLLLFLNPDAFSGPQACTHFFSRVAKANVDLLPRGAPERQRLLPAALTCWGVRGSLLSEADVRALGGLACDLPGRFVAESAEVVLPRLVRCLGPLDQDQQEAARAALQRGGPPYGPPSTWSISTLDDLQSLLPVLGQPVIHSIPQGILAAWRQRSSRDPSWQQPEQTVLRPRFRRDVERTTCPPEKEVHEIDESLIFYKKRELEACVDPALLAAQMDRVDAIPFTYEQLDVLKHKLDELYPQGYPESVIRHLGHLFLKMSPEDIRKWNVTSLETLKALLKVSKGHEMSAQWPVPQVATLIDRVVVGRGQLDKDTVDTLTAFCPGCLCSLSPERLSSVPPSVIGAVRPQDLDTCGPRQLDVLYPKARLAFQNMSGSEYFVKIRPFLGGAPTEDVKALSQQNVSMDLATFMKLRREAVLPLTVAEVQKLLGPHVEGLKVEEQHSPVRDWILKQRQDDLDTLGLGLQGGIPNGYLILDLSVREALSGTPCLLGPGPVLTVLALLLASTLA

317 (megakaryocyte potentiator amino acid sequence)

SEQ ID NO:318 (mature mesothelial amino acid sequence)

EVEKTACPSGKKAREIDESLIFYKKWELEACVDAALLATQMDRVNAIPFTYEQLDVLKHKLDELYPQGYPESVIQHLGYLFLKMSPEDIRKWNVTSLETLKALLEVNKGHEMSPQVATLIDRFVKGRGQLDKDTLDTLTAFYPGYLCSLSPEELSSVPPSSIWAVRPQDLDTCDPRQLDVLYPKARLAFQNMNGSEYFVKIQSFLGGAPTEDLKALSQQNVSMDLATFMKLRTDAVLPLTVAEVQKLLGPHVEGLKAEERHRPVRDWILRQRQDDLDTLGLGLQGGIPNGYLVLDLSMQEALSGTPCLLGPGPVLTVLALLLASTLA

319 (FSH. beta.33-53 amino acid sequence)

YTRDLVYKDPARPKIQKTCTF

SEQ ID NO: 320(FSH beta 51-65 amino acid sequence)

CTFKELVYETVRVPGC

321(FSH beta 81-95 amino acid sequence)

QCHCGKCDSDSTDCT

322(FSH beta 87-94+ FSH beta 25-42 amino acid sequence)

CDSDSTDCILQCMGCCFSRAYPTPLR

323(FSH beta 87-94+ FSH beta 25-42+ FSH beta 27-45 amino acid sequence)

CDSDSTDCILQCMGCCFSRAYPTPLRWCAGYCYCYTRDVKDPARP

SEQ ID NO: 324 (anti-FSHR peptide 33-53 amino acid sequence)

YTRDLVYKDPARPKIQKTC

325 (anti-FSHR peptide 51-65 amino acid sequence)

KTCTFKELVYETVRV

SEQ ID NO:326 (anti-FSHR peptide 81-95 amino acid sequence)

GSQCHCGKCDSDSTDCTAS

SEQ ID NO: 327 (anti-FSHR antagonist A amino acid sequence)

GSCDSDSTDCILQCMGCCFSRAYPTPLRAS

SEQ ID NO: 328 (anti-FSHR antagonist B amino acid sequence)

GSRLPTPYARSFCCGMCQLICDTSDSDCAS

SEQ ID NO: 329 (anti-FSHR agonist A amino acid sequence)

GSCDSDSTDCILQCMGCCFSRAYPTPLRWCAGYCYCYTRDLVKDPARPA S

330 (anti-FSHR agonist B amino acid sequence)

PRAPDKVLDRTYCYCYGACWRLPTPYARSFCCGMCQLICDTSDSDC

331 (anti-FSHR peptide alpha + beta chain amino acid sequence)

GSNSCELTNITIAIEKEECRFCISINTTWCAGYCYTRDLVYKDPARPKIQKTCTFKELVYETVRVPGCAHHADSLYTYPVATQCHCGKCDSDSTDCTVRGLGPSYCSFGEMKEAPDVQDCPECTLQENPFFSQPGAPILQCMGCCFSRAYPTPLRSKKTMLVQKNVTSESTCCVAKSYNRVTVMGGFKVENHTACHCSTCYYHKSAS

332(Fc fusion FSH beta 33-53 amino acid sequence)

YTRDLVYKDPARPKIQKTCTFEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

333(Fc fusion FSH beta 33-53 nucleic acid sequence)

TACACCCGGGACCTGGTGTATAAGGATCCCGCCAGACCTAAGATCCAGAAGACCTGCACATTCGAGCCCAAGTCCTGTGATAAGACCCACACATGCCCCCCTTGTCCTGCTCCAGAGCTGCTGGGCGGCCCTAGCGTGTTCCTGTTTCCACCCAAGCCTAAGGACACCCTGATGATCTCTCGGACCCCAGAGGTGACATGCGTGGTGGTGGACGTGAGCCACGAGGATCCCGAGGTGAAGTTTAACTGGTATGTGGATGGCGTGGAGGTGCACAATGCCAAGACCAAGCCCAGAGAGGAGCAGTACAACTCCACCTATAGGGTGGTGTCTGTGCTGACAGTGCTGCACCAGGACTGGCTCAACGGCAAGGAGTATAAGTGCAAGGTGTCCAATAAGGCCCTGCCCGCCCCTATCGAGAAGACCATCTCTAAGGCCAAGGGCCAGCCTCGGGAGCCACAGGTGTACACACTGCCTCCATCCAGAGACGAGCTGACCAAGAACCAGGTGTCTCTGACATGTCTGGTCAAGGGCTTCTATCCCTCTGATATCGCCGTGGAGTGGGAGAGCAATGGCCAGCCTGAGAACAATTACAAGACCACACCCCCTGTGCTGGACTCCGATGGCTCTTTCTTTCTGTATAGCAAGCTGACCGTGGATAAGTCCCGGTGGCAGCAGGGCAACGTGTTCAGCTGTTCCGTGATGCACGAGGCACTGCACAACCATTACACCCAGAAGTCACTGTCACTGTCCCCAGGCAAG

334 (linker amino acid sequence)

GGGGS

SEQ ID NO:335 (linker amino acid sequence)

GGGGSGGGGS

SEQ ID NO: 336 (linker amino acid sequence)

GGGGSGGGGSGGGGS

SEQ ID NO: 337 (linker amino acid sequence)

GGGGSGGGGSGGGGSGGGGS

SEQ ID NO: 338 (linker amino acid sequence)

GGGGSGGGGSGGGGSGGGGSGGGGS

SEQ ID NO: 339(EF1 alpha promoter nucleic acid sequence)

GAGTAATTCATACAAAAGGACTCGCCCCTGCCTTGGGGAATCCCAGGGACCGTCGTTAAACTCCCACTAACGTAGAACCCAGAGATCGCTGCGTTCCCGCCCCCTCACCCGCCCGCTCTCGTCATCACTGAGGTGGAGAAGAGCATGCGTGAGGCTCCGGTGCCCGTCAGTGGGCAGAGCGCACATCGCCCACAGTCCCCGAGAAGTTGGGGGGAGGGGTCGGCAATTGAACCGGTGCCTAGAGAAGGTGGCGCGGGGTAAACTGGGAAAGTGATGTCGTGTACTGGCTCCGCCTTTTTCCCGAGGGTGGGGGAGAACCGTATATAAGTGCAGTAGTCGCCGTGAACGTTCTTTTTCGCAACGGGTTTGCCGCCAGAACACAGGTAAGTGCCGTGTGTGGTTCCCGCGGGCCTGGCCTCTTTACGGGTTATGGCCCTTGCGTGCCTTGAATTACTTCCACGCCCCTGGCTGCAGTACGTGATTCTTGATCCCGAGCTTCGGGTTGGAAGTGGGTGGGAGAGTTCGAGGCCTTGCGCTTAAGGAGCCCCTTCGCCTCGTGCTTGAGTTGAGGCCTGGCTTGGGCGCTGGGGCCGCCGCGTGCGAATCTGGTGGCACCTTCGCGCCTGTCTCGCTGCTTTCGATAAGTCTCTAGCCATTTAAAATTTTTGATGACCTGCTGCGACGCTTTTTTTCTGGCAAGATAGTCTTGTAAATGCGGGCCAAGATCTGCACACTGGTATTTCGGTTTTTGGGGCCGCGGGCGGCGACGGGGCCCGTGCGTCCCAGCGCACATGTTCGGCGAGGCGGGGCCTGCGAGCGCGGCCACCGAGAATCGGACGGGGGTAGTCTCAAGCTGGCCGGCCTGCTCTGGTGCCTGGCCTCGCGCCGCCGTGTATCGCCCCGCCCTGGGCGGCAAGGCTGGCCCGGTCGGCACCAGTTGCGTGAGCGGAAAGATGGCCGCTTCCCGGCCCTGCTGCAGGGAGCTCAAAATGGAGGACGCGGCGCTCGGGAGAGCGGGCGGGTGAGTCACCCACACAAAGGAAAAGGGCCTTTCCGTCCTCAGCCGTCGCTTCATGTGACTCCACGGAGTACCGGGCGCCGTCCAGGCACCTCGATTAGTTCTCGAGCTTTTGGAGTACGTCGTCTTTAGGTTGGGGGGAGGGGTTTTATGCGATGGAGTTTCCCCACACTGAGTGGGTGGAGACTGAAGTTAGGCCAGCTTGGCACTTGATGTAATTCTCCTTGGAATTTGCCCTTTTTGAGTTTGGATCTTGGTTCATTCTCAAGCCTCAGACAGTGGTTCAAAGTTTTTTTCTTCCATTTCAGGTGTCGTGA

SEQ ID NO: 340(CD8 alpha signal peptide amino acid sequence)

MALPVTALLLPLALLLHAARP

341(CD 8. alpha. hinge amino acid sequence)

TTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACD

342(CD8 alpha transmembrane domain amino acid sequence)

IYIWAPLAGTCGVLLLSLVITLYC

SEQ ID NO: 343(CD137 intracellular domain amino acid sequence)

KRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL

SEQ ID NO: 344(CD28 intracellular domain amino acid sequence)

RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS

SEQ ID NO: 345(CD3 zeta intracellular domain amino acid sequence)

RVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

346(P2A element amino acid sequence)

GSGATNFSLLKQAGDVEENPGP

347 (dnTGF. beta. RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

SEQ ID NO: 348(FSH beta 33-53+ AD58-1-26VH3VL1 scFv tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVKQAPGQGLEWIGYINPSTGHTDYNQKFKDRATLTADTSTSTVYMELSSLRSEDTAVYYCARSNWAWFPYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGGGTKLEIK

349(FSH beta 33-53+ AS51489 scFv tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNLYYYSIHWVRQAPGKGLEWVAYISSSSSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYPYYGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGFSYYPITFGQGTKVEIK

350(FSH beta 33-53+ AS92110 scFv tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIYYSSMHWVRQAPGKGLEWVAYIYPYYSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYALDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASSGYHYLITFGQGTKVEIK

351(FSH beta 33-53+ AS91156 scFv tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIYSSSIHWVRQAPGKGLEWVASISSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGPYYHPITFGQGTKVEIK

352(FSH beta 33-53+ AS91189 scFv tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNLSYSSIHWVRQAPGKGLEWVASIYSYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYWGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYWYYPITFGQGTKVEIK

353 SEQ ID NO (FSH beta 33-53+ AS51674 scFv tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNLYSYYMHWVRQAPGKGLEWVASIYSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARPFGWGYAGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGYAPITFGQGTKVEIK

354(FSH beta 33-53+ AS65233 sdAb tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVHLVESGGGSVQAGGSLRLSCAASEFTYSMGWFRQAPGKEREGVAHIYTRGGTTVYADSVKGRFVLSRYNAKSIMYLQMNSVKLEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTQVTVSS

355(FSH beta 33-53+ AS60685 sdAb tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVQLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASMYVGGGYTYYDDSVKGRFTISRDNAKNTLYLQMNSLKPEDTAMYYCAAISIALTREFCAPIVSRYNYWGQGTQVTVSS

356(FSH beta 33-53+ AS60702 sdAb tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVKLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASIYVGGGYTNYADSVRGRFTISQDNAKNTLYLQMNSLKPEDTAMYYCAAITVALTRAFCAPIPSRYTNWGQGTQVTVSS

357(FSH beta 33-53+ AS60676 sdAb tandem amino acid sequence)

YTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVQLVESGGGSVQAGGSLRLSCAASGYTVSSGCMGWFRQAPGKERERVAQIGRDATTTYADSVKGRFTIARDDAENTLYLQMNSLKPEDTAMYSCTAYWGVYCLSPGRYWGQGTQVTVSS

SEQ ID NO: 358(AD58126VH3VL1 CAR amino acid sequence)

359(AS51489 CAR amino acid sequence)

SEQ ID NO: 360(AS92110 CAR amino acid sequence)

361(AS91156 CAR amino acid sequence)

362(AS91189 CAR amino acid sequence)

363(AS51674 CAR amino acid sequence)

SEQ ID NO: 364(AS65233 CAR amino acid sequence)

SEQ ID NO: 365(AS60685 CAR amino acid sequence)

366(AS60702 CAR amino acid sequence)

367(AS60676 CAR amino acid sequence)

SEQ ID NO: 368(SS1 CAR amino acid sequence)

MALPVTALLLPLALLLHAARPQVQLQQSGPELEKPGASVKISCKASGYSFTGYTMNWVKQSHGKSLEWIGLITPYNGASSYNQKFRGKATLTVDKSSSTAYMDLLSLTSEDSAVYFCARGGYDGRGFDYWGQGTTVTVSSGGGGSGGGGSGGGGSDIELTQSPAIMSASPGEKVTMTCSASSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPGRFSGSGSGNSYSLTISSVEAEDDATYYCQQWSGYPLTFGAGTKLEITTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 369(M5 CAR amino acid sequence)

MALPVTALLLPLALLLHAARPQVQLVQSGAEVEKPGASVKVSCKASGYTFTDYYMHWVRQAPGQGLEWMGWINPNSGGTNYAQKFQGRVTMTRDTSISTAYMELSRLRSDDTAVYYCASGWDFDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSDIVMTQSPSSLSASVGDRVTITCRASQSIRYYLSWYQQKPGKAPKLLIYTASILQNGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCLQTYTTPDFGPGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

370(FSH beta 33-53+ AD58-1-26VH3VL1 tandem CAR amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVKQAPGQGLEWIGYINPSTGHTDYNQKFKDRATLTADTSTSTVYMELSSLRSEDTAVYYCARSNWAWFPYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGGGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

371(FSH β 33-53+ AS51489 tandem CAR amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNLYYYSIHWVRQAPGKGLEWVAYISSSSSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYPYYGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGFSYYPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 372(FSH beta 33-53+ AS92110 tandem CAR amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIYYSSMHWVRQAPGKGLEWVAYIYPYYSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYALDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASSGYHYLITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

373 (amino acid sequence of CAR-linked with FSH β 33-53+ AS 91156)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNIYSSSIHWVRQAPGKGLEWVASISSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGPYYHPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

374(FSH beta 33-53+ AS91189 tandem CAR amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNLSYSSIHWVRQAPGKGLEWVASIYSYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYWGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYWYYPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

375(FSH beta 33-53+ AS51674 tandem CAR amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFNLYSYYMHWVRQAPGKGLEWVASIYSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARPFGWGYAGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGYAPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 376(FSH beta 33-53+ AS65233 tandem CAR amino acid sequence)

377(FSH beta 33-53+ AS60685 tandem CAR amino acid sequence)

SEQ ID NO: 378(FSH beta 33-53+ AS60702 tandem CAR amino acid sequence)

SEQ ID NO: 379(FSH beta 33-53+ AS60676 series CAR amino acid sequence)

380(AD58126VH3VL1+ FSH beta 33-53 double CAR amino acid sequence)

MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVKQAPGQGLEWIGYINPSTGHTDYNQKFKDRATLTADTSTSTVYMELSSLRSEDTAVYYCARSNWAWFPYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGGGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

381(AS51489+ FSH beta 33-53 Dual CAR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNLYYYSIHWVRQAPGKGLEWVAYISSSSSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYPYYGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGFSYYPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 382(AS92110+ FSH beta 33-53 double CAR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNIYYSSMHWVRQAPGKGLEWVAYIYPYYSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYALDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASSGYHYLITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 383(AS91156+ FSH beta 33-53 Dual CAR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNIYSSSIHWVRQAPGKGLEWVASISSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGPYYHPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 384(AS91189+ FSH beta 33-53 double CAR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNLSYSSIHWVRQAPGKGLEWVASIYSYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYWGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYWYYPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

385(AS51674+ FSH beta 33-53 double CAR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNLYSYYMHWVRQAPGKGLEWVASIYSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARPFGWGYAGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGYAPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 386(AS65233+ FSH beta 33-53 double CAR amino acid sequence)

MALPVTALLLPLALLLHAARPQVHLVESGGGSVQAGGSLRLSCAASEFTYSMGWFRQAPGKEREGVAHIYTRGGTTVYADSVKGRFVLSRYNAKSIMYLQMNSVKLEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

SEQ ID NO: 387(AS60685+ FSH beta 33-53 double CAR amino acid sequence)

MALPVTALLLPLALLLHAARPQVQLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASMYVGGGYTYYDDSVKGRFTISRDNAKNTLYLQMNSLKPEDTAMYYCAAISIALTREFCAPIVSRYNYWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

388(AS60702+ FSH beta 33-53 dual CAR amino acid sequence)

MALPVTALLLPLALLLHAARPQVKLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASIYVGGGYTNYADSVRGRFTISQDNAKNTLYLQMNSLKPEDTAMYYCAAITVALTRAFCAPIPSRYTNWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

389(AS60676+ FSH beta 33-53 double CAR amino acid sequence)

MALPVTALLLPLALLLHAARPQVQLVESGGGSVQAGGSLRLSCAASGYTVSSGCMGWFRQAPGKERERVAQIGRDATTTYADSVKGRFTIARDDAENTLYLQMNSLKPEDTAMYSCTAYWGVYCLSPGRYWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

390(AD58-1-26VH3VL1 CAR, with dnTGF. beta. RII amino acid sequence)

MALPVTALLLPLALLLHAARPQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMHWVKQAPGQGLEWIGYINPSTGHTDYNQKFKDRATLTADTSTSTVYMELSSLRSEDTAVYYCARSNWAWFPYWGQGTLVTVSSGGGGSGGGGSGGGGSDIVMTQSPDSLAVSLGERATINCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGGGTKLEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

391(AS51489 CAR, having the amino acid sequence dnTGF. beta. RII)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNLYYYSIHWVRQAPGKGLEWVAYISSSSSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYPYYGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGFSYYPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

SEQ ID NO: 392(AS92110 CAR, with dnTGF. beta. RII amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNIYYSSMHWVRQAPGKGLEWVAYIYPYYSYTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARGYALDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQASSGYHYLITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

SEQ ID NO: 393(AS91156 CAR, with dnTGF. beta. RII amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNIYSSSIHWVRQAPGKGLEWVASISSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYYAMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGPYYHPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

394(AS91189 CAR, having the amino acid sequence dnTGF. beta. RII)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNLSYSSIHWVRQAPGKGLEWVASIYSYSGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARYWGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQYYWYYPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

395(AS51674 CAR, having the amino acid sequence dnTGF. beta. RII)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFNLYSYYMHWVRQAPGKGLEWVASIYSYSSYTSYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARPFGWGYAGMDYWGQGTLVTVSSGGGGSGGGGSGGGGSDIQMTQSPSSLSASVGDRVTITCRASQSVSSAVAWYQQKPGKAPKLLIYSASSLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQGYAPITFGQGTKVEIKTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

396(AS65233 CAR, having the amino acid sequence dnTGF. beta. RII)

397(AS60685 CAR, having the amino acid sequence dnTGF. beta. RII)

398(AS60702 CAR with dnTGF. beta. RII amino acid sequence)

SEQ ID NO: 399(AS60676 CAR, with dnTGF beta RII amino acid sequence)

SEQ ID NO: 400(FSH beta 33-53+ AD58126VH3VL1 tandem CAR, with dnTGF beta RII amino acid sequence)

401(FSH beta 33-53+ AS51489 tandem CAR with dnTGF beta RII amino acid sequence)

402(FSH beta 33-53+ AS92110 tandem CAR with dnTGF beta RII amino acid sequence)

403(FSH beta 33-53+ AS91156 tandem CAR, with dnTGF beta RII amino acid sequence)

404(FSH beta 33-53+ AS91189 tandem CAR with dnTGF beta RII amino acid sequence)

405(FSH beta 33-53+ AS51674 tandem CAR, having the amino acid sequence dnTGF beta RII)

406(FSH beta 33-53+ AS65233 tandem CAR, having the amino acid sequence dnTGF beta RII)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVHLVESGGGSVQAGGSLRLSCAASEFTYSMGWFRQAPGKEREGVAHIYTRGGTTVYADSVKGRFVLSRYNAKSIMYLQMNSVKLEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

SEQ ID NO: 407(FSH beta 33-53+ AS60685 tandem CAR with dnTGF beta RII amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVQLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASMYVGGGYTYYDDSVKGRFTISRDNAKNTLYLQMNSLKPEDTAMYYCAAISIALTREFCAPIVSRYNYWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

408(FSH beta 33-53+ AS60702 tandem CAR with dnTGF beta RII amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVKLVESGGGSVQAGGSLRLSCAASGNVYNNMCMGWFRQAPGKEREGVASIYVGGGYTNYADSVRGRFTISQDNAKNTLYLQMNSLKPEDTAMYYCAAITVALTRAFCAPIPSRYTNWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

409(FSH beta 33-53+ AS60676 tandem CAR with dnTGF beta RII amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVQLVESGGGSVQAGGSLRLSCAASGYTVSSGCMGWFRQAPGKERERVAQIGRDATTTYADSVKGRFTIARDDAENTLYLQMNSLKPEDTAMYSCTAYWGVYCLSPGRYWGQGTQVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSS

SEQ ID NO: 410(AD58-1-26VH3VL1+ FSH β 33-53 Dual CAR with a dnTGF β RII amino acid sequence)

411(AS51489+ FSH beta 33-53 Dual CAR with dnTGF beta RII amino acid sequence)

SEQ ID NO: 412(AS92110+ FSH beta 33-53 Dual CAR with dnTGF beta RII amino acid sequence)

413(AS91156+ FSH beta 33-53 Dual CAR with a dnTGF beta RII amino acid sequence)

414(AS91189+ FSH beta 33-53 Dual CAR with dnTGF beta RII amino acid sequence)

415(AS51674+ FSH beta 33-53 Dual CAR with dnTGF beta RII amino acid sequence)

416(AS65233+ FSH β 33-53 Dual CAR with dnTGF β RII amino acid sequence)

417(AS60685+ FSH beta 33-53 dual CAR with dnTGF beta RII amino acid sequence)

418(AS60702+ FSH beta 33-53 Dual CAR with dnTGF beta RII amino acid sequence)

419(AS60676+ FSH beta 33-53 dual CAR with dnTGF beta RII amino acid sequence)

SEQ NO:420(AS65233VH4)

EVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGLEGVSHIYTRGGTTVYADSVKGRFVLSRDNSKNTLYLQMNSLRAEDTAVYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSS

SEQ NO:421(AS65233VH5)

EVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGLEGVAHIYTRGGTTVYADSVKGRFVLSRDNSKNTMYLQMNSLRAEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSS

SEQ NO:422(AS65233VH6)

EVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGREGVAHIYTRGGTTVYADSVKGRFVLSRDNSKNTMYLQMNSLRAEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSS

SEQ NO:423(AS80444VH4)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGLEGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSS

SEQ NO：424(AS80444VH5)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGLEGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSS

SEQ NO:425(AS80444VH6)

EVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGREGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSS

SEQ NO:426(AS80533VH4)

QVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGLEGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATDRRPGTSMLAINGYNRWGQGTTVTVSS

SEQ NO:427(AS80533VH5)

QVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGLEGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTSMLAINGYNRWGQGTTVTVSS

SEQ NO：428(AS80533VH6)

QVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGREGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTSMLAINGYNRWGQGTTVTVSS

SEQ NO:429(TC-210)

MQSGTHWRVLGLCLLSVGVWGQEVQLVESGGGLVQPGGSLRLSCAASGGDWSANFMYWYRQAPGKQRELVARISGRGVVDYVESVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAVASYWGQGTLVTVSSGGGGSGGGGSGGGGSDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

430(CD3 epsilon signal peptide)

MQSGTHWRVLGLCLLSVGVWGQ

431(CD3 gamma signal peptide)

MEQGKGLAVLILAIILLQGTLA

432(CD3 delta signal peptide)

MEHSTFLSGLVLATLLSQVSP

433(CD3 epsilon extracellular domain)

DGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMD

434(CD3 gamma extracellular domain)

QSIKGNHLVKVYDYQEDGSVLLTCDAEAKNITWFKDGKMIGFLTEDKKKWNLGSNAKDPRGMYQCKGSQNKSKPLQVYYRMCQNCIELNAATIS

435(CD3 delta extracellular domain) SEQ NO

FKIPIEELEDRVFVNCNTSITWVEGTVGTLLSDITRLDLGKRILDPRGIYRCNGTDIYKDKESTVQVHYRMCQSCVELDPATVA

436(CD3 epsilon transmembrane domain)

VMSVATIVIVDICITGGLLLLVYYWS

437(CD3 gamma transmembrane domain)

GFLFAEIVSIFVLAVGVYFIA

438(CD3 delta transmembrane domain)

GIIVTDVIATLLLALGVFCFA

439(CD3 epsilon intracellular domain)

KNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

440(CD3 gamma intracellular domain)

GQDGVRQSRASDKQTLLPNDQLYQPLKDREDDQYSHLQGNQLRRN

SEQ NO:441(CD3 delta intracellular Domain)

GHETGRLSGAADTQALLRNDQVYQPLRDRDDAQYSHLGGNWARNK

442(FSH beta 33-53 epsilon TCR amino acid sequence)

MQSGTHWRVLGLCLLSVGVWGQYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

443(FSH beta 33-53 gamma TCR amino acid sequence)

MEQGKGLAVLILAIILLQGTLAYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQSIKGNHLVKVYDYQEDGSVLLTCDAEAKNITWFKDGKMIGFLTEDKKKWNLGSNAKDPRGMYQCKGSQNKSKPLQVYYRMCQNCIELNAATISGFLFAEIVSIFVLAVGVYFIAGQDGVRQSRASDKQTLLPNDQLYQPLKDREDDQYSHLQGNQLRRN

444(FSH beta 33-53 delta TCR amino acid sequence)

MEHSTFLSGLVLATLLSQVSPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSFKIPIEELEDRVFVNCNTSITWVEGTVGTLLSDITRLDLGKRILDPRGIYRCNGTDIYKDKESTVQVHYRMCQSCVELDPATVAGIIVTDVIATLLLALGVFCFAGHETGRLSGAADTQALLRNDQVYQPLRDRDDAQYSHLGGNWARNK

SEQ ID NO:445(AS65233VH5 CAR amino acid sequence)

446(AS80444VH5 CAR amino acid sequence)

SEQ ID NO: 447(AS80533VH4 CAR amino acid sequence)

448(FSH beta 33-53+ AS65233VH5 tandem CAR amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGLEGVAHIYTRGGTTVYADSVKGRFVLSRDNSKNTMYLQMNSLRAEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

449(FSH beta 33-53+ AS80444VH5 tandem CAR amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGLEGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

450(FSH beta 33-53+ AS80533VH4 tandem CAR amino acid sequence)

MALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGLEGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATDRRPGTSMLAINGYNRWGQGTTVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

451(AS65233VH5+ FSH beta 33-53 double CAR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGLEGVAHIYTRGGTTVYADSVKGRFVLSRDNSKNTMYLQMNSLRAEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

452(AS80444VH5+ FSH β 33-53 dual CAR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGLEGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

453(AS80533VH4+ FSH β 33-53 dual CAR amino acid sequence)

MALPVTALLLPLALLLHAARPQVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGLEGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATDRRPGTSMLAINGYNRWGQGTTVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

454(AS65233VH5 CAR + FSH beta 33-53 epsilon TCR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGLEGVAHIYTRGGTTVYADSVKGRFVLSRDNSKNTMYLQMNSLRAEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMQSGTHWRVLGLCLLSVGVWGQYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

455(AS80444VH5 CAR + FSH β 33-53 ε TCR amino acid sequence)

MALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGLEGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMQSGTHWRVLGLCLLSVGVWGQYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

456(AS80533VH4 CAR + FSH β 33-53 ε TCR amino acid sequence)

MALPVTALLLPLALLLHAARPQVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGLEGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATDRRPGTSMLAINGYNRWGQGTTVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMQSGTHWRVLGLCLLSVGVWGQYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

457(FSH beta 33-53 epsilon TCR with dnTGF beta RII amino acid sequence)

458(FSH beta 33-53 gamma TCR with dnTGF beta RII amino acid sequence)

459(FSH beta 33-53 delta TCR with dnTGF beta RII amino acid sequence)

460(AS65233VH5 CAR, with dnTGF. beta. RII amino acid sequence)

461(AS80444VH5 CAR, with dnTGF. beta. RII amino acid sequence)

462(AS80533VH4 CAR with dnTGF. beta. RII amino acid sequence)

463(FSH beta 33-53+ AS65233VH5 tandem CAR with dnTGF beta RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGLEGVAHIYTRGGTTVYADSVKGRFVLSRDNSKNTMYLQMNSLRAEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

464(FSH beta 33-53+ AS80444VH5 tandem CAR, with dnTGF beta RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGLEGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

465(FSH beta 33-53+ AS80533VH4 tandem CAR with dnTGF beta RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSQVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGLEGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATDRRPGTSMLAINGYNRWGQGTTVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

466(AS65233VH5+ FSH beta 33-53 Dual CAR with dnTGF. beta. RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGLEGVAHIYTRGGTTVYADSVKGRFVLSRDNSKNTMYLQMNSLRAEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

467(AS80444VH5+ FSH beta 33-53 Dual CAR with dnTGF beta RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGLEGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

468(AS80533VH4+ FSH beta 33-53 Dual CAR with dnTGF beta RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPQVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGLEGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATDRRPGTSMLAINGYNRWGQGTTVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPYTRDLVYKDPARPKIQKTCTFTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCRSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRSRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPR

469(AS65233VH5 CAR + FSH β 33-53 ε TCR with dnTGF β RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASEFTYSMGWFRQAPGKGLEGVAHIYTRGGTTVYADSVKGRFVLSRDNSKNTMYLQMNSLRAEDTAMYYCAARTIFEGSWSSPSSFDFWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMQSGTHWRVLGLCLLSVGVWGQYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

470(AS80444VH5 CAR + FSH β 33-53 ε TCR with dnTGF β RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPEVQLVESGGGLVQPGGSLRLSCAASGFTFSRNTMGWFRQAPGKGLEGVSAIPYTSTGIVYSDSVGGRFTISRDNSKNTVYLQMNSLRAEDTAMYYCATDRRPGTTMLAVNGYNHWGQGTLVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMQSGTHWRVLGLCLLSVGVWGQYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

471(AS80533VH4 CAR + FSH β 33-53 ε TCR with dnTGF β RII amino acid sequence)

MGRGLLRGLWPLHIVLWTRIASTIPPHVQKSVNNDMIVTDNNGAVKFPQLCKFCDVRFSTCDNQKSCMSNCSITSICEKPQEVCVAVWRKNDENITLETVCHDPKLPYHDFILEDAASPKCIMKEKKKPGETFFMCSCSSDECNDNIIFSEEYNTSNPDLLLVIFQVTGISLLPPLGVAISVIIIFYCYRVNRQQKLSSGSGATNFSLLKQAGDVEENPGPMALPVTALLLPLALLLHAARPQVQLVESGGGVVQPGGSLRLSCAASGLSFSTYTVAWFRQAPGKGLEGVAAIPYTSQHMVYTDSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCATDRRPGTSMLAINGYNRWGQGTTVTVSSTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCELRVKFSRSADAPAYKQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDTYDALHMQALPPRGSGATNFSLLKQAGDVEENPGPMQSGTHWRVLGLCLLSVGVWGQYTRDLVYKDPARPKIQKTCTFGGGGSGGGGSGGGGSDGNEEMGGITQTPYKVSISGTTVILTCPQYPGSEILWQHNDKNIGGDEDDKNIGSDEDHLSLKEFSELEQSGYYVCYPRGSKPEDANFYLYLRARVCENCMEMDVMSVATIVIVDICITGGLLLLVYYWSKNRKAKAKPVTRGAGAGGRQRGQNKERPPPVPNPDYEPIRKGQRDLYSGLNQRRI

Sequence listing

<110> Nanjing legend Biotechnology Ltd

<120> anti-mesothelin Chimeric Antigen Receptor (CAR) constructs and uses thereof

