Activatable cytokine polypeptides and methods of use thereof
阅读说明：本技术 可活化细胞因子多肽及其使用方法 (Activatable cytokine polypeptides and methods of use thereof ) 是由 W·温斯顿 D·希克林 V·巴斯卡尔 L·叶夫宁 P·博伊尔勒 J·A·萨尔梅隆加西亚 于 2019-05-14 设计创作，主要内容包括：本申请的特征在于作为感兴趣的细胞因子的条件活性变体的融合蛋白。在一个方面,即使本申请的全长多肽含有功能性细胞因子多肽,其具有降低或最小的细胞因子受体活化活性。活化后,例如通过裂解将例如空间阻断多肽的阻断部分按顺序连接到活性细胞因子的接头,所述细胞因子可结合其受体并影响信号传导。通常,所述融合蛋白还包含体内半衰期延长元件,其可在肿瘤微环境中从所述细胞因子裂解。(The present application features fusion proteins that are conditionally active variants of a cytokine of interest. In one aspect, even though the full-length polypeptide of the present application contains a functional cytokine polypeptide, it has reduced or minimal cytokine receptor activation activity. Following activation, the blocking moiety, e.g., a steric blocking polypeptide, is sequentially linked, e.g., by cleavage, to the linker of the active cytokine, which can bind its receptor and affect signaling. Typically, the fusion protein further comprises an in vivo half-life extending element, which is cleavable from the cytokine in the tumor microenvironment.)
1. A fusion polypeptide comprising at least one of each of:
a) a cytokine polypeptide [ A ];
b) a cytokine blocking moiety [ D ]; and
c) a protease cleavable polypeptide linker [ L ];
wherein the cytokine polypeptide and the cytokine blocking moiety are operably linked by the protease-cleavable polypeptide linker, and the fusion polypeptide has reduced cytokine receptor activation activity, wherein the cytokine receptor activation activity of the fusion polypeptide is at least about 10-fold less than the cytokine receptor activation activity of a polypeptide containing a cytokine polypeptide produced by cleavage of the protease-cleavable linker.
2. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the cytokine polypeptide is selected from the group consisting of: IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23, TGF beta, IFN alpha, IFN beta, IFN gamma, TNF, TGF beta, CXCL10, CCL19, CCL20, CCL21 and active fragments thereof.
3. The fusion polypeptide of claim 1 or 2, wherein the cytokine polypeptide is a short half-life cytokine polypeptide.
4. The fusion polypeptide of any one of claims 1 to 3, wherein each protease-cleavable linker polypeptide independently comprises a sequence that is cleavable by a protease selected from the group consisting of: kallikrein, thrombin, chymotrypsin, carboxypeptidase A, cathepsin G, cathepsin L, elastase, PR-3, granzyme M, calpain, Matrix Metalloproteinase (MMP), ADAM, FAP, cathepsin L, plasminogen activator, cathepsin, caspase, tryptase and tumor cell surface protease.
5. The fusion polypeptide of claim 8, wherein each protease-cleavable polypeptide independently comprises two or more cleavage sites of the same protease or two or more cleavage sites cleaved by different proteases, or at least one of the protease-cleavable polypeptides comprises cleavage sites of two or more different proteases.
6. The fusion polypeptide of any one of claims 1-4, wherein the cytokine blocking moiety is also a half-life extending element.
7. The fusion polypeptide of any one of claims 1-5, wherein the cytokine blocking moiety sterically blocks the agonist activity of the cytokine.
8. The fusion polypeptide of claim 5 or 6, wherein the cytokine blocking moiety is human serum albumin, an antigen binding protein, or an antigen binding polypeptide that binds human serum albumin, or a fragment thereof.
9. Rights in claim error! No reference source is found. The fusion polypeptide of any one of to 7, wherein the cytokine is free to dissociate from the cytokine blocking moiety after the protease-cleavable polypeptide linker is cleaved by a protease.
10. A fusion polypeptide according to any one of claims 1 to 8 wherein the cytokine blocking moiety inhibits the cytokine polypeptide from activating its cognate receptor.
11. The fusion polypeptide of any one of claims 1-9, wherein the fusion polypeptide binds the cognate receptor of the cytokine polypeptide prior to cleavage of the protease-cleavable linker.
12. The fusion polypeptide of any one of claims 1-10, further comprising at least one half-life extending element.
13. The fusion polypeptide of any one of claims 1-11, wherein the cytokine blocking moiety is non-covalently associated with the cytokine polypeptide, independent of the linker peptide bond.
14. The fusion polypeptide of claim 12, wherein the non-covalent association is pH-dependent.
15. The fusion polypeptide of claim 11, wherein the half-life extending element sterically inhibits or blocks activation of and/or binding of the cytokine polypeptide to its cognate receptor.
16. The fusion polypeptide of claim 14, wherein the half-life extending element is human serum albumin, human IgG, humanized IgG, scFv, Fab, sdAb, or a fragment thereof.
17. A fusion polypeptide according to claim 9 wherein the cytokine blocking moiety comprises a ligand binding domain, a single domain antibody or scFv that binds the cytokine polypeptide, or an antibody or antibody fragment selected from a single domain antibody and scFv that binds a receptor for the cytokine polypeptide.
18. The fusion polypeptide of any one of claims 1-16, wherein the cytokine receptor activation activity is determined using a standard in vitro receptor activation assay and equal amounts of the cytokine polypeptide and fusion protein on a molar basis.
19. The fusion polypeptide of any one of claims 10-17, wherein a cytokine loses contact with the cytokine blocking moiety and/or half-life extending element after cleavage of the protease cleavable sequence by a protease.
20. The fusion polypeptide of any one of claims 1 to 18, wherein the fusion polypeptide comprises at least one of each of [ a ], [ D ], and [ L ] in any one of the following orientations:
a)[A]-[L]-[D]；
b)[D]-[L]-[A]；
c)[D]-[L]-[A]-[L]-[D]-[L]-[A]；
d)[A]-[L]-[D]-[L]-[A]-[L]-[D]；
e)[D]-[L]-[A]-[L]-[D]；
f)[D]-[L]-[A]-[L]-[A]-[L]-[D]；
g) [ D ] - [ L ] - [ A ] - [ L ] - [ D ] - [ L ] - [ A ] - [ L ] - [ D ]; and
h)[D]-[L]-[A]-[A]-[L]-[D]。
21. the fusion polypeptide of any one of claims 1-19, wherein the fusion polypeptide comprises two cytokine polypeptides.
22. The fusion polypeptide of claim 1, having the formula:
[A]-[L1]-[D]-[L2]-[A]-[L2]-[D]
wherein the content of the first and second substances,
a is a cytokine polypeptide;
l1 and L2 are each independently a protease cleavable polypeptide linker;
d is a cytokine blocking moiety optionally capable of extending serum half-life; and is
Wherein L1 is a substrate for a first protease and wherein L2 is a substrate for a second protease.
23. The fusion polypeptide of any one of claims 11, wherein the at least one half-life extending element is one half-life extending element, two half-life extending elements, or three half-life extending elements.
24. Rights in claim error! No reference source is found. The fusion polypeptide of any one of to 22, comprising one protease-cleavable linker, two protease-cleavable linkers, three protease-cleavable linkers, four protease-cleavable linkers, five protease-cleavable linkers, six protease-cleavable linkers, or seven protease-cleavable linkers.
25. Rights in claim error! No reference source is found. The fusion polypeptide of any one of to 23, further comprising a tumor specific antigen binding peptide.
26. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the tumor specific antigen binding peptide is operably linked to the cytokine polypeptide by a non-cleavable linker.
27. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the tumor specific antigen binding peptide is operably linked to the cytokine polypeptide by a cleavable linker.
28. The fusion polypeptide of any one of claims 1-26, wherein the serum half-life of the cytokine polypeptide is comparable to the corresponding naturally occurring cytokine.
29. The fusion polypeptide of any one of claims 1-26, wherein the serum half-life of the polypeptide comprising the cytokine polypeptide produced by cleavage of the fusion protein is comparable to the corresponding naturally occurring cytokine.
30. The fusion polypeptide of any one of claims 1-26, wherein the cytokine polypeptide is a mutein that has a short serum half-life and is rapidly cleared upon cleavage of the fusion polypeptide.