<130> 689296.13CN1

<160> 471

<170> PatentIn version 3.5

<210> 1

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126-VH CDR1

<400> 1

Gly Tyr Thr Phe Thr Ser Tyr Trp Met His

1 5 10

<210> 2

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126-VL CDR1

<400> 2

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu

1 5 10 15

Thr

<210> 3

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58116-VH CDR1

<400> 3

Gly Tyr Thr Phe Thr Glu Tyr Thr Met Asn

1 5 10

<210> 4

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58116-VL CDR1

<400> 4

Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 5

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58117-VH CDR1

<400> 5

Phe Tyr Thr Phe Thr Ala Tyr Ser Met His

1 5 10

<210> 6

<211> 15

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58117-VL CDR1

<400> 6

Arg Ala Ser Glu Ser Val Asp Ser Tyr Gly Asn Ser Phe Met Asn

1 5 10 15

<210> 7

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58127-VH CDR1

<400> 7

Gly Tyr Thr Phe Thr Asp Tyr Glu Ile His

1 5 10

<210> 8

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58127-VL CDR1

<400> 8

Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10 15

<210> 9

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58143-VH CDR1

<400> 9

Gly Tyr Thr Phe Thr Asp Tyr Glu Met His

1 5 10

<210> 10

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58143-VL CDR1

<400> 10

Arg Ser Ser Gln Ser Leu Val His Ser Asn Gly Asn Thr Tyr Leu His

1 5 10 15

<210> 11

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58159-VH CDR1

<400> 11

Gly Tyr Thr Ile Thr Asn Tyr Trp Leu Gly

1 5 10

<210> 12

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58159-VL CDR1

<400> 12

Ser Ala Ser Gln Asp Ile Ser Asn Tyr Leu Asn

1 5 10

<210> 13

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58115-VH CDR1

<400> 13

Gly Tyr Thr Phe Thr Glu Tyr Thr Met Asn

1 5 10

<210> 14

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58115-VL CDR1

<400> 14

Lys Ser Ser Gln Ser Leu Leu Asp Ser Asp Gly Lys Thr Tyr Leu Asn

1 5 10 15

<210> 15

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58123-VH CDR1

<400> 15

Gly Phe Ser Leu Ser Arg Tyr Ser Val His

1 5 10

<210> 16

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58123-VL CDR1

<400> 16

Lys Ser Ser Gln Ser Val Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu

1 5 10 15

Ala

<210> 17

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58145-VH CDR1

<400> 17

Gly Tyr Thr Phe Thr Ser Tyr Trp Met His

1 5 10

<210> 18

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58145-VL CDR1

<400> 18

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu

1 5 10 15

Thr

<210> 19

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489-VH CDR1

<400> 19

Gly Phe Asn Leu Tyr Tyr Tyr Ser Ile His

1 5 10

<210> 20

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489-VL CDR1

<400> 20

Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala

1 5 10

<210> 21

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51491-VH CDR1

<400> 21

Gly Phe Asn Leu Tyr Ser Tyr Ser Met His

1 5 10

<210> 22

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51491-VL CDR1

<400> 22

Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala

1 5 10

<210> 23

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110-VH CDR1

<400> 23

Gly Phe Asn Ile Tyr Tyr Ser Ser Met His

1 5 10

<210> 24

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110-VL CDR1

<400> 24

Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala

1 5 10

<210> 25

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156-VH CDR1

<400> 25

Gly Phe Asn Ile Tyr Ser Ser Ser Ile His

1 5 10

<210> 26

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156-VL CDR1

<400> 26

Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala

1 5 10

<210> 27

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189-VH CDR1

<400> 27

Gly Phe Asn Leu Ser Tyr Ser Ser Ile His

1 5 10

<210> 28

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189-VL CDR1

<400> 28

Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala

1 5 10

<210> 29

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674-VH CDR1

<400> 29

Gly Phe Asn Leu Tyr Ser Tyr Tyr Met His

1 5 10

<210> 30

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674-VL CDR1

<400> 30

Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala

1 5 10

<210> 31

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66073 CDR1

<400> 31

Lys Tyr Ser Ser Leu Tyr Cys Met Ala

1 5

<210> 32

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66439 CDR1

<400> 32

Gly Phe Thr Ser Ser Asp Cys Asp Met Asp

1 5 10

<210> 33

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65955 CDR1

<400> 33

Gly Asp Arg Val Ser Thr Gly Cys Met Gly

1 5 10

<210> 34

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 CDR1

<400> 34

Glu Phe Thr Tyr Ser Met Gly

1 5

<210> 35

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65926 CDR1

<400> 35

Gly Asn Leu Tyr Asn Asn Met Cys Met Gly

1 5 10

<210> 36

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66159 CDR1

<400> 36

Gly Asn Val Tyr Asn Asn Met Cys Met Gly

1 5 10

<210> 37

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66416 CDR1

<400> 37

Gly Asn Leu Tyr Asn Asn Met Cys Met Gly

1 5 10

<210> 38

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65850 CDR1

<400> 38

Gly Phe Ser Tyr Ser Asn Ile Cys Met Gly

1 5 10

<210> 39

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65183 CDR1

<400> 39

Asn Gly Tyr Tyr Asn Arg Arg Tyr Cys Met Ala

1 5 10

<210> 40

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65062 CDR1

<400> 40

Gly Val Ser Val Val Asn Phe Ala Met Arg

1 5 10

<210> 41

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65065 CDR1

<400> 41

Gly Tyr Ser Tyr Cys Arg Ser Thr Met Arg

1 5 10

<210> 42

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65556 CDR1

<400> 42

Gly Tyr Asn Ala Ser Ile Cys Arg Met Ser

1 5 10

<210> 43

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65069 CDR1

<400> 43

Gly Asp Thr Gly Tyr Gln Pro Thr Met Arg

1 5 10

<210> 44

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65691 CDR1

<400> 44

Gly Tyr Thr Asp Tyr Arg Leu Val Leu Arg

1 5 10

<210> 45

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65064 CDR1

<400> 45

Gly Asp Thr Val Gln Thr Asn Cys Met Ala

1 5 10

<210> 46

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65081 CDR1

<400> 46

Gly Val Pro Ala Ser Ser Tyr Cys Met Gly

1 5 10

<210> 47

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65115 CDR1

<400> 47

Gly Tyr Ile Tyr Gly Cys Met Gly

1 5

<210> 48

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65271 CDR1

<400> 48

Gly Lys Thr Tyr Gly Arg Cys Met Ala

1 5

<210> 49

<211> 12

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65166 CDR1

<400> 49

Glu Asp Leu Ser Ile Tyr Gly Tyr Asn Cys Met Gly

1 5 10

<210> 50

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65450 CDR1

<400> 50

Gly Asp Met Asn Gly Tyr Lys Cys Met Gly

1 5 10

<210> 51

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65454 CDR1

<400> 51

Gly Asp Met Asn Gly Tyr Lys Cys Met Gly

1 5 10

<210> 52

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65131 CDR1

<400> 52

Glu Tyr Val Thr His Leu Gly

1 5

<210> 53

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65182 CDR1

<400> 53

Gly Tyr Thr Tyr Ser Tyr Gly Tyr Met Gly

1 5 10

<210> 54

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 CDR1

<400> 54

Gly Asn Val Tyr Asn Asn Met Cys Met Gly

1 5 10

<210> 55

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 CDR1

<400> 55

Gly Asn Val Tyr Asn Asn Met Cys Met Gly

1 5 10

<210> 56

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60705 CDR1

<400> 56

Gly Tyr Ala Tyr Ser Gly Ser Cys Met Met Ala

1 5 10

<210> 57

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60660 CDR1

<400> 57

Gly Asp Thr Gly Tyr Gln Pro Thr Met Arg

1 5 10

<210> 58

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60662 CDR1

<400> 58

Gly Tyr Arg Asn Cys Arg Ser Thr Met Arg

1 5 10

<210> 59

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60664 CDR1

<400> 59

Gly Lys Thr Tyr Gly Arg Cys Met Ala

1 5

<210> 60

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60668 CDR1

<400> 60

Gly Asp Met Asn Gly Tyr Lys Cys Met Gly

1 5 10

<210> 61

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 CDR1

<400> 61

Gly Tyr Thr Val Ser Ser Gly Cys Met Gly

1 5 10

<210> 62

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60678 CDR1

<400> 62

Gly Tyr Thr Ser Ser Arg Gly Cys Met Ser

1 5 10

<210> 63

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60679 CDR1

<400> 63

Gly Val Thr Tyr Cys Arg Leu Thr Met Arg

1 5 10

<210> 64

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81326 CDR1

<400> 64

Glu Ser Arg Asp Cys Met Ala

1 5

<210> 65

<211> 13

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81187 CDR1

<400> 65

Gly Tyr Thr Tyr Ser Ser Tyr Ser Ser Asn Cys Leu Gly

1 5 10

<210> 66

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533 CDR1

<400> 66

Gly Leu Ser Phe Ser Thr Tyr Thr Val Ala

1 5 10

<210> 67

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444 CDR1

<400> 67

Gly Phe Thr Phe Ser Arg Asn Thr Met Gly

1 5 10

<210> 68

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81487 CDR1

<400> 68

Lys Leu Thr Ala Trp Arg Ser Cys Val Gly

1 5 10

<210> 69

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126-VH CDR2

<400> 69

Tyr Ile Asn Pro Ser Thr Gly His Thr Asp Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 70

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126-VL CDR2

<400> 70

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 71

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58116-VH CDR2

<400> 71

Gly Ile Ile Pro Asn Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe Lys

1 5 10 15

Gly

<210> 72

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58116-VL CDR2

<400> 72

Leu Val Ser Lys Leu Asp Ser

1 5

<210> 73

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58117-VH CDR2

<400> 73

Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe Lys

1 5 10 15

Gly

<210> 74

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58117-VL CDR2

<400> 74

Leu Ala Ser Tyr Leu Glu Ser

1 5

<210> 75

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58127-VH CDR2

<400> 75

Gly Ile Asp Pro Glu Thr Gly Gly Ala Ala Tyr Thr Gln Lys Phe Lys

1 5 10 15

Gly

<210> 76

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58127-VL CDR2

<400> 76

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 77

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58143-VH CDR2

<400> 77

Gly Ile Asp Pro Glu Thr Gly Gly Ala Ala Tyr Thr Gln Lys Phe Lys

1 5 10 15

Gly

<210> 78

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58143-VL CDR2

<400> 78

Lys Val Ser Asn Arg Phe Ser

1 5

<210> 79

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58159-VH CDR2

<400> 79

Asp Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe Lys

1 5 10 15

Gly

<210> 80

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58159-VL CDR2

<400> 80

Tyr Thr Ser Ser Leu His Ser

1 5

<210> 81

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58115-VH CDR2

<400> 81

Gly Ile Ile Pro Asn Asn Gly Asp Thr Ser Tyr Lys Gln Glu Phe Lys

1 5 10 15

Gly

<210> 82

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58115-VL CDR2

<400> 82

Leu Val Ser Lys Leu Asp Ser

1 5

<210> 83

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58123-VH CDR2

<400> 83

Met Ile Trp Gly Gly Gly Asn Thr Asp Tyr Asn Ser Ala Leu Lys Ser

1 5 10 15

<210> 84

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58123-VL CDR2

<400> 84

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 85

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58145-VH CDR2

<400> 85

Tyr Ile Asn Pro Ser Thr Gly Tyr Thr Asp Tyr Asn Gln Lys Phe Lys

1 5 10 15

Asp

<210> 86

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58145-VL CDR2

<400> 86

Trp Ala Ser Thr Arg Glu Ser

1 5

<210> 87

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489-VH CDR2

<400> 87

Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 88

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489-VL CDR2

<400> 88

Ser Ala Ser Ser Leu Tyr Ser

1 5

<210> 89

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51491-VH CDR2

<400> 89

Tyr Ile Tyr Pro Tyr Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 90

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51491-VL CDR2

<400> 90

Ser Ala Ser Ser Leu Tyr Ser

1 5

<210> 91

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110-VH CDR2

<400> 91

Tyr Ile Tyr Pro Tyr Tyr Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 92

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110-VL CDR2

<400> 92

Ser Ala Ser Ser Leu Tyr Ser

1 5

<210> 93

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156-VH CDR2

<400> 93

Ser Ile Ser Ser Tyr Ser Ser Tyr Thr Ser Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 94

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156-VL CDR2

<400> 94

Ser Ala Ser Ser Leu Tyr Ser

1 5

<210> 95

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189-VH CDR2

<400> 95

Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 96

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189-VL CDR2

<400> 96

Ser Ala Ser Ser Leu Tyr Ser

1 5

<210> 97

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674-VH CDR2

<400> 97

Ser Ile Tyr Ser Tyr Ser Ser Tyr Thr Ser Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 98

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674-VL CDR2

<400> 98

Ser Ala Ser Ser Leu Tyr Ser

1 5

<210> 99

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66073 CDR2

<400> 99

Val Ile Ser Ser Gly Gly Phe Thr Asn Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 100

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66439 CDR2

<400> 100

Ser Leu Leu Ser Thr Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val Arg

1 5 10 15

Gly

<210> 101

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65955 CDR2

<400> 101

Gln Ile His Asn Tyr Asn Ile Ala Lys Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 102

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 CDR2

<400> 102

His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 103

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65926 CDR2

<400> 103

Ser Ile Tyr Ile Gly Gly Gly Tyr Thr Asn Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 104

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66159 CDR2

<400> 104

Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn Tyr Ala Asp Ser Val Arg

1 5 10 15

Gly

<210> 105

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66416 CDR2

<400> 105

Ser Ile Tyr Ile Gly Gly Gly Tyr Thr Asn Tyr Ser Glu Ser Val Arg

1 5 10 15

Gly

<210> 106

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65850 CDR2

<400> 106

Ala Ile Tyr Ser Asn Gly Ser Thr Ile Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 107

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65183 CDR2

<400> 107

Thr Met Thr Thr Thr Ser Gly Arg Thr Tyr Tyr Ala Asp Ala Val Lys

1 5 10 15

Gly

<210> 108

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65062 CDR2

<400> 108

Ala Met Tyr Arg Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val Arg Gly

1 5 10 15

<210> 109

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65065 CDR2

<400> 109

Ala Ile Tyr Ser Asp Gly Thr Thr Ser Tyr Thr Asp Ser Val Lys Gly

1 5 10 15

<210> 110

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65556 CDR2

<400> 110

Ser Ser Tyr Arg Asp Gly Ser Gln Ser Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 111

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65069 CDR2

<400> 111

Ala Ile Tyr Ser Asp Gln Thr Thr Ser Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 112

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65691 CDR2

<400> 112

Ala Ile Tyr Ser Asp Gly Val Thr Ser Tyr Ser Asp Ser Val Lys Gly

1 5 10 15

<210> 113

<211> 20

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65064 CDR2

<400> 113

Ser Ile Leu Ser Leu Tyr Ser Ser Gly Gly Lys Thr Val Tyr Ala Asp

1 5 10 15

Ser Val Lys Gly

<210> 114

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65081 CDR2

<400> 114

Gly Ile Val Ser Asp Thr Thr Thr Thr Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 115

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65115 CDR2

<400> 115

Thr Ile Tyr Arg Asp Gly Thr Ala Tyr Tyr Ala Asn Ser Val Glu Gly

1 5 10 15

<210> 116

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65271 CDR2

<400> 116

Ala Thr Tyr Ile Ser Gly Gly Arg Pro Tyr Val Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 117

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65166 CDR2

<400> 117

Ala Ile Tyr Thr Gly Arg Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 118

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65450 CDR2

<400> 118

Gly Ile Tyr Thr Gly Arg Gly Thr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Asp

<210> 119

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65454 CDR2

<400> 119

Gly Ile Tyr Thr Gly Arg Asn Thr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Asp

<210> 120

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65131 CDR2

<400> 120

Ile Glu Ser Phe Arg Ile Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 121

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65182 CDR2

<400> 121

Lys Ile Tyr Asn Gly Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 122

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 CDR2

<400> 122

Ser Met Tyr Val Gly Gly Gly Tyr Thr Tyr Tyr Asp Asp Ser Val Lys

1 5 10 15

Gly

<210> 123

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 CDR2

<400> 123

Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn Tyr Ala Asp Ser Val Arg

1 5 10 15

Gly

<210> 124

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60705 CDR2

<400> 124

Val Ser Val Arg Arg Thr Gly Ser Ala Phe Tyr Ala Asp Ser Val Lys

1 5 10 15

Ala

<210> 125

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60660 CDR2

<400> 125

Ala Ile Tyr Ser Asp Gln Thr Thr Ser Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 126

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60662 CDR2

<400> 126

Ser Ile Tyr Thr Asp Gly Thr Thr Ser Tyr Thr Asp Ser Val Lys Gly

1 5 10 15

<210> 127

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60664 CDR2

<400> 127

Ala Thr Tyr Ile Ser Gly Gly Arg Pro Tyr Val Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 128

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60668 CDR2

<400> 128

Gly Ile Tyr Thr Gly Arg Asn Thr Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Asp

<210> 129

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 CDR2

<400> 129

Gln Ile Gly Arg Asp Ala Thr Thr Thr Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 130

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60678 CDR2

<400> 130

Tyr Ile Asn Met Arg Val Leu Thr Thr Ile Tyr Ala Ala Ser Val Lys

1 5 10 15

Asp

<210> 131

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60679 CDR2

<400> 131

Ala Ile Tyr Ser Asp Gly Ser Thr Ala Tyr Ala Asp Ser Val Lys Gly

1 5 10 15

<210> 132

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81326 CDR2

<400> 132

Ser Ile Tyr Ala Pro Asp Gly Ser Thr Thr Tyr Ala Asp Thr Val Lys

1 5 10 15

Gly

<210> 133

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81187 CDR2

<400> 133

Arg Ile Tyr Pro Asn Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 134

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533 CDR2

<400> 134

Ala Ile Pro Tyr Thr Ser Gln His Met Val Tyr Thr Asp Ser Val Lys

1 5 10 15

Gly

<210> 135

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444 CDR2

<400> 135

Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val Tyr Ser Asp Ser Val Gly

1 5 10 15

Gly

<210> 136

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81487 CDR2

<400> 136

Ala Ile Tyr Ser Gly Thr Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys

1 5 10 15

Gly

<210> 137

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126-VH CDR3

<400> 137

Ser Asn Trp Ala Trp Phe Pro Tyr

1 5

<210> 138

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126-VL CDR3

<400> 138

Gln Asn Asp Tyr Ser Tyr Pro Leu Thr

1 5

<210> 139

<211> 4

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58116-VH CDR3

<400> 139

Arg Phe Ala Tyr

<210> 140

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58116-VL CDR3

<400> 140

Trp Gln Gly Thr His Phe Pro Phe Thr

1 5

<210> 141

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58117-VH CDR3

<400> 141

Gly Leu Arg Arg Phe Ala Tyr

1 5

<210> 142

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58117-VL CDR3

<400> 142

Gln Gln Asn Asn Glu Asp Pro Tyr Thr

1 5

<210> 143

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58127-VH CDR3

<400> 143

Tyr Gly Asn Tyr Pro Leu Asp Ser

1 5

<210> 144

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58127-VL CDR3

<400> 144

Ser Gln Ser Thr His Val Pro Leu Thr

1 5

<210> 145

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58143-VH CDR3

<400> 145

Tyr Gly Asn Tyr Pro Leu Asp Ser

1 5

<210> 146

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58143-VL CDR3

<400> 146

Ser Gln Ser Thr His Val Pro Leu Thr

1 5

<210> 147

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58159-VH CDR3

<400> 147

Gly Gly Ser Ser Tyr Trp Tyr Phe Asp Val

1 5 10

<210> 148

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58159-VL CDR3

<400> 148

Gln Gln Tyr Ser Lys Val Pro Tyr Thr

1 5

<210> 149

<211> 4

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58115-VH CDR3

<400> 149

Arg Phe Ala Tyr

<210> 150

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58115-VL CDR3

<400> 150

Trp Gln Gly Thr His Phe Pro Phe Thr

1 5

<210> 151

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58123-VH CDR3

<400> 151

Ser Leu Gly Trp Tyr Phe Asp Ile

1 5

<210> 152

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58123-VL CDR3

<400> 152

His Gln Tyr Leu Ser Ser Trp Thr

1 5

<210> 153

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58145-VH CDR3

<400> 153

Ser Asn Trp Ala Trp Phe Pro Tyr

1 5

<210> 154

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58145-VL CDR3

<400> 154

Gln Asn Asp Tyr Ser Tyr Pro Leu Thr

1 5

<210> 155

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489-VH CDR3

<400> 155

Tyr Tyr Pro Tyr Tyr Gly Met Asp Tyr

1 5

<210> 156

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489-VL CDR3

<400> 156

Gln Gln Gly Phe Ser Tyr Tyr Pro Ile Thr

1 5 10

<210> 157

<211> 6

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51491-VH CDR3

<400> 157

Gly Tyr Gly Met Asp Tyr

1 5

<210> 158

<211> 9

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51491-VL CDR3

<400> 158

Gln Gln Ser Tyr Tyr Trp Leu Phe Thr

1 5

<210> 159

<211> 6

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110-VH CDR3

<400> 159

Gly Tyr Ala Leu Asp Tyr

1 5

<210> 160

<211> 12

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110-VL CDR3

<400> 160

Gln Gln Ala Ser Ser Gly Tyr His Tyr Leu Ile Thr

1 5 10

<210> 161

<211> 6

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156-VH CDR3

<400> 161

Tyr Tyr Ala Met Asp Tyr

1 5

<210> 162

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156-VL CDR3

<400> 162

Gln Gln Gly Pro Tyr Tyr His Pro Ile Thr

1 5 10

<210> 163

<211> 6

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189-VH CDR3

<400> 163

Tyr Trp Gly Met Asp Tyr

1 5

<210> 164

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189-VL CDR3

<400> 164

Gln Gln Tyr Tyr Trp Tyr Tyr Pro Ile Thr

1 5 10

<210> 165

<211> 11

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674-VH CDR3

<400> 165

Pro Phe Gly Trp Gly Tyr Ala Gly Met Asp Tyr

1 5 10

<210> 166

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674-VL CDR3

<400> 166

Gln Gln Gly Tyr Ala Pro Ile Thr

1 5

<210> 167

<211> 14

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66073 CDR3

<400> 167

Gly Leu Ser Tyr Cys His Ser Ser Thr Ala Thr Ala Thr Tyr

1 5 10

<210> 168

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66439 CDR3

<400> 168

Ala Glu Trp Gly Gly Met Asp Tyr

1 5

<210> 169

<211> 19

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65955 CDR3

<400> 169

Pro Val Asp Cys Ser Trp Ser Met Phe Leu Gln Asp Pro Leu Ala Leu

1 5 10 15

Ser Pro Pro

<210> 170

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 CDR3

<400> 170

Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser Phe Asp Phe

1 5 10 15

<210> 171

<211> 19

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65926 CDR3

<400> 171

Val Ser Ile Ala Leu Thr Arg Glu Phe Cys Ala Pro Ile Val Ser Arg

1 5 10 15

Tyr Asn Tyr

<210> 172

<211> 19

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66159 CDR3

<400> 172

Ile Thr Val Ala Leu Thr Arg Ala Phe Cys Ala Pro Ile Pro Ser Arg

1 5 10 15

Tyr Thr Asn

<210> 173

<211> 19

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66416 CDR3

<400> 173

Ile Pro Ile Ala Leu Thr Arg Ala Phe Cys Ala Pro Ile Val Ser Arg

1 5 10 15

Tyr Thr Tyr

<210> 174

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65850 CDR3

<400> 174

Gly Arg Cys Gly Gly Pro Asn Tyr

1 5

<210> 175

<211> 23

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65183 CDR3

<400> 175

His Leu Pro Ser Ser Trp Val Thr Ser Thr Asp Tyr Cys Asp Asn Leu

1 5 10 15

Gln Ala Gly Phe Tyr Asn Ser

<210> 176

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65062 CDR3

<400> 176

Thr Ser Pro Met Gly Asp Thr Tyr

1 5

<210> 177

<211> 13

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65065 CDR3

<400> 177

Asp Leu Val Gly Cys Asn Val Ala Gly Gly Ser Pro Tyr

1 5 10

<210> 178

<211> 7

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65556 CDR3

<400> 178

Ala Cys Pro Trp Arg Ala Tyr

1 5

<210> 179

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65069 CDR3

<400> 179

Thr Thr Arg Arg Gly Ser Glu Tyr

1 5

<210> 180

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65691 CDR3

<400> 180

Thr Gly Ser Gly Gly Val Ala Tyr

1 5

<210> 181

<211> 22

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65064 CDR3

<400> 181

Val Arg Val Thr Val Thr Trp Ala Glu Lys Leu Arg Arg Cys Thr Gly

1 5 10 15

Phe Ser Gly Met Asp Tyr

<210> 182

<211> 20

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65081 CDR3

<400> 182

Ser His Phe Leu Leu Cys Ala Arg Lys Pro Arg Trp Asp Asp Leu Ile

1 5 10 15

Lys Tyr Glu Tyr

<210> 183

<211> 13

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65115 CDR3

<400> 183

Arg Thr Thr Gly Cys Asn Trp Asp Ile Ser Gly Val Tyr

1 5 10

<210> 184

<211> 18

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65271 CDR3

<400> 184

Gly Ser Ala Gly Arg Gly Pro Cys Asp Arg Phe Asp Gln Asn Gln Tyr

1 5 10 15

Thr Phe

<210> 185

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65166 CDR3

<400> 185

Lys Tyr Cys Ala Val Val Ala Asp Phe Gly Asn Ser Arg Leu Val Arg

1 5 10 15

Tyr

<210> 186

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65450 CDR3

<400> 186

Lys Tyr Cys Ala Val Val Ala Glu Phe Gly Gly Pro Arg Leu Val Arg

1 5 10 15

Tyr

<210> 187

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65454 CDR3

<400> 187

Tyr Cys Ala Val Val Ala Glu Phe Arg Gly Pro Arg Leu Asp Arg Tyr

1 5 10 15

<210> 188

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65131 CDR3

<400> 188

Arg Gln Asp Arg Ser Gly Ala Ser Met Val Asn Arg Asp Ser Tyr Asn

1 5 10 15

Tyr

<210> 189

<211> 20

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65182 CDR3

<400> 189

Asn Arg Leu Pro Asn Ser Asp Val Asp Leu Val Leu Pro Arg Phe Gly

1 5 10 15

Arg Phe Gly Tyr

<210> 190

<211> 19

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 CDR3

<400> 190

Ile Ser Ile Ala Leu Thr Arg Glu Phe Cys Ala Pro Ile Val Ser Arg

1 5 10 15

Tyr Asn Tyr

<210> 191

<211> 19

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 CDR3

<400> 191

Ile Thr Val Ala Leu Thr Arg Ala Phe Cys Ala Pro Ile Pro Ser Arg

1 5 10 15

Tyr Thr Asn

<210> 192

<211> 15

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60705 CDR3

<400> 192

Asp Phe Thr Cys Arg Thr Trp Thr Leu Asn Lys Asn Tyr Asn His

1 5 10 15

<210> 193

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60660 CDR3

<400> 193

Thr Thr Arg Arg Gly Ser Glu Tyr

1 5

<210> 194

<211> 13

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60662 CDR3

<400> 194

Asp Leu Val Gly Cys Asn Val Ala Gly Gly Ser Pro Tyr

1 5 10

<210> 195

<211> 18

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60664 CDR3

<400> 195

Gly Ser Ala Gly Arg Gly Pro Cys Asp Arg Phe Asp Gln Asn Gln Tyr

1 5 10 15

Thr Phe

<210> 196

<211> 17

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60668 CDR3

<400> 196

Lys Tyr Cys Ala Val Val Ala Glu Phe Gly Gly Pro Arg Leu Val Arg

1 5 10 15

Tyr

<210> 197

<211> 12

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 CDR3

<400> 197

Tyr Trp Gly Val Tyr Cys Leu Ser Pro Gly Arg Tyr

1 5 10

<210> 198

<211> 15

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60678 CDR3

<400> 198

Gly Tyr Asn Gly Gln Trp Cys Glu His Ala Ser Asp Val Thr Ala

1 5 10 15

<210> 199

<211> 8

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60679 CDR3

<400> 199

Asn Cys Ala Ser Gly Leu Thr Ala

1 5

<210> 200

<211> 18

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81326 CDR3

<400> 200

Gly Gly Leu Ser Arg Asn Thr Cys Gly Tyr Leu Arg Gly Gly Tyr Phe

1 5 10 15

Ala Tyr

<210> 201

<211> 18

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81187 CDR3

<400> 201

Ala Val Gly Val Gly Asp Asn Trp Cys Ala Ser Gly Ala Ala Tyr Phe

1 5 10 15

Gly Tyr

<210> 202

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533 CDR3

<400> 202

Asp Arg Arg Pro Gly Thr Ser Met Leu Ala Ile Asn Gly Tyr Asn Arg

1 5 10 15

<210> 203

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444 CDR3

<400> 203

Asp Arg Arg Pro Gly Thr Thr Met Leu Ala Val Asn Gly Tyr Asn His

1 5 10 15

<210> 204

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81487 CDR3

<400> 204

Thr Ser Ile Arg Ser Ser Cys Gly Leu Val Arg Asp Glu Tyr Ala Tyr

1 5 10 15

<210> 205

<211> 245

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126 scFv

<400> 205

Gln Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Ala Lys Pro Gly Ala

1 5 10 15

Ser Val Glu Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Ser Thr Gly His Thr Asp Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Asn Trp Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Thr

130 135 140

Val Thr Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser

145 150 155 160

Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln

165 170 175

Lys Pro Gly Lys Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg

180 185 190

Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr

210 215 220

Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Ser Gly Thr

225 230 235 240

Arg Leu Glu Ile Lys

245

<210> 206

<211> 245

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126VH3VL1 scFv

<400> 206

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Ser Thr Gly His Thr Asp Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr Ser Thr Val Tyr

65 70 75 80

Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Asn Trp Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala

130 135 140

Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser

145 150 155 160

Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln

165 170 175

Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg

180 185 190

Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr

210 215 220

Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Gly Gly Thr

225 230 235 240

Lys Leu Glu Ile Lys

245

<210> 207

<211> 240

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58116 scFv

<400> 207

Gln Val Gln Leu Lys Glu Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr

20 25 30

Thr Met Asn Trp Val Arg Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Gly Ile Ile Pro Asn Asn Gly Asp Thr Ser Tyr Asn Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Gly Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

115 120 125

Asp Ile Val Met Thr Gln Ala Pro Leu Thr Leu Ser Val Thr Ile Gly

130 135 140

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

145 150 155 160

Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Arg Pro Gly Gln Ser

165 170 175

Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

180 185 190

Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

195 200 205

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly

210 215 220

Thr His Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

225 230 235 240

<210> 208

<211> 242

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58117 scFv

<400> 208

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu

1 5 10 15

Thr Val Lys Ile Ser Cys Lys Ala Ser Phe Tyr Thr Phe Thr Ala Tyr

20 25 30

Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Met

35 40 45

Gly Trp Ile Asn Thr Glu Thr Gly Glu Pro Thr Tyr Ala Asp Asp Phe

50 55 60

Lys Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Thr Thr Ala Tyr

65 70 75 80

Leu Gln Ile Asn Asn Leu Lys Asn Glu Asp Thr Ala Thr Phe Phe Cys

85 90 95

Ala Arg Gly Leu Arg Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Thr Ser Leu Ala Val

130 135 140

Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Arg Ala Ser Glu Ser Val

145 150 155 160

Asp Ser Tyr Gly Asn Ser Phe Met Asn Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Gln Pro Pro Lys Leu Leu Ile Tyr Leu Ala Ser Tyr Leu Glu Ser Gly

180 185 190

Val Pro Ala Arg Phe Ser Gly Ser Gly Ser Arg Thr Asp Phe Thr Leu

195 200 205

Thr Ile Asp Pro Val Glu Ala Asp Asp Ala Ala Thr Tyr Tyr Cys Gln

210 215 220

Gln Asn Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Arg Leu Glu

225 230 235 240

Ile Lys

<210> 209

<211> 244

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58127 scFv

<400> 209

Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Ile His Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Gly Ala Ala Tyr Thr Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Thr Tyr Gly Asn Tyr Pro Leu Asp Ser Trp Gly Gln Gly Thr Thr

100 105 110

Leu Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Gly Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro

130 135 140

Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser

145 150 155 160

Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys

165 170 175

Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe

180 185 190

Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Phe

210 215 220

Cys Ser Gln Ser Thr His Val Pro Leu Thr Phe Gly Ala Gly Thr Arg

225 230 235 240

Leu Glu Ile Lys

<210> 210

<211> 244

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58143 scFv

<400> 210

Gln Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Ala

1 5 10 15

Ser Val Thr Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Glu Met His Trp Val Lys Gln Thr Pro Val His Gly Leu Glu Trp Ile

35 40 45

Gly Gly Ile Asp Pro Glu Thr Gly Gly Ala Ala Tyr Thr Gln Lys Phe

50 55 60

Lys Gly Lys Ala Thr Pro Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Thr Thr Tyr Gly Asn Tyr Pro Leu Asp Ser Trp Gly Gln Gly Thr Thr

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Pro Leu Ser Leu Pro

130 135 140

Val Ser Leu Gly Asp Gln Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser

145 150 155 160

Leu Val His Ser Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys

165 170 175

Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe

180 185 190

Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Lys Ile Ser Gly Val Glu Ala Glu Asp Leu Gly Val Tyr Phe

210 215 220

Cys Ser Gln Ser Thr His Val Pro Leu Thr Phe Gly Ala Gly Thr Lys

225 230 235 240

Leu Glu Leu Lys

<210> 211

<211> 241

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58159 scFv

<400> 211

Gln Val Gln Leu Lys Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Ile Thr Asn Tyr

20 25 30

Trp Leu Gly Trp Val Lys Gln Arg Pro Gly His Gly Leu Glu Trp Ile

35 40 45

Gly Asp Ile Tyr Pro Gly Gly Gly Tyr Thr Asn Tyr Asn Glu Lys Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Ala Asp Thr Ser Ser Ile Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Gly Gly Ser Ser Tyr Trp Tyr Phe Asp Val Trp Gly Ala Gly

100 105 110

Thr Ser Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Thr Thr Ser Ser

130 135 140

Leu Ser Ala Ser Leu Gly Asp Arg Val Thr Ile Ser Cys Ser Ala Ser

145 150 155 160

Gln Asp Ile Ser Asn Tyr Leu Asn Trp Tyr Gln Gln Lys Pro Asp Gly

165 170 175

Thr Val Lys Leu Leu Ile Tyr Tyr Thr Ser Ser Leu His Ser Gly Val

180 185 190

Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Tyr Ser Leu Thr

195 200 205

Ile Ser Asn Leu Glu Pro Glu Asp Ile Ala Thr Tyr Tyr Cys Gln Gln

210 215 220

Tyr Ser Lys Val Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Leu

225 230 235 240

Lys

<210> 212

<211> 240

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58115 scFv

<400> 212

Gln Val Gln Leu Lys Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Thr Ser Gly Tyr Thr Phe Thr Glu Tyr

20 25 30

Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Gly Ile Ile Pro Asn Asn Gly Asp Thr Ser Tyr Lys Gln Glu Phe

50 55 60

Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Arg Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Gly Arg Phe Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

100 105 110

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

115 120 125

Asp Ile Val Met Thr Gln Thr Pro Leu Thr Leu Ser Val Thr Ile Gly

130 135 140

Gln Pro Ala Ser Ile Ser Cys Lys Ser Ser Gln Ser Leu Leu Asp Ser

145 150 155 160

Asp Gly Lys Thr Tyr Leu Asn Trp Phe Leu Gln Arg Pro Gly Gln Ser

165 170 175

Pro Lys Arg Leu Ile Tyr Leu Val Ser Lys Leu Asp Ser Gly Val Pro

180 185 190

Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile

195 200 205

Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Trp Gln Gly

210 215 220

Thr His Phe Pro Phe Thr Phe Gly Ser Gly Thr Lys Leu Glu Ile Lys

225 230 235 240

<210> 213

<211> 243

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58123 scFv

<400> 213

Glu Val Gln Leu Gln Gln Ser Gly Pro Gly Leu Val Ala Pro Ser Gln

1 5 10 15

Ser Leu Ser Ile Thr Cys Thr Val Ser Gly Phe Ser Leu Ser Arg Tyr

20 25 30

Ser Val His Trp Val Arg Gln Pro Pro Gly Lys Gly Leu Glu Trp Leu

35 40 45

Gly Met Ile Trp Gly Gly Gly Asn Thr Asp Tyr Asn Ser Ala Leu Lys

50 55 60

Ser Arg Leu Ser Ile Ser Lys Asp Asn Ser Lys Ser Gln Val Phe Leu

65 70 75 80

Lys Met Asn Ser Leu Gln Thr Asp Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Arg Ser Leu Gly Trp Tyr Phe Asp Ile Trp Gly Ala Gly Thr Thr Val

100 105 110

Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly

115 120 125

Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Ser Ser Leu Ala Val

130 135 140

Ser Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser Val

145 150 155 160

Leu Tyr Ser Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys

165 170 175

Pro Gly Gln Ser Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu

180 185 190

Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe

195 200 205

Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr

210 215 220

Cys His Gln Tyr Leu Ser Ser Trp Thr Phe Gly Gly Gly Thr Lys Leu

225 230 235 240

Glu Ile Lys

<210> 214

<211> 245

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58145 scFv

<400> 214

Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Ala Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Met Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr

20 25 30

Trp Met His Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile

35 40 45

Gly Tyr Ile Asn Pro Ser Thr Gly Tyr Thr Asp Tyr Asn Gln Lys Phe

50 55 60

Lys Asp Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Ser Asn Trp Ala Trp Phe Pro Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

115 120 125

Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Thr

130 135 140

Val Thr Ala Gly Glu Lys Val Thr Met Ser Cys Lys Ser Ser Gln Ser

145 150 155 160

Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr Trp Tyr Gln Gln

165 170 175

Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg

180 185 190

Glu Ser Gly Val Pro Asp Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp

195 200 205

Phe Thr Leu Thr Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr

210 215 220

Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Leu Thr Phe Gly Ala Gly Thr

225 230 235 240

Lys Leu Glu Leu Lys

245

<210> 215

<211> 241

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489 scFv

<400> 215

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Leu Tyr Tyr Tyr

20 25 30

Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Tyr Pro Tyr Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr

100 105 110

Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

115 120 125

Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu

130 135 140

Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln

145 150 155 160

Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala

165 170 175

Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro

180 185 190

Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile

195 200 205

Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly

210 215 220

Phe Ser Tyr Tyr Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

225 230 235 240

Lys

<210> 216

<211> 237

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51491 scFv

<400> 216

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Leu Tyr Ser Tyr

20 25 30

Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Tyr Ile Tyr Pro Tyr Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Tyr Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

130 135 140

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser

145 150 155 160

Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

165 170 175

Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe

180 185 190

Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

195 200 205

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Tyr Trp

210 215 220

Leu Phe Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

225 230 235

<210> 217

<211> 240

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110 scFv

<400> 217

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Tyr Tyr Ser

20 25 30

Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Tyr Ile Tyr Pro Tyr Tyr Ser Tyr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Gly Tyr Ala Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

130 135 140

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser

145 150 155 160

Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

165 170 175

Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe

180 185 190

Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

195 200 205

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala Ser Ser Gly

210 215 220

Tyr His Tyr Leu Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

225 230 235 240

<210> 218

<211> 238

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156 scFv

<400> 218

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Ile Tyr Ser Ser

20 25 30

Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Ser Ser Tyr Ser Ser Tyr Thr Ser Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

130 135 140

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser

145 150 155 160

Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

165 170 175

Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe

180 185 190

Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

195 200 205

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Pro Tyr Tyr

210 215 220

His Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

225 230 235

<210> 219

<211> 238

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189 scFv

<400> 219

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Leu Ser Tyr Ser

20 25 30

Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Tyr Trp Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser

130 135 140

Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser

145 150 155 160

Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu

165 170 175

Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe

180 185 190

Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu

195 200 205

Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Trp Tyr

210 215 220

Tyr Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys

225 230 235

<210> 220

<211> 241

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674 scFv

<400> 220

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn Leu Tyr Ser Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ala Ser Ile Tyr Ser Tyr Ser Ser Tyr Thr Ser Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Pro Phe Gly Trp Gly Tyr Ala Gly Met Asp Tyr Trp Gly Gln

100 105 110

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

130 135 140

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

145 150 155 160

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

180 185 190

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

195 200 205

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

210 215 220

Gln Gly Tyr Ala Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu Ile

225 230 235 240

Lys

<210> 221

<211> 121

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66073 sdAb

<400> 221

Gln Val Gln Leu Val Glu Ser Gly Gly Asp Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Thr Leu Ala Cys Thr Gly Arg Lys Tyr Ser Ser Leu Tyr Cys

20 25 30

Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Ala Arg Glu Gly Val Ala

35 40 45

Val Ile Ser Ser Gly Gly Phe Thr Asn Tyr Ala Asp Ser Val Lys Gly

50 55 60

Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Ala

65 70 75 80

Met Asn Gly Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala

85 90 95

Gly Leu Ser Tyr Cys His Ser Ser Thr Ala Thr Ala Thr Tyr Arg Gly

100 105 110

Gln Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 222

<211> 119

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66439 sdAb

<400> 222

Gln Met Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Pro Gly Phe Thr Ser Ser Asp Cys

20 25 30

Asp Met Asp Trp Tyr Arg Gln Ala Ala Gly Asn Gln Arg Glu Trp Val

35 40 45

Ser Ser Leu Leu Ser Thr Asp Gly Ser Thr Ser Tyr Ala Asp Ser Val

50 55 60

Arg Gly Arg Phe Thr Ile Ser Lys Asp Pro Ala Lys Asp Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Phe Cys

85 90 95

Arg Cys Val Val Ala Glu Trp Gly Gly Met Asp Tyr Trp Gly Lys Gly

100 105 110

Thr Leu Val Thr Val Ser Ser

115

<210> 223

<211> 127

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65955 sdAb

<400> 223

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Arg Val Ser Thr Gly

20 25 30

Cys Met Gly Trp Phe Arg Gln Gly Pro Gly Glu Glu Arg Glu Gly Leu

35 40 45

Ala Gln Ile His Asn Tyr Asn Ile Ala Lys Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Ile Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Leu Tyr Ile Cys Thr

85 90 95

Ala Pro Val Asp Cys Ser Trp Ser Met Phe Leu Gln Asp Pro Leu Ala

100 105 110

Leu Ser Pro Pro Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 224

<211> 122

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 sdAb

<400> 224

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Tyr Ser Met Gly

20 25 30

Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala His Ile

35 40 45

Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys Gly Arg

50 55 60

Phe Val Leu Ser Arg Tyr Asn Ala Lys Ser Ile Met Tyr Leu Gln Met

65 70 75 80

Asn Ser Val Lys Leu Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Arg

85 90 95

Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser Phe Asp Phe Trp

100 105 110

Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 225

<211> 131

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65926 sdAb

<400> 225

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Leu Tyr Asn Asn Met

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Ser Ile Tyr Ile Gly Gly Gly Tyr Thr Asn Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Pro Ile Ser Arg Asp Asn Ala Lys Ser

65 70 75 80

Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met

85 90 95

Tyr Tyr Cys Ala Ala Val Ser Ile Ala Leu Thr Arg Glu Phe Cys Ala

100 105 110

Pro Ile Val Ser Arg Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr

115 120 125

Val Ser Ser

130

<210> 226

<211> 128

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66159 sdAb

<400> 226

Gln Val Arg Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Val Tyr Asn Asn Met

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn Tyr Ala Asp Ser Val

50 55 60

Arg Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ala Ile Thr Val Ala Leu Thr Arg Ala Phe Cys Ala Pro Ile Pro

100 105 110

Ser Arg Tyr Thr Asn Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 227

<211> 128

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66416 sdAb

<400> 227

Gln Val Gln Leu Ala Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Leu Tyr Asn Asn Met

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Gly Ser Ile Tyr Ile Gly Gly Gly Tyr Thr Asn Tyr Ser Glu Ser Val

50 55 60

Arg Gly Arg Phe Thr Ile Ser Leu Asp Asn Ala Lys Lys Thr Leu Asn

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ala Ile Pro Ile Ala Leu Thr Arg Ala Phe Cys Ala Pro Ile Val

100 105 110

Ser Arg Tyr Thr Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 228

<211> 116

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65850 sdAb

<400> 228

Glu Val Gln Leu Met Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Tyr Ser Asn Ile

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Ala Ile Tyr Ser Asn Gly Ser Thr Ile Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Val Ser Lys Glu Phe Ala Lys Asn Thr Gln Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala

85 90 95

Ala Gly Arg Cys Gly Gly Pro Asn Tyr Trp Gly Gln Gly Thr Gln Val

100 105 110

Thr Val Ser Ser

115

<210> 229

<211> 132

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65183 sdAb

<400> 229

Glu Val Gln Leu Ala Glu Ser Gly Gly Gly Ser Ala Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ser Asn Gly Tyr Tyr Asn Arg Arg Tyr

20 25 30

Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Thr Met Thr Thr Thr Ser Gly Arg Thr Tyr Tyr Ala Asp Ala Val

50 55 60

Lys Gly Arg Phe Thr Val Ser Gln Asp Asn Ala Lys Ser Thr Leu Tyr

65 70 75 80

Leu Gln Met Ser Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ala His Leu Pro Ser Ser Trp Val Thr Ser Thr Asp Tyr Cys Asp

100 105 110

Asn Leu Gln Ala Gly Phe Tyr Asn Ser Trp Gly Gln Gly Thr Gln Val

115 120 125

Thr Val Ser Ser

130

<210> 230

<211> 116

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65062 sdAb

<400> 230

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Ser Val Val Asn Phe

20 25 30

Ala Met Arg Trp Tyr Arg Gln Ala Pro Gly Asn Glu Arg Glu Phe Val

35 40 45

Ser Ala Met Tyr Arg Ser Gly Ser Thr Ser Tyr Ala Asp Ser Val Arg

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Ser Ala Leu Asn Thr Val Phe Leu

65 70 75 80

Gln Met Ser Gly Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Gln

85 90 95

Ala Thr Ser Pro Met Gly Asp Thr Tyr Trp Gly Gln Gly Thr Gln Val

100 105 110

Thr Val Ser Ser

115

<210> 231

<211> 121

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65065 sdAb

<400> 231

Glu Val Gln Leu Ala Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Tyr Cys Arg Ser

20 25 30

Thr Met Arg Trp Tyr Arg Gln Ala Pro Gly Asn Val Arg Glu Phe Val

35 40 45

Ser Ala Ile Tyr Ser Asp Gly Thr Thr Ser Tyr Thr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Gln Pro Glu Asp Thr Ala Met Tyr Tyr Cys Arg

85 90 95

Ile Asp Leu Val Gly Cys Asn Val Ala Gly Gly Ser Pro Tyr Trp Gly

100 105 110

Gln Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 232

<211> 115

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65556 sdAb

<400> 232

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Val Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Asn Ala Ser Ile Cys

20 25 30

Arg Met Ser Trp Tyr Arg Gln Ala Pro Gly Thr Glu Arg Glu Phe Val

35 40 45

Ser Ser Ser Tyr Arg Asp Gly Ser Gln Ser Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Thr Ser Arg Asp Ser Ala Lys Asn Thr Val Phe Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Ser Asp Thr Ala Met Tyr Tyr Cys Asn

85 90 95

Ala Ala Cys Pro Trp Arg Ala Tyr Trp Gly Gln Gly Thr Gln Val Thr

100 105 110

Val Ser Ser

115

<210> 233

<211> 116

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65069 sdAb

<400> 233

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Asp Thr Gly Tyr Gln Pro

20 25 30

Thr Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Ala Ile Tyr Ser Asp Gln Thr Thr Ser Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Arg Lys Thr Val Tyr Leu

65 70 75 80

Gln Met Ala Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys

85 90 95

Leu Thr Thr Arg Arg Gly Ser Glu Tyr Trp Gly Gln Gly Thr Gln Val

100 105 110

Thr Val Ser Ser

115

<210> 234

<211> 116

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65691 sdAb

<400> 234

Gln Met Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Val Ser Gly Tyr Thr Asp Tyr Arg Leu

20 25 30

Val Leu Arg Trp Tyr Arg Gln Ala Leu Gly Lys Glu Arg Glu Phe Ile

35 40 45

Ser Ala Ile Tyr Ser Asp Gly Val Thr Ser Tyr Ser Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Ala Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Ser Glu Asp Thr Ala Met Tyr Tyr Cys Lys

85 90 95

Ala Thr Gly Ser Gly Gly Val Ala Tyr Trp Gly Gln Gly Thr Gln Val

100 105 110

Thr Val Ser Ser

115

<210> 235

<211> 134

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65064 sdAb

<400> 235

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Lys Leu Ser Cys Ala Val Ser Gly Asp Thr Val Gln Thr Asn

20 25 30

Cys Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val

35 40 45

Ala Ser Ile Leu Ser Leu Tyr Ser Ser Gly Gly Lys Thr Val Tyr Ala

50 55 60

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Pro Asp Asn Ala Gln Asn

65 70 75 80

Thr Val Ser Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met

85 90 95

Tyr Tyr Cys Ala Thr Val Arg Val Thr Val Thr Trp Ala Glu Lys Leu

100 105 110

Arg Arg Cys Thr Gly Phe Ser Gly Met Asp Tyr Trp Gly Lys Gly Thr

115 120 125

Leu Val Thr Val Ser Ser

130

<210> 236

<211> 128

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65081 sdAb

<400> 236

Gln Val His Leu Met Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Val Pro Ala Ser Ser Tyr

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Gly Ile Val Ser Asp Thr Thr Thr Thr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Lys Asp Asn Ala Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Thr Tyr Tyr Cys Ala

85 90 95

Ala Ser His Phe Leu Leu Cys Ala Arg Lys Pro Arg Trp Asp Asp Leu

100 105 110

Ile Lys Tyr Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 237

<211> 119

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65115 sdAb

<400> 237

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ile Tyr Gly Cys Met

20 25 30

Gly Trp Phe Arg Arg Ala Pro Gly Lys Ala Arg Glu Glu Val Ala Thr

35 40 45

Ile Tyr Arg Asp Gly Thr Ala Tyr Tyr Ala Asn Ser Val Glu Gly Arg

50 55 60

Phe Thr Ala Ser Arg Asn Asn Ala Glu Asn Thr Leu Ser Leu Glu Met

65 70 75 80

Asn Ser Leu Asn Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Arg

85 90 95

Thr Thr Gly Cys Asn Trp Asp Ile Ser Gly Val Tyr Trp Gly Gln Gly

100 105 110

Thr Gln Val Thr Val Ser Ser

115

<210> 238

<211> 126

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65271 sdAb

<400> 238

Gln Met Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Lys Thr Tyr Gly Arg Cys

20 25 30

Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala

35 40 45

Ala Thr Tyr Ile Ser Gly Gly Arg Pro Tyr Val Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Met Ser Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Asp Asp Ser Ala Met Tyr Tyr Cys Ala

85 90 95

Ala Gly Ser Ala Gly Arg Gly Pro Cys Asp Arg Phe Asp Gln Asn Gln

100 105 110

Tyr Thr Phe Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 239

<211> 128

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65166 sdAb

<400> 239

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Glu Asp Leu Ser Ile Tyr Gly

20 25 30

Tyr Asn Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu

35 40 45

Ala Val Ala Ala Ile Tyr Thr Gly Arg Gly Thr Thr Tyr Tyr Ala Asp

50 55 60

Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr

65 70 75 80

Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr

85 90 95

Tyr Cys Ala Ser Lys Tyr Cys Ala Val Val Ala Asp Phe Gly Asn Ser

100 105 110

Arg Leu Val Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 240

<211> 126

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65450 sdAb

<400> 240

Gln Val Arg Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Met Asn Gly Tyr Lys

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val

35 40 45

Ala Gly Ile Tyr Thr Gly Arg Gly Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Asp Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ala Lys Tyr Cys Ala Val Val Ala Glu Phe Gly Gly Pro Arg Leu

100 105 110

Val Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 241

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65454 sdAb

<400> 241

Gln Val Arg Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Met Asn Gly Tyr Lys

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val

35 40 45

Ala Gly Ile Tyr Thr Gly Arg Asn Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Asp Leu Phe Thr Ile Ser Gln Asp Asn Ala Gln Asn Thr Val Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ser Tyr Cys Ala Val Val Ala Glu Phe Arg Gly Pro Arg Leu Asp

100 105 110

Arg Tyr Trp Gly Tyr Gly Thr Gln Val Thr Val Thr Ser

115 120 125

<210> 242

<211> 123

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65131 sdAb

<400> 242

Glu Val Gln Leu Ala Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Thr Leu Ser Cys Thr Ala Ser Glu Tyr Val Thr His Leu Gly

20 25 30

Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Ile Glu

35 40 45

Ser Phe Arg Ile Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg

50 55 60

Phe Thr Ile Ser His Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met

65 70 75 80

Asn Ser Leu Lys Pro Glu Asp Thr Ala Ile Tyr Tyr Cys Ala Ala Arg

85 90 95

Gln Asp Arg Ser Gly Ala Ser Met Val Asn Arg Asp Ser Tyr Asn Tyr

100 105 110

Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 243

<211> 129

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65182 sdAb

<400> 243

Gln Val Lys Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Tyr Gly

20 25 30

Tyr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Lys Ile Tyr Asn Gly Asp Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Gln Asp Arg Arg Asn Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Ala Pro Glu Asp Thr Gly Met Tyr Tyr Cys

85 90 95

Ala Thr Asn Arg Leu Pro Asn Ser Asp Val Asp Leu Val Leu Pro Arg

100 105 110

Phe Gly Arg Phe Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser

115 120 125

Ser

<210> 244

<211> 128

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 sdAb

<400> 244

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Val Tyr Asn Asn Met

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Ser Met Tyr Val Gly Gly Gly Tyr Thr Tyr Tyr Asp Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ala Ile Ser Ile Ala Leu Thr Arg Glu Phe Cys Ala Pro Ile Val

100 105 110

Ser Arg Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 245

<211> 128

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 sdAb

<400> 245

Gln Val Lys Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Val Tyr Asn Asn Met

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn Tyr Ala Asp Ser Val

50 55 60

Arg Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ala Ile Thr Val Ala Leu Thr Arg Ala Phe Cys Ala Pro Ile Pro

100 105 110

Ser Arg Tyr Thr Asn Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 246

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60705 sdAb

<400> 246

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ser Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ala Tyr Ser Gly Ser

20 25 30

Cys Met Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly

35 40 45

Val Ala Val Ser Val Arg Arg Thr Gly Ser Ala Phe Tyr Ala Asp Ser

50 55 60

Val Lys Ala Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu

65 70 75 80

Tyr Leu Gln Met Asn Asn Leu Lys Val Glu Asp Thr Ala Met Tyr Tyr

85 90 95

Cys Ala Ala Asp Phe Thr Cys Arg Thr Trp Thr Leu Asn Lys Asn Tyr

100 105 110

Asn His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 247

<211> 116

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60660 sdAb

<400> 247

Gln Val His Leu Met Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Asp Thr Gly Tyr Gln Pro

20 25 30

Thr Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe Val

35 40 45

Ser Ala Ile Tyr Ser Asp Gln Thr Thr Ser Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Arg Lys Thr Val Tyr Leu

65 70 75 80

Gln Met Ala Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys

85 90 95

Leu Thr Thr Arg Arg Gly Ser Glu Tyr Trp Gly Gln Gly Thr Gln Val

100 105 110

Thr Val Ser Ser

115

<210> 248

<211> 121

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60662 sdAb

<400> 248

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Tyr Arg Asn Cys Arg Ser

20 25 30

Thr Met Arg Trp Tyr Arg Gln Gly Pro Gly Gln Val Arg Asp Trp Val

35 40 45

Ser Ser Ile Tyr Thr Asp Gly Thr Thr Ser Tyr Thr Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ala Gln Asp Lys Gly Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Gln Pro Glu Asp Thr Ala Met Tyr Tyr Cys Arg

85 90 95

Ile Asp Leu Val Gly Cys Asn Val Ala Gly Gly Ser Pro Tyr Trp Gly

100 105 110

His Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 249

<211> 126

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60664 sdAb

<400> 249

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Lys Thr Tyr Gly Arg Cys

20 25 30

Met Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Leu Val Ala

35 40 45

Ala Thr Tyr Ile Ser Gly Gly Arg Pro Tyr Val Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Ser Thr Met Ser Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Pro Asp Asp Ser Ala Met Tyr Tyr Cys Ala

85 90 95

Ala Gly Ser Ala Gly Arg Gly Pro Cys Asp Arg Phe Asp Gln Asn Gln

100 105 110

Tyr Thr Phe Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 250

<211> 126

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60668 sdAb

<400> 250

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asp Met Asn Gly Tyr Lys

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Ala Val

35 40 45

Ala Gly Ile Tyr Thr Gly Arg Asn Thr Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Asp Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Val Phe

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ser Lys Tyr Cys Ala Val Val Ala Glu Phe Gly Gly Pro Arg Leu

100 105 110

Val Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 251

<211> 120

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 sdAb

<400> 251

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Val Ser Ser Gly

20 25 30

Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Gln Ile Gly Arg Asp Ala Thr Thr Thr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ala Arg Asp Asp Ala Glu Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Ser Cys Thr

85 90 95

Ala Tyr Trp Gly Val Tyr Cys Leu Ser Pro Gly Arg Tyr Trp Gly Gln

100 105 110

Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 252

<211> 124

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60678 sdAb

<400> 252

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Thr Ser Ser Arg Gly

20 25 30

Cys Met Ser Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Arg Val

35 40 45

Ala Tyr Ile Asn Met Arg Val Leu Thr Thr Ile Tyr Ala Ala Ser Val

50 55 60

Lys Asp Arg Phe Ala Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Asp

65 70 75 80

Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Ala Gly Tyr Asn Gly Gln Trp Cys Glu His Ala Ser Asp Val Thr

100 105 110

Ala Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 253

<211> 116

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60679 sdAb

<400> 253

Gln Val His Leu Met Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Arg Ser Gly Val Thr Tyr Cys Arg Leu

20 25 30

Thr Met Arg Trp Tyr Arg Gln Ala Pro Gly Ser Glu Arg Glu Phe Val

35 40 45

Ser Ala Ile Tyr Ser Asp Gly Ser Thr Ala Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Met Ser Gln Asp Asp Ala Lys Asn Thr Val Tyr Leu

65 70 75 80

Gln Met Asn Ser Val Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys Lys

85 90 95

Leu Asn Cys Ala Ser Gly Leu Thr Ala Trp Gly Gln Gly Thr Gln Val

100 105 110

Thr Val Ser Ser

115

<210> 254

<211> 124

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81326 sdAb

<400> 254

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Thr Leu Ser Cys Ala Ala Ser Glu Ser Arg Asp Cys Met Ala

20 25 30

Trp Phe Arg Gln Ala Pro Gly Lys Ala Arg Glu Gly Val Ala Ser Ile

35 40 45

Tyr Ala Pro Asp Gly Ser Thr Thr Tyr Ala Asp Thr Val Lys Gly Arg

50 55 60

Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met

65 70 75 80

Asn Ser Leu Gln Pro Glu Asp Ala Ala Met Tyr His Cys Ala Ile Gly

85 90 95

Gly Leu Ser Arg Asn Thr Cys Gly Tyr Leu Arg Gly Gly Tyr Phe Ala

100 105 110

Tyr Phe Gly Arg Gly Thr Gln Val Thr Val Ser Ser

115 120

<210> 255

<211> 130

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81187 sdAb

<400> 255

Gln Val Arg Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Tyr Ser Ser Tyr

20 25 30

Ser Ser Asn Cys Leu Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg

35 40 45

Glu Ala Val Ala Arg Ile Tyr Pro Asn Ser Gly Ser Thr Tyr Tyr Ala

50 55 60

Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys Asn

65 70 75 80

Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met

85 90 95

Tyr Tyr Cys Ala Val Ala Val Gly Val Gly Asp Asn Trp Cys Ala Ser

100 105 110

Gly Ala Ala Tyr Phe Gly Tyr Trp Gly Gln Gly Thr Gln Val Thr Val

115 120 125

Ser Ser

130

<210> 256

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533 sdAb

<400> 256

Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val Gln Thr Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Thr Ala Ser Gly Leu Ser Phe Ser Thr Tyr

20 25 30

Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val Tyr Thr Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Met Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu Ala Ile Asn Gly Tyr

100 105 110

Asn Arg Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 257

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444 sdAb

<400> 257

Glu Val Gln Leu Ala Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Asn

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val Tyr Ser Asp Ser Val

50 55 60

Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Thr Lys Asn Met Val Tyr

65 70 75 80

Leu Gln Met Asn Asn Leu Glu Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu Ala Val Asn Gly Tyr

100 105 110

Asn His Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 258

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81487 sdAb

<400> 258

Gln Val Arg Leu Val Glu Ser Gly Gly Gly Ser Val Gln Ala Gly Gly

1 5 10 15

Ser Leu Arg Val Ser Cys Leu Val Ser Lys Leu Thr Ala Trp Arg Ser

20 25 30

Cys Val Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly Val

35 40 45

Ala Ala Ile Tyr Ser Gly Thr Gly Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ala Gln Asp Tyr Ala Lys Asn Met Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Gly Thr Ser Ile Arg Ser Ser Cys Gly Leu Val Arg Asp Glu Tyr