31. A fusion polypeptide comprising at least one of each of:
a) an interferon polypeptide [ A ];
b) an interferon blocking moiety [ D ]; and
c) a protease cleavable polypeptide linker [ L ]; and is
Wherein the interferon polypeptide and the interferon blocking moiety are operably linked by the protease-cleavable polypeptide linker, the fusion polypeptide having attenuated interferon receptor activation activity, wherein the interferon receptor activation activity of the fusion polypeptide is at least about 10-fold less than the interferon receptor activation activity of the interferon polypeptide produced by cleavage of the protease-cleavable linker.
32. Rights in claim error! No reference source is found. The fusion polypeptide of formula (la):
[D]-[L1]-[A]-[L2]-[D]；
wherein the content of the first and second substances,
a is an interferon alpha (IFN α) polypeptide;
l1 and L2 are each independently a protease cleavable polypeptide linker;
d is also capable of extending the in vivo half-life of IFN alpha blocking part; and is
Wherein the interferon alpha polypeptide and the interferon alpha blocking moiety are operably linked by the protease cleavable polypeptide linker, the fusion polypeptide having attenuated interferon alpha receptor activation activity, wherein the interferon alpha receptor activation activity of the fusion polypeptide is at least about 10-fold less than the interferon receptor activation activity of the interferon alpha polypeptide produced by cleavage of the protease cleavable linker, and wherein the in vivo half-life of the interferon alpha polypeptide is substantially similar to the half-life of naturally occurring interferon alpha when both linkers are cleaved.
33. Rights in claim error! No reference source is found. The fusion polypeptide of formula (la):
[D]-[L1]-[A]-[L2]-[D]-[L3]-[A]-[L4]-[D]；
wherein the content of the first and second substances,
a is an interferon gamma (IFN gamma) polypeptide;
l1, L2, L3 and L4 are each independently protease cleavable polypeptide linkers;
d is an IFN γ blocking moiety capable of extending serum half-life; and is
Wherein the interferon gamma polypeptide and the interferon gamma blocking moiety are operably linked by the protease cleavable polypeptide linker, the fusion polypeptide having attenuated interferon gamma receptor activation activity, wherein the interferon gamma receptor activation activity of the fusion polypeptide is at least about 10-fold less than the interferon gamma receptor activation activity of the interferon gamma polypeptide produced by cleavage of the protease cleavable linker, and wherein the in vivo half-life of the interferon gamma polypeptide is substantially similar to the half-life of naturally occurring interferon gamma when both linkers are cleaved.
34. The fusion polypeptide of any one of claims 27 to 29, wherein the protease-cleavable linker polypeptide comprises a sequence that is cleavable by a protease selected from the group consisting of: kallikrein, thrombin, chymotrypsin, carboxypeptidase A, cathepsin G, cathepsin L, elastase, PR-3, granzyme M, calpain, Matrix Metalloproteinase (MMP), ADAM, FAP, cathepsin L, plasminogen activator, cathepsin, caspase, tryptase and tumor cell surface protease.
35. The fusion polypeptide of claim 34, wherein each protease-cleavable polypeptide independently comprises two or more cleavage sites of the same protease or two or more cleavage sites cleaved by different proteases, or at least one of the protease-cleavable polypeptides comprises cleavage sites of two or more different proteases.
36. Rights in claim error! No reference source is found. The fusion polypeptide of claim 30, wherein the interferon is interferon alpha or interferon gamma.
37. Rights in claim error! No reference source is found. The fusion polypeptide of formula (la):
[A]-[L1]-[D]-[L2]-[A]-[L2]-[D]
wherein the content of the first and second substances,
a is an interferon polypeptide;
l1 and L2 are each independently a protease cleavable polypeptide linker;
d is an interferon blocking moiety optionally capable of extending serum half-life; and is
Wherein L1 is a substrate for a first protease and wherein L2 is a substrate for a second protease.
38. The fusion polypeptide of any one of claims 27-32, wherein the interferon blocking moiety is also a half-life extending element.
39. The fusion polypeptide of any one of claims 27-33, wherein the interferon-blocking moiety sterically blocks the agonist activity of the cytokine.