100 105 110

Ala Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

115 120 125

<210> 259

<211> 735

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126 scFV

<400> 259

caggtgcagc tgaagcagtc tggggctgaa ctggcaaaac ctggggcctc agtggagatg 60

tcctgcaagg cttctggcta cacctttact agctactgga tgcactgggt aaaacagagg 120

cctggacagg gtctggaatg gattggatac attaatccta gtactggtca tactgactac 180

aatcagaagt tcaaggacaa ggccacattg actgcagaca aatcctccag cacagcctac 240

atgcaactga gcagcctgac atctgaggac tctgcagtct attactgtgc aagatccaac 300

tgggcctggt ttccttactg gggccaaggg actctggtca ctgtctcgag cggtggaggc 360

ggttcaggcg gaggtggctc tggcggtggc gggtcggaca ttgtgatgac tcagtctcca 420

tcctccctga ctgtgacagc aggagagaag gtcactatga gctgcaagtc cagtcagagt 480

ctgttaaaca gtggaaatca aaagaactac ttgacctggt accagcagaa accagggaag 540

cctcctaaac tgttgatcta ctgggcatcc actagggaat ctggggtccc tgatcgcttc 600

acaggcagtg gatctggaac agatttcact ctcaccatca gcagtgtgca ggctgaagac 660

ctggcagttt attactgtca gaatgattat agttatccgc tcacgttcgg ttctgggacc 720

agactggaaa taaaa 735

<210> 260

<211> 735

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126VH3VL1 scFV

<400> 260

caggtgcagc tggtgcagtc cggagcagag gtgaagaagc caggagccag cgtgaaggtg 60

tcctgcaagg cctctggcta caccttcaca agctattgga tgcactgggt gaagcaggca 120

ccaggacagg gactggagtg gatcggctac atcaatccct ccacaggcca caccgactat 180

aaccagaagt ttaaggatcg ggccaccctg acagccgaca cctctacaag caccgtgtac 240

atggagctga gctccctgag gtccgaggat acagccgtgt actattgcgc ccgctctaat 300

tgggcctggt tcccctattg gggccagggc acactggtga ccgtgtctag cggaggagga 360

ggatccggag gaggaggatc tggcggcggc ggcagcgata tcgtgatgac acagtcccct 420

gactctctgg ccgtgtctct gggagagagg gcaaccatca actgtaagtc ctctcagagc 480

ctgctgaact ccggcaatca gaagaactac ctgacctggt atcagcagaa gcctggccag 540

ccccctaagc tgctgatcta ctgggcatct acaagggaga gcggagtgcc agatagattc 600

tccggctctg gcagcggcac cgactttaca ctgaccatca gctccctgca ggccgaggat 660

gtggccgtgt actattgtca gaatgactac agctatcccc tgacatttgg cggcggcacc 720

aagctggaga tcaag 735

<210> 261

<211> 720

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58116 scFV

<400> 261

caggtgcagc tgaaggagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata 60

tcctgcaaga cttctggata cacattcact gaatacacca tgaactgggt gaggcagagc 120

catggaaaga gccttgagtg gattggaggt attattccta acaatggtga tactagctac 180

aaccagaagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240

atggaactcc gcagcctgac atctgaggat tctgcagtct attactgtgc agggcggttt 300

gcttactggg gccaagggac tctggtcact gtctcgagcg gtggaggcgg ttcaggcgga 360

ggtggctctg gcggtggcgg gtcggatatt gtgatgaccc aggctccact cactttgtcg 420

gttaccattg gacaaccagc ctccatctct tgcaagtcaa gtcagagcct cttagatagt 480

gatggaaaga catatttgaa ttggttctta cagaggccag gccagtctcc aaagcgccta 540

atctatctgg tgtctaaact ggactctgga gtccctgaca ggttcactgg cagtggatca 600

gggacagatt tcacactgaa aatcagcaga gtggaggctg aggatttggg agtttattat 660

tgctggcaag gtacacattt tccattcacg ttcggctcgg gcacaaagtt ggaaataaaa 720

<210> 262

<211> 726

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58117 scFV

<400> 262

caggtccagc tgcagcagtc tggacctgag ctgaagaagc ctggagagac cgtcaagatc 60

tcctgcaagg cttcttttta taccttcaca gcctattcaa tgcactgggt gaagcaggct 120

ccaggaaagg gtttaaagtg gatgggctgg ataaacactg agactggtga gccaacatat 180

gcagatgact tcaagggacg gtttgccttc tctttggaaa cctctgccac cactgcctat 240

ttgcagatca acaacctcaa aaatgaggac acggctacat ttttctgtgc taggggacta 300

cggcggtttg cttactgggg ccaggggact ctggtcactg tctcgagcgg tggaggcggt 360

tcaggcggag gtggctctgg cggtggcggg tcggacattg tgatgacaca gtctccaact 420

tctttggctg tgtctctagg gcagagggcc accatatcct gcagagccag tgaaagtgtt 480

gatagttatg gcaatagttt tatgaattgg taccagcaga aaccaggaca gccacccaaa 540

ctcctcatct atcttgcatc ctacctagaa tctggggtcc ctgccaggtt cagtggcagt 600

gggtctagga cagacttcac cctcaccatt gatcctgtgg aggctgatga tgctgcaacc 660

tattactgtc agcaaaataa tgaggatccg tacacgttcg gaggggggac cagactggaa 720

ataaaa 726

<210> 263

<211> 732

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58127 scFV

<400> 263

caggttcagc tgcagcagtc tggggctgaa ctggtgaggc ctggggcttc agtgacgctg 60

tcctgcaagg cttcgggcta cacatttact gactatgaaa ttcactgggt gaagcagaca 120

cctgtgcatg gcctggaatg gattggaggt attgatcctg aaactggtgg tgctgcctac 180

actcagaagt tcaagggcaa ggccacactg actgcagaca aatcctccag cacagcctac 240

atggagctcc gcagcctgac atctgaggac tctgccgtct attactgtac aacttatggt 300

aactaccccc ttgactcctg gggccaaggc accactctca cagtctcgag cggtggaggc 360

ggttcaggcg gaggtggctc tggcggtggc gggtcgggta ttgtgatgac ccagactcca 420

ctctccctgc ctgtcagtct tggagatcaa gcctccatct cttgcagatc tagtcagagc 480

cttgtacaca gtaatggaaa cacctattta cattggtacc tgcagaagcc aggccagtct 540

ccaaagctcc tgatctacaa agtttccaac cgattttctg gggtcccaga caggttcagt 600

ggcagtggat cagggacaga tttcacactc aagatcagca gagtggaggc tgaggatctg 660

ggagtttatt tctgctctca aagtacacat gttccgctca cgttcggtgc tgggaccaga 720

ctggaaataa aa 732

<210> 264

<211> 732

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58143 scFV

<400> 264

caggtgcaac tgaagcagtc tggggctgaa ctggtgaggc ctggggcttc agtgacgctg 60

tcctgcaagg cttcgggcta cacatttact gactatgaaa tgcactgggt gaagcagaca 120

cctgtgcatg gcctggaatg gatcggaggt attgatcctg aaactggtgg tgctgcctac 180

actcagaagt tcaagggcaa ggccacaccg actgcagaca aatcctccag cacagcctac 240

atggagctcc gcagcctgac atctgaggac tctgccgtct attactgtac aacttatggt 300

aactaccccc ttgactcctg gggccaaggc accacggtca ccgtctcgag cggtggaggc 360

ggttcaggcg gaggtggctc tggcggtggc gggtcggata tccagatgac acagactcca 420

ctctccctgc ctgtcagtct tggagatcaa gcctccatct cttgcagatc tagtcagagc 480

cttgtacaca gtaatggaaa cacctattta cattggtacc tgcagaagcc aggccagtct 540

ccaaagctcc tgatctacaa agtttccaac cgattttctg gggtcccaga caggttcagt 600

ggcagtggat cagggacaga tttcacactc aagatcagcg gagtggaggc tgaggatctg 660

ggagtttatt tctgctctca aagtacacat gttccgctca cgttcggtgc tgggaccaag 720

ctggagctga aa 732

<210> 265

<211> 723

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58159 scFV

<400> 265

caggtgcaac tgaagcagtc tggagctgag ctggtaaggc ctgggacttc agtgaagata 60

tcctgcaagg cttctggcta caccatcact aactactggc taggttgggt aaagcagagg 120

ccaggacatg gacttgagtg gattggagat atttaccctg gaggtggtta tactaactac 180

aatgagaagt tcaagggcaa ggccacactg actgcagaca catcctccat cactgcctac 240

atgcagctca gtagcctgac atctgaggac tctgctgtct atttctgtgc aagaggcggt 300

agtagctact ggtacttcga tgtctggggc gcagggacct cagtcaccgt ctcgagcggt 360

ggaggcggtt caggcggagg tggctctggc ggtggcgggt cggatatcca gatgacacag 420

actacatcct ccctgtctgc ctctctggga gacagagtca ccatcagttg cagtgcaagt 480

caggacatta gcaattattt aaactggtat cagcagaaac cagatggaac tgttaaactc 540

ctgatctatt acacatcaag tttacactca ggagtcccat caaggttcag tggcagtggg 600

tctgggacag attattctct caccatcagc aacctggaac ctgaagatat tgccacttac 660

tattgtcagc agtatagtaa ggttccgtac acgttcggag gggggaccaa gctggagctg 720

aaa 723

<210> 266

<211> 720

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58115 scFV

<400> 266

caggtgcagc tgaagcagtc tggacctgag ctggtgaagc ctggggcttc agtgaagata 60

tcctgcaaga cttctggata cacattcact gaatacacca tgaactgggt gaagcagagc 120

catggaaaga gccttgagtg gattggagga attattccta acaatggtga tactagctac 180

aaacaggagt tcaagggcaa ggccacattg actgtagaca agtcctccag cacagcctac 240

atggagctcc gcagcctgac atctgacgat tctgcagtct attactgtgc agggcggttt 300

gcttactggg gccaagggac tctggtcact gtctcgagcg gtggaggcgg ttcaggcgga 360

ggtggctctg gcggtggcgg gtcggatatt gtgatgaccc agactccact cactttgtcg 420

gttaccattg gacaaccagc ctccatctct tgcaagtcaa gtcagagcct cttagatagt 480

gatggaaaga catatttgaa ttggttctta cagaggccag gccagtctcc aaagcgccta 540

atctatctgg tgtctaaact ggactctgga gtccctgaca ggttcactgg cagtggatca 600

gggacagatt tcacactgaa aatcagcaga gtggaggctg aggatttggg agtttattat 660

tgctggcaag gtacacattt tccattcacg ttcggctcgg gcacaaagtt ggaaataaaa 720

<210> 267

<211> 729

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58123 scFV

<400> 267

gaggtccagc tgcagcagtc aggacctggc ctggtggcac cctcacagag cctgtccatc 60

acatgcactg tctctgggtt ctcattatcc agatatagtg tacactgggt tcgccagcct 120

ccaggaaagg gtctggagtg gctgggaatg atatggggtg gtggaaacac agactataat 180

tcagctctca aatccagact gagcatcagc aaggacaact ccaagagcca agttttctta 240

aaaatgaaca gtctgcaaac tgatgacaca gccatgtact actgtgccag aagcctgggc 300

tggtacttcg atatctgggg cgcagggacc acggtcaccg tctcgagcgg tggaggcggt 360

tcaggcggag gtggctctgg cggtggcggg tcggacattg tgatgacaca gtcgccatca 420

tctctggctg tgtctgcagg agaaaaggtc actatgagct gtaagtccag tcaaagtgtt 480

ttatacagtt caaatcagaa gaactacttg gcctggtacc agcagaaacc agggcagtct 540

cctaaactgc tgatctactg ggcatccact agggaatctg gtgtccctga tcgcttcaca 600

ggcagtggat ctgggacaga ttttactctt accatcagca gtgtacaagc tgaagacctg 660

gcagtttatt actgtcatca atacctctcc tcgtggacgt tcggtggagg cacaaagctg 720

gaaatcaaa 729

<210> 268

<211> 735

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58145 scFV

<400> 268

gaggttcagc tgcaacagtc tggggctgaa ctggcaaaac ctggggcctc agtgaagatg 60

tcctgcaagg cttctggcta cacctttact agctactgga tgcactgggt aaaacagagg 120

cctggacagg gtctggaatg gattggatac attaatccta gcactggtta tactgactac 180

aatcagaagt tcaaggacaa ggccacattg actgcagaca aatcctccag cacagcctac 240

atgcaactga gcagcctgac atctgaggac tctgcagtct attactgtgc aagatccaac 300

tgggcctggt ttccttactg gggccaaggg actctggtca ctgtctcgag cggtggaggc 360

ggttcaggcg gaggtggctc tggcggtggc gggtcggaca tccagatgac acagtctcca 420

tcctccctga ctgtgacagc aggagagaag gtcactatga gctgcaagtc cagtcagagt 480

ctgttaaaca gtggaaatca aaagaactac ttgacctggt accagcagaa accagggcag 540

cctcctaaac tgttgatcta ctgggcatcc actagggaat ctggggtccc tgatcgcttc 600

acaggcagtg gatctggaac agatttcact ctcaccatca gcagtgtgca ggctgaagac 660

ctggcagttt attactgtca gaatgattat agttatccgc tcacgttcgg tgctgggacc 720

aagctggagc tgaaa 735

<210> 269

<211> 723

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489 scFV

<400> 269

gaggttcaac tggtggagag cggtggtggt ctggttcagc cgggtggtag cctgcgtctg 60

agctgcgcag cttctggctt caacctctat tattattcta tccactgggt gcgtcaggcg 120

ccgggtaaag gcctggaatg ggttgcatat atttcttctt cttctagcta tacttattat 180

gccgatagcg tcaagggccg tttcaccatc agcgcggata ccagcaaaaa caccgcatac 240

ctgcaaatga acagcctgcg tgcggaagat accgccgtct attattgtgc tcgctactac 300

ccgtactacg gtatggacta ctggggtcaa ggcaccctgg ttaccgtgag cagcggtgga 360

ggcggttcag gcggaggtgg ctctggcggt ggcgggtcgg acatccagat gacccagagc 420

ccgagcagcc tgagcgcgag cgttggtgac cgtgttacca ttacctgccg tgcgagccag 480

agcgttagca gcgcggtggc gtggtaccag caaaagccgg gtaaagcgcc gaagctgctg 540

atctatagcg cgagcagcct gtatagcggc gttccgagcc gtttcagcgg tagccgtagc 600

ggcaccgact ttaccctgac cattagcagc ctgcagccgg aagatttcgc aacttattac 660

tgtcagcaag gtttctctta ctacccgatc acgttcggac agggcaccaa agttgagatt 720

aaa 723

<210> 270

<211> 711

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51491 scFV

<400> 270

gaggttcaac tggtggagag cggtggtggt ctggttcagc cgggtggtag cctgcgtctg 60

agctgcgcag cttctggctt caacctctat tcttattcta tgcactgggt gcgtcaggcg 120

ccgggtaaag gcctggaatg ggttgcatat atttatcctt attctggctc tacttattat 180

gccgatagcg tcaagggccg tttcaccatc agcgcggata ccagcaaaaa caccgcatac 240

ctgcaaatga acagcctgcg tgcggaagat accgccgtct attattgtgc tcgcggttac 300

ggtatggact actggggtca aggcaccctg gttaccgtga gcagcggtgg aggcggttca 360

ggcggaggtg gctctggcgg tggcgggtcg gacatccaga tgacccagag cccgagcagc 420

ctgagcgcga gcgttggtga ccgtgttacc attacctgcc gtgcgagcca gagcgttagc 480

agcgcggtgg cgtggtacca gcaaaagccg ggtaaagcgc cgaagctgct gatctatagc 540

gcgagcagcc tgtatagcgg cgttccgagc cgtttcagcg gtagccgtag cggcaccgac 600

tttaccctga ccattagcag cctgcagccg gaagatttcg caacttatta ctgtcagcaa 660

tcttactact ggctgttcac gttcggacag ggcaccaaag ttgagattaa a 711

<210> 271

<211> 720

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110 scFV

<400> 271

gaggttcaac tggtggagag cggtggtggt ctggttcagc cgggtggtag cctgcgtctg 60

agctgcgcag cttctggctt caacatctat tattcttcta tgcactgggt gcgtcaggcg 120

ccgggtaaag gcctggaatg ggttgcatat atttatcctt attatagcta tacttattat 180

gccgatagcg tcaagggccg tttcaccatc agcgcggata ccagcaaaaa caccgcatac 240

ctgcaaatga acagcctgcg tgcggaagat accgccgtct attattgtgc tcgcggttac 300

gctttggact actggggtca aggcaccctg gttaccgtga gcagcggtgg aggcggttca 360

ggcggaggtg gctctggcgg tggcgggtcg gacatccaga tgacccagag cccgagcagc 420

ctgagcgcga gcgttggtga ccgtgttacc attacctgcc gtgcgagcca gagcgttagc 480

agcgcggtgg cgtggtacca gcaaaagccg ggtaaagcgc cgaagctgct gatctatagc 540

gcgagcagcc tgtatagcgg cgttccgagc cgtttcagcg gtagccgtag cggcaccgac 600

tttaccctga ccattagcag cctgcagccg gaagatttcg caacttatta ctgtcagcaa 660

gcttcttctg gttaccatta cctgatcacg ttcggacagg gcaccaaagt tgagattaaa 720

<210> 272

<211> 714

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156 scFV

<400> 272

gaggttcaac tggtggagag cggtggtggt ctggttcagc cgggtggtag cctgcgtctg 60

agctgcgcag cttctggctt caacatctat tcttcttcta tccactgggt gcgtcaggcg 120

ccgggtaaag gcctggaatg ggttgcatct atttcttctt attctagcta tacttcttat 180

gccgatagcg tcaagggccg tttcaccatc agcgcggata ccagcaaaaa caccgcatac 240

ctgcaaatga acagcctgcg tgcggaagat accgccgtct attattgtgc tcgctactac 300

gctatggact actggggtca aggcaccctg gttaccgtga gcagcggtgg aggcggttca 360

ggcggaggtg gctctggcgg tggcgggtcg gacatccaga tgacccagag cccgagcagc 420

ctgagcgcga gcgttggtga ccgtgttacc attacctgcc gtgcgagcca gagcgttagc 480

agcgcggtgg cgtggtacca gcaaaagccg ggtaaagcgc cgaagctgct gatctatagc 540

gcgagcagcc tgtatagcgg cgttccgagc cgtttcagcg gtagccgtag cggcaccgac 600

tttaccctga ccattagcag cctgcagccg gaagatttcg caacttatta ctgtcagcaa 660

ggtccgtact accatccgat cacgttcgga cagggcacca aagttgagat taaa 714

<210> 273

<211> 714

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189 scFV

<400> 273

gaggttcaac tggtggagag cggtggtggt ctggttcagc cgggtggtag cctgcgtctg 60

agctgcgcag cttctggctt caacctctct tattcttcta tccactgggt gcgtcaggcg 120

ccgggtaaag gcctggaatg ggttgcatct atttattctt attctggctc tacttattat 180

gccgatagcg tcaagggccg tttcaccatc agcgcggata ccagcaaaaa caccgcatac 240

ctgcaaatga acagcctgcg tgcggaagat accgccgtct attattgtgc tcgctactgg 300

ggtatggact actggggtca aggcaccctg gttaccgtga gcagcggtgg aggcggttca 360

ggcggaggtg gctctggcgg tggcgggtcg gacatccaga tgacccagag cccgagcagc 420

ctgagcgcga gcgttggtga ccgtgttacc attacctgcc gtgcgagcca gagcgttagc 480

agcgcggtgg cgtggtacca gcaaaagccg ggtaaagcgc cgaagctgct gatctatagc 540

gcgagcagcc tgtatagcgg cgttccgagc cgtttcagcg gtagccgtag cggcaccgac 600

tttaccctga ccattagcag cctgcagccg gaagatttcg caacttatta ctgtcagcaa 660

tactactggt actacccgat cacgttcgga cagggcacca aagttgagat taaa 714

<210> 274

<211> 723

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674 scFV

<400> 274

gaggttcaac tggtggagag cggtggtggt ctggttcagc cgggtggtag cctgcgtctg 60

agctgcgcag cttctggctt caacctctat tcttattata tgcactgggt gcgtcaggcg 120

ccgggtaaag gcctggaatg ggttgcatct atttattctt attctagcta tacttcttat 180

gccgatagcg tcaagggccg tttcaccatc agcgcggata ccagcaaaaa caccgcatac 240

ctgcaaatga acagcctgcg tgcggaagat accgccgtct attattgtgc tcgcccgttc 300

ggttggggtt acgctggtat ggactactgg ggtcaaggca ccctggttac tgtgagcagc 360

ggtggaggcg gttcaggcgg aggtggctct ggcggtggcg ggtcggacat ccagatgacc 420

cagagcccga gcagcctgag cgcgagcgtt ggtgaccgtg ttaccattac ctgccgtgcg 480

agccagagcg ttagcagcgc ggtggcgtgg taccagcaaa agccgggtaa agcgccgaag 540

ctgctgatct atagcgcgag cagcctgtat agcggcgttc cgagccgttt cagcggtagc 600

cgtagcggca ccgactttac cctgaccatt agcagcctgc agccggaaga tttcgcaact 660

tattactgtc agcaaggtta cgctccgatc acgttcggac agggcaccaa agttgagatt 720

aaa 723

<210> 275

<211> 363

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66073 sdAb

<400> 275

caggttcagc tggtggagtc tgggggagac tcggtgcagg ctggggggtc tctgacactc 60

gcctgtacag ggcgtaaata cagcagtcta tactgcatgg cctggttccg ccaggctcca 120

gggaaggcgc gcgagggggt cgcagttatt agcagtggcg gcttcacaaa ttacgctgac 180

tccgtaaagg gccgattcac catctccaga gacaactcca agaacacgct gtatctggca 240

atgaacggcc tgaaacctga ggacactgcc atgtactact gtgcggcagg cctatcctat 300

tgccattcaa gcacagcaac cgccacgtac cggggccagg ggacccaggt caccgtctcc 360

tca 363

<210> 276

<211> 357

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66439 sdAb

<400> 276

cagatgcagc tggtggagtc tgggggaggc tcggtgcagg ctggggggtc tctgagactc 60

tcctgcacag cccctggatt cacctccagt gactgcgaca tggactggta ccgccaggct 120

gcagggaatc agcgcgaatg ggtctcatct cttcttagta ctgacggtag cacaagctat 180

gcggactccg tgaggggccg attcaccatc tccaaagacc cagccaagga cacggtgtat 240

ctgcaaatga acagcctgaa acctgaggac acggccatgt atttctgtag gtgtgtcgtg 300

gctgagtggg gcggcatgga ctactggggc aaaggaaccc tggtcaccgt ctcctca 357

<210> 277

<211> 381

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65955 sdAb

<400> 277

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggcga ccgcgtcagt actggctgta tgggctggtt ccgccagggt 120

ccaggcgagg agcgcgaggg gctcgcacaa attcacaatt ataatatcgc aaagtacgca 180

gactccgtga agggccgatt caccatctcc aaagacaacg ccaagaacat tctgtatctg 240

caaatgaaca gcctgaaacc tgaggacact ggcttgtaca tctgtacggc tcctgtagat 300

tgtagctgga gcatgtttct gcaagaccca cttgcgttgt ctccacctag gggccagggg 360

acccaggtca ccgtctcctc a 381

<210> 278

<211> 366

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 sdAb

<400> 278

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctgaatt cacgtacagt atgggctggt tccgccaggc tccagggaag 120

gagcgcgagg gcgtcgcaca tatttacact cgtggtggta ccacggtcta tgccgactcc 180

gtgaagggcc gattcgtcct ctcccgatac aacgccaaga gcataatgta tctacaaatg 240

aacagcgtga aacttgagga cactgccatg tattactgtg cggcccggac catattcgaa 300

ggtagctggt cgtccccatc ctcgtttgac ttctggggcc aggggaccca ggtcaccgtc 360

tcctca 366

<210> 279

<211> 393

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65926 sdAb

<400> 279

caggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggaaa cctctacaat aacatgtgca tgggctggtt ccggcaggct 120

ccagggaagg agcgcgaggg ggtcgcaagt atttatattg gtggtggtta caccaactat 180

gccgactccg tgaagggccg attcaccatc tcccccatct cccgagacaa cgccaagagc 240

acgctgtatc tgcaaatgaa cagcctgaaa cctgaggaca ctgccatgta ctactgtgcg 300

gcagtctcca tcgcgcttac gagggaattc tgcgccccga tcgtttctcg gtataattac 360

tggggccagg ggacccaggt caccgtctcc tca 393

<210> 280

<211> 384

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66159 sdAb

<400> 280

caggtgaggt tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcatgtgcag cctctggaaa cgtctacaat aacatgtgca tgggctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcgcaagt atctatgttg gtggtggtta caccaactat 180

gccgactccg tgaggggccg attcaccatc tcccaagaca acgccaagaa cacgctgtat 240

ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc ggcaattacc 300

gtcgcgctta cgagggcttt ctgcgccccg atcccttctc ggtataccaa ctggggccag 360

gggacccagg tcaccgtctc ctca 384

<210> 281

<211> 384

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS66416 sdAb

<400> 281

caggtgcagc tggcggagtc tgggggaggt tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggaaa cctctacaat aacatgtgca tgggctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcggaagt atttatattg gtggtggtta caccaactat 180

tccgaatccg tgaggggccg attcaccatc tccctagaca acgccaagaa gacgctgaat 240

ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc ggcaatcccc 300

atcgcgctta cgagggcttt ctgcgccccg atcgtttctc ggtatacgta ctggggccag 360

gggacccagg tcaccgtctc ctca 384

<210> 282

<211> 348

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65850 sdAb

<400> 282

gaggtgcagc tgatggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggatt ctcctacagt aacatctgta tgggctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcgcggct atttatagta atggtagcac aatctacgca 180

gactccgtga agggccgatt caccgtctcc aaagaattcg ccaagaacac tcagtatctg 240

caaatgaaca gcctgaaacc tgaggacact gccatgtact actgtgcggc aggccggtgt 300

gggggcccta actactgggg ccaggggacc caggtcaccg tctcctca 348

<210> 283

<211> 396

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65183 sdAb

<400> 283

gaggtgcaac tggcggagtc tgggggaggc tcggcgcagg ctggagggtc tctgagactc 60

tcctgtgcaa gcaatgggta ctacaaccgt cgctattgta tggcctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcgcgact atgactacta ctagtggtcg cacatactat 180

gccgacgccg tgaagggccg attcaccgtc tcccaagaca acgccaagtc cacgctgtat 240

ctgcaaatga gcagcctgaa acctgaggac actgccatgt actactgtgc ggcgcacctt 300

cccagttctt gggtgacgtc gactgattac tgcgacaact tgcaagccgg cttttataac 360

tcctggggcc aggggaccca ggtcaccgtc tcctca 396

<210> 284

<211> 348

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65062 sdAb

<400> 284

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggagt cagcgtggtt aacttcgcca tgaggtggta ccgccaggct 120

ccagggaacg agcgcgagtt cgtctcagcg atgtaccgtt ctggtagcac gtcttacgct 180

gactccgtga ggggccgatt caccatctcc cgagacagcg ccttgaacac ggtgtttctt 240

caaatgagcg gcctgaaacc tgaggacacg gccacgtatt actgtcaagc gacatcacct 300

atgggcgaca cctactgggg ccaggggacc caggtcaccg tctcctca 348

<210> 285

<211> 363

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65065 sdAb

<400> 285

gaggtgcaac tggcggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggata cagctactgt aggtccacca tgcgctggta ccgccaggct 120

ccagggaacg tgcgcgaatt tgtctcagct atctatagtg atggtaccac aagctacaca 180

gactccgtga agggccgatt caccatctcc caagacaacg ccaagaacac tgtgtatcta 240

caaatgaaca gcctgcaacc tgaagacacg gccatgtatt actgtcggat agatcttgtc 300

ggatgcaacg tagctggtgg cagtccttac tggggccagg ggacccaggt caccgtctcc 360

tca 363

<210> 286

<211> 345

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65556 sdAb

<400> 286

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ttggagggtc tctgagactc 60

tcctgtgcag cctctggata caacgcctct atctgccgca tgagctggta ccgccaggct 120

cccgggactg agcgcgagtt cgtctcatcg tcttacaggg atggtagcca aagctacgca 180

gactccgtga aggggcgatt caccacatcc cgagactccg ccaagaacac ggtgtttctg 240

caaatgaaca gcctgaaacc ttcggacacg gccatgtatt actgtaacgc agcttgcccc 300

tggcgggcct actggggcca ggggacccag gtcaccgtct cctca 345

<210> 287

<211> 348

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65069 sdAb

<400> 287

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgtag cctctggaga caccggctac caacctacga tgaggtggta ccgccaggct 120

ccagggaagg agcgcgagtt cgtctccgct atttatagtg atcagaccac aagctatgca 180

gactccgtga agggccggtt caccatctcc caagacaacg ccagaaaaac ggtgtatctg 240

caaatggcta gcctgaaacc tgaggacacg gccatgtatt actgtaaact cactactcgc 300

agggggtctg agtactgggg ccaggggaca caggtcaccg tctcctca 348

<210> 288

<211> 348

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65691 sdAb

<400> 288

cagatgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtacag tctctggata caccgactat aggctcgtac tgaggtggta ccgccaggct 120

ctagggaagg agcgcgagtt catctcagct atttatagtg atggagtcac aagctactca 180

gactccgtga agggccgatt caccatctcc cgagacaacg ccaagaacac ggcgtatctg 240

caaatgaaca gcctgaaatc tgaggacacg gccatgtatt actgtaaagc aaccgggtcc 300

ggtggcgttg cctactgggg ccagggaacc caggtcaccg tctcctca 348

<210> 289

<211> 402

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65064 sdAb

<400> 289

caggttcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgaaactc 60

tcctgtgcag tctctggaga caccgtccag actaactgta tggcctggtt ccgccaggct 120

ccagggaagg agcgcgaggc ggtcgccagc attttgagtc tttattctag tggaggtaag 180

acagtctatg ccgactccgt gaagggccga ttcaccatct ccccagacaa cgcccagaac 240

acggtgtcgc tgcaaatgaa caatttgaaa cctgaggaca ctgccatgta ctactgtgcg 300

actgtccgcg tgaccgtcac ttgggccgaa aagttgaggc gttgtaccgg attcagcggc 360

atggactact ggggcaaagg aaccctggtc accgtctcct ca 402

<210> 290

<211> 384

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65081 sdAb

<400> 290

caggtgcacc tgatggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggagt ccccgctagt agctactgca tgggctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcgcaggt attgtcagtg atactaccac aacctacgca 180

gactccgtga agggccgatt caccatctcc aaagacaacg ccaagaacac tctgtatctg 240

caaatgaaca gcctgaaacc tgaggacact gccacgtact actgtgcggc ctcccatttt 300

ctattgtgcg ccagaaaacc ccgctgggat gacctcatta aatatgagta ctggggccag 360

gggacccagg tcaccgtctc ctca 384

<210> 291

<211> 357

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65115 sdAb

<400> 291

caggttcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgcgactc 60

tcctgtgcag cctctggata catttacggc tgcatgggct ggttccgccg ggctccaggg 120

aaggcgcgcg aggaggttgc gactatttac cgcgatggta cagcatacta cgcaaactcc 180

gtagagggcc gattcaccgc ctccagaaac aacgccgaga acactctgtc tctggagatg 240

aacagtctga acgctgagga cactgccatg tactactgtg cggcaagaac aactggttgt 300

aactgggaca tatctggggt ttactggggc caggggaccc aggtcaccgt ctcctca 357

<210> 292

<211> 378

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65271 sdAb

<400> 292

cagatgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgacactc 60

tcctgtgcag cctctggaaa aacctacgga cgctgcatgg cctggttccg ccaggctcca 120

gggaaggagc gcgagttagt cgctgctact tatattagtg gtgggcgacc ctacgttgcc 180

gactccgtga agggccgatt caccatttcc cgggacaacg ccaagagtac gatgtctctg 240

caaatgaaca gcctgagacc tgacgacagc gccatgtact actgtgcggc gggttcggcg 300

ggtcggggac cttgtgatcg cttcgaccaa aatcaatata ccttctgggg ccaggggacc 360

caggtcaccg tctcctca 378

<210> 293

<211> 384

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65166 sdAb

<400> 293

caggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtacag cctctgaaga cttatctatt tacggttaca attgcatggg ctggttccgc 120

caggctccag ggaaggagcg cgaggcggtc gcagctattt atactggccg tggtaccaca 180

tactatgccg actccgtgaa gggccgattc accatctccc aagacaacgc caagaacact 240

gtgtatctgc aaatgaacag cctgaaacct gaggacactg ccatgtacta ctgtgcgtca 300

aaatactgtg cggtggtagc tgatttcggg aattctcgac tcgttcgtta ctggggccag 360

gggacccagg tcaccgtctc ctca 384

<210> 294

<211> 378

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65450 sdAb

<400> 294

caggtgaggt tagtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggaga catgaacggt tacaagtgca tggggtggtt ccgccaggct 120

ccagggaagg agcgcgaggc ggtcgcaggt atttatactg gccgtgggac cacatactat 180

gccgactccg tgaaggaccg attcaccatc tcccaagaca acgccaagaa cactgtgtat 240

ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc agcaaaatac 300

tgtgcggtgg tagctgaatt cgggggtcct cgactcgttc gttactgggg ccaggggacc 360

caggtcaccg tctcctca 378

<210> 295

<211> 378

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65454 sdAb

<400> 295

caggtgaggt tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactg 60

tcctgtgcag cctctggaga catgaacggt tacaagtgca tggggtggtt ccgccaggct 120

ccagggaagg agcgagaggc ggtcgcaggt atttatactg gccgtaatac tacatactat 180

gccgactccg tgaaggacct attcaccatc tcccaagaca acgcctagaa cactgtgttt 240

ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc gtcataatac 300

tgtgcggtgg tagctgaatt ccggggtcct cgactcgatc gttactgggg ctatgggacc 360

caggtcaccg tcacctca 378

<210> 296

<211> 369

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65131 sdAb

<400> 296

gaggtgcagc tggcggagtc tgggggaggc tcggtgcagg ctggagggtc tctgacactc 60

tcctgtacag cctctgaata cgtcacacac ttgggctggt tccgccaggc tccagggaag 120

gagcgcgagg gggtcgcaat cgaaagtttt cgtattggtt atacatacta tgccgactcc 180

gtgaagggtc gattcaccat ctcccacgac aacgccaaga acacgctgta tctgcaaatg 240

aacagcctga aacctgagga cactgccata tactactgtg cggctcggca ggaccgatcg 300

ggggcttcca tggtaaatcg agattcatat aattactggg gcaaggggac ccaggtcacc 360

gtctcctca 369

<210> 297

<211> 387

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65182 sdAb

<400> 297

caggtgaagt tagtggagtc agggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cgtctggata cacgtacagt tacggctaca tgggctggtt ccggcaggct 120

ccagggaagg agcgcgaggg ggtcgcaaag atttataatg gtgacggtag tacatactat 180

gccgactccg tgaagggccg attcaccatc tcccaagacc gccgcaacaa cacgctgtat 240

ctgcaaatga acagtctggc acctgaggac actggcatgt actactgtgc gacaaaccga 300

ctcccaaata gcgacgttga cttggtcctt ccccggttcg gccgttttgg ttactggggc 360

caggggaccc aggtcaccgt ctcctca 387

<210> 298

<211> 384

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 sdAb

<400> 298

caggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggtaa tgtctacaat aacatgtgca tgggctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcgcaagt atgtatgttg gtggtggtta cacctactat 180

gacgactccg tgaagggccg attcaccatc tcccgagaca acgccaagaa cacgctgtat 240

ctgcaaatga acagcctgaa acctgaagac actgccatgt actactgtgc ggcaatctcc 300

atcgcgctta cgagggaatt ctgcgccccg atcgtttctc ggtataatta ttggggccag 360

gggacccagg tcaccgtctc ctca 384

<210> 299

<211> 384

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 sdAb

<400> 299

caggtgaagt tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcatgtgcag cctctggaaa cgtctacaat aacatgtgca tgggctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcgcaagt atctatgttg gtggtggtta caccaactat 180

gccgactccg tgaggggccg attcaccatc tcccaagaca acgccaagaa cacgctgtat 240

ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc ggcaattacc 300

gtcgcgctta cgagggcttt ctgcgccccg atcccttctc ggtataccaa ctggggccag 360

gggacccagg tcaccgtctc ctca 384

<210> 300

<211> 375

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60705 sdAb

<400> 300

caggtgcagc tggtggagtc tgggggaggc tcggtgcagt ctggagggtc tctgagactc 60

tcctgtgcag cctctggata cgcctacagt gggtcttgca tgatggcctg gttccgccag 120

gctccaggga aggagcgcga gggggtcgca gttagcgttc gtcgtacggg aagcgcattc 180

tatgccgact ccgtgaaggc ccgattcacc atctcccgcg acaatgccaa gaacacgctg 240

tatctgcaaa tgaataacct gaaagttgag gacactgcca tgtactactg tgcggcagat 300

tttacttgtc gtacgtggac tctcaataaa aattacaacc actggggcca ggggacccag 360

gtcaccgtct cctca 375

<210> 301

<211> 348

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60660 sdAb

<400> 301

caggtgcacc tgatggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgtag cctctggaga caccggctac caacctacga tgaggtggta ccgccaggct 120

ccagggaagg agcgcgagtt cgtctccgct atttatagtg atcagaccac aagctatgca 180

gactccgtga agggccggtt caccatctcc caagacaacg ccagaaaaac ggtgtatctg 240

caaatggcta gcctgaaacc tgaggacacg gccatgtatt actgtaaact cactactcgc 300

agggggtctg agtactgggg ccaggggaca caggtcaccg tctcctca 348

<210> 302

<211> 363

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60662 sdAb

<400> 302

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgtag cctctggata caggaactgt aggtccacca tgcgctggta ccgccagggt 120

ccaggacagg tgcgagactg ggtctcaagt atctatactg atggtaccac aagctacaca 180

gactccgtga agggccgatt caccatcgcc caagacaaag gcaagaacac ggtgtatcta 240

caaatgaaca gcctgcaacc tgaagacacg gccatgtatt actgtcggat agatcttgtc 300

ggatgcaatg tagctggtgg cagtccttac tggggccatg ggacccaggt caccgtctcc 360

tca 363

<210> 303

<211> 378

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60664 sdAb

<400> 303

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgacactc 60

tcctgtgcag cctctggaaa aacctacgga cgctgcatgg cctggttccg ccaggctcca 120

gggaaggagc gcgagttagt cgctgctact tatattagtg gtgggcgacc ctacgttgcc 180

gactccgtga agggccgatt caccatttcc cgggacaacg ccaagagtac gatgtctctg 240

caaatgaaca gcctgagacc tgacgacagc gccatgtact actgtgcggc gggttcggcg 300

ggtcggggac cttgtgatcg cttcgaccaa aatcaatata ccttctgggg ccaggggacc 360

caggtcaccg tctcctca 378

<210> 304

<211> 378

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60668 sdAb

<400> 304

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactg 60

tcctgtgcag cctctggaga catgaacggt tacaagtgca tggggtggtt ccgccaggct 120

ccagggaagg agcgcgaggc ggtcgcaggt atttatactg gccgtaatac tacatactat 180

gccgactccg tgaaggaccg attcaccatc tcccaagaca acgccaagaa cactgtgttt 240

ctgcaaatga acagcctgaa acctgaggac actgccatgt actactgtgc gtcaaaatac 300

tgtgcggtgg tagctgaatt cgggggtcct cgactcgttc gttactgggg ccaggggacc 360

caggtcaccg tctcctca 378

<210> 305

<211> 360

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 sdAb

<400> 305

caggtgcagc tggtggagtc tgggggaggg tcggtgcagg ctggagggtc tctgagactc 60

tcctgcgcag cctctggata caccgtcagt agcggctgca tgggctggtt ccgccaggct 120

ccagggaagg agcgcgagcg ggtcgcacag attggtcgtg atgctaccac gacctacgca 180

gactccgtga agggccgatt caccatcgcc agagacgacg ccgagaacac tctgtatctg 240

caaatgaaca gcctgaaacc tgaagacact gccatgtaca gctgtacggc ctattggggt 300

gtatactgtt tatctccagg acgctactgg ggccagggga cccaggtcac cgtctcctca 360

<210> 306

<211> 372

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60678 sdAb

<400> 306

caggtgcacc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag tctctggata cacctccagt cgcggttgca tgagctggtt ccgccaggct 120

ccagggaagg agcgcgagag ggtcgcatac attaatatgc gtgtcctaac cacaatctat 180

gccgcctccg tgaaggaccg attcgccatc tccagagaca acgccaagaa cacggtggat 240

ctgcaaatga acaacctgaa acctgaggac actgccatgt actactgcgc ggcggggtac 300

aatggacaat ggtgcgaaca tgctagtgac gttactgcct ggggtcaggg gacccaggtc 360

accgtctcct ca 372

<210> 307

<211> 348

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60679 sdAb

<400> 307

caggtgcacc tgatggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcac gctctggagt cacctattgt aggttgacca tgaggtggta ccgccaggct 120

ccagggagcg agcgcgagtt cgtctccgct atttatagtg atggtagcac agcctacgca 180

gactccgtga agggtcgatt caccatgtcc caagacgacg ccaagaacac ggtgtatctg 240

caaatgaaca gcgtgaaacc tgaggacacg gccatgtatt attgtaaatt gaattgtgcg 300

tccggcttga ctgcctgggg ccaggggacc caggtcaccg tctcctca 348

<210> 308

<211> 372

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81326 sdAb

<400> 308

gaggtgcagc tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgacactc 60

tcctgtgcag cctccgagag tagggattgt atggcctggt tccgccaggc tccagggaag 120

gcgcgcgagg gggtcgcatc tatttatgct ccggatggta gcacaaccta tgccgacacc 180

gtgaagggcc gattcaccat ctcccaagac aacgccaaga acacgctgta tctgcaaatg 240

aacagcctgc aacctgagga cgctgccatg taccactgtg cgatcggggg gctgtcacgc 300

aatacttgtg gttacctcag aggcggatac tttgcttact ttggccgggg gacccaggtc 360

accgtctcct ca 372

<210> 309

<211> 390

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81187 sdAb

<400> 309

caggtgaggt tggtggagtc tgggggcggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggata cacctacagc agctacagta gcaactgcct gggctggttc 120

cgccaggctc cagggaagga gcgcgaggca gtcgcacgta tctatcctaa cagtggtagc 180

acatactatg ccgactccgt gaagggccgc ttcaccatct cccaagacaa cgccaagaac 240

acggtgtatc tacaaatgaa cagcctgaaa cctgaggaca ctgccatgta ctactgtgcg 300

gtagcagtgg gagtcggtga taattggtgt gcgtcagggg ccgcatactt tggttactgg 360

ggccagggga cccaggtcac cgtctcctca 390

<210> 310

<211> 375

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533 sdAb

<400> 310

caggtgcacc tggtggagtc tgggggaggc tcggtgcaga ctggagggtc tctaagactc 60

tcctgtacag cctctggact cagcttcagt acctacacgg tggcctggtt ccgccaggct 120

ccaggaaagg agcgcgaggg ggtcgcggct attccatata ctagtcaaca catggtctat 180

accgactccg tgaagggccg attcaccatc tcccgagaca acacaaagaa catggtgtat 240

ctgcaaatga acagcctgaa accggaggac accgccatgt actactgtgc gacagatcgg 300

cgccctggaa cgagtatgtt ggctataaat gggtataacc gctggggcca ggggacccag 360

gtcaccgtct cctca 375

<210> 311

<211> 375

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444 sdAb

<400> 311

gaggtgcagc tggcggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagactc 60

tcctgtgcag cctctggatt caccttcagt cgcaacacga tgggctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcgcggct attccatata ctagtactgg catagtctat 180

tccgactccg tgggcggccg attcaccatc tcccgagaca acacaaagaa catggtgtat 240

ctgcaaatga acaacctgga accggaggac actgccatgt actactgtgc gacagatcgg 300

cgccctggaa cgactatgtt ggcggtaaat gggtataacc actggggcca ggggacccag 360

gtcaccgtct cctca 375

<210> 312

<211> 375

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS81487 sdAb

<400> 312

caggtgaggt tggtggagtc tgggggaggc tcggtgcagg ctggagggtc tctgagagtc 60

tcctgtttag tctctaaact caccgcatgg cgcagctgcg tgggctggtt ccgccaggct 120

ccagggaagg agcgcgaggg ggtcgcagct atatattctg gtactggtag tacatactat 180

gccgactccg tgaagggccg attcaccatc gcccaagact acgccaagaa catggtgtac 240

ttgcaaatga acagcctgaa acctgaagac actgccatgt actactgtgc gggcacgtcg 300

atacgcagca gttgtggctt agtgcgcgat gaatacgcct actggggcca ggggacccag 360

gtcaccgtct cctca 375

<210> 313

<211> 239

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> SS1 scFv

<400> 313

Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Glu Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr

20 25 30

Thr Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile

35 40 45

Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser Tyr Asn Gln Lys Phe

50 55 60

Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr

65 70 75 80

Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys

85 90 95

Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp Tyr Trp Gly Gln Gly

100 105 110

Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

115 120 125

Ser Gly Gly Gly Gly Ser Asp Ile Glu Leu Thr Gln Ser Pro Ala Ile

130 135 140

Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met Thr Cys Ser Ala Ser

145 150 155 160

Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln Lys Ser Gly Thr Ser

165 170 175

Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu Ala Ser Gly Val Pro

180 185 190

Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile

195 200 205

Ser Ser Val Glu Ala Glu Asp Asp Ala Thr Tyr Tyr Cys Gln Gln Trp

210 215 220

Ser Gly Tyr Pro Leu Thr Phe Gly Ala Gly Thr Lys Leu Glu Ile

225 230 235

<210> 314

<211> 241

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> M5 scFv

<400> 314

Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Glu Lys Pro Gly Ala

1 5 10 15

Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr

20 25 30

Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met

35 40 45

Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn Tyr Ala Gln Lys Phe

50 55 60

Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser Ile Ser Thr Ala Tyr

65 70 75 80

Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Ser Gly Trp Asp Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr

100 105 110

Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly

115 120 125

Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro Ser

130 135 140

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

145 150 155 160

Ser Gln Ser Ile Arg Tyr Tyr Leu Ser Trp Tyr Gln Gln Lys Pro Gly

165 170 175

Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser Ile Leu Gln Asn Gly

180 185 190

Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu

195 200 205

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Leu

210 215 220

Gln Thr Tyr Thr Thr Pro Asp Phe Gly Pro Gly Thr Lys Val Glu Ile

225 230 235 240

Lys

<210> 315

<211> 622

<212> PRT

<213> Intelligent (Homo sapiens)

<400> 315

Met Ala Leu Pro Thr Ala Arg Pro Leu Leu Gly Ser Cys Gly Thr Pro

1 5 10 15

Ala Leu Gly Ser Leu Leu Phe Leu Leu Phe Ser Leu Gly Trp Val Gln

20 25 30

Pro Ser Arg Thr Leu Ala Gly Glu Thr Gly Gln Glu Ala Ala Pro Leu

35 40 45

Asp Gly Val Leu Ala Asn Pro Pro Asn Ile Ser Ser Leu Ser Pro Arg

50 55 60

Gln Leu Leu Gly Phe Pro Cys Ala Glu Val Ser Gly Leu Ser Thr Glu

65 70 75 80

Arg Val Arg Glu Leu Ala Val Ala Leu Ala Gln Lys Asn Val Lys Leu

85 90 95

Ser Thr Glu Gln Leu Arg Cys Leu Ala His Arg Leu Ser Glu Pro Pro

100 105 110

Glu Asp Leu Asp Ala Leu Pro Leu Asp Leu Leu Leu Phe Leu Asn Pro

115 120 125

Asp Ala Phe Ser Gly Pro Gln Ala Cys Thr Arg Phe Phe Ser Arg Ile

130 135 140

Thr Lys Ala Asn Val Asp Leu Leu Pro Arg Gly Ala Pro Glu Arg Gln

145 150 155 160

Arg Leu Leu Pro Ala Ala Leu Ala Cys Trp Gly Val Arg Gly Ser Leu

165 170 175

Leu Ser Glu Ala Asp Val Arg Ala Leu Gly Gly Leu Ala Cys Asp Leu

180 185 190

Pro Gly Arg Phe Val Ala Glu Ser Ala Glu Val Leu Leu Pro Arg Leu

195 200 205

Val Ser Cys Pro Gly Pro Leu Asp Gln Asp Gln Gln Glu Ala Ala Arg

210 215 220

Ala Ala Leu Gln Gly Gly Gly Pro Pro Tyr Gly Pro Pro Ser Thr Trp

225 230 235 240

Ser Val Ser Thr Met Asp Ala Leu Arg Gly Leu Leu Pro Val Leu Gly

245 250 255

Gln Pro Ile Ile Arg Ser Ile Pro Gln Gly Ile Val Ala Ala Trp Arg

260 265 270

Gln Arg Ser Ser Arg Asp Pro Ser Trp Arg Gln Pro Glu Arg Thr Ile

275 280 285

Leu Arg Pro Arg Phe Arg Arg Glu Val Glu Lys Thr Ala Cys Pro Ser

290 295 300

Gly Lys Lys Ala Arg Glu Ile Asp Glu Ser Leu Ile Phe Tyr Lys Lys

305 310 315 320

Trp Glu Leu Glu Ala Cys Val Asp Ala Ala Leu Leu Ala Thr Gln Met

325 330 335

Asp Arg Val Asn Ala Ile Pro Phe Thr Tyr Glu Gln Leu Asp Val Leu

340 345 350

Lys His Lys Leu Asp Glu Leu Tyr Pro Gln Gly Tyr Pro Glu Ser Val

355 360 365

Ile Gln His Leu Gly Tyr Leu Phe Leu Lys Met Ser Pro Glu Asp Ile

370 375 380

Arg Lys Trp Asn Val Thr Ser Leu Glu Thr Leu Lys Ala Leu Leu Glu

385 390 395 400

Val Asn Lys Gly His Glu Met Ser Pro Gln Val Ala Thr Leu Ile Asp

405 410 415

Arg Phe Val Lys Gly Arg Gly Gln Leu Asp Lys Asp Thr Leu Asp Thr

420 425 430

Leu Thr Ala Phe Tyr Pro Gly Tyr Leu Cys Ser Leu Ser Pro Glu Glu

435 440 445

Leu Ser Ser Val Pro Pro Ser Ser Ile Trp Ala Val Arg Pro Gln Asp

450 455 460

Leu Asp Thr Cys Asp Pro Arg Gln Leu Asp Val Leu Tyr Pro Lys Ala

465 470 475 480

Arg Leu Ala Phe Gln Asn Met Asn Gly Ser Glu Tyr Phe Val Lys Ile

485 490 495

Gln Ser Phe Leu Gly Gly Ala Pro Thr Glu Asp Leu Lys Ala Leu Ser

500 505 510

Gln Gln Asn Val Ser Met Asp Leu Ala Thr Phe Met Lys Leu Arg Thr

515 520 525

Asp Ala Val Leu Pro Leu Thr Val Ala Glu Val Gln Lys Leu Leu Gly

530 535 540

Pro His Val Glu Gly Leu Lys Ala Glu Glu Arg His Arg Pro Val Arg

545 550 555 560

Asp Trp Ile Leu Arg Gln Arg Gln Asp Asp Leu Asp Thr Leu Gly Leu

565 570 575

Gly Leu Gln Gly Gly Ile Pro Asn Gly Tyr Leu Val Leu Asp Leu Ser

580 585 590

Met Gln Glu Ala Leu Ser Gly Thr Pro Cys Leu Leu Gly Pro Gly Pro

595 600 605

Val Leu Thr Val Leu Ala Leu Leu Leu Ala Ser Thr Leu Ala

610 615 620

<210> 316

<211> 623

<212> PRT

<213> Cynomolgus monkey (Cynomolgus)

<400> 316

Met Ala Leu Pro Met Ala Arg Pro Leu Ser Gly Ser Cys Gly Thr Pro

1 5 10 15

Ala Leu Gly Ser Leu Leu Phe Leu Leu Phe Ser Leu Gly Trp Val Gln

20 25 30

Pro Ser Arg Val Leu Ala Gly Glu Thr Arg Gln Val Arg Ser Pro Leu

35 40 45

Gly Lys Pro Gly Arg Val Phe Ser Leu Ser Pro Arg Gln Leu Leu Gly

50 55 60

Phe Thr Cys Val Glu Val Ser Gly Leu Ser Thr Glu Leu Val Gln Glu

65 70 75 80

Leu Ala Val Ala Leu Gly Gln Lys Asn Val Lys Leu Ser Ala Glu Gln

85 90 95

Leu Arg Cys Leu Ala His Gln Leu Ser Glu Pro Pro Glu Asp Leu Asp

100 105 110

Ala Leu Pro Leu Asp Leu Leu Leu Phe Leu Asn Pro Asp Ala Phe Ser

115 120 125

Gly Pro Gln Ala Cys Thr His Phe Phe Ser Arg Val Ala Lys Ala Asn

130 135 140

Val Asp Leu Leu Pro Arg Gly Ala Pro Glu Arg Gln Arg Leu Leu Pro

145 150 155 160

Ala Ala Leu Thr Cys Trp Gly Val Arg Gly Ser Leu Leu Ser Glu Ala

165 170 175

Asp Val Arg Ala Leu Gly Gly Leu Ala Cys Asp Leu Pro Gly Arg Phe

180 185 190

Val Ala Glu Ser Ala Glu Val Val Leu Pro Arg Leu Val Arg Cys Leu

195 200 205

Gly Pro Leu Asp Gln Asp Gln Gln Glu Ala Ala Arg Ala Ala Leu Gln

210 215 220

Arg Gly Gly Pro Pro Tyr Gly Pro Pro Ser Thr Trp Ser Ile Ser Thr

225 230 235 240

Leu Asp Asp Leu Gln Ser Leu Leu Pro Val Leu Gly Gln Pro Val Ile

245 250 255

His Ser Ile Pro Gln Gly Ile Leu Ala Ala Trp Arg Gln Arg Ser Ser

260 265 270

Arg Asp Pro Ser Trp Gln Gln Pro Glu Gln Thr Val Leu Arg Pro Arg

275 280 285

Phe Arg Arg Asp Val Glu Arg Thr Thr Cys Pro Pro Glu Lys Glu Val

290 295 300

His Glu Ile Asp Glu Ser Leu Ile Phe Tyr Lys Lys Arg Glu Leu Glu

305 310 315 320

Ala Cys Val Asp Pro Ala Leu Leu Ala Ala Gln Met Asp Arg Val Asp

325 330 335

Ala Ile Pro Phe Thr Tyr Glu Gln Leu Asp Val Leu Lys His Lys Leu

340 345 350

Asp Glu Leu Tyr Pro Gln Gly Tyr Pro Glu Ser Val Ile Arg His Leu

355 360 365

Gly His Leu Phe Leu Lys Met Ser Pro Glu Asp Ile Arg Lys Trp Asn

370 375 380

Val Thr Ser Leu Glu Thr Leu Lys Ala Leu Leu Lys Val Ser Lys Gly

385 390 395 400

His Glu Met Ser Ala Gln Trp Pro Val Pro Gln Val Ala Thr Leu Ile

405 410 415

Asp Arg Val Val Val Gly Arg Gly Gln Leu Asp Lys Asp Thr Val Asp

420 425 430

Thr Leu Thr Ala Phe Cys Pro Gly Cys Leu Cys Ser Leu Ser Pro Glu

435 440 445

Arg Leu Ser Ser Val Pro Pro Ser Val Ile Gly Ala Val Arg Pro Gln

450 455 460

Asp Leu Asp Thr Cys Gly Pro Arg Gln Leu Asp Val Leu Tyr Pro Lys

465 470 475 480

Ala Arg Leu Ala Phe Gln Asn Met Ser Gly Ser Glu Tyr Phe Val Lys

485 490 495

Ile Arg Pro Phe Leu Gly Gly Ala Pro Thr Glu Asp Val Lys Ala Leu

500 505 510

Ser Gln Gln Asn Val Ser Met Asp Leu Ala Thr Phe Met Lys Leu Arg

515 520 525

Arg Glu Ala Val Leu Pro Leu Thr Val Ala Glu Val Gln Lys Leu Leu

530 535 540

Gly Pro His Val Glu Gly Leu Lys Val Glu Glu Gln His Ser Pro Val

545 550 555 560

Arg Asp Trp Ile Leu Lys Gln Arg Gln Asp Asp Leu Asp Thr Leu Gly

565 570 575

Leu Gly Leu Gln Gly Gly Ile Pro Asn Gly Tyr Leu Ile Leu Asp Leu

580 585 590

Ser Val Arg Glu Ala Leu Ser Gly Thr Pro Cys Leu Leu Gly Pro Gly

595 600 605

Pro Val Leu Thr Val Leu Ala Leu Leu Leu Ala Ser Thr Leu Ala

610 615 620

<210> 317

<211> 295

<212> PRT

<213> Intelligent (Homo sapiens)

<400> 317

Met Ala Leu Pro Thr Ala Arg Pro Leu Leu Gly Ser Cys Gly Thr Pro

1 5 10 15

Ala Leu Gly Ser Leu Leu Phe Leu Leu Phe Ser Leu Gly Trp Val Gln

20 25 30

Pro Ser Arg Thr Leu Ala Gly Glu Thr Gly Gln Glu Ala Ala Pro Leu

35 40 45

Asp Gly Val Leu Ala Asn Pro Pro Asn Ile Ser Ser Leu Ser Pro Arg

50 55 60

Gln Leu Leu Gly Phe Pro Cys Ala Glu Val Ser Gly Leu Ser Thr Glu

65 70 75 80

Arg Val Arg Glu Leu Ala Val Ala Leu Ala Gln Lys Asn Val Lys Leu

85 90 95

Ser Thr Glu Gln Leu Arg Cys Leu Ala His Arg Leu Ser Glu Pro Pro

100 105 110

Glu Asp Leu Asp Ala Leu Pro Leu Asp Leu Leu Leu Phe Leu Asn Pro

115 120 125

Asp Ala Phe Ser Gly Pro Gln Ala Cys Thr Arg Phe Phe Ser Arg Ile

130 135 140

Thr Lys Ala Asn Val Asp Leu Leu Pro Arg Gly Ala Pro Glu Arg Gln

145 150 155 160

Arg Leu Leu Pro Ala Ala Leu Ala Cys Trp Gly Val Arg Gly Ser Leu

165 170 175

Leu Ser Glu Ala Asp Val Arg Ala Leu Gly Gly Leu Ala Cys Asp Leu

180 185 190

Pro Gly Arg Phe Val Ala Glu Ser Ala Glu Val Leu Leu Pro Arg Leu

195 200 205

Val Ser Cys Pro Gly Pro Leu Asp Gln Asp Gln Gln Glu Ala Ala Arg

210 215 220

Ala Ala Leu Gln Gly Gly Gly Pro Pro Tyr Gly Pro Pro Ser Thr Trp

225 230 235 240

Ser Val Ser Thr Met Asp Ala Leu Arg Gly Leu Leu Pro Val Leu Gly

245 250 255

Gln Pro Ile Ile Arg Ser Ile Pro Gln Gly Ile Val Ala Ala Trp Arg

260 265 270

Gln Arg Ser Ser Arg Asp Pro Ser Trp Arg Gln Pro Glu Arg Thr Ile

275 280 285

Leu Arg Pro Arg Phe Arg Arg

290 295

<210> 318

<211> 327

<212> PRT

<213> Intelligent (Homo sapiens)

<400> 318

Glu Val Glu Lys Thr Ala Cys Pro Ser Gly Lys Lys Ala Arg Glu Ile

1 5 10 15

Asp Glu Ser Leu Ile Phe Tyr Lys Lys Trp Glu Leu Glu Ala Cys Val

20 25 30

Asp Ala Ala Leu Leu Ala Thr Gln Met Asp Arg Val Asn Ala Ile Pro

35 40 45

Phe Thr Tyr Glu Gln Leu Asp Val Leu Lys His Lys Leu Asp Glu Leu

50 55 60

Tyr Pro Gln Gly Tyr Pro Glu Ser Val Ile Gln His Leu Gly Tyr Leu

65 70 75 80

Phe Leu Lys Met Ser Pro Glu Asp Ile Arg Lys Trp Asn Val Thr Ser

85 90 95

Leu Glu Thr Leu Lys Ala Leu Leu Glu Val Asn Lys Gly His Glu Met

100 105 110

Ser Pro Gln Val Ala Thr Leu Ile Asp Arg Phe Val Lys Gly Arg Gly

115 120 125

Gln Leu Asp Lys Asp Thr Leu Asp Thr Leu Thr Ala Phe Tyr Pro Gly

130 135 140

Tyr Leu Cys Ser Leu Ser Pro Glu Glu Leu Ser Ser Val Pro Pro Ser

145 150 155 160

Ser Ile Trp Ala Val Arg Pro Gln Asp Leu Asp Thr Cys Asp Pro Arg

165 170 175

Gln Leu Asp Val Leu Tyr Pro Lys Ala Arg Leu Ala Phe Gln Asn Met

180 185 190

Asn Gly Ser Glu Tyr Phe Val Lys Ile Gln Ser Phe Leu Gly Gly Ala

195 200 205

Pro Thr Glu Asp Leu Lys Ala Leu Ser Gln Gln Asn Val Ser Met Asp

210 215 220

Leu Ala Thr Phe Met Lys Leu Arg Thr Asp Ala Val Leu Pro Leu Thr

225 230 235 240

Val Ala Glu Val Gln Lys Leu Leu Gly Pro His Val Glu Gly Leu Lys

245 250 255

Ala Glu Glu Arg His Arg Pro Val Arg Asp Trp Ile Leu Arg Gln Arg

260 265 270

Gln Asp Asp Leu Asp Thr Leu Gly Leu Gly Leu Gln Gly Gly Ile Pro

275 280 285

Asn Gly Tyr Leu Val Leu Asp Leu Ser Met Gln Glu Ala Leu Ser Gly

290 295 300

Thr Pro Cys Leu Leu Gly Pro Gly Pro Val Leu Thr Val Leu Ala Leu

305 310 315 320

Leu Leu Ala Ser Thr Leu Ala

325

<210> 319

<211> 21

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSHβ 33-53

<400> 319

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe

<210> 320

<211> 16

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSHβ 51-65

<400> 320

Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg Val Pro Gly Cys

1 5 10 15

<210> 321

<211> 15

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSHβ 81-95

<400> 321

Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys Thr

1 5 10 15

<210> 322

<211> 26

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSHβ 87-94 + FSHβ 25-42

<400> 322

Cys Asp Ser Asp Ser Thr Asp Cys Ile Leu Gln Cys Met Gly Cys Cys

1 5 10 15

Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg

20 25

<210> 323

<211> 45

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSHβ 87-94 + FSHβ 25-42 + FSHβ 27-45

<400> 323

Cys Asp Ser Asp Ser Thr Asp Cys Ile Leu Gln Cys Met Gly Cys Cys

1 5 10 15

Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Trp Cys Ala Gly Tyr Cys

20 25 30

Tyr Cys Tyr Thr Arg Asp Val Lys Asp Pro Ala Arg Pro

35 40 45

<210> 324

<211> 19

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> anti-FSHR peptide 33-53

<400> 324

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys

<210> 325

<211> 15

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> anti-FSHR peptide 51-65

<400> 325

Lys Thr Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg Val

1 5 10 15

<210> 326

<211> 19

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> anti-FSHR peptide 81-95

<400> 326

Gly Ser Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys

1 5 10 15

Thr Ala Ser

<210> 327

<211> 30

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> anti-FSHR antagonist a

<400> 327

Gly Ser Cys Asp Ser Asp Ser Thr Asp Cys Ile Leu Gln Cys Met Gly

1 5 10 15

Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Ala Ser

20 25 30

<210> 328

<211> 30

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> anti-FSHR antagonist B

<400> 328

Gly Ser Arg Leu Pro Thr Pro Tyr Ala Arg Ser Phe Cys Cys Gly Met

1 5 10 15

Cys Gln Leu Ile Cys Asp Thr Ser Asp Ser Asp Cys Ala Ser

20 25 30

<210> 329

<211> 50

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> anti-FSHR agonist a

<400> 329

Gly Ser Cys Asp Ser Asp Ser Thr Asp Cys Ile Leu Gln Cys Met Gly

1 5 10 15

Cys Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Trp Cys Ala Gly

20 25 30

Tyr Cys Tyr Cys Tyr Thr Arg Asp Leu Val Lys Asp Pro Ala Arg Pro

35 40 45

Ala Ser

<210> 330

<211> 46

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> anti-FSHR agonist B

<400> 330

Pro Arg Ala Pro Asp Lys Val Leu Asp Arg Thr Tyr Cys Tyr Cys Tyr

1 5 10 15

Gly Ala Cys Trp Arg Leu Pro Thr Pro Tyr Ala Arg Ser Phe Cys Cys

20 25 30

Gly Met Cys Gln Leu Ile Cys Asp Thr Ser Asp Ser Asp Cys

35 40 45

<210> 331

<211> 207

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> anti-FSHR peptide alpha + beta

<400> 331

Gly Ser Asn Ser Cys Glu Leu Thr Asn Ile Thr Ile Ala Ile Glu Lys

1 5 10 15

Glu Glu Cys Arg Phe Cys Ile Ser Ile Asn Thr Thr Trp Cys Ala Gly

20 25 30

Tyr Cys Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys

35 40 45

Ile Gln Lys Thr Cys Thr Phe Lys Glu Leu Val Tyr Glu Thr Val Arg

50 55 60

Val Pro Gly Cys Ala His His Ala Asp Ser Leu Tyr Thr Tyr Pro Val

65 70 75 80

Ala Thr Gln Cys His Cys Gly Lys Cys Asp Ser Asp Ser Thr Asp Cys

85 90 95

Thr Val Arg Gly Leu Gly Pro Ser Tyr Cys Ser Phe Gly Glu Met Lys

100 105 110

Glu Ala Pro Asp Val Gln Asp Cys Pro Glu Cys Thr Leu Gln Glu Asn

115 120 125

Pro Phe Phe Ser Gln Pro Gly Ala Pro Ile Leu Gln Cys Met Gly Cys

130 135 140

Cys Phe Ser Arg Ala Tyr Pro Thr Pro Leu Arg Ser Lys Lys Thr Met

145 150 155 160

Leu Val Gln Lys Asn Val Thr Ser Glu Ser Thr Cys Cys Val Ala Lys

165 170 175

Ser Tyr Asn Arg Val Thr Val Met Gly Gly Phe Lys Val Glu Asn His

180 185 190

Thr Ala Cys His Cys Ser Thr Cys Tyr Tyr His Lys Ser Ala Ser

195 200 205

<210> 332

<211> 253

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> Fc fusion FSH beta 33-53

<400> 332

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys

20 25 30

Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu

35 40 45

Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu

50 55 60

Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Lys

65 70 75 80

Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys

85 90 95

Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val Ser Val Leu

100 105 110

Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys

115 120 125

Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys

130 135 140

Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser

145 150 155 160

Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys

165 170 175

Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln

180 185 190

Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly

195 200 205

Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln

210 215 220

Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn

225 230 235 240

His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

245 250

<210> 333

<211> 759

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> Fc fusion FSH beta 33-53

<400> 333

tacacccggg acctggtgta taaggatccc gccagaccta agatccagaa gacctgcaca 60

ttcgagccca agtcctgtga taagacccac acatgccccc cttgtcctgc tccagagctg 120

ctgggcggcc ctagcgtgtt cctgtttcca cccaagccta aggacaccct gatgatctct 180

cggaccccag aggtgacatg cgtggtggtg gacgtgagcc acgaggatcc cgaggtgaag 240

tttaactggt atgtggatgg cgtggaggtg cacaatgcca agaccaagcc cagagaggag 300

cagtacaact ccacctatag ggtggtgtct gtgctgacag tgctgcacca ggactggctc 360

aacggcaagg agtataagtg caaggtgtcc aataaggccc tgcccgcccc tatcgagaag 420

accatctcta aggccaaggg ccagcctcgg gagccacagg tgtacacact gcctccatcc 480

agagacgagc tgaccaagaa ccaggtgtct ctgacatgtc tggtcaaggg cttctatccc 540

tctgatatcg ccgtggagtg ggagagcaat ggccagcctg agaacaatta caagaccaca 600

ccccctgtgc tggactccga tggctctttc tttctgtata gcaagctgac cgtggataag 660

tcccggtggc agcagggcaa cgtgttcagc tgttccgtga tgcacgaggc actgcacaac 720

cattacaccc agaagtcact gtcactgtcc ccaggcaag 759

<210> 334

<211> 5

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> joint

<400> 334

Gly Gly Gly Gly Ser

1 5

<210> 335

<211> 10

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> joint

<400> 335

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10

<210> 336

<211> 15

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> joint

<400> 336

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

1 5 10 15

<210> 337

<211> 20

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> joint

<400> 337

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser

<210> 338

<211> 25

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> joint

<400> 338

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly Ser Gly Gly Gly Gly Ser

20 25

<210> 339

<211> 1335

<212> DNA

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> EF1 alpha promoter

<400> 339

gagtaattca tacaaaagga ctcgcccctg ccttggggaa tcccagggac cgtcgttaaa 60

ctcccactaa cgtagaaccc agagatcgct gcgttcccgc cccctcaccc gcccgctctc 120

gtcatcactg aggtggagaa gagcatgcgt gaggctccgg tgcccgtcag tgggcagagc 180

gcacatcgcc cacagtcccc gagaagttgg ggggaggggt cggcaattga accggtgcct 240

agagaaggtg gcgcggggta aactgggaaa gtgatgtcgt gtactggctc cgcctttttc 300

ccgagggtgg gggagaaccg tatataagtg cagtagtcgc cgtgaacgtt ctttttcgca 360

acgggtttgc cgccagaaca caggtaagtg ccgtgtgtgg ttcccgcggg cctggcctct 420

ttacgggtta tggcccttgc gtgccttgaa ttacttccac gcccctggct gcagtacgtg 480

attcttgatc ccgagcttcg ggttggaagt gggtgggaga gttcgaggcc ttgcgcttaa 540

ggagcccctt cgcctcgtgc ttgagttgag gcctggcttg ggcgctgggg ccgccgcgtg 600

cgaatctggt ggcaccttcg cgcctgtctc gctgctttcg ataagtctct agccatttaa 660

aatttttgat gacctgctgc gacgcttttt ttctggcaag atagtcttgt aaatgcgggc 720

caagatctgc acactggtat ttcggttttt ggggccgcgg gcggcgacgg ggcccgtgcg 780

tcccagcgca catgttcggc gaggcggggc ctgcgagcgc ggccaccgag aatcggacgg 840

gggtagtctc aagctggccg gcctgctctg gtgcctggcc tcgcgccgcc gtgtatcgcc 900

ccgccctggg cggcaaggct ggcccggtcg gcaccagttg cgtgagcgga aagatggccg 960

cttcccggcc ctgctgcagg gagctcaaaa tggaggacgc ggcgctcggg agagcgggcg 1020

ggtgagtcac ccacacaaag gaaaagggcc tttccgtcct cagccgtcgc ttcatgtgac 1080

tccacggagt accgggcgcc gtccaggcac ctcgattagt tctcgagctt ttggagtacg 1140

tcgtctttag gttgggggga ggggttttat gcgatggagt ttccccacac tgagtgggtg 1200

gagactgaag ttaggccagc ttggcacttg atgtaattct ccttggaatt tgcccttttt 1260

gagtttggat cttggttcat tctcaagcct cagacagtgg ttcaaagttt ttttcttcca 1320

tttcaggtgt cgtga 1335

<210> 340

<211> 21

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD8 alpha Signal peptide

<400> 340

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro

<210> 341

<211> 45

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD8 alpha hinge domain

<400> 341

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

1 5 10 15

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

20 25 30

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

35 40 45

<210> 342

<211> 24

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD8 alpha transmembrane domain

<400> 342

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

1 5 10 15

Ser Leu Val Ile Thr Leu Tyr Cys

<210> 343

<211> 42

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD137 intracellular domain

<400> 343

Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met

1 5 10 15

Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe

20 25 30

Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

35 40

<210> 344

<211> 41

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD28 intracellular Domain

<400> 344

Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr

1 5 10 15

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

20 25 30

Pro Arg Asp Phe Ala Ala Tyr Arg Ser

35 40

<210> 345

<211> 112

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 alpha intracellular domain

<400> 345

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

1 5 10 15

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

20 25 30

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

35 40 45

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

50 55 60

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

65 70 75 80

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

85 90 95

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

100 105 110

<210> 346

<211> 22

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> P2A element

<400> 346

Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val

1 5 10 15

Glu Glu Asn Pro Gly Pro

<210> 347

<211> 199

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> dnTGFβRII

<400> 347

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser

195

<210> 348

<211> 281

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AD58126VH3VL1 scFV tandem

<400> 348

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys

35 40 45

Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr

50 55 60

Phe Thr Ser Tyr Trp Met His Trp Val Lys Gln Ala Pro Gly Gln Gly

65 70 75 80

Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Thr Gly His Thr Asp Tyr

85 90 95

Asn Gln Lys Phe Lys Asp Arg Ala Thr Leu Thr Ala Asp Thr Ser Thr

100 105 110

Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala

115 120 125

Val Tyr Tyr Cys Ala Arg Ser Asn Trp Ala Trp Phe Pro Tyr Trp Gly

130 135 140

Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly

145 150 155 160

Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser Pro

165 170 175

Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys

180 185 190

Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu Thr

195 200 205

Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Trp

210 215 220

Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly

225 230 235 240

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp

245 250 255

Val Ala Val Tyr Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Leu Thr Phe

260 265 270

Gly Gly Gly Thr Lys Leu Glu Ile Lys

275 280

<210> 349

<211> 277

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS51489 scFV tandem

<400> 349

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

35 40 45

Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn

50 55 60

Leu Tyr Tyr Tyr Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly

65 70 75 80

Leu Glu Trp Val Ala Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Tyr Tyr

85 90 95

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys

100 105 110

Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

115 120 125

Val Tyr Tyr Cys Ala Arg Tyr Tyr Pro Tyr Tyr Gly Met Asp Tyr Trp

130 135 140

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

145 150 155 160

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser

165 170 175

Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys

180 185 190

Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys

195 200 205

Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr

210 215 220

Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe

225 230 235 240

Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr

245 250 255

Cys Gln Gln Gly Phe Ser Tyr Tyr Pro Ile Thr Phe Gly Gln Gly Thr

260 265 270

Lys Val Glu Ile Lys

275

<210> 350

<211> 276

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AD92110 scFV tandem

<400> 350

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

35 40 45

Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn

50 55 60

Ile Tyr Tyr Ser Ser Met His Trp Val Arg Gln Ala Pro Gly Lys Gly

65 70 75 80

Leu Glu Trp Val Ala Tyr Ile Tyr Pro Tyr Tyr Ser Tyr Thr Tyr Tyr

85 90 95

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys

100 105 110

Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

115 120 125

Val Tyr Tyr Cys Ala Arg Gly Tyr Ala Leu Asp Tyr Trp Gly Gln Gly

130 135 140

Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

165 170 175

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

180 185 190

Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys

195 200 205

Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val

210 215 220

Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr

225 230 235 240

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

245 250 255

Ala Ser Ser Gly Tyr His Tyr Leu Ile Thr Phe Gly Gln Gly Thr Lys

260 265 270

Val Glu Ile Lys

275

<210> 351

<211> 274

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS91156 scFV tandem

<400> 351

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

35 40 45

Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn

50 55 60

Ile Tyr Ser Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly

65 70 75 80

Leu Glu Trp Val Ala Ser Ile Ser Ser Tyr Ser Ser Tyr Thr Ser Tyr

85 90 95

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys

100 105 110

Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

115 120 125

Val Tyr Tyr Cys Ala Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln Gly

130 135 140

Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

165 170 175

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

180 185 190

Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys

195 200 205

Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val

210 215 220

Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr

225 230 235 240

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

245 250 255

Gly Pro Tyr Tyr His Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu

260 265 270

Ile Lys

<210> 352

<211> 274

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS91189 scFV tandem

<400> 352

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

35 40 45

Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn

50 55 60

Leu Ser Tyr Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys Gly

65 70 75 80

Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Tyr Tyr

85 90 95

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys

100 105 110

Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

115 120 125

Val Tyr Tyr Cys Ala Arg Tyr Trp Gly Met Asp Tyr Trp Gly Gln Gly

130 135 140

Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

145 150 155 160

Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser

165 170 175

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser

180 185 190

Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys

195 200 205

Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val

210 215 220

Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr

225 230 235 240

Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln

245 250 255

Tyr Tyr Trp Tyr Tyr Pro Ile Thr Phe Gly Gln Gly Thr Lys Val Glu

260 265 270

Ile Lys

<210> 353

<211> 277

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS51674 scFV tandem

<400> 353

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val

35 40 45

Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Asn

50 55 60

Leu Tyr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys Gly

65 70 75 80

Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Ser Tyr Thr Ser Tyr

85 90 95

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys

100 105 110

Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala

115 120 125

Val Tyr Tyr Cys Ala Arg Pro Phe Gly Trp Gly Tyr Ala Gly Met Asp

130 135 140

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

145 150 155 160

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

165 170 175

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

180 185 190

Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln

195 200 205

Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser

210 215 220

Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr

225 230 235 240

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

245 250 255

Tyr Tyr Cys Gln Gln Gly Tyr Ala Pro Ile Thr Phe Gly Gln Gly Thr

260 265 270

Lys Val Glu Ile Lys

275

<210> 354

<211> 158

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS65233 sdAb tandem

<400> 354

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Gln Val His Leu Val Glu Ser Gly Gly Gly Ser Val

35 40 45

Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr

50 55 60

Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Gly

65 70 75 80

Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser

85 90 95

Val Lys Gly Arg Phe Val Leu Ser Arg Tyr Asn Ala Lys Ser Ile Met

100 105 110

Tyr Leu Gln Met Asn Ser Val Lys Leu Glu Asp Thr Ala Met Tyr Tyr

115 120 125

Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser

130 135 140

Phe Asp Phe Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

145 150 155

<210> 355

<211> 164

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60685 sdAb tandem

<400> 355

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val

35 40 45

Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Val

50 55 60

Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu

65 70 75 80

Arg Glu Gly Val Ala Ser Met Tyr Val Gly Gly Gly Tyr Thr Tyr Tyr

85 90 95

Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys

100 105 110

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala

115 120 125

Met Tyr Tyr Cys Ala Ala Ile Ser Ile Ala Leu Thr Arg Glu Phe Cys

130 135 140

Ala Pro Ile Val Ser Arg Tyr Asn Tyr Trp Gly Gln Gly Thr Gln Val

145 150 155 160

Thr Val Ser Ser

<210> 356

<211> 164

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60702 sdAb tandem

<400> 356

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Gln Val Lys Leu Val Glu Ser Gly Gly Gly Ser Val

35 40 45

Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn Val

50 55 60

Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu

65 70 75 80

Arg Glu Gly Val Ala Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn Tyr

85 90 95

Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala Lys

100 105 110

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala

115 120 125

Met Tyr Tyr Cys Ala Ala Ile Thr Val Ala Leu Thr Arg Ala Phe Cys

130 135 140

Ala Pro Ile Pro Ser Arg Tyr Thr Asn Trp Gly Gln Gly Thr Gln Val

145 150 155 160

Thr Val Ser Ser

<210> 357

<211> 156

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60676 sdAb tandem

<400> 357

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

1 5 10 15

Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

20 25 30

Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser Val

35 40 45

Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr

50 55 60

Val Ser Ser Gly Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu

65 70 75 80

Arg Glu Arg Val Ala Gln Ile Gly Arg Asp Ala Thr Thr Thr Tyr Ala

85 90 95

Asp Ser Val Lys Gly Arg Phe Thr Ile Ala Arg Asp Asp Ala Glu Asn

100 105 110

Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Met

115 120 125

Tyr Ser Cys Thr Ala Tyr Trp Gly Val Tyr Cys Leu Ser Pro Gly Arg

130 135 140

Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser

145 150 155

<210> 358

<211> 489

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126VH3VL1 CAR

<400> 358

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Thr Phe Thr Ser Tyr Trp Met His Trp Val Lys Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Thr Gly His Thr Asp

65 70 75 80

Tyr Asn Gln Lys Phe Lys Asp Arg Ala Thr Leu Thr Ala Asp Thr Ser

85 90 95

Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Ser Asn Trp Ala Trp Phe Pro Tyr Trp

115 120 125

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser

145 150 155 160

Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys

165 170 175

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu

180 185 190

Thr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu

225 230 235 240

Asp Val Ala Val Tyr Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Leu Thr

245 250 255

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg

485

<210> 359

<211> 485

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489 CAR

<400> 359

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Tyr Tyr Tyr Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Pro Tyr Tyr Gly Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

165 170 175

Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu

195 200 205

Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp

210 215 220

Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Gly Phe Ser Tyr Tyr Pro Ile Thr Phe Gly Gln Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg

485

<210> 360

<211> 484

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110 CAR

<400> 360

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Ile Tyr Tyr Ser Ser Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Tyr Ile Tyr Pro Tyr Tyr Ser Tyr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ala Leu Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Ala Ser Ser Gly Tyr His Tyr Leu Ile Thr Phe Gly Gln Gly Thr

245 250 255

Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

260 265 270

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

275 280 285

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

290 295 300

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

305 310 315 320

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

325 330 335

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

340 345 350

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

355 360 365

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

370 375 380

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

385 390 395 400

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

405 410 415

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

420 425 430

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

Leu Pro Pro Arg

<210> 361

<211> 482

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156 CAR

<400> 361

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Ile Tyr Ser Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Ser Ser Tyr Ser Ser Tyr Thr Ser

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Gly Pro Tyr Tyr His Pro Ile Thr Phe Gly Gln Gly Thr Lys Val

245 250 255

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

260 265 270

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

275 280 285

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

290 295 300

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

305 310 315 320

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

325 330 335

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

340 345 350

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

355 360 365

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

370 375 380

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

385 390 395 400

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

405 410 415

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

420 425 430

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

435 440 445

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

450 455 460

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

465 470 475 480

Pro Arg

<210> 362

<211> 482

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189 CAR

<400> 362

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Ser Tyr Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Gly Met Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Tyr Tyr Trp Tyr Tyr Pro Ile Thr Phe Gly Gln Gly Thr Lys Val

245 250 255

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

260 265 270

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

275 280 285

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

290 295 300

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

305 310 315 320

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

325 330 335

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

340 345 350

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

355 360 365

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

370 375 380

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

385 390 395 400

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

405 410 415

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

420 425 430

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

435 440 445

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

450 455 460

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

465 470 475 480

Pro Arg

<210> 363

<211> 485

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674 CAR

<400> 363

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Tyr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Ser Tyr Thr Ser

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Pro Phe Gly Trp Gly Tyr Ala Gly Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

145 150 155 160

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

165 170 175

Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser

195 200 205

Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly

210 215 220

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

225 230 235 240

Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Pro Ile Thr Phe Gly Gln Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg

485

<210> 364

<211> 366

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 CAR

<400> 364

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val His Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe

35 40 45

Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu

50 55 60

Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Val Leu Ser Arg Tyr Asn Ala Lys Ser Ile

85 90 95

Met Tyr Leu Gln Met Asn Ser Val Lys Leu Glu Asp Thr Ala Met Tyr

100 105 110

Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser

115 120 125

Ser Phe Asp Phe Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr

130 135 140

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

145 150 155 160

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

165 170 175

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

180 185 190

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

195 200 205

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

210 215 220

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

225 230 235 240

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

245 250 255

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

260 265 270

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

275 280 285

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

290 295 300

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

305 310 315 320

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

325 330 335

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

340 345 350

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

355 360 365

<210> 365

<211> 372

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 CAR

<400> 365

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn

35 40 45

Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Gly Val Ala Ser Met Tyr Val Gly Gly Gly Tyr Thr Tyr

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ala Ile Ser Ile Ala Leu Thr Arg Glu Phe

115 120 125

Cys Ala Pro Ile Val Ser Arg Tyr Asn Tyr Trp Gly Gln Gly Thr Gln

130 135 140

Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

145 150 155 160

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

165 170 175

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

180 185 190

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

195 200 205

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

210 215 220

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

225 230 235 240

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

245 250 255

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

260 265 270

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

275 280 285

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

290 295 300

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

305 310 315 320

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

325 330 335

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

340 345 350

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

355 360 365

Leu Pro Pro Arg

370

<210> 366

<211> 372

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 CAR

<400> 366

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Lys Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn

35 40 45

Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Gly Val Ala Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn

65 70 75 80

Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ala Ile Thr Val Ala Leu Thr Arg Ala Phe

115 120 125

Cys Ala Pro Ile Pro Ser Arg Tyr Thr Asn Trp Gly Gln Gly Thr Gln

130 135 140

Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

145 150 155 160

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

165 170 175

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

180 185 190

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

195 200 205

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

210 215 220

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

225 230 235 240

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

245 250 255

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

260 265 270

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

275 280 285

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

290 295 300

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

305 310 315 320

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

325 330 335

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

340 345 350

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

355 360 365

Leu Pro Pro Arg

370

<210> 367

<211> 364

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 CAR

<400> 367

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr

35 40 45

Thr Val Ser Ser Gly Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Arg Val Ala Gln Ile Gly Arg Asp Ala Thr Thr Thr Tyr

65 70 75 80

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ala Arg Asp Asp Ala Glu

85 90 95

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala

100 105 110

Met Tyr Ser Cys Thr Ala Tyr Trp Gly Val Tyr Cys Leu Ser Pro Gly

115 120 125

Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr

130 135 140

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

145 150 155 160

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

165 170 175

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

180 185 190

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

195 200 205

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

210 215 220

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

225 230 235 240

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

245 250 255

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

260 265 270

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

275 280 285

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

290 295 300

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

305 310 315 320

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

325 330 335

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

340 345 350

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

355 360

<210> 368

<211> 483

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> SS1 CAR

<400> 368

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Gln Gln Ser Gly Pro Glu Leu

20 25 30

Glu Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Ser Phe Thr Gly Tyr Thr Met Asn Trp Val Lys Gln Ser His Gly Lys

50 55 60

Ser Leu Glu Trp Ile Gly Leu Ile Thr Pro Tyr Asn Gly Ala Ser Ser

65 70 75 80

Tyr Asn Gln Lys Phe Arg Gly Lys Ala Thr Leu Thr Val Asp Lys Ser

85 90 95

Ser Ser Thr Ala Tyr Met Asp Leu Leu Ser Leu Thr Ser Glu Asp Ser

100 105 110

Ala Val Tyr Phe Cys Ala Arg Gly Gly Tyr Asp Gly Arg Gly Phe Asp

115 120 125

Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly

130 135 140

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Glu Leu Thr

145 150 155 160

Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly Glu Lys Val Thr Met

165 170 175

Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met His Trp Tyr Gln Gln

180 185 190

Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr Asp Thr Ser Lys Leu

195 200 205

Ala Ser Gly Val Pro Gly Arg Phe Ser Gly Ser Gly Ser Gly Asn Ser

210 215 220

Tyr Ser Leu Thr Ile Ser Ser Val Glu Ala Glu Asp Asp Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Trp Ser Gly Tyr Pro Leu Thr Phe Gly Ala Gly Thr