40. The fusion polypeptide of claim 34, wherein the interferon blocking moiety is human serum albumin or an antigen binding polypeptide that binds human serum albumin.
41. The fusion polypeptide of any one of claims 27-35, wherein the interferon is free to dissociate from the interferon blocking moiety after the protease-cleavable polypeptide linker is cleaved by a protease.
42. The fusion polypeptide of any one of claims 27-36, wherein the interferon blocking moiety inhibits activation of its cognate receptor by the interferon polypeptide.
43. Claims to error! No reference source is found. Error! No reference source is found. The fusion polypeptide of any one of, wherein the fusion polypeptide binds to the cognate receptor of the interferon polypeptide prior to cleavage of the protease-cleavable linker.
44. Rights in claim error! No reference source is found. The fusion polypeptide of any one of, further comprising at least one half-life extending element.
45. Rights in claim error! No reference source is found. The fusion polypeptide of any one of, wherein the interferon blocking moiety is non-covalently associated with the interferon polypeptide.
46. Claims 27 to error! No reference source is found. The fusion polypeptide of any one of, wherein the non-covalent association is pH-dependent.
47. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the half-life extending element sterically inhibits or blocks activation of and/or binding of the interferon polypeptide to its cognate receptor.
48. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the half-life extending element is human serum albumin, human IgG, or a fragment thereof.
49. Rights in claim error! No reference source is found. To error! No reference source is found. The fusion polypeptide of (a), wherein the half-life extending element does not bind to the interferon polypeptide.
50. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the interferon blocking moiety comprises a ligand binding domain or fragment of a cognate receptor for the interferon, a single domain antibody or scFv that binds the interferon polypeptide, or an antibody or antibody fragment (e.g., single domain antibody, scFv) that binds the receptor for the interferon.
51. In claims 27 to 45 errors! No reference source is found. The fusion polypeptide of any one of, wherein the cognate interferon receptor activation activity is determined using a standard in vitro receptor activation assay and molar-based equivalents of the fusion polypeptide and interferon polypeptide.
52. Rights in claim error! No reference source is found. To error! No reference source is found. The fusion polypeptide of any one of, wherein interferon is free to dissociate from the interferon blocking moiety and/or half-life extending element following cleavage of the protease cleavable sequence by a protease.
53. Rights in claim error! No reference source is found. To error! No reference source is found. The fusion polypeptide of any one of, wherein the fusion polypeptide comprises at least one of each of [ a ], [ B ], and [ L ] in any one of the following orientations:
a)[A]-[L]-[D]；
b)[D]-[L]-[A]；
c)[D]-[L]-[A]-[L]-[D]-[L]-[A]；
d)[A]-[L]-[D]-[L]-[A]-[L]-[D]；
e)[D]-[L]-[A]-[L]-[D]；
f)[D]-[L]-[A]-[L]-[A]-[L]-[D]；
g) [ D ] - [ L ] - [ A ] - [ L ] - [ D ] - [ L ] - [ A ] - [ L ] - [ D ]; and
h)[D]-[L]-[A]-[A]-[L]-[D]。
54. rights in claim error! No reference source is found. The fusion polypeptide of any one of claims 48, wherein the fusion polypeptide comprises two cytokine peptides.
55. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the two cytokine polypeptides are two different cytokine peptides.
56. Claims 39 to 50 error! No reference source is found. The fusion polypeptide of any one of, wherein the at least one half-life extending element is one half-life extending element or two half-life extending elements.
57. Rights in claim error! No reference source is found. The fusion polypeptide of any one of, comprising one protease-cleavable polypeptide linker that is one protease-cleavable linker, two protease-cleavable linkers, three protease-cleavable linkers, four protease-cleavable linkers, five protease-cleavable linkers, six protease-cleavable linkers, or seven protease-cleavable linkers.
58. Rights in claim error! No reference source is found. To error! No reference source is found. The fusion polypeptide of any one of, further comprising a tumor specific antigen binding peptide.
59. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the tumor specific antigen binding peptide is operably linked to the interferon polypeptide by a non-cleavable linker.
60. Rights in claim error! No reference source is found. The fusion polypeptide of (a), wherein the tumor specific antigen binding peptide is operably linked to the interferon polypeptide by a cleavable linker.