245 250 255

Lys Leu Glu Ile Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

260 265 270

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

275 280 285

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

290 295 300

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

305 310 315 320

Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu

325 330 335

Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln

340 345 350

Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly

355 360 365

Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

370 375 380

Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

385 390 395 400

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

405 410 415

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

420 425 430

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

435 440 445

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

450 455 460

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

465 470 475 480

Pro Pro Arg

<210> 369

<211> 485

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> M5 CAR

<400> 369

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Glu Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Thr Phe Thr Asp Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Met Gly Trp Ile Asn Pro Asn Ser Gly Gly Thr Asn

65 70 75 80

Tyr Ala Gln Lys Phe Gln Gly Arg Val Thr Met Thr Arg Asp Thr Ser

85 90 95

Ile Ser Thr Ala Tyr Met Glu Leu Ser Arg Leu Arg Ser Asp Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Ser Gly Trp Asp Phe Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met

145 150 155 160

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

165 170 175

Ile Thr Cys Arg Ala Ser Gln Ser Ile Arg Tyr Tyr Leu Ser Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Thr Ala Ser

195 200 205

Ile Leu Gln Asn Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly

210 215 220

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

225 230 235 240

Thr Tyr Tyr Cys Leu Gln Thr Tyr Thr Thr Pro Asp Phe Gly Pro Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg

485

<210> 370

<211> 525

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AD58126VH3VL1 tandem CAR

<400> 370

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser

50 55 60

Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys

65 70 75 80

Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met His Trp Val Lys Gln

85 90 95

Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Thr

100 105 110

Gly His Thr Asp Tyr Asn Gln Lys Phe Lys Asp Arg Ala Thr Leu Thr

115 120 125

Ala Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg

130 135 140

Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Asn Trp Ala Trp

145 150 155 160

Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val

180 185 190

Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala

195 200 205

Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln

210 215 220

Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys

225 230 235 240

Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg

245 250 255

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser

260 265 270

Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn Asp Tyr Ser

275 280 285

Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Thr Thr

290 295 300

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

305 310 315 320

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

325 330 335

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

340 345 350

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

355 360 365

Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

370 375 380

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

385 390 395 400

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

405 410 415

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln

420 425 430

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

435 440 445

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

450 455 460

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

465 470 475 480

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

485 490 495

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

500 505 510

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

515 520 525

<210> 371

<211> 521

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS51489 tandem CAR

<400> 371

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Leu Tyr Tyr Tyr Ser Ile His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Ser Ser

100 105 110

Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Pro Tyr Tyr

145 150 155 160

Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

180 185 190

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

195 200 205

Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala

210 215 220

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser

225 230 235 240

Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg

245 250 255

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

260 265 270

Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Phe Ser Tyr Tyr Pro Ile Thr

275 280 285

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

290 295 300

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

305 310 315 320

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

325 330 335

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

340 345 350

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

355 360 365

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

370 375 380

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

385 390 395 400

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

405 410 415

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

420 425 430

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

435 440 445

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

450 455 460

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

465 470 475 480

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

485 490 495

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

500 505 510

Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 372

<211> 520

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS92110 tandem CAR

<400> 372

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Ile Tyr Tyr Ser Ser Met His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Tyr Ile Tyr Pro Tyr Tyr

100 105 110

Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ala Leu Asp

145 150 155 160

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

180 185 190

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

195 200 205

Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln

210 215 220

Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser

225 230 235 240

Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr

245 250 255

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

260 265 270

Tyr Tyr Cys Gln Gln Ala Ser Ser Gly Tyr His Tyr Leu Ile Thr Phe

275 280 285

Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg

290 295 300

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

305 310 315 320

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

325 330 335

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

340 345 350

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg

355 360 365

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

370 375 380

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

385 390 395 400

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

405 410 415

Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

420 425 430

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

435 440 445

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

450 455 460

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

465 470 475 480

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

485 490 495

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

500 505 510

His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 373

<211> 518

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS91156 tandem CAR

<400> 373

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Ile Tyr Ser Ser Ser Ile His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ser Ile Ser Ser Tyr Ser

100 105 110

Ser Tyr Thr Ser Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Ala Met Asp

145 150 155 160

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

180 185 190

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

195 200 205

Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln

210 215 220

Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser

225 230 235 240

Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr

245 250 255

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

260 265 270

Tyr Tyr Cys Gln Gln Gly Pro Tyr Tyr His Pro Ile Thr Phe Gly Gln

275 280 285

Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro

290 295 300

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

305 310 315 320

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

325 330 335

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

340 345 350

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

355 360 365

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

370 375 380

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

385 390 395 400

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

405 410 415

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

420 425 430

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

435 440 445

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

450 455 460

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

465 470 475 480

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

485 490 495

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

500 505 510

Gln Ala Leu Pro Pro Arg

515

<210> 374

<211> 518

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS91189 tandem CAR

<400> 374

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Leu Ser Tyr Ser Ser Ile His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser

100 105 110

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Gly Met Asp

145 150 155 160

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

180 185 190

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

195 200 205

Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln

210 215 220

Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser

225 230 235 240

Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr

245 250 255

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

260 265 270

Tyr Tyr Cys Gln Gln Tyr Tyr Trp Tyr Tyr Pro Ile Thr Phe Gly Gln

275 280 285

Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro

290 295 300

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

305 310 315 320

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

325 330 335

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

340 345 350

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

355 360 365

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

370 375 380

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

385 390 395 400

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

405 410 415

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

420 425 430

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

435 440 445

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

450 455 460

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

465 470 475 480

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

485 490 495

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

500 505 510

Gln Ala Leu Pro Pro Arg

515

<210> 375

<211> 521

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS51674 tandem CAR

<400> 375

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Leu Tyr Ser Tyr Tyr Met His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser

100 105 110

Ser Tyr Thr Ser Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Phe Gly Trp Gly

145 150 155 160

Tyr Ala Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

180 185 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

195 200 205

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala

210 215 220

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

225 230 235 240

Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

245 250 255

Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

260 265 270

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Pro Ile Thr

275 280 285

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

290 295 300

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

305 310 315 320

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

325 330 335

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

340 345 350

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

355 360 365

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

370 375 380

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

385 390 395 400

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

405 410 415

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

420 425 430

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

435 440 445

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

450 455 460

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

465 470 475 480

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

485 490 495

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

500 505 510

Leu His Met Gln Ala Leu Pro Pro Arg

515 520

<210> 376

<211> 402

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS65233 tandem CAR

<400> 376

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val His Leu Val Glu Ser

50 55 60

Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Glu Phe Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly

85 90 95

Lys Glu Arg Glu Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr

100 105 110

Val Tyr Ala Asp Ser Val Lys Gly Arg Phe Val Leu Ser Arg Tyr Asn

115 120 125

Ala Lys Ser Ile Met Tyr Leu Gln Met Asn Ser Val Lys Leu Glu Asp

130 135 140

Thr Ala Met Tyr Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp

145 150 155 160

Ser Ser Pro Ser Ser Phe Asp Phe Trp Gly Gln Gly Thr Gln Val Thr

165 170 175

Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

180 185 190

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

195 200 205

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

210 215 220

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

225 230 235 240

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

245 250 255

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

260 265 270

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

275 280 285

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

290 295 300

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

305 310 315 320

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

325 330 335

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

340 345 350

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

355 360 365

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

370 375 380

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

385 390 395 400

Pro Arg

<210> 377

<211> 408

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60685 tandem CAR

<400> 377

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Asn Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln

85 90 95

Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Ser Met Tyr Val Gly Gly

100 105 110

Gly Tyr Thr Tyr Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys

130 135 140

Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Ile Ser Ile Ala Leu

145 150 155 160

Thr Arg Glu Phe Cys Ala Pro Ile Val Ser Arg Tyr Asn Tyr Trp Gly

165 170 175

Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg

180 185 190

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

195 200 205

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

210 215 220

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

225 230 235 240

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg

245 250 255

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

260 265 270

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

275 280 285

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

290 295 300

Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

305 310 315 320

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

325 330 335

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

340 345 350

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

355 360 365

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

370 375 380

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

385 390 395 400

His Met Gln Ala Leu Pro Pro Arg

405

<210> 378

<211> 408

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60702 tandem CAR

<400> 378

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Lys Leu Val Glu Ser

50 55 60

Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Asn Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln

85 90 95

Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Ser Ile Tyr Val Gly Gly

100 105 110

Gly Tyr Thr Asn Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser

115 120 125

Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys

130 135 140

Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Ile Thr Val Ala Leu

145 150 155 160

Thr Arg Ala Phe Cys Ala Pro Ile Pro Ser Arg Tyr Thr Asn Trp Gly

165 170 175

Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg

180 185 190

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

195 200 205

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

210 215 220

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

225 230 235 240

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg

245 250 255

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

260 265 270

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

275 280 285

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

290 295 300

Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

305 310 315 320

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

325 330 335

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

340 345 350

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

355 360 365

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

370 375 380

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

385 390 395 400

His Met Gln Ala Leu Pro Pro Arg

405

<210> 379

<211> 400

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60676 tandem CAR

<400> 379

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Tyr Thr Val Ser Ser Gly Cys Met Gly Trp Phe Arg Gln

85 90 95

Ala Pro Gly Lys Glu Arg Glu Arg Val Ala Gln Ile Gly Arg Asp Ala

100 105 110

Thr Thr Thr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ala Arg

115 120 125

Asp Asp Ala Glu Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro

130 135 140

Glu Asp Thr Ala Met Tyr Ser Cys Thr Ala Tyr Trp Gly Val Tyr Cys

145 150 155 160

Leu Ser Pro Gly Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser

165 170 175

Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

180 185 190

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

195 200 205

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

210 215 220

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

225 230 235 240

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

245 250 255

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

260 265 270

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

275 280 285

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

290 295 300

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

305 310 315 320

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

325 330 335

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

340 345 350

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

355 360 365

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

370 375 380

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

385 390 395 400

<210> 380

<211> 775

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126VH3VL1 + FSH β 33-53 Dual CAR

<400> 380

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Thr Phe Thr Ser Tyr Trp Met His Trp Val Lys Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Thr Gly His Thr Asp

65 70 75 80

Tyr Asn Gln Lys Phe Lys Asp Arg Ala Thr Leu Thr Ala Asp Thr Ser

85 90 95

Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Ser Asn Trp Ala Trp Phe Pro Tyr Trp

115 120 125

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser

145 150 155 160

Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys

165 170 175

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu

180 185 190

Thr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu

225 230 235 240

Asp Val Ala Val Tyr Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Leu Thr

245 250 255

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe

485 490 495

Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met

500 505 510

Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His

515 520 525

Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg

530 535 540

Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg

545 550 555 560

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

565 570 575

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

580 585 590

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

595 600 605

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser

610 615 620

Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg

625 630 635 640

Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg

645 650 655

Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp

660 665 670

Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

675 680 685

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

690 695 700

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

705 710 715 720

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

725 730 735

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

740 745 750

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

755 760 765

Met Gln Ala Leu Pro Pro Arg

770 775

<210> 381

<211> 771

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489 + FSH beta 33-53 Dual CAR

<400> 381

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Tyr Tyr Tyr Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Pro Tyr Tyr Gly Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

165 170 175

Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu

195 200 205

Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp

210 215 220

Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Gly Phe Ser Tyr Tyr Pro Ile Thr Phe Gly Gln Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys

485 490 495

Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val

500 505 510

Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro

515 520 525

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

530 535 540

Lys Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

545 550 555 560

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

565 570 575

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

580 585 590

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

595 600 605

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg

610 615 620

Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro

625 630 635 640

Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala

645 650 655

Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

660 665 670

Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

675 680 685

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

690 695 700

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

705 710 715 720

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

725 730 735

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

740 745 750

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

755 760 765

Pro Pro Arg

770

<210> 382

<211> 770

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110 + FSH beta 33-53 Dual CAR

<400> 382

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Ile Tyr Tyr Ser Ser Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Tyr Ile Tyr Pro Tyr Tyr Ser Tyr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ala Leu Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Ala Ser Ser Gly Tyr His Tyr Leu Ile Thr Phe Gly Gln Gly Thr

245 250 255

Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

260 265 270

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

275 280 285

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

290 295 300

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

305 310 315 320

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

325 330 335

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

340 345 350

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

355 360 365

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

370 375 380

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

385 390 395 400

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

405 410 415

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

420 425 430

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

485 490 495

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr

500 505 510

Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr

515 520 525

Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys

530 535 540

Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

545 550 555 560

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

565 570 575

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

580 585 590

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

595 600 605

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu

610 615 620

Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr

625 630 635 640

Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr

645 650 655

Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

660 665 670

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

675 680 685

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

690 695 700

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

705 710 715 720

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

725 730 735

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

740 745 750

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

755 760 765

Pro Arg

770

<210> 383

<211> 768

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156 + FSH beta 33-53 Dual CAR

<400> 383

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Ile Tyr Ser Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Ser Ser Tyr Ser Ser Tyr Thr Ser

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Gly Pro Tyr Tyr His Pro Ile Thr Phe Gly Gln Gly Thr Lys Val

245 250 255

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

260 265 270

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

275 280 285

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

290 295 300

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

305 310 315 320

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

325 330 335

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

340 345 350

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

355 360 365

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

370 375 380

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

385 390 395 400

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

405 410 415

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

420 425 430

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

435 440 445

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

450 455 460

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

465 470 475 480

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

485 490 495

Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu

500 505 510

Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg

515 520 525

Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys

530 535 540

Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

545 550 555 560

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

565 570 575

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

580 585 590

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

595 600 605

Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His

610 615 620

Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys

625 630 635 640

His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser

645 650 655

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

660 665 670

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

675 680 685

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

690 695 700

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

705 710 715 720

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

725 730 735

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

740 745 750

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

755 760 765

<210> 384

<211> 768

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189 + FSH beta 33-53 Dual CAR

<400> 384

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Ser Tyr Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Gly Met Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Tyr Tyr Trp Tyr Tyr Pro Ile Thr Phe Gly Gln Gly Thr Lys Val

245 250 255

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

260 265 270

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

275 280 285

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

290 295 300

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

305 310 315 320

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

325 330 335

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

340 345 350

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

355 360 365

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

370 375 380

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

385 390 395 400

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

405 410 415

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

420 425 430

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

435 440 445

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

450 455 460

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

465 470 475 480

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

485 490 495

Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu

500 505 510

Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg

515 520 525

Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys

530 535 540

Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

545 550 555 560

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

565 570 575

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

580 585 590

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

595 600 605

Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His

610 615 620

Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys

625 630 635 640

His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser

645 650 655

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

660 665 670

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

675 680 685

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

690 695 700

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

705 710 715 720

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

725 730 735

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

740 745 750

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

755 760 765

<210> 385

<211> 771

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674 + FSH beta 33-53 Dual CAR

<400> 385

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Tyr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Ser Tyr Thr Ser

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Pro Phe Gly Trp Gly Tyr Ala Gly Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

145 150 155 160

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

165 170 175

Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser

195 200 205

Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly

210 215 220

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

225 230 235 240

Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Pro Ile Thr Phe Gly Gln Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys

485 490 495

Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val

500 505 510

Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro

515 520 525

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

530 535 540

Lys Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

545 550 555 560

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

565 570 575

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

580 585 590

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

595 600 605

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg

610 615 620

Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro

625 630 635 640

Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala

645 650 655

Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

660 665 670

Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

675 680 685

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

690 695 700

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

705 710 715 720

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

725 730 735

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

740 745 750

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

755 760 765

Pro Pro Arg

770

<210> 386

<211> 652

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 + FSH beta 33-53 Dual CAR

<400> 386

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val His Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe

35 40 45

Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu

50 55 60

Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Val Leu Ser Arg Tyr Asn Ala Lys Ser Ile

85 90 95

Met Tyr Leu Gln Met Asn Ser Val Lys Leu Glu Asp Thr Ala Met Tyr

100 105 110

Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser

115 120 125

Ser Phe Asp Phe Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr

130 135 140

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

145 150 155 160

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

165 170 175

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

180 185 190

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

195 200 205

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

210 215 220

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

225 230 235 240

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

245 250 255

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

260 265 270

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

275 280 285

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

290 295 300

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

305 310 315 320

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

325 330 335

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

340 345 350

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

355 360 365

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

370 375 380

Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu

385 390 395 400

Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr

405 410 415

Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr

420 425 430

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

435 440 445

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

450 455 460

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

465 470 475 480

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

485 490 495

Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met

500 505 510

Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro

515 520 525

Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe

530 535 540

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

545 550 555 560

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

565 570 575

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

580 585 590

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

595 600 605

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

610 615 620

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

625 630 635 640

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

645 650

<210> 387

<211> 658

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 + FSH beta 33-53 Dual CAR

<400> 387

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn

35 40 45

Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Gly Val Ala Ser Met Tyr Val Gly Gly Gly Tyr Thr Tyr

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ala Ile Ser Ile Ala Leu Thr Arg Glu Phe

115 120 125

Cys Ala Pro Ile Val Ser Arg Tyr Asn Tyr Trp Gly Gln Gly Thr Gln

130 135 140

Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

145 150 155 160

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

165 170 175

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

180 185 190

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

195 200 205

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

210 215 220

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

225 230 235 240

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

245 250 255

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

260 265 270

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

275 280 285

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

290 295 300

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

305 310 315 320

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

325 330 335

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

340 345 350

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

355 360 365

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

370 375 380

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr

385 390 395 400

Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr

405 410 415

Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys

420 425 430

Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

435 440 445

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

450 455 460

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

465 470 475 480

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

485 490 495

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu

500 505 510

Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr

515 520 525

Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr

530 535 540

Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

545 550 555 560

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

565 570 575

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

580 585 590

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

595 600 605

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

610 615 620

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

625 630 635 640

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

645 650 655

Pro Arg

<210> 388

<211> 658

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 + FSH beta 33-53 Dual CAR

<400> 388

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Lys Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn

35 40 45

Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Gly Val Ala Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn

65 70 75 80

Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ala Ile Thr Val Ala Leu Thr Arg Ala Phe

115 120 125

Cys Ala Pro Ile Pro Ser Arg Tyr Thr Asn Trp Gly Gln Gly Thr Gln

130 135 140

Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

145 150 155 160

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

165 170 175

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

180 185 190

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

195 200 205

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

210 215 220

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

225 230 235 240

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

245 250 255

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

260 265 270

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

275 280 285

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

290 295 300

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

305 310 315 320

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

325 330 335

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

340 345 350

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

355 360 365

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

370 375 380

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr

385 390 395 400

Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr

405 410 415

Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys

420 425 430

Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

435 440 445

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

450 455 460

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

465 470 475 480

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

485 490 495

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu

500 505 510

Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr

515 520 525

Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr

530 535 540

Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

545 550 555 560

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

565 570 575

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

580 585 590

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

595 600 605

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

610 615 620

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

625 630 635 640

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

645 650 655

Pro Arg

<210> 389

<211> 650

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 + FSH beta 33-53 Dual CAR

<400> 389

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr

35 40 45

Thr Val Ser Ser Gly Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Arg Val Ala Gln Ile Gly Arg Asp Ala Thr Thr Thr Tyr

65 70 75 80

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ala Arg Asp Asp Ala Glu

85 90 95

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala

100 105 110

Met Tyr Ser Cys Thr Ala Tyr Trp Gly Val Tyr Cys Leu Ser Pro Gly

115 120 125

Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr

130 135 140

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

145 150 155 160

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

165 170 175

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

180 185 190

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

195 200 205

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

210 215 220

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

225 230 235 240

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

245 250 255

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

260 265 270

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

275 280 285

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

290 295 300

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

305 310 315 320

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

325 330 335

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

340 345 350

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala

355 360 365

Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro

370 375 380

Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu

385 390 395 400

Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp

405 410 415

Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr Thr Pro

420 425 430

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

435 440 445

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

450 455 460

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

465 470 475 480

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

485 490 495

Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met

500 505 510

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

515 520 525

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg

530 535 540

Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn

545 550 555 560

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

565 570 575

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

580 585 590

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

595 600 605

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

610 615 620

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

625 630 635 640

Ala Leu His Met Gln Ala Leu Pro Pro Arg

645 650

<210> 390

<211> 710

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126VH3VL1 CAR, having dnTGF β RII

<400> 390

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Thr Phe Thr Ser Tyr Trp Met His Trp Val Lys Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Thr Gly His Thr Asp

65 70 75 80

Tyr Asn Gln Lys Phe Lys Asp Arg Ala Thr Leu Thr Ala Asp Thr Ser

85 90 95

Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Ser Asn Trp Ala Trp Phe Pro Tyr Trp

115 120 125

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser

145 150 155 160

Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys

165 170 175

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu

180 185 190

Thr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu

225 230 235 240

Asp Val Ala Val Tyr Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Leu Thr

245 250 255

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe

485 490 495

Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met

500 505 510

Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp

515 520 525

Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn

530 535 540

Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln

545 550 555 560

Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys

565 570 575

Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln

580 585 590

Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu

595 600 605

Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu

610 615 620

Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro

625 630 635 640

Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp

645 650 655

Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu

660 665 670

Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly

675 680 685

Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg

690 695 700

Gln Gln Lys Leu Ser Ser

705 710

<210> 391

<211> 706

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489 CAR, having dnTGF beta RII

<400> 391

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Tyr Tyr Tyr Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Pro Tyr Tyr Gly Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

165 170 175

Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu

195 200 205

Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp

210 215 220

Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Gly Phe Ser Tyr Tyr Pro Ile Thr Phe Gly Gln Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys

485 490 495

Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu

500 505 510

Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala

515 520 525

Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile

530 535 540

Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe

545 550 555 560

Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser

565 570 575

Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val

580 585 590

Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys

595 600 605

His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala

610 615 620

Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe

625 630 635 640

Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe

645 650 655

Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe

660 665 670

Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser

675 680 685

Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu

690 695 700

Ser Ser

705

<210> 392

<211> 705

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110 CAR, having dnTGF beta RII

<400> 392

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Ile Tyr Tyr Ser Ser Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Tyr Ile Tyr Pro Tyr Tyr Ser Tyr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ala Leu Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Ala Ser Ser Gly Tyr His Tyr Leu Ile Thr Phe Gly Gln Gly Thr

245 250 255

Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

260 265 270

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

275 280 285

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

290 295 300

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

305 310 315 320

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

325 330 335

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

340 345 350

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

355 360 365

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

370 375 380

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

385 390 395 400

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

405 410 415

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

420 425 430

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

485 490 495

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu

500 505 510

Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser

515 520 525

Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val

530 535 540

Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys

545 550 555 560

Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn

565 570 575

Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala

580 585 590

Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His

595 600 605

Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser

610 615 620

Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe

625 630 635 640

Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser

645 650 655

Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln

660 665 670

Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val

675 680 685

Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser

690 695 700

Ser

705

<210> 393

<211> 703

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156 CAR, having dnTGF beta RII

<400> 393

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Ile Tyr Ser Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Ser Ser Tyr Ser Ser Tyr Thr Ser

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Gly Pro Tyr Tyr His Pro Ile Thr Phe Gly Gln Gly Thr Lys Val

245 250 255

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

260 265 270

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

275 280 285

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

290 295 300

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

305 310 315 320

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

325 330 335

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

340 345 350

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

355 360 365

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

370 375 380

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

385 390 395 400

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

405 410 415

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

420 425 430

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

435 440 445

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

450 455 460

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

465 470 475 480

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

485 490 495

Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly

500 505 510

Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile

515 520 525

Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp

530 535 540

Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val

545 550 555 560

Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser

565 570 575

Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp

580 585 590

Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro

595 600 605

Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys

610 615 620

Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys

625 630 635 640

Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu

645 650 655

Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr

660 665 670

Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile

675 680 685

Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

690 695 700

<210> 394

<211> 703

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189 CAR, having dnTGF-beta RII

<400> 394

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Ser Tyr Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Gly Met Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Tyr Tyr Trp Tyr Tyr Pro Ile Thr Phe Gly Gln Gly Thr Lys Val

245 250 255

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

260 265 270

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

275 280 285

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

290 295 300

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

305 310 315 320

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

325 330 335

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

340 345 350

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

355 360 365

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

370 375 380

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

385 390 395 400

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

405 410 415

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

420 425 430

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

435 440 445

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

450 455 460

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

465 470 475 480

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

485 490 495

Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly

500 505 510

Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile

515 520 525

Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp

530 535 540

Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val

545 550 555 560

Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser

565 570 575

Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp

580 585 590

Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro

595 600 605

Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys

610 615 620

Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys

625 630 635 640

Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu

645 650 655

Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr

660 665 670

Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile

675 680 685

Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

690 695 700

<210> 395

<211> 706

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674 CAR, having dnTGF beta RII

<400> 395

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Tyr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Ser Tyr Thr Ser

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Pro Phe Gly Trp Gly Tyr Ala Gly Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

145 150 155 160

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

165 170 175

Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser

195 200 205

Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly

210 215 220

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

225 230 235 240

Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Pro Ile Thr Phe Gly Gln Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys

485 490 495

Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu

500 505 510

Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala

515 520 525

Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile

530 535 540

Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe

545 550 555 560

Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser

565 570 575

Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val

580 585 590

Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys

595 600 605

His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala

610 615 620

Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe

625 630 635 640

Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe

645 650 655

Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe

660 665 670

Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser

675 680 685

Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu

690 695 700

Ser Ser

705

<210> 396

<211> 587

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 CAR, having dnTGF beta RII

<400> 396

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val His Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe

35 40 45

Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu

50 55 60

Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Val Leu Ser Arg Tyr Asn Ala Lys Ser Ile

85 90 95

Met Tyr Leu Gln Met Asn Ser Val Lys Leu Glu Asp Thr Ala Met Tyr

100 105 110

Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser

115 120 125

Ser Phe Asp Phe Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr

130 135 140

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

145 150 155 160

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

165 170 175

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

180 185 190

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

195 200 205

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

210 215 220

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

225 230 235 240

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

245 250 255

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

260 265 270

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

275 280 285

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

290 295 300

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

305 310 315 320

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

325 330 335

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

340 345 350

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

355 360 365

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

370 375 380

Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu

385 390 395 400

His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val

405 410 415

Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala

420 425 430

Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr

435 440 445

Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile

450 455 460

Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp

465 470 475 480

Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr

485 490 495

His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys

500 505 510

Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser

515 520 525

Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser

530 535 540

Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu

545 550 555 560

Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys

565 570 575

Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

580 585

<210> 397

<211> 593

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 CAR, having dnTGF beta RII

<400> 397

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn

35 40 45

Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Gly Val Ala Ser Met Tyr Val Gly Gly Gly Tyr Thr Tyr

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ala Ile Ser Ile Ala Leu Thr Arg Glu Phe

115 120 125

Cys Ala Pro Ile Val Ser Arg Tyr Asn Tyr Trp Gly Gln Gly Thr Gln

130 135 140

Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

145 150 155 160

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

165 170 175

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

180 185 190

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

195 200 205

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

210 215 220

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

225 230 235 240

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

245 250 255

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

260 265 270

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

275 280 285

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

290 295 300

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

305 310 315 320

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

325 330 335

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

340 345 350

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

355 360 365

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

370 375 380

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu

385 390 395 400

Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser

405 410 415

Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val

420 425 430

Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys

435 440 445

Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn

450 455 460

Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala

465 470 475 480

Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His

485 490 495

Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser

500 505 510

Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe

515 520 525

Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser

530 535 540

Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln

545 550 555 560

Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val

565 570 575

Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser

580 585 590

Ser

<210> 398

<211> 593

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 CAR, having dnTGF beta RII

<400> 398

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Lys Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn

35 40 45

Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Gly Val Ala Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn

65 70 75 80

Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ala Ile Thr Val Ala Leu Thr Arg Ala Phe

115 120 125

Cys Ala Pro Ile Pro Ser Arg Tyr Thr Asn Trp Gly Gln Gly Thr Gln

130 135 140

Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

145 150 155 160

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

165 170 175

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

180 185 190

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

195 200 205

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

210 215 220

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

225 230 235 240

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

245 250 255

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

260 265 270

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

275 280 285

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

290 295 300

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

305 310 315 320

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

325 330 335

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

340 345 350

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

355 360 365

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

370 375 380

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu

385 390 395 400

Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser

405 410 415

Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val

420 425 430

Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys

435 440 445

Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn

450 455 460

Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala

465 470 475 480

Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His

485 490 495

Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser

500 505 510

Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe

515 520 525

Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser

530 535 540

Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln

545 550 555 560

Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val

565 570 575

Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser

580 585 590

Ser

<210> 399

<211> 585

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 CAR, having dnTGF beta RII

<400> 399

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr

35 40 45

Thr Val Ser Ser Gly Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Arg Val Ala Gln Ile Gly Arg Asp Ala Thr Thr Thr Tyr

65 70 75 80

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ala Arg Asp Asp Ala Glu

85 90 95

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala

100 105 110

Met Tyr Ser Cys Thr Ala Tyr Trp Gly Val Tyr Cys Leu Ser Pro Gly

115 120 125

Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr

130 135 140

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

145 150 155 160

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

165 170 175

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

180 185 190

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

195 200 205

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

210 215 220

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

225 230 235 240

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

245 250 255

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

260 265 270

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

275 280 285

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

290 295 300

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

305 310 315 320

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

325 330 335

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

340 345 350

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala

355 360 365

Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro

370 375 380

Gly Pro Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile

385 390 395 400

Val Leu Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys

405 410 415

Ser Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys

420 425 430

Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp

435 440 445

Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu

450 455 460

Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn

465 470 475 480

Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp

485 490 495

Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys

500 505 510

Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu

515 520 525

Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro

530 535 540

Asp Leu Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro

545 550 555 560

Pro Leu Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg

565 570 575

Val Asn Arg Gln Gln Lys Leu Ser Ser

580 585

<210> 400

<211> 746

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AD58126VH3VL1 tandem CAR with dnTGF beta RII

<400> 400

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Gln Ser

50 55 60

Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys

65 70 75 80

Ala Ser Gly Tyr Thr Phe Thr Ser Tyr Trp Met His Trp Val Lys Gln

85 90 95

Ala Pro Gly Gln Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Thr

100 105 110

Gly His Thr Asp Tyr Asn Gln Lys Phe Lys Asp Arg Ala Thr Leu Thr

115 120 125

Ala Asp Thr Ser Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg

130 135 140

Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Ser Asn Trp Ala Trp

145 150 155 160

Phe Pro Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly

165 170 175

Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val

180 185 190

Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala

195 200 205

Thr Ile Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln

210 215 220

Lys Asn Tyr Leu Thr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys

225 230 235 240

Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg

245 250 255

Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser

260 265 270

Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Asn Asp Tyr Ser

275 280 285

Tyr Pro Leu Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Thr Thr

290 295 300

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

305 310 315 320

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

325 330 335

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

340 345 350

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

355 360 365

Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln

370 375 380

Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser

385 390 395 400

Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys

405 410 415

Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln

420 425 430

Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu

435 440 445

Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg

450 455 460

Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met

465 470 475 480

Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly

485 490 495

Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp

500 505 510

Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly

515 520 525

Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn

530 535 540

Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His

545 550 555 560

Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln

565 570 575

Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val

580 585 590

Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys

595 600 605

Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys

610 615 620

Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu

625 630 635 640

Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His

645 650 655

Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu

660 665 670

Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp

675 680 685

Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn

690 695 700

Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu

705 710 715 720

Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr

725 730 735

Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

740 745

<210> 401

<211> 742

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS51489 tandem CAR with dnTGF beta RII

<400> 401

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Leu Tyr Tyr Tyr Ser Ile His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Ser Ser

100 105 110

Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Pro Tyr Tyr

145 150 155 160

Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly

165 170 175

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile

180 185 190

Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg

195 200 205

Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala

210 215 220

Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser

225 230 235 240

Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg

245 250 255

Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp

260 265 270

Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Phe Ser Tyr Tyr Pro Ile Thr

275 280 285

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

290 295 300

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

305 310 315 320

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

325 330 335

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

340 345 350

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

355 360 365

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

370 375 380

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

385 390 395 400

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

405 410 415

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

420 425 430

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

435 440 445

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

450 455 460

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

465 470 475 480

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

485 490 495

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

500 505 510

Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe

515 520 525

Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met

530 535 540

Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp

545 550 555 560

Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn

565 570 575

Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln

580 585 590

Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys

595 600 605

Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln

610 615 620

Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu

625 630 635 640

Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu

645 650 655

Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro

660 665 670

Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp

675 680 685

Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu

690 695 700

Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly

705 710 715 720

Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg

725 730 735

Gln Gln Lys Leu Ser Ser

740

<210> 402

<211> 741

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS92110 tandem CAR, having dnTGF beta RII

<400> 402

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Ile Tyr Tyr Ser Ser Met His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Tyr Ile Tyr Pro Tyr Tyr

100 105 110

Ser Tyr Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ala Leu Asp

145 150 155 160

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

180 185 190

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

195 200 205

Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln

210 215 220

Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser

225 230 235 240

Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr

245 250 255

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

260 265 270

Tyr Tyr Cys Gln Gln Ala Ser Ser Gly Tyr His Tyr Leu Ile Thr Phe

275 280 285

Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg

290 295 300

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

305 310 315 320

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

325 330 335

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

340 345 350

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg

355 360 365

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

370 375 380

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

385 390 395 400

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

405 410 415

Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

420 425 430

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

435 440 445

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

450 455 460

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

465 470 475 480

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

485 490 495

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

500 505 510

His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser

515 520 525

Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly

530 535 540

Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr

545 550 555 560

Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn

565 570 575

Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu

580 585 590

Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser

595 600 605

Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu

610 615 620

Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu

625 630 635 640

Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu

645 650 655

Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly

660 665 670

Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn

675 680 685

Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu

690 695 700

Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val

705 710 715 720

Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln

725 730 735

Gln Lys Leu Ser Ser

740

<210> 403

<211> 739

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS91156 tandem CAR, having dnTGF beta RII

<400> 403

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Ile Tyr Ser Ser Ser Ile His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ser Ile Ser Ser Tyr Ser

100 105 110

Ser Tyr Thr Ser Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Ala Met Asp

145 150 155 160

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

180 185 190

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

195 200 205

Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln

210 215 220

Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser

225 230 235 240

Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr

245 250 255

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

260 265 270

Tyr Tyr Cys Gln Gln Gly Pro Tyr Tyr His Pro Ile Thr Phe Gly Gln

275 280 285

Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro

290 295 300

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

305 310 315 320

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

325 330 335

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

340 345 350

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

355 360 365

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

370 375 380

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

385 390 395 400

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

405 410 415

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

420 425 430

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

435 440 445

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

450 455 460

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

465 470 475 480

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

485 490 495

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

500 505 510

Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu

515 520 525

Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly

530 535 540

Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile

545 550 555 560

Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met

565 570 575

Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys

580 585 590

Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met

595 600 605

Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys

610 615 620

Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val

625 630 635 640

Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala

645 650 655

Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr

660 665 670

Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile

675 680 685

Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile

690 695 700

Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile

705 710 715 720

Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys

725 730 735

Leu Ser Ser

<210> 404

<211> 739

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS91189 tandem CAR, having dnTGF beta RII

<400> 404

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Leu Ser Tyr Ser Ser Ile His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser

100 105 110

Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Gly Met Asp

145 150 155 160

Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr

180 185 190

Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile

195 200 205

Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln

210 215 220

Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser

225 230 235 240

Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr

245 250 255

Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr

260 265 270

Tyr Tyr Cys Gln Gln Tyr Tyr Trp Tyr Tyr Pro Ile Thr Phe Gly Gln

275 280 285

Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro

290 295 300

Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu

305 310 315 320

Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp

325 330 335

Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly

340 345 350

Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg

355 360 365

Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln

370 375 380

Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu

385 390 395 400

Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala

405 410 415

Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu

420 425 430

Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp

435 440 445

Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu

450 455 460

Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile

465 470 475 480

Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr

485 490 495

Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met

500 505 510

Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu

515 520 525

Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly

530 535 540

Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile

545 550 555 560

Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met

565 570 575

Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys

580 585 590

Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met

595 600 605

Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys

610 615 620

Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val

625 630 635 640

Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala

645 650 655

Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr

660 665 670

Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile

675 680 685

Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile

690 695 700

Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile

705 710 715 720

Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys

725 730 735

Leu Ser Ser

<210> 405

<211> 742

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS51674 tandem CAR, having dnTGF beta RII

<400> 405

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Asn Leu Tyr Ser Tyr Tyr Met His Trp Val Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser

100 105 110

Ser Tyr Thr Ser Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Ala Asp Thr Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Pro Phe Gly Trp Gly

145 150 155 160

Tyr Ala Gly Met Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser

165 170 175

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser

180 185 190

Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly

195 200 205

Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala

210 215 220

Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile

225 230 235 240

Tyr Ser Ala Ser Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly

245 250 255

Ser Arg Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro

260 265 270

Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Pro Ile Thr

275 280 285

Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro

290 295 300

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

305 310 315 320

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

325 330 335

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

340 345 350

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

355 360 365

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

370 375 380

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

385 390 395 400

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

405 410 415

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

420 425 430

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

435 440 445

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

450 455 460

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

465 470 475 480

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

485 490 495

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

500 505 510

Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe

515 520 525

Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met

530 535 540

Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp

545 550 555 560

Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn

565 570 575

Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln

580 585 590

Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys

595 600 605

Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln

610 615 620

Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu

625 630 635 640

Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu

645 650 655

Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro

660 665 670

Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp

675 680 685

Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu

690 695 700

Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly

705 710 715 720

Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg

725 730 735

Gln Gln Lys Leu Ser Ser

740

<210> 406

<211> 623

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS65233 tandem CAR, having dnTGF beta RII

<400> 406

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val His Leu Val Glu Ser

50 55 60

Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Glu Phe Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly

85 90 95

Lys Glu Arg Glu Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr

100 105 110

Val Tyr Ala Asp Ser Val Lys Gly Arg Phe Val Leu Ser Arg Tyr Asn

115 120 125

Ala Lys Ser Ile Met Tyr Leu Gln Met Asn Ser Val Lys Leu Glu Asp

130 135 140

Thr Ala Met Tyr Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp

145 150 155 160

Ser Ser Pro Ser Ser Phe Asp Phe Trp Gly Gln Gly Thr Gln Val Thr

165 170 175

Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

180 185 190

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

195 200 205

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

210 215 220

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

225 230 235 240

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

245 250 255

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

260 265 270

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

275 280 285

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

290 295 300

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

305 310 315 320

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

325 330 335

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

340 345 350

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

355 360 365

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

370 375 380

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

385 390 395 400

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

405 410 415

Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly

420 425 430

Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile

435 440 445

Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp

450 455 460

Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val

465 470 475 480

Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser

485 490 495

Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp

500 505 510

Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro

515 520 525

Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys

530 535 540

Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys

545 550 555 560

Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu

565 570 575

Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr

580 585 590

Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile

595 600 605

Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

610 615 620

<210> 407

<211> 629

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60685 tandem CAR with dnTGF beta RII

<400> 407

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Asn Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln

85 90 95

Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Ser Met Tyr Val Gly Gly

100 105 110

Gly Tyr Thr Tyr Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Arg Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys

130 135 140

Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Ile Ser Ile Ala Leu

145 150 155 160

Thr Arg Glu Phe Cys Ala Pro Ile Val Ser Arg Tyr Asn Tyr Trp Gly

165 170 175

Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg

180 185 190

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

195 200 205

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

210 215 220

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

225 230 235 240

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg

245 250 255

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

260 265 270

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

275 280 285

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

290 295 300

Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

305 310 315 320

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

325 330 335

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

340 345 350

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

355 360 365

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

370 375 380

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

385 390 395 400

His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser

405 410 415

Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly

420 425 430

Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr

435 440 445

Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn

450 455 460

Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu

465 470 475 480

Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser

485 490 495

Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu

500 505 510

Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu

515 520 525

Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu

530 535 540

Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly

545 550 555 560

Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn

565 570 575

Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu

580 585 590

Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val

595 600 605

Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln

610 615 620

Gln Lys Leu Ser Ser

625

<210> 408

<211> 629

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60702 tandem CAR with dnTGF beta RII

<400> 408

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Lys Leu Val Glu Ser

50 55 60

Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Asn Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln

85 90 95

Ala Pro Gly Lys Glu Arg Glu Gly Val Ala Ser Ile Tyr Val Gly Gly

100 105 110

Gly Tyr Thr Asn Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser

115 120 125

Gln Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys

130 135 140

Pro Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Ile Thr Val Ala Leu

145 150 155 160

Thr Arg Ala Phe Cys Ala Pro Ile Pro Ser Arg Tyr Thr Asn Trp Gly

165 170 175

Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg

180 185 190

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

195 200 205

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

210 215 220

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

225 230 235 240

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg

245 250 255

Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro

260 265 270

Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu

275 280 285

Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala

290 295 300

Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu

305 310 315 320

Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly

325 330 335

Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu

340 345 350

Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser

355 360 365

Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly

370 375 380

Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu

385 390 395 400

His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser

405 410 415

Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly

420 425 430

Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr

435 440 445

Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn

450 455 460

Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu

465 470 475 480

Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser

485 490 495

Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu

500 505 510

Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu

515 520 525

Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu

530 535 540

Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly

545 550 555 560

Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn

565 570 575

Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu

580 585 590

Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val

595 600 605

Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln

610 615 620

Gln Lys Leu Ser Ser

625

<210> 409

<211> 621

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS60676 tandem CAR with dnTGF beta RII

<400> 409

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Ser Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Tyr Thr Val Ser Ser Gly Cys Met Gly Trp Phe Arg Gln

85 90 95

Ala Pro Gly Lys Glu Arg Glu Arg Val Ala Gln Ile Gly Arg Asp Ala

100 105 110

Thr Thr Thr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ala Arg

115 120 125

Asp Asp Ala Glu Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro

130 135 140

Glu Asp Thr Ala Met Tyr Ser Cys Thr Ala Tyr Trp Gly Val Tyr Cys

145 150 155 160

Leu Ser Pro Gly Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser

165 170 175

Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

180 185 190

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

195 200 205

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

210 215 220

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

225 230 235 240

Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile

245 250 255

Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp

260 265 270

Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu

275 280 285

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

290 295 300

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

305 310 315 320

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

325 330 335

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

340 345 350

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

355 360 365

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

370 375 380

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

385 390 395 400

Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val

405 410 415

Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly Leu Trp

420 425 430

Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro

435 440 445

His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn

450 455 460

Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe

465 470 475 480

Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr

485 490 495

Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys

500 505 510

Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu

515 520 525

Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile

530 535 540

Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys

545 550 555 560

Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn

565 570 575

Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr Gly Ile

580 585 590

Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile Ile Phe

595 600 605

Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

610 615 620

<210> 410

<211> 996

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AD58126VH3VL1 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 410

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val

20 25 30

Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr

35 40 45

Thr Phe Thr Ser Tyr Trp Met His Trp Val Lys Gln Ala Pro Gly Gln

50 55 60

Gly Leu Glu Trp Ile Gly Tyr Ile Asn Pro Ser Thr Gly His Thr Asp

65 70 75 80

Tyr Asn Gln Lys Phe Lys Asp Arg Ala Thr Leu Thr Ala Asp Thr Ser

85 90 95

Thr Ser Thr Val Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Ser Asn Trp Ala Trp Phe Pro Tyr Trp

115 120 125

Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Met Thr Gln Ser

145 150 155 160

Pro Asp Ser Leu Ala Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys

165 170 175

Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Tyr Leu

180 185 190

Thr Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr

195 200 205

Trp Ala Ser Thr Arg Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser

210 215 220

Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu

225 230 235 240

Asp Val Ala Val Tyr Tyr Cys Gln Asn Asp Tyr Ser Tyr Pro Leu Thr

245 250 255

Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Thr Thr Thr Pro Ala Pro

260 265 270

Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu

275 280 285

Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg

290 295 300

Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly

305 310 315 320

Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys

325 330 335

Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg

340 345 350

Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro

355 360 365

Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser

370 375 380

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

385 390 395 400

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

405 410 415

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

420 425 430

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

435 440 445

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

450 455 460

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

465 470 475 480

Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe

485 490 495

Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met

500 505 510

Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His

515 520 525

Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg

530 535 540

Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg

545 550 555 560

Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg

565 570 575

Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly

580 585 590

Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr

595 600 605

Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser

610 615 620

Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg

625 630 635 640

Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg

645 650 655

Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp

660 665 670

Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn

675 680 685

Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg

690 695 700

Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly

705 710 715 720

Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu

725 730 735

Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu

740 745 750

Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His

755 760 765

Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu

770 775 780

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg

785 790 795 800

Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg

805 810 815

Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp

820 825 830

Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys

835 840 845

Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys

850 855 860

Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val

865 870 875 880

Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr

885 890 895

Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp

900 905 910

Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu

915 920 925

Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile

930 935 940

Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val

945 950 955 960

Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala

965 970 975

Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln

980 985 990

Lys Leu Ser Ser

995

<210> 411

<211> 992

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51489 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 411

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Tyr Tyr Tyr Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Tyr Ile Ser Ser Ser Ser Ser Tyr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Pro Tyr Tyr Gly Met Asp Tyr

115 120 125

Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser

130 135 140

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln

145 150 155 160

Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr

165 170 175

Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln

180 185 190

Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu

195 200 205

Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp

210 215 220

Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr

225 230 235 240

Tyr Cys Gln Gln Gly Phe Ser Tyr Tyr Pro Ile Thr Phe Gly Gln Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys

485 490 495

Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val

500 505 510

Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro

515 520 525

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

530 535 540

Lys Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

545 550 555 560

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

565 570 575

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

580 585 590

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

595 600 605

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg

610 615 620

Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro

625 630 635 640

Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala

645 650 655

Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

660 665 670

Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

675 680 685

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

690 695 700

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

705 710 715 720

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

725 730 735

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

740 745 750

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

755 760 765

Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala

770 775 780

Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg

785 790 795 800

Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr

805 810 815

Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr

820 825 830

Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp

835 840 845

Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys

850 855 860

Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val

865 870 875 880

Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp

885 890 895

Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro

900 905 910

Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met

915 920 925

Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu

930 935 940

Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val

945 950 955 960

Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile

965 970 975

Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

980 985 990

<210> 412

<211> 991

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS92110 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 412

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Ile Tyr Tyr Ser Ser Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Tyr Ile Tyr Pro Tyr Tyr Ser Tyr Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Gly Tyr Ala Leu Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Ala Ser Ser Gly Tyr His Tyr Leu Ile Thr Phe Gly Gln Gly Thr

245 250 255

Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

260 265 270

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

275 280 285

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

290 295 300

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

305 310 315 320

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

325 330 335

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

340 345 350

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

355 360 365

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

370 375 380

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

385 390 395 400

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

405 410 415

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

420 425 430

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

435 440 445

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

450 455 460

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

465 470 475 480

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

485 490 495

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr

500 505 510

Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr

515 520 525

Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys

530 535 540

Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

545 550 555 560

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

565 570 575

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

580 585 590

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

595 600 605

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu

610 615 620

Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr

625 630 635 640

Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr

645 650 655

Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

660 665 670

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

675 680 685

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

690 695 700

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

705 710 715 720

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

725 730 735

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

740 745 750

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

755 760 765

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

770 775 780

Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly

785 790 795 800

Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile

805 810 815

Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp

820 825 830

Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val

835 840 845

Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser

850 855 860

Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp

865 870 875 880

Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro

885 890 895

Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys

900 905 910

Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys

915 920 925

Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu

930 935 940

Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr

945 950 955 960

Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile

965 970 975

Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

980 985 990

<210> 413

<211> 989

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91156 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 413

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Ile Tyr Ser Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Ser Ser Tyr Ser Ser Tyr Thr Ser

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Tyr Ala Met Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Gly Pro Tyr Tyr His Pro Ile Thr Phe Gly Gln Gly Thr Lys Val

245 250 255

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

260 265 270

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

275 280 285

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

290 295 300

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

305 310 315 320

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

325 330 335

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

340 345 350

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

355 360 365

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

370 375 380

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

385 390 395 400

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

405 410 415

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

420 425 430

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

435 440 445

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

450 455 460

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

465 470 475 480

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

485 490 495

Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu

500 505 510

Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg

515 520 525

Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys

530 535 540

Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

545 550 555 560

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

565 570 575

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

580 585 590

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

595 600 605

Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His

610 615 620

Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys

625 630 635 640

His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser

645 650 655

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

660 665 670

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

675 680 685

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

690 695 700

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

705 710 715 720

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

725 730 735

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

740 745 750

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

755 760 765

Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val

770 775 780

Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly Leu Trp

785 790 795 800

Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro

805 810 815

His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn

820 825 830

Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe

835 840 845

Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr

850 855 860

Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys

865 870 875 880

Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu

885 890 895

Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile

900 905 910

Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys

915 920 925

Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn

930 935 940

Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr Gly Ile

945 950 955 960

Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile Ile Phe

965 970 975

Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

980 985

<210> 414

<211> 989

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS91189 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 414

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Ser Tyr Ser Ser Ile His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Gly Ser Thr Tyr

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Tyr Trp Gly Met Asp Tyr Trp Gly Gln

115 120 125

Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser

145 150 155 160

Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala

165 170 175

Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr Gln Gln Lys Pro Gly

180 185 190

Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser Ser Leu Tyr Ser Gly

195 200 205

Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly Thr Asp Phe Thr Leu

210 215 220

Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln

225 230 235 240

Gln Tyr Tyr Trp Tyr Tyr Pro Ile Thr Phe Gly Gln Gly Thr Lys Val

245 250 255

Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

260 265 270

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

275 280 285

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

290 295 300

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

305 310 315 320

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

325 330 335

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

340 345 350

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

355 360 365

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

370 375 380

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

385 390 395 400

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

405 410 415

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

420 425 430

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

435 440 445

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

450 455 460

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

465 470 475 480

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

485 490 495

Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu

500 505 510

Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg

515 520 525

Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys

530 535 540

Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

545 550 555 560

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

565 570 575

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

580 585 590

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

595 600 605

Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His

610 615 620

Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys

625 630 635 640

His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser

645 650 655

Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly

660 665 670

Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr

675 680 685

Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys

690 695 700

Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys

705 710 715 720

Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg

725 730 735

Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala

740 745 750

Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

755 760 765

Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val

770 775 780

Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly Leu Trp

785 790 795 800

Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro

805 810 815

His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn

820 825 830

Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe

835 840 845

Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr

850 855 860

Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys

865 870 875 880

Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu

885 890 895

Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile

900 905 910

Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys

915 920 925

Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn

930 935 940

Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr Gly Ile

945 950 955 960

Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile Ile Phe

965 970 975

Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

980 985

<210> 415

<211> 992

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS51674 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 415

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Asn Leu Tyr Ser Tyr Tyr Met His Trp Val Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Trp Val Ala Ser Ile Tyr Ser Tyr Ser Ser Tyr Thr Ser

65 70 75 80

Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser

85 90 95

Lys Asn Thr Ala Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Arg Pro Phe Gly Trp Gly Tyr Ala Gly Met

115 120 125

Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly

130 135 140

Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met

145 150 155 160

Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr

165 170 175

Ile Thr Cys Arg Ala Ser Gln Ser Val Ser Ser Ala Val Ala Trp Tyr

180 185 190

Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ser Ala Ser

195 200 205

Ser Leu Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Arg Ser Gly

210 215 220

Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala

225 230 235 240

Thr Tyr Tyr Cys Gln Gln Gly Tyr Ala Pro Ile Thr Phe Gly Gln Gly

245 250 255

Thr Lys Val Glu Ile Lys Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

260 265 270

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

275 280 285

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

290 295 300

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

305 310 315 320

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

325 330 335

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

340 345 350

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

355 360 365

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

370 375 380

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

385 390 395 400

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

405 410 415

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

420 425 430

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

435 440 445

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

450 455 460

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

465 470 475 480

Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys

485 490 495

Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val

500 505 510

Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro

515 520 525

Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln

530 535 540

Lys Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

545 550 555 560

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

565 570 575

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

580 585 590

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

595 600 605

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg

610 615 620

Leu Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro

625 630 635 640

Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala

645 650 655

Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr

660 665 670

Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg

675 680 685

Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met

690 695 700

Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu

705 710 715 720

Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys

725 730 735

Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu

740 745 750

Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu

755 760 765

Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala

770 775 780

Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg

785 790 795 800

Gly Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr

805 810 815

Ile Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr

820 825 830

Asp Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp

835 840 845

Val Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys

850 855 860

Ser Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val

865 870 875 880

Trp Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp

885 890 895

Pro Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro

900 905 910

Lys Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met

915 920 925

Cys Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu

930 935 940

Glu Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val

945 950 955 960

Thr Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile

965 970 975

Ile Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

980 985 990

<210> 416

<211> 873

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 416

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val His Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe

35 40 45

Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu

50 55 60

Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Val Leu Ser Arg Tyr Asn Ala Lys Ser Ile

85 90 95

Met Tyr Leu Gln Met Asn Ser Val Lys Leu Glu Asp Thr Ala Met Tyr

100 105 110

Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser

115 120 125

Ser Phe Asp Phe Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr

130 135 140

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

145 150 155 160

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

165 170 175

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

180 185 190

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

195 200 205

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

210 215 220

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

225 230 235 240

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

245 250 255

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

260 265 270

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

275 280 285

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

290 295 300

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

305 310 315 320

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

325 330 335

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

340 345 350

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

355 360 365

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

370 375 380

Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu

385 390 395 400

Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr

405 410 415

Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr

420 425 430

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

435 440 445

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

450 455 460

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

465 470 475 480

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

485 490 495

Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met

500 505 510

Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro

515 520 525

Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe

530 535 540

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

545 550 555 560

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

565 570 575

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

580 585 590

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

595 600 605

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

610 615 620

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

625 630 635 640

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala

645 650 655

Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro

660 665 670

Gly Pro Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile

675 680 685

Val Leu Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys

690 695 700

Ser Val Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys

705 710 715 720

Phe Pro Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp

725 730 735

Asn Gln Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu

740 745 750

Lys Pro Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn

755 760 765

Ile Thr Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp

770 775 780

Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys

785 790 795 800

Lys Lys Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu

805 810 815

Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro

820 825 830

Asp Leu Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro

835 840 845

Pro Leu Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg

850 855 860

Val Asn Arg Gln Gln Lys Leu Ser Ser

865 870

<210> 417

<211> 879

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60685 + FSH beta 33-53 Dual CAR, having dnTGF beta RII

<400> 417

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn

35 40 45

Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Gly Val Ala Ser Met Tyr Val Gly Gly Gly Tyr Thr Tyr

65 70 75 80

Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ala Ile Ser Ile Ala Leu Thr Arg Glu Phe

115 120 125

Cys Ala Pro Ile Val Ser Arg Tyr Asn Tyr Trp Gly Gln Gly Thr Gln

130 135 140

Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

145 150 155 160

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

165 170 175

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

180 185 190

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

195 200 205

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

210 215 220

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

225 230 235 240

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

245 250 255

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

260 265 270

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

275 280 285

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

290 295 300

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

305 310 315 320

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

325 330 335

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

340 345 350

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

355 360 365

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

370 375 380

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr

385 390 395 400

Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr

405 410 415

Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys

420 425 430

Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

435 440 445

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

450 455 460

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

465 470 475 480

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

485 490 495

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu

500 505 510

Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr

515 520 525

Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr

530 535 540

Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

545 550 555 560

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

565 570 575

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

580 585 590

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

595 600 605

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

610 615 620

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

625 630 635 640

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

645 650 655

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

660 665 670

Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly

675 680 685

Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile

690 695 700

Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp

705 710 715 720

Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val

725 730 735

Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser

740 745 750

Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp

755 760 765

Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro

770 775 780

Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys

785 790 795 800

Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys

805 810 815

Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu

820 825 830

Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr

835 840 845

Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile

850 855 860

Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

865 870 875

<210> 418

<211> 879

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60702 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 418

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Lys Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Asn

35 40 45

Val Tyr Asn Asn Met Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Gly Val Ala Ser Ile Tyr Val Gly Gly Gly Tyr Thr Asn

65 70 75 80

Tyr Ala Asp Ser Val Arg Gly Arg Phe Thr Ile Ser Gln Asp Asn Ala

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Ala Ile Thr Val Ala Leu Thr Arg Ala Phe

115 120 125

Cys Ala Pro Ile Pro Ser Arg Tyr Thr Asn Trp Gly Gln Gly Thr Gln

130 135 140

Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro

145 150 155 160

Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys

165 170 175

Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala

180 185 190

Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu

195 200 205

Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys

210 215 220

Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr

225 230 235 240

Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly

245 250 255

Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala

260 265 270

Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg

275 280 285

Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu

290 295 300

Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn

305 310 315 320

Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met

325 330 335

Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly

340 345 350

Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala

355 360 365

Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln

370 375 380

Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr

385 390 395 400

Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr

405 410 415

Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys

420 425 430

Thr Cys Thr Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala

435 440 445

Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg

450 455 460

Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys

465 470 475 480

Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu

485 490 495

Leu Ser Leu Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu

500 505 510

Leu His Ser Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr

515 520 525

Arg Lys His Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr

530 535 540

Arg Ser Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

545 550 555 560

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

565 570 575

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

580 585 590

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

595 600 605

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

610 615 620

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

625 630 635 640

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

645 650 655

Pro Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly

660 665 670

Asp Val Glu Glu Asn Pro Gly Pro Met Gly Arg Gly Leu Leu Arg Gly

675 680 685

Leu Trp Pro Leu His Ile Val Leu Trp Thr Arg Ile Ala Ser Thr Ile

690 695 700

Pro Pro His Val Gln Lys Ser Val Asn Asn Asp Met Ile Val Thr Asp

705 710 715 720

Asn Asn Gly Ala Val Lys Phe Pro Gln Leu Cys Lys Phe Cys Asp Val

725 730 735

Arg Phe Ser Thr Cys Asp Asn Gln Lys Ser Cys Met Ser Asn Cys Ser

740 745 750

Ile Thr Ser Ile Cys Glu Lys Pro Gln Glu Val Cys Val Ala Val Trp

755 760 765

Arg Lys Asn Asp Glu Asn Ile Thr Leu Glu Thr Val Cys His Asp Pro

770 775 780

Lys Leu Pro Tyr His Asp Phe Ile Leu Glu Asp Ala Ala Ser Pro Lys

785 790 795 800

Cys Ile Met Lys Glu Lys Lys Lys Pro Gly Glu Thr Phe Phe Met Cys

805 810 815

Ser Cys Ser Ser Asp Glu Cys Asn Asp Asn Ile Ile Phe Ser Glu Glu

820 825 830

Tyr Asn Thr Ser Asn Pro Asp Leu Leu Leu Val Ile Phe Gln Val Thr

835 840 845

Gly Ile Ser Leu Leu Pro Pro Leu Gly Val Ala Ile Ser Val Ile Ile

850 855 860

Ile Phe Tyr Cys Tyr Arg Val Asn Arg Gln Gln Lys Leu Ser Ser

865 870 875

<210> 419

<211> 871

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS60676 + FSH beta 33-53 Dual CAR with dnTGF beta RII

<400> 419

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Ser

20 25 30

Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr

35 40 45

Thr Val Ser Ser Gly Cys Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Glu Arg Glu Arg Val Ala Gln Ile Gly Arg Asp Ala Thr Thr Thr Tyr

65 70 75 80

Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ala Arg Asp Asp Ala Glu

85 90 95

Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala

100 105 110

Met Tyr Ser Cys Thr Ala Tyr Trp Gly Val Tyr Cys Leu Ser Pro Gly

115 120 125

Arg Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser Thr Thr Thr

130 135 140

Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro

145 150 155 160

Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val

165 170 175

His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro

180 185 190

Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu

195 200 205

Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro

210 215 220

Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys

225 230 235 240

Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe

245 250 255

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

260 265 270

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

275 280 285

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

290 295 300

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

305 310 315 320

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

325 330 335

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

340 345 350

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala

355 360 365

Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro

370 375 380

Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu

385 390 395 400

Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp

405 410 415

Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr Thr Pro

420 425 430

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

435 440 445

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

450 455 460

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

465 470 475 480

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

485 490 495

Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met

500 505 510

Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala

515 520 525

Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg

530 535 540

Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn

545 550 555 560

Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg

565 570 575

Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro

580 585 590

Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala

595 600 605

Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His

610 615 620

Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp

625 630 635 640

Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr Asn

645 650 655

Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro

660 665 670

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

675 680 685

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

690 695 700

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

705 710 715 720

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

725 730 735

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

740 745 750

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

755 760 765

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

770 775 780

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

785 790 795 800

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

805 810 815

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

820 825 830

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

835 840 845

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

850 855 860

Arg Gln Gln Lys Leu Ser Ser

865 870

<210> 420

<211> 122

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH4

<400> 420

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Tyr Ser Met Gly

20 25 30

Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val Ser His Ile

35 40 45

Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys Gly Arg

50 55 60

Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met

65 70 75 80

Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Arg

85 90 95

Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser Phe Asp Phe Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 421

<211> 122

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH5

<400> 421

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Tyr Ser Met Gly

20 25 30

Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val Ala His Ile

35 40 45

Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys Gly Arg

50 55 60

Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr Met Tyr Leu Gln Met

65 70 75 80

Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Arg

85 90 95

Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser Phe Asp Phe Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 422

<211> 122

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH6

<400> 422

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Tyr Ser Met Gly

20 25 30

Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val Ala His Ile

35 40 45

Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys Gly Arg

50 55 60

Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr Met Tyr Leu Gln Met

65 70 75 80

Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala Ala Arg

85 90 95

Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser Phe Asp Phe Trp

100 105 110

Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 423

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH4

<400> 423

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Asn

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val

35 40 45

Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val Tyr Ser Asp Ser Val

50 55 60

Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu Ala Val Asn Gly Tyr

100 105 110

Asn His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 424

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH5

<400> 424

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Asn

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val

35 40 45

Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val Tyr Ser Asp Ser Val

50 55 60

Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu Ala Val Asn Gly Tyr

100 105 110

Asn His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 425

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH6

<400> 425

Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Arg Asn

20 25 30

Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val

35 40 45

Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val Tyr Ser Asp Ser Val

50 55 60

Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu Ala Val Asn Gly Tyr

100 105 110

Asn His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120 125

<210> 426

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH4

<400> 426

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ser Phe Ser Thr Tyr

20 25 30

Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val

35 40 45

Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val Tyr Thr Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu Ala Ile Asn Gly Tyr

100 105 110

Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 427

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH5

<400> 427

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ser Phe Ser Thr Tyr

20 25 30

Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val

35 40 45

Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val Tyr Thr Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu Ala Ile Asn Gly Tyr

100 105 110

Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 428

<211> 125

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH6

<400> 428

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ser Phe Ser Thr Tyr

20 25 30

Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Arg Glu Gly Val

35 40 45

Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val Tyr Thr Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Val Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys

85 90 95

Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu Ala Ile Asn Gly Tyr

100 105 110

Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser

115 120 125

<210> 429

<211> 333

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> TC-210

<400> 429

Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser

1 5 10 15

Val Gly Val Trp Gly Gln Glu Val Gln Leu Val Glu Ser Gly Gly Gly

20 25 30

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

35 40 45

Gly Asp Trp Ser Ala Asn Phe Met Tyr Trp Tyr Arg Gln Ala Pro Gly

50 55 60

Lys Gln Arg Glu Leu Val Ala Arg Ile Ser Gly Arg Gly Val Val Asp

65 70 75 80

Tyr Val Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Val Ala Ser Tyr Trp Gly Gln Gly Thr Leu

115 120 125

Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

130 135 140

Gly Gly Gly Ser Asp Gly Asn Glu Glu Met Gly Gly Ile Thr Gln Thr

145 150 155 160

Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr Cys Pro

165 170 175

Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys Asn Ile

180 185 190

Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp His Leu

195 200 205

Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys

210 215 220

Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu

225 230 235 240

Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val Met Ser Val

245 250 255

Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu Leu Leu

260 265 270

Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys Pro Val

275 280 285

Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn Lys Glu

290 295 300

Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg Lys Gly

305 310 315 320

Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile

325 330

<210> 430

<211> 22

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 epsilon Signal peptide

<400> 430

Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser

1 5 10 15

Val Gly Val Trp Gly Gln

<210> 431

<211> 22

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 gamma signal peptide

<400> 431

Met Glu Gln Gly Lys Gly Leu Ala Val Leu Ile Leu Ala Ile Ile Leu

1 5 10 15

Leu Gln Gly Thr Leu Ala

<210> 432

<211> 21

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 delta signal peptide

<400> 432

Met Glu His Ser Thr Phe Leu Ser Gly Leu Val Leu Ala Thr Leu Leu

1 5 10 15

Ser Gln Val Ser Pro

<210> 433

<211> 104

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 epsilon extracellular domain

<400> 433

Asp Gly Asn Glu Glu Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val

1 5 10 15

Ser Ile Ser Gly Thr Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly

20 25 30

Ser Glu Ile Leu Trp Gln His Asn Asp Lys Asn Ile Gly Gly Asp Glu

35 40 45

Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp His Leu Ser Leu Lys Glu

50 55 60

Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly

65 70 75 80

Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val

85 90 95

Cys Glu Asn Cys Met Glu Met Asp

100

<210> 434

<211> 94

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 gamma extracellular domain

<400> 434

Gln Ser Ile Lys Gly Asn His Leu Val Lys Val Tyr Asp Tyr Gln Glu

1 5 10 15

Asp Gly Ser Val Leu Leu Thr Cys Asp Ala Glu Ala Lys Asn Ile Thr

20 25 30

Trp Phe Lys Asp Gly Lys Met Ile Gly Phe Leu Thr Glu Asp Lys Lys

35 40 45

Lys Trp Asn Leu Gly Ser Asn Ala Lys Asp Pro Arg Gly Met Tyr Gln

50 55 60

Cys Lys Gly Ser Gln Asn Lys Ser Lys Pro Leu Gln Val Tyr Tyr Arg

65 70 75 80

Met Cys Gln Asn Cys Ile Glu Leu Asn Ala Ala Thr Ile Ser

85 90

<210> 435

<211> 84

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 delta extracellular domain

<400> 435

Phe Lys Ile Pro Ile Glu Glu Leu Glu Asp Arg Val Phe Val Asn Cys

1 5 10 15

Asn Thr Ser Ile Thr Trp Val Glu Gly Thr Val Gly Thr Leu Leu Ser

20 25 30

Asp Ile Thr Arg Leu Asp Leu Gly Lys Arg Ile Leu Asp Pro Arg Gly

35 40 45

Ile Tyr Arg Cys Asn Gly Thr Asp Ile Tyr Lys Asp Lys Glu Ser Thr

50 55 60

Val Gln Val His Tyr Arg Met Cys Gln Ser Cys Val Glu Leu Asp Pro

65 70 75 80

Ala Thr Val Ala

<210> 436

<211> 26

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 epsilon transmembrane domain

<400> 436

Val Met Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly

1 5 10 15

Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser

20 25

<210> 437

<211> 21

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 gamma transmembrane domain

<400> 437

Gly Phe Leu Phe Ala Glu Ile Val Ser Ile Phe Val Leu Ala Val Gly

1 5 10 15

Val Tyr Phe Ile Ala

<210> 438

<211> 21

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 delta transmembrane domain

<400> 438

Gly Ile Ile Val Thr Asp Val Ile Ala Thr Leu Leu Leu Ala Leu Gly

1 5 10 15

Val Phe Cys Phe Ala

<210> 439

<211> 55

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 epsilon intracellular domain

<400> 439

Lys Asn Arg Lys Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala

1 5 10 15

Gly Gly Arg Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro

20 25 30

Asn Pro Asp Tyr Glu Pro Ile Arg Lys Gly Gln Arg Asp Leu Tyr Ser

35 40 45

Gly Leu Asn Gln Arg Arg Ile

50 55

<210> 440

<211> 45

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 gamma intracellular domain

<400> 440

Gly Gln Asp Gly Val Arg Gln Ser Arg Ala Ser Asp Lys Gln Thr Leu

1 5 10 15

Leu Pro Asn Asp Gln Leu Tyr Gln Pro Leu Lys Asp Arg Glu Asp Asp

20 25 30

Gln Tyr Ser His Leu Gln Gly Asn Gln Leu Arg Arg Asn

35 40 45

<210> 441

<211> 45

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> CD3 delta intracellular domain

<400> 441

Gly His Glu Thr Gly Arg Leu Ser Gly Ala Ala Asp Thr Gln Ala Leu

1 5 10 15

Leu Arg Asn Asp Gln Val Tyr Gln Pro Leu Arg Asp Arg Asp Asp Ala

20 25 30

Gln Tyr Ser His Leu Gly Gly Asn Trp Ala Arg Asn Lys

35 40 45

<210> 442

<211> 243

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSHβ 33-53 εTCR

<400> 442

Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser

1 5 10 15

Val Gly Val Trp Gly Gln Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro

20 25 30

Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser

35 40 45

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Gly Asn Glu Glu Met

50 55 60

Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr

65 70 75 80

Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln

85 90 95

His Asn Asp Lys Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly

100 105 110

Ser Asp Glu Asp His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln

115 120 125

Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala

130 135 140

Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu

145 150 155 160

Met Asp Val Met Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile

165 170 175

Thr Gly Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys

180 185 190

Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln

195 200 205

Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr

210 215 220

Glu Pro Ile Arg Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln

225 230 235 240

Arg Arg Ile

<210> 443

<211> 218

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSHβ 33-53 γTCR

<400> 443

Met Glu Gln Gly Lys Gly Leu Ala Val Leu Ile Leu Ala Ile Ile Leu

1 5 10 15

Leu Gln Gly Thr Leu Ala Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro

20 25 30

Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser

35 40 45

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Ser Ile Lys Gly Asn

50 55 60

His Leu Val Lys Val Tyr Asp Tyr Gln Glu Asp Gly Ser Val Leu Leu

65 70 75 80

Thr Cys Asp Ala Glu Ala Lys Asn Ile Thr Trp Phe Lys Asp Gly Lys

85 90 95

Met Ile Gly Phe Leu Thr Glu Asp Lys Lys Lys Trp Asn Leu Gly Ser

100 105 110

Asn Ala Lys Asp Pro Arg Gly Met Tyr Gln Cys Lys Gly Ser Gln Asn

115 120 125

Lys Ser Lys Pro Leu Gln Val Tyr Tyr Arg Met Cys Gln Asn Cys Ile

130 135 140

Glu Leu Asn Ala Ala Thr Ile Ser Gly Phe Leu Phe Ala Glu Ile Val

145 150 155 160

Ser Ile Phe Val Leu Ala Val Gly Val Tyr Phe Ile Ala Gly Gln Asp

165 170 175

Gly Val Arg Gln Ser Arg Ala Ser Asp Lys Gln Thr Leu Leu Pro Asn

180 185 190

Asp Gln Leu Tyr Gln Pro Leu Lys Asp Arg Glu Asp Asp Gln Tyr Ser

195 200 205

His Leu Gln Gly Asn Gln Leu Arg Arg Asn

210 215

<210> 444

<211> 207

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSHβ 33-53 δTCR

<400> 444

Met Glu His Ser Thr Phe Leu Ser Gly Leu Val Leu Ala Thr Leu Leu

1 5 10 15

Ser Gln Val Ser Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Phe Lys Ile Pro Ile Glu Glu

50 55 60

Leu Glu Asp Arg Val Phe Val Asn Cys Asn Thr Ser Ile Thr Trp Val

65 70 75 80

Glu Gly Thr Val Gly Thr Leu Leu Ser Asp Ile Thr Arg Leu Asp Leu

85 90 95

Gly Lys Arg Ile Leu Asp Pro Arg Gly Ile Tyr Arg Cys Asn Gly Thr

100 105 110

Asp Ile Tyr Lys Asp Lys Glu Ser Thr Val Gln Val His Tyr Arg Met

115 120 125

Cys Gln Ser Cys Val Glu Leu Asp Pro Ala Thr Val Ala Gly Ile Ile

130 135 140

Val Thr Asp Val Ile Ala Thr Leu Leu Leu Ala Leu Gly Val Phe Cys

145 150 155 160

Phe Ala Gly His Glu Thr Gly Arg Leu Ser Gly Ala Ala Asp Thr Gln

165 170 175

Ala Leu Leu Arg Asn Asp Gln Val Tyr Gln Pro Leu Arg Asp Arg Asp

180 185 190

Asp Ala Gln Tyr Ser His Leu Gly Gly Asn Trp Ala Arg Asn Lys

195 200 205

<210> 445

<211> 366

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH5 CAR

<400> 445

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe

35 40 45

Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

50 55 60

Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Met Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr

100 105 110

Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser

115 120 125

Ser Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr

130 135 140

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

145 150 155 160

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

165 170 175

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

180 185 190

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

195 200 205

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

210 215 220

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

225 230 235 240

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

245 250 255

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

260 265 270

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

275 280 285

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

290 295 300

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

305 310 315 320

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

325 330 335

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

340 345 350

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

355 360 365

<210> 446

<211> 369

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH5 CAR

<400> 446

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Arg Asn Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Gly Val Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val

65 70 75 80

Tyr Ser Asp Ser Val Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu

115 120 125

Ala Val Asn Gly Tyr Asn His Trp Gly Gln Gly Thr Leu Val Thr Val

130 135 140

Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

145 150 155 160

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

165 170 175

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

180 185 190

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

195 200 205

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

210 215 220

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

225 230 235 240

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

245 250 255

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln

260 265 270

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

275 280 285

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

290 295 300

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

305 310 315 320

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

325 330 335

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

340 345 350

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

355 360 365

Arg

<210> 447

<211> 369

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH4 CAR

<400> 447

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu

35 40 45

Ser Phe Ser Thr Tyr Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Gly Val Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val