61. A nucleic acid encoding a nucleic acid as claimed in claim error! No reference source is found. The fusion polypeptide of any one of claims 60.
62. A vector comprising the nucleic acid of claim 61.
63. A host cell comprising the vector of claim 62 or the nucleic acid of claim 61.
64. A method of preparing a pharmaceutical composition, the method comprising culturing the host cell of claim 63 under suitable conditions for expression and collection of a desired polypeptide.
65. A pharmaceutical composition comprising i) the composition as defined in claim Authority! No reference source is found. The fusion polypeptide of any one of to 60 and ii) a pharmaceutically acceptable excipient.
66. A method for treating a tumor, the method comprising administering to a subject in need thereof an effective amount of a composition of claim VISE! No reference source is found. The fusion polypeptide of any one of claims 60.
67. Rights in claim error! No reference source is found. The fusion polypeptide of any one of to 60 for use as a medicament.
68. Rights in claim error! No reference source is found. The fusion polypeptide of any one of to 60 for use in treating a tumor in a subject in need thereof.
69. A pharmaceutical composition for treating a tumor in a subject in need thereof, comprising as an active ingredient the compound of claim mausua! No reference source is found. The fusion polypeptide of any one of claims 60.
Background
The development of mature, immunocompetent lymphoid cells from less committed precursors, their subsequent antigen-driven immune responses, and the suppression of these and unwanted autoreactive responses are highly dependent on and regulated by cytokines, including interleukin-2 [ IL-2], IL-4, IL-7, IL-9, IL-15, and IL-21, that utilize receptors in the common gamma chain (yc) family (Rochman et al, 2009) as well as family members including IL-12, 18, and 23. IL-2 is essential for thymic development of Treg cells and tightly regulates several key aspects of mature peripheral tregs and antigen-activated conventional T cells. IL-2 has been extensively studied due to its potent T cell growth factor activity in vitro, in part because this activity provides a potential means to directly enhance immunity in patients with, for example, cancer and AIDS-HIV, or to provide a target against unwanted responses such as transplant rejection and autoimmune diseases. Although in vitro studies with IL-2 provide a powerful basis for these studies, the function of IL-2 in vivo is clearly much more complex, as first demonstrated in IL-2 deficient mice, where rapidly lethal autoimmune syndrome is observed without lack of immunity (Sadlack et al, 1993,1995). A similar observation was later made when genes encoding IL-2R α (Il2ra) and IL-2R β (Il2rb) were ablated separately (Suzuki et al, 1995; Willerford et al, 1995).
The present application relates to conditionally active and/or targeted cytokines for the treatment of cancer and other diseases that depend on immune up-or down-regulation. For example, the anti-tumor activity of some cytokines is well known and described, and some cytokines have been used in humans for therapeutic purposes. Cytokines such as interleukin-2 (IL-2) and interferon alpha (IFN α) exhibit positive anti-tumor activity in patients with different types of tumors such as renal metastasis, hairy cell leukemia, Kaposi's sarcoma (Kaposi sarcoma), melanoma, multiple myeloma, and the like. Other cytokines such as IFN β, Tumor Necrosis Factor (TNF) α, TNF β, IL-1, 4, 6, 12, 15 and CSF exhibit some anti-tumor activity against some types of tumors and are therefore the subject of further investigation.
Disclosure of Invention
Provided herein are therapeutic proteins, nucleic acids encoding the proteins, and compositions and methods of using the proteins and nucleic acids to treat diseases or disorders, such as proliferative diseases, neoplastic diseases, inflammatory diseases, immunological disorders, autoimmune diseases, infectious diseases, viral diseases, allergic reactions, parasitic reactions, graft-versus-host diseases, and the like.