65 70 75 80

Tyr Thr Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu

115 120 125

Ala Ile Asn Gly Tyr Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val

130 135 140

Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

145 150 155 160

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

165 170 175

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

180 185 190

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

195 200 205

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

210 215 220

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

225 230 235 240

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

245 250 255

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln

260 265 270

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

275 280 285

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

290 295 300

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

305 310 315 320

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

325 330 335

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

340 345 350

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

355 360 365

Arg

<210> 448

<211> 402

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS65233VH5 tandem CAR

<400> 448

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Glu Phe Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly

85 90 95

Lys Gly Leu Glu Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr

100 105 110

Val Tyr Ala Asp Ser Val Lys Gly Arg Phe Val Leu Ser Arg Asp Asn

115 120 125

Ser Lys Asn Thr Met Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

130 135 140

Thr Ala Met Tyr Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp

145 150 155 160

Ser Ser Pro Ser Ser Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr

165 170 175

Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

180 185 190

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

195 200 205

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

210 215 220

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

225 230 235 240

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

245 250 255

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

260 265 270

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

275 280 285

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

290 295 300

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

305 310 315 320

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

325 330 335

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

340 345 350

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

355 360 365

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

370 375 380

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

385 390 395 400

Pro Arg

<210> 449

<211> 405

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS80444VH5 tandem CAR

<400> 449

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Phe Thr Phe Ser Arg Asn Thr Met Gly Trp Phe Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Gly Val Ser Ala Ile Pro Tyr Thr Ser

100 105 110

Thr Gly Ile Val Tyr Ser Asp Ser Val Gly Gly Arg Phe Thr Ile Ser

115 120 125

Arg Asp Asn Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly

145 150 155 160

Thr Thr Met Leu Ala Val Asn Gly Tyr Asn His Trp Gly Gln Gly Thr

165 170 175

Leu Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

180 185 190

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

195 200 205

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

210 215 220

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

225 230 235 240

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

245 250 255

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

260 265 270

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

275 280 285

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

290 295 300

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

305 310 315 320

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

325 330 335

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

340 345 350

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

355 360 365

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

370 375 380

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

385 390 395 400

Ala Leu Pro Pro Arg

405

<210> 450

<211> 405

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS80533VH4 tandem CAR

<400> 450

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala

20 25 30

Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly

35 40 45

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser

50 55 60

Gly Gly Gly Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala

65 70 75 80

Ala Ser Gly Leu Ser Phe Ser Thr Tyr Thr Val Ala Trp Phe Arg Gln

85 90 95

Ala Pro Gly Lys Gly Leu Glu Gly Val Ala Ala Ile Pro Tyr Thr Ser

100 105 110

Gln His Met Val Tyr Thr Asp Ser Val Lys Gly Arg Phe Thr Ile Ser

115 120 125

Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg

130 135 140

Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly

145 150 155 160

Thr Ser Met Leu Ala Ile Asn Gly Tyr Asn Arg Trp Gly Gln Gly Thr

165 170 175

Thr Val Thr Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr

180 185 190

Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala

195 200 205

Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe

210 215 220

Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val

225 230 235 240

Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys

245 250 255

Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr

260 265 270

Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu

275 280 285

Gly Gly Cys Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro

290 295 300

Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly

305 310 315 320

Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro

325 330 335

Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr

340 345 350

Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly

355 360 365

Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln

370 375 380

Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln

385 390 395 400

Ala Leu Pro Pro Arg

405

<210> 451

<211> 652

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH5 + FSH beta 33-53 Dual CAR

<400> 451

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe

35 40 45

Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

50 55 60

Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Met Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr

100 105 110

Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser

115 120 125

Ser Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr

130 135 140

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

145 150 155 160

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

165 170 175

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

180 185 190

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

195 200 205

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

210 215 220

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

225 230 235 240

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

245 250 255

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

260 265 270

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

275 280 285

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

290 295 300

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

305 310 315 320

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

325 330 335

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

340 345 350

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

355 360 365

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

370 375 380

Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu

385 390 395 400

Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr

405 410 415

Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr

420 425 430

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

435 440 445

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

450 455 460

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

465 470 475 480

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

485 490 495

Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met

500 505 510

Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro

515 520 525

Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe

530 535 540

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

545 550 555 560

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

565 570 575

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

580 585 590

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

595 600 605

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

610 615 620

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

625 630 635 640

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

645 650

<210> 452

<211> 655

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH5 + FSH β 33-53 Dual CAR

<400> 452

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Arg Asn Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Gly Val Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val

65 70 75 80

Tyr Ser Asp Ser Val Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu

115 120 125

Ala Val Asn Gly Tyr Asn His Trp Gly Gln Gly Thr Leu Val Thr Val

130 135 140

Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

145 150 155 160

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

165 170 175

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

180 185 190

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

195 200 205

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

210 215 220

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

225 230 235 240

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

245 250 255

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln

260 265 270

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

275 280 285

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

290 295 300

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

305 310 315 320

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

325 330 335

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

340 345 350

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

355 360 365

Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp

370 375 380

Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu

385 390 395 400

Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp

405 410 415

Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr

420 425 430

Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

435 440 445

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

450 455 460

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

465 470 475 480

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

485 490 495

Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser

500 505 510

Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His

515 520 525

Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg

530 535 540

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln

545 550 555 560

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

565 570 575

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

580 585 590

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

595 600 605

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

610 615 620

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

625 630 635 640

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

645 650 655

<210> 453

<211> 655

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH4 FSH beta 33-53 Dual CAR

<400> 453

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu

35 40 45

Ser Phe Ser Thr Tyr Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Gly Val Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val

65 70 75 80

Tyr Thr Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu

115 120 125

Ala Ile Asn Gly Tyr Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val

130 135 140

Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

145 150 155 160

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

165 170 175

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

180 185 190

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

195 200 205

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

210 215 220

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

225 230 235 240

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

245 250 255

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln

260 265 270

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

275 280 285

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

290 295 300

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

305 310 315 320

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

325 330 335

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

340 345 350

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

355 360 365

Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp

370 375 380

Val Glu Glu Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu

385 390 395 400

Leu Pro Leu Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp

405 410 415

Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr

420 425 430

Phe Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile

435 440 445

Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala

450 455 460

Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr

465 470 475 480

Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu

485 490 495

Val Ile Thr Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser

500 505 510

Asp Tyr Met Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His

515 520 525

Tyr Gln Pro Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg

530 535 540

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln

545 550 555 560

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

565 570 575

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

580 585 590

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

595 600 605

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

610 615 620

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

625 630 635 640

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

645 650 655

<210> 454

<211> 631

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH5 CAR + FSHβ 33-53 εTCR

<400> 454

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe

35 40 45

Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

50 55 60

Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Met Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr

100 105 110

Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser

115 120 125

Ser Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr

130 135 140

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

145 150 155 160

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

165 170 175

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

180 185 190

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

195 200 205

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

210 215 220

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

225 230 235 240

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

245 250 255

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

260 265 270

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

275 280 285

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

290 295 300

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

305 310 315 320

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

325 330 335

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

340 345 350

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

355 360 365

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

370 375 380

Asn Pro Gly Pro Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu

385 390 395 400

Cys Leu Leu Ser Val Gly Val Trp Gly Gln Tyr Thr Arg Asp Leu Val

405 410 415

Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly

420 425 430

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Gly

435 440 445

Asn Glu Glu Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val Ser Ile

450 455 460

Ser Gly Thr Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly Ser Glu

465 470 475 480

Ile Leu Trp Gln His Asn Asp Lys Asn Ile Gly Gly Asp Glu Asp Asp

485 490 495

Lys Asn Ile Gly Ser Asp Glu Asp His Leu Ser Leu Lys Glu Phe Ser

500 505 510

Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly Ser Lys

515 520 525

Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val Cys Glu

530 535 540

Asn Cys Met Glu Met Asp Val Met Ser Val Ala Thr Ile Val Ile Val

545 550 555 560

Asp Ile Cys Ile Thr Gly Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser

565 570 575

Lys Asn Arg Lys Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala

580 585 590

Gly Gly Arg Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro

595 600 605

Asn Pro Asp Tyr Glu Pro Ile Arg Lys Gly Gln Arg Asp Leu Tyr Ser

610 615 620

Gly Leu Asn Gln Arg Arg Ile

625 630

<210> 455

<211> 634

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH5 CAR + FSHβ 33-53 εTCR

<400> 455

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe

35 40 45

Thr Phe Ser Arg Asn Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Gly Val Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val

65 70 75 80

Tyr Ser Asp Ser Val Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Met Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu

115 120 125

Ala Val Asn Gly Tyr Asn His Trp Gly Gln Gly Thr Leu Val Thr Val

130 135 140

Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

145 150 155 160

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

165 170 175

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

180 185 190

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

195 200 205

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

210 215 220

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

225 230 235 240

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

245 250 255

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln

260 265 270

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

275 280 285

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

290 295 300

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

305 310 315 320

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

325 330 335

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

340 345 350

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

355 360 365

Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp

370 375 380

Val Glu Glu Asn Pro Gly Pro Met Gln Ser Gly Thr His Trp Arg Val

385 390 395 400

Leu Gly Leu Cys Leu Leu Ser Val Gly Val Trp Gly Gln Tyr Thr Arg

405 410 415

Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys

420 425 430

Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

435 440 445

Ser Asp Gly Asn Glu Glu Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys

450 455 460

Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro

465 470 475 480

Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys Asn Ile Gly Gly Asp

485 490 495

Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp His Leu Ser Leu Lys

500 505 510

Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg

515 520 525

Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg

530 535 540

Val Cys Glu Asn Cys Met Glu Met Asp Val Met Ser Val Ala Thr Ile

545 550 555 560

Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu Leu Leu Leu Val Tyr

565 570 575

Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys Pro Val Thr Arg Gly

580 585 590

Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro

595 600 605

Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg Lys Gly Gln Arg Asp

610 615 620

Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile

625 630

<210> 456

<211> 634

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH4 CAR + FSHβ 33-53 εTCR

<400> 456

Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu

1 5 10 15

His Ala Ala Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val

20 25 30

Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu

35 40 45

Ser Phe Ser Thr Tyr Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys

50 55 60

Gly Leu Glu Gly Val Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val

65 70 75 80

Tyr Thr Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser

85 90 95

Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr

100 105 110

Ala Val Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu

115 120 125

Ala Ile Asn Gly Tyr Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val

130 135 140

Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr

145 150 155 160

Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala

165 170 175

Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile

180 185 190

Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser

195 200 205

Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr

210 215 220

Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu

225 230 235 240

Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu

245 250 255

Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln

260 265 270

Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu

275 280 285

Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly

290 295 300

Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln

305 310 315 320

Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu

325 330 335

Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr

340 345 350

Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro

355 360 365

Arg Gly Ser Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp

370 375 380

Val Glu Glu Asn Pro Gly Pro Met Gln Ser Gly Thr His Trp Arg Val

385 390 395 400

Leu Gly Leu Cys Leu Leu Ser Val Gly Val Trp Gly Gln Tyr Thr Arg

405 410 415

Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys

420 425 430

Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

435 440 445

Ser Asp Gly Asn Glu Glu Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys

450 455 460

Val Ser Ile Ser Gly Thr Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro

465 470 475 480

Gly Ser Glu Ile Leu Trp Gln His Asn Asp Lys Asn Ile Gly Gly Asp

485 490 495

Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu Asp His Leu Ser Leu Lys

500 505 510

Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg

515 520 525

Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg

530 535 540

Val Cys Glu Asn Cys Met Glu Met Asp Val Met Ser Val Ala Thr Ile

545 550 555 560

Val Ile Val Asp Ile Cys Ile Thr Gly Gly Leu Leu Leu Leu Val Tyr

565 570 575

Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala Lys Pro Val Thr Arg Gly

580 585 590

Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro

595 600 605

Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile Arg Lys Gly Gln Arg Asp

610 615 620

Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile

625 630

<210> 457

<211> 464

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 epsilon TCR with dnTGF RII

<400> 457

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Gln Ser

210 215 220

Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu Ser Val Gly Val

225 230 235 240

Trp Gly Gln Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro

245 250 255

Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly

260 265 270

Gly Ser Gly Gly Gly Gly Ser Asp Gly Asn Glu Glu Met Gly Gly Ile

275 280 285

Thr Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr Thr Val Ile Leu

290 295 300

Thr Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp Gln His Asn Asp

305 310 315 320

Lys Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile Gly Ser Asp Glu

325 330 335

Asp His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu Gln Ser Gly Tyr

340 345 350

Tyr Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp Ala Asn Phe Tyr

355 360 365

Leu Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met Glu Met Asp Val

370 375 380

Met Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys Ile Thr Gly Gly

385 390 395 400

Leu Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg Lys Ala Lys Ala

405 410 415

Lys Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg Gln Arg Gly Gln

420 425 430

Asn Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp Tyr Glu Pro Ile

435 440 445

Arg Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn Gln Arg Arg Ile

450 455 460

<210> 458

<211> 439

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 gamma TCR with dnTGF RII

<400> 458

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu Gln

210 215 220

Gly Lys Gly Leu Ala Val Leu Ile Leu Ala Ile Ile Leu Leu Gln Gly

225 230 235 240

Thr Leu Ala Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro

245 250 255

Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly

260 265 270

Gly Ser Gly Gly Gly Gly Ser Gln Ser Ile Lys Gly Asn His Leu Val

275 280 285

Lys Val Tyr Asp Tyr Gln Glu Asp Gly Ser Val Leu Leu Thr Cys Asp

290 295 300

Ala Glu Ala Lys Asn Ile Thr Trp Phe Lys Asp Gly Lys Met Ile Gly

305 310 315 320

Phe Leu Thr Glu Asp Lys Lys Lys Trp Asn Leu Gly Ser Asn Ala Lys

325 330 335

Asp Pro Arg Gly Met Tyr Gln Cys Lys Gly Ser Gln Asn Lys Ser Lys

340 345 350

Pro Leu Gln Val Tyr Tyr Arg Met Cys Gln Asn Cys Ile Glu Leu Asn

355 360 365

Ala Ala Thr Ile Ser Gly Phe Leu Phe Ala Glu Ile Val Ser Ile Phe

370 375 380

Val Leu Ala Val Gly Val Tyr Phe Ile Ala Gly Gln Asp Gly Val Arg

385 390 395 400

Gln Ser Arg Ala Ser Asp Lys Gln Thr Leu Leu Pro Asn Asp Gln Leu

405 410 415

Tyr Gln Pro Leu Lys Asp Arg Glu Asp Asp Gln Tyr Ser His Leu Gln

420 425 430

Gly Asn Gln Leu Arg Arg Asn

435

<210> 459

<211> 428

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 delta TCR with dnTGF RII

<400> 459

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Glu His

210 215 220

Ser Thr Phe Leu Ser Gly Leu Val Leu Ala Thr Leu Leu Ser Gln Val

225 230 235 240

Ser Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys

245 250 255

Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly

260 265 270

Ser Gly Gly Gly Gly Ser Phe Lys Ile Pro Ile Glu Glu Leu Glu Asp

275 280 285

Arg Val Phe Val Asn Cys Asn Thr Ser Ile Thr Trp Val Glu Gly Thr

290 295 300

Val Gly Thr Leu Leu Ser Asp Ile Thr Arg Leu Asp Leu Gly Lys Arg

305 310 315 320

Ile Leu Asp Pro Arg Gly Ile Tyr Arg Cys Asn Gly Thr Asp Ile Tyr

325 330 335

Lys Asp Lys Glu Ser Thr Val Gln Val His Tyr Arg Met Cys Gln Ser

340 345 350

Cys Val Glu Leu Asp Pro Ala Thr Val Ala Gly Ile Ile Val Thr Asp

355 360 365

Val Ile Ala Thr Leu Leu Leu Ala Leu Gly Val Phe Cys Phe Ala Gly

370 375 380

His Glu Thr Gly Arg Leu Ser Gly Ala Ala Asp Thr Gln Ala Leu Leu

385 390 395 400

Arg Asn Asp Gln Val Tyr Gln Pro Leu Arg Asp Arg Asp Asp Ala Gln

405 410 415

Tyr Ser His Leu Gly Gly Asn Trp Ala Arg Asn Lys

420 425

<210> 460

<211> 587

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH5 CAR, having dnTGF RII

<400> 460

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Tyr Ser

260 265 270

Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val Ala

275 280 285

His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys

290 295 300

Gly Arg Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr Met Tyr Leu

305 310 315 320

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala

325 330 335

Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser Phe Asp

340 345 350

Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro

355 360 365

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

370 375 380

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

385 390 395 400

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

405 410 415

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

420 425 430

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

435 440 445

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

450 455 460

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

465 470 475 480

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

485 490 495

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

500 505 510

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

515 520 525

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

530 535 540

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

545 550 555 560

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

565 570 575

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

580 585

<210> 461

<211> 590

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH5 CAR, having dnTGF RII

<400> 461

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

260 265 270

Arg Asn Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

275 280 285

Gly Val Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val Tyr Ser Asp

290 295 300

Ser Val Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

305 310 315 320

Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr

325 330 335

Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu Ala Val Asn

340 345 350

Gly Tyr Asn His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr

355 360 365

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

370 375 380

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

385 390 395 400

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

405 410 415

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

420 425 430

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

435 440 445

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

450 455 460

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

465 470 475 480

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

485 490 495

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

500 505 510

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

515 520 525

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

530 535 540

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

545 550 555 560

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

565 570 575

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

580 585 590

<210> 462

<211> 590

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH4 CAR, having dnTGF RII

<400> 462

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ser Phe Ser

260 265 270

Thr Tyr Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

275 280 285

Gly Val Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val Tyr Thr Asp

290 295 300

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

305 310 315 320

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

325 330 335

Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu Ala Ile Asn

340 345 350

Gly Tyr Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr

355 360 365

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

370 375 380

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

385 390 395 400

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

405 410 415

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

420 425 430

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

435 440 445

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

450 455 460

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

465 470 475 480

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

485 490 495

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

500 505 510

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

515 520 525

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

530 535 540

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

545 550 555 560

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

565 570 575

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

580 585 590

<210> 463

<211> 623

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS65233VH5 tandem CAR with dnTGF RII

<400> 463

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys

245 250 255

Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly

260 265 270

Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

275 280 285

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu

290 295 300

Phe Thr Tyr Ser Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu

305 310 315 320

Glu Gly Val Ala His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala

325 330 335

Asp Ser Val Lys Gly Arg Phe Val Leu Ser Arg Asp Asn Ser Lys Asn

340 345 350

Thr Met Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met

355 360 365

Tyr Tyr Cys Ala Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro

370 375 380

Ser Ser Phe Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

385 390 395 400

Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala

405 410 415

Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly

420 425 430

Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile

435 440 445

Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val

450 455 460

Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe

465 470 475 480

Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly

485 490 495

Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg

500 505 510

Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln

515 520 525

Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp

530 535 540

Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro

545 550 555 560

Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp

565 570 575

Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg

580 585 590

Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr

595 600 605

Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

610 615 620

<210> 464

<211> 626

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS80444VH5 tandem CAR with dnTGF RII

<400> 464

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys

245 250 255

Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly

260 265 270

Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly

275 280 285

Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

290 295 300

Phe Thr Phe Ser Arg Asn Thr Met Gly Trp Phe Arg Gln Ala Pro Gly

305 310 315 320

Lys Gly Leu Glu Gly Val Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile

325 330 335

Val Tyr Ser Asp Ser Val Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn

340 345 350

Ser Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

355 360 365

Thr Ala Met Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Thr Met

370 375 380

Leu Ala Val Asn Gly Tyr Asn His Trp Gly Gln Gly Thr Leu Val Thr

385 390 395 400

Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

405 410 415

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

420 425 430

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

435 440 445

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

450 455 460

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

465 470 475 480

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

485 490 495

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

500 505 510

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

515 520 525

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

530 535 540

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

545 550 555 560

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

565 570 575

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

580 585 590

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

595 600 605

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

610 615 620

Pro Arg

625

<210> 465

<211> 626

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> FSH beta 33-53 + AS80533VH4 tandem CAR with dnTGF RII

<400> 465

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro Ala Arg Pro Lys

245 250 255

Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly Ser Gly Gly Gly Gly

260 265 270

Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly

275 280 285

Val Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly

290 295 300

Leu Ser Phe Ser Thr Tyr Thr Val Ala Trp Phe Arg Gln Ala Pro Gly

305 310 315 320

Lys Gly Leu Glu Gly Val Ala Ala Ile Pro Tyr Thr Ser Gln His Met

325 330 335

Val Tyr Thr Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn

340 345 350

Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp

355 360 365

Thr Ala Val Tyr Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Ser Met

370 375 380

Leu Ala Ile Asn Gly Tyr Asn Arg Trp Gly Gln Gly Thr Thr Val Thr

385 390 395 400

Val Ser Ser Thr Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro

405 410 415

Thr Ile Ala Ser Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro

420 425 430

Ala Ala Gly Gly Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp

435 440 445

Ile Tyr Ile Trp Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu

450 455 460

Ser Leu Val Ile Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu

465 470 475 480

Tyr Ile Phe Lys Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu

485 490 495

Glu Asp Gly Cys Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys

500 505 510

Glu Leu Arg Val Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys

515 520 525

Gln Gly Gln Asn Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu

530 535 540

Glu Tyr Asp Val Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly

545 550 555 560

Gly Lys Pro Arg Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu

565 570 575

Gln Lys Asp Lys Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly

580 585 590

Glu Arg Arg Arg Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser

595 600 605

Thr Ala Thr Lys Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro

610 615 620

Pro Arg

625

<210> 466

<211> 873

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH5 + FSH beta 33-53 Dual CAR with dnTGF RII

<400> 466

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Tyr Ser

260 265 270

Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val Ala

275 280 285

His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys

290 295 300

Gly Arg Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr Met Tyr Leu

305 310 315 320

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala

325 330 335

Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser Phe Asp

340 345 350

Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro

355 360 365

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

370 375 380

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

385 390 395 400

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

405 410 415

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

420 425 430

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

435 440 445

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

450 455 460

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

465 470 475 480

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

485 490 495

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

500 505 510

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

515 520 525

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

530 535 540

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

545 550 555 560

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

565 570 575

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr

580 585 590

Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly

595 600 605

Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu

610 615 620

Leu His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr Lys Asp Pro

625 630 635 640

Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr Thr Pro Ala

645 650 655

Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu Ser

660 665 670

Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His Thr

675 680 685

Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu Ala

690 695 700

Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr Cys

705 710 715 720

Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met Asn Met Thr

725 730 735

Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro Tyr Ala Pro

740 745 750

Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe Ser Arg Ser

755 760 765

Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr Asn Glu

770 775 780

Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys Arg Arg

785 790 795 800

Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn Pro Gln

805 810 815

Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu Ala Tyr

820 825 830

Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly His Asp

835 840 845

Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr Asp Ala

850 855 860

Leu His Met Gln Ala Leu Pro Pro Arg

865 870

<210> 467

<211> 876

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH5 + FSH beta 33-53 Dual CAR with dnTGF RII

<400> 467

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

260 265 270

Arg Asn Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

275 280 285

Gly Val Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val Tyr Ser Asp

290 295 300

Ser Val Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

305 310 315 320

Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr

325 330 335

Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu Ala Val Asn

340 345 350

Gly Tyr Asn His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr

355 360 365

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

370 375 380

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

385 390 395 400

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

405 410 415

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

420 425 430

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

435 440 445

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

450 455 460

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

465 470 475 480

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

485 490 495

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

500 505 510

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

515 520 525

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

530 535 540

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

545 550 555 560

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

565 570 575

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

580 585 590

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

595 600 605

Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu

610 615 620

Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr

625 630 635 640

Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr

645 650 655

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

660 665 670

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

675 680 685

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

690 695 700

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

705 710 715 720

Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met

725 730 735

Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro

740 745 750

Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe

755 760 765

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

770 775 780

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

785 790 795 800

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

805 810 815

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

820 825 830

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

835 840 845

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

850 855 860

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

865 870 875

<210> 468

<211> 876

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH4 + FSH beta 33-53 Dual CAR with dnTGF RII

<400> 468

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ser Phe Ser

260 265 270

Thr Tyr Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

275 280 285

Gly Val Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val Tyr Thr Asp

290 295 300

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

305 310 315 320

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

325 330 335

Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu Ala Ile Asn

340 345 350

Gly Tyr Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr

355 360 365

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

370 375 380

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

385 390 395 400

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

405 410 415

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

420 425 430

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

435 440 445

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

450 455 460

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

465 470 475 480

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

485 490 495

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

500 505 510

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

515 520 525

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

530 535 540

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

545 550 555 560

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

565 570 575

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

580 585 590

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

595 600 605

Asn Pro Gly Pro Met Ala Leu Pro Val Thr Ala Leu Leu Leu Pro Leu

610 615 620

Ala Leu Leu Leu His Ala Ala Arg Pro Tyr Thr Arg Asp Leu Val Tyr

625 630 635 640

Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Thr Thr

645 650 655

Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln

660 665 670

Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala

675 680 685

Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala

690 695 700

Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr

705 710 715 720

Leu Tyr Cys Arg Ser Lys Arg Ser Arg Leu Leu His Ser Asp Tyr Met

725 730 735

Asn Met Thr Pro Arg Arg Pro Gly Pro Thr Arg Lys His Tyr Gln Pro

740 745 750

Tyr Ala Pro Pro Arg Asp Phe Ala Ala Tyr Arg Ser Arg Val Lys Phe

755 760 765

Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu

770 775 780

Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp

785 790 795 800

Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys

805 810 815

Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala

820 825 830

Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys

835 840 845

Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr

850 855 860

Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg

865 870 875

<210> 469

<211> 852

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS65233VH5 CAR + FSH beta 33-53 epsilon TCR with dnTGF RII

<400> 469

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Glu Phe Thr Tyr Ser

260 265 270

Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu Gly Val Ala

275 280 285

His Ile Tyr Thr Arg Gly Gly Thr Thr Val Tyr Ala Asp Ser Val Lys

290 295 300

Gly Arg Phe Val Leu Ser Arg Asp Asn Ser Lys Asn Thr Met Tyr Leu

305 310 315 320

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr Tyr Cys Ala

325 330 335

Ala Arg Thr Ile Phe Glu Gly Ser Trp Ser Ser Pro Ser Ser Phe Asp

340 345 350

Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr Thr Thr Pro

355 360 365

Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser Gln Pro Leu

370 375 380

Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly Ala Val His

385 390 395 400

Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp Ala Pro Leu

405 410 415

Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile Thr Leu Tyr

420 425 430

Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys Gln Pro Phe

435 440 445

Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys Ser Cys Arg

450 455 460

Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val Lys Phe Ser

465 470 475 480

Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn Gln Leu Tyr

485 490 495

Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val Leu Asp Lys

500 505 510

Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg Arg Lys Asn

515 520 525

Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys Met Ala Glu

530 535 540

Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg Gly Lys Gly

545 550 555 560

His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys Asp Thr Tyr

565 570 575

Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser Gly Ala Thr

580 585 590

Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly

595 600 605

Pro Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu Cys Leu Leu

610 615 620

Ser Val Gly Val Trp Gly Gln Tyr Thr Arg Asp Leu Val Tyr Lys Asp

625 630 635 640

Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly Gly Gly Gly

645 650 655

Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Gly Asn Glu Glu

660 665 670

Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val Ser Ile Ser Gly Thr

675 680 685

Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly Ser Glu Ile Leu Trp

690 695 700

Gln His Asn Asp Lys Asn Ile Gly Gly Asp Glu Asp Asp Lys Asn Ile

705 710 715 720

Gly Ser Asp Glu Asp His Leu Ser Leu Lys Glu Phe Ser Glu Leu Glu

725 730 735

Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly Ser Lys Pro Glu Asp

740 745 750

Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val Cys Glu Asn Cys Met

755 760 765

Glu Met Asp Val Met Ser Val Ala Thr Ile Val Ile Val Asp Ile Cys

770 775 780

Ile Thr Gly Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser Lys Asn Arg

785 790 795 800

Lys Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala Gly Gly Arg

805 810 815

Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro Asn Pro Asp

820 825 830

Tyr Glu Pro Ile Arg Lys Gly Gln Arg Asp Leu Tyr Ser Gly Leu Asn

835 840 845

Gln Arg Arg Ile

850

<210> 470

<211> 855

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80444VH5 CAR + FSH β 33-53 ε TCR with dnTGF RII

<400> 470

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser

260 265 270

Arg Asn Thr Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

275 280 285

Gly Val Ser Ala Ile Pro Tyr Thr Ser Thr Gly Ile Val Tyr Ser Asp

290 295 300

Ser Val Gly Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

305 310 315 320

Val Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Met Tyr

325 330 335

Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Thr Met Leu Ala Val Asn

340 345 350

Gly Tyr Asn His Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Thr

355 360 365

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

370 375 380

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

385 390 395 400

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

405 410 415

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

420 425 430

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

435 440 445

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

450 455 460

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

465 470 475 480

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

485 490 495

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

500 505 510

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

515 520 525

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

530 535 540

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

545 550 555 560

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

565 570 575

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

580 585 590

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

595 600 605

Asn Pro Gly Pro Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu

610 615 620

Cys Leu Leu Ser Val Gly Val Trp Gly Gln Tyr Thr Arg Asp Leu Val

625 630 635 640

Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly

645 650 655

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Gly

660 665 670

Asn Glu Glu Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val Ser Ile

675 680 685

Ser Gly Thr Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly Ser Glu

690 695 700

Ile Leu Trp Gln His Asn Asp Lys Asn Ile Gly Gly Asp Glu Asp Asp

705 710 715 720

Lys Asn Ile Gly Ser Asp Glu Asp His Leu Ser Leu Lys Glu Phe Ser

725 730 735

Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly Ser Lys

740 745 750

Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val Cys Glu

755 760 765

Asn Cys Met Glu Met Asp Val Met Ser Val Ala Thr Ile Val Ile Val

770 775 780

Asp Ile Cys Ile Thr Gly Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser

785 790 795 800

Lys Asn Arg Lys Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala

805 810 815

Gly Gly Arg Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro

820 825 830

Asn Pro Asp Tyr Glu Pro Ile Arg Lys Gly Gln Arg Asp Leu Tyr Ser

835 840 845

Gly Leu Asn Gln Arg Arg Ile

850 855

<210> 471

<211> 855

<212> PRT

<213> Artificial Sequence (Artificial Sequence)

<220>

<223> AS80533VH4 CAR + FSH β 33-53 ε TCR with dnTGF RII

<400> 471

Met Gly Arg Gly Leu Leu Arg Gly Leu Trp Pro Leu His Ile Val Leu

1 5 10 15

Trp Thr Arg Ile Ala Ser Thr Ile Pro Pro His Val Gln Lys Ser Val

20 25 30

Asn Asn Asp Met Ile Val Thr Asp Asn Asn Gly Ala Val Lys Phe Pro

35 40 45

Gln Leu Cys Lys Phe Cys Asp Val Arg Phe Ser Thr Cys Asp Asn Gln

50 55 60

Lys Ser Cys Met Ser Asn Cys Ser Ile Thr Ser Ile Cys Glu Lys Pro

65 70 75 80

Gln Glu Val Cys Val Ala Val Trp Arg Lys Asn Asp Glu Asn Ile Thr

85 90 95

Leu Glu Thr Val Cys His Asp Pro Lys Leu Pro Tyr His Asp Phe Ile

100 105 110

Leu Glu Asp Ala Ala Ser Pro Lys Cys Ile Met Lys Glu Lys Lys Lys

115 120 125

Pro Gly Glu Thr Phe Phe Met Cys Ser Cys Ser Ser Asp Glu Cys Asn

130 135 140

Asp Asn Ile Ile Phe Ser Glu Glu Tyr Asn Thr Ser Asn Pro Asp Leu

145 150 155 160

Leu Leu Val Ile Phe Gln Val Thr Gly Ile Ser Leu Leu Pro Pro Leu

165 170 175

Gly Val Ala Ile Ser Val Ile Ile Ile Phe Tyr Cys Tyr Arg Val Asn

180 185 190

Arg Gln Gln Lys Leu Ser Ser Gly Ser Gly Ala Thr Asn Phe Ser Leu

195 200 205

Leu Lys Gln Ala Gly Asp Val Glu Glu Asn Pro Gly Pro Met Ala Leu

210 215 220

Pro Val Thr Ala Leu Leu Leu Pro Leu Ala Leu Leu Leu His Ala Ala

225 230 235 240

Arg Pro Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro

245 250 255

Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Leu Ser Phe Ser

260 265 270

Thr Tyr Thr Val Ala Trp Phe Arg Gln Ala Pro Gly Lys Gly Leu Glu

275 280 285

Gly Val Ala Ala Ile Pro Tyr Thr Ser Gln His Met Val Tyr Thr Asp

290 295 300

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

305 310 315 320

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

325 330 335

Tyr Cys Ala Thr Asp Arg Arg Pro Gly Thr Ser Met Leu Ala Ile Asn

340 345 350

Gly Tyr Asn Arg Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Thr

355 360 365

Thr Thr Pro Ala Pro Arg Pro Pro Thr Pro Ala Pro Thr Ile Ala Ser

370 375 380

Gln Pro Leu Ser Leu Arg Pro Glu Ala Cys Arg Pro Ala Ala Gly Gly

385 390 395 400

Ala Val His Thr Arg Gly Leu Asp Phe Ala Cys Asp Ile Tyr Ile Trp

405 410 415

Ala Pro Leu Ala Gly Thr Cys Gly Val Leu Leu Leu Ser Leu Val Ile

420 425 430

Thr Leu Tyr Cys Lys Arg Gly Arg Lys Lys Leu Leu Tyr Ile Phe Lys

435 440 445

Gln Pro Phe Met Arg Pro Val Gln Thr Thr Gln Glu Glu Asp Gly Cys

450 455 460

Ser Cys Arg Phe Pro Glu Glu Glu Glu Gly Gly Cys Glu Leu Arg Val

465 470 475 480

Lys Phe Ser Arg Ser Ala Asp Ala Pro Ala Tyr Lys Gln Gly Gln Asn

485 490 495

Gln Leu Tyr Asn Glu Leu Asn Leu Gly Arg Arg Glu Glu Tyr Asp Val

500 505 510

Leu Asp Lys Arg Arg Gly Arg Asp Pro Glu Met Gly Gly Lys Pro Arg

515 520 525

Arg Lys Asn Pro Gln Glu Gly Leu Tyr Asn Glu Leu Gln Lys Asp Lys

530 535 540

Met Ala Glu Ala Tyr Ser Glu Ile Gly Met Lys Gly Glu Arg Arg Arg

545 550 555 560

Gly Lys Gly His Asp Gly Leu Tyr Gln Gly Leu Ser Thr Ala Thr Lys

565 570 575

Asp Thr Tyr Asp Ala Leu His Met Gln Ala Leu Pro Pro Arg Gly Ser

580 585 590

Gly Ala Thr Asn Phe Ser Leu Leu Lys Gln Ala Gly Asp Val Glu Glu

595 600 605

Asn Pro Gly Pro Met Gln Ser Gly Thr His Trp Arg Val Leu Gly Leu

610 615 620

Cys Leu Leu Ser Val Gly Val Trp Gly Gln Tyr Thr Arg Asp Leu Val

625 630 635 640

Tyr Lys Asp Pro Ala Arg Pro Lys Ile Gln Lys Thr Cys Thr Phe Gly

645 650 655

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Gly

660 665 670

Asn Glu Glu Met Gly Gly Ile Thr Gln Thr Pro Tyr Lys Val Ser Ile

675 680 685

Ser Gly Thr Thr Val Ile Leu Thr Cys Pro Gln Tyr Pro Gly Ser Glu

690 695 700

Ile Leu Trp Gln His Asn Asp Lys Asn Ile Gly Gly Asp Glu Asp Asp

705 710 715 720

Lys Asn Ile Gly Ser Asp Glu Asp His Leu Ser Leu Lys Glu Phe Ser

725 730 735

Glu Leu Glu Gln Ser Gly Tyr Tyr Val Cys Tyr Pro Arg Gly Ser Lys

740 745 750

Pro Glu Asp Ala Asn Phe Tyr Leu Tyr Leu Arg Ala Arg Val Cys Glu

755 760 765

Asn Cys Met Glu Met Asp Val Met Ser Val Ala Thr Ile Val Ile Val

770 775 780

Asp Ile Cys Ile Thr Gly Gly Leu Leu Leu Leu Val Tyr Tyr Trp Ser

785 790 795 800

Lys Asn Arg Lys Ala Lys Ala Lys Pro Val Thr Arg Gly Ala Gly Ala

805 810 815

Gly Gly Arg Gln Arg Gly Gln Asn Lys Glu Arg Pro Pro Pro Val Pro

820 825 830

Asn Pro Asp Tyr Glu Pro Ile Arg Lys Gly Gln Arg Asp Leu Tyr Ser

835 840 845

Gly Leu Asn Gln Arg Arg Ile

850 855

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Anti-mesothelin Chimeric Antigen Receptor (CAR) constructs and uses thereof

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