The present application features fusion proteins that are conditionally active variants of a cytokine of interest. In one aspect, even though the full-length polypeptide of the present application contains a functional cytokine polypeptide, it has reduced or minimal cytokine receptor activation activity. Upon activation, for example, by cleavage of a linker that links a blocking moiety (e.g., a steric blocking polypeptide) to an active cytokine in turn, the cytokine (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23, IFN α, IFN β, IFN γ, TNF α, lymphotoxin, TGF- β 1, TGF β 2, TGF β 3, GM-CSF, CXCL10, CCL19, CCL20, CCL21, or a functional fragment or mutein of any of the foregoing) can bind its receptor and affect signaling. If desired, the full-length polypeptide may include a blocking polypeptide portion that may also provide additional advantageous properties. For example, the full-length polypeptide may contain a blocking polypeptide moiety that may also increase serum half-life and/or target the full-length polypeptide to the desired cytokine active site. Alternatively, the full-length fusion polypeptide may contain a serum half-life extending element and/or targeting domain that is different from the blocking polypeptide moiety. Preferably, the fusion protein contains at least one element or domain capable of extending the circulating half-life in vivo. Preferably, this element is enzymatically removed at the desired in vivo location (e.g., proteolytic cleavage in the tumor microenvironment), thereby restoring the pharmacokinetic properties of a payload molecule (e.g., IL2 or IFNa) that are substantially similar to naturally occurring payload molecules. The fusion protein can be targeted to a desired cell or tissue. Targeting is achieved by the action of a blocking polypeptide moiety that also binds to the desired target or by a targeting domain, as described herein. The domain that recognizes the target antigen (e.g., tumor specific antigen) on the preferred target can be linked to the cytokine through a cleavable or non-cleavable linker. If linked by a non-cleavable linker, the targeting domain may further contribute to the retention of the cytokine in the tumor, and may be considered a retention domain. The targeting domain need not necessarily be directly linked to the payload molecule, but may be directly linked to another element of the fusion protein. This is particularly true if the targeting domains are linked by a cleavable linker.
In one aspect, there is provided a fusion polypeptide comprising a cytokine polypeptide or a functional fragment or mutein thereof; and blocking moieties, such as steric blocking domains. The blocking moiety is fused to the cytokine polypeptide, either directly or through a linker, and may be separated from the cytokine polypeptide by cleavage (e.g., protease-mediated cleavage) of the fusion polypeptide at or near the fusion site or linker or in the blocking moiety. For example, when the cytokine polypeptide is fused to the blocking moiety through a linker containing a protease cleavage site, the cytokine polypeptide is released from the blocking moiety upon protease-mediated cleavage of the linker and can bind to its receptor. The linker is designed to cleave at the site of desired cytokine activity, e.g., in the tumor microenvironment, thereby avoiding off-target cytokine activity and reducing the overall toxicity of cytokine therapy.
The blocking moiety may also serve as a serum half-life extending element. In some embodiments, the fusion polypeptide further comprises a separate serum half-life extending element. In some embodiments, the fusion polypeptide further comprises a targeting domain. In various embodiments, the serum half-life extending element is a water-soluble polypeptide, such as an optional branched or multi-arm polyethylene glycol (PEG), full-length Human Serum Albumin (HSA), or a fragment that retains binding to FcRn, an Fc fragment, or a nanobody that binds directly to FcRn or to human serum albumin.
In addition to the serum half-life extending element, the pharmaceutical compositions described herein preferably comprise at least one or more targeting domains that bind to one or more target antigens or one or more regions on a single target antigen. It is contemplated herein that the polypeptide constructs of the present application will cleave at a protease cleavage site, e.g., in a disease-specific microenvironment or in the blood of a subject, and that the one or more targeting domains will bind to a target antigen on a target cell. The at least one target antigen is involved in and/or associated with a disease, disorder or condition. Exemplary target antigens include those associated with a proliferative disease, a neoplastic disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, a graft-versus-host disease, or a host-versus-graft disease.
In some embodiments, the target antigen is a cell surface molecule, such as a protein, lipid, or polysaccharide. In some embodiments, the target antigen is on a tumor cell, a virus-infected cell, a bacteria-infected cell, an injured red blood cell, an arterial plaque cell, or a fibrotic tissue cell.
In some cases, the target antigen is expressed on the surface of a diseased cell or tissue (e.g., a tumor or cancer cell). Target antigens for tumors include, but are not limited to, fibroblast activation protein alpha (FAPa), trophoblast glycoprotein (5T4), tumor associated calcium signaling protein 2(Trop2), fibronectin EDB (EDB-FN), fibronectin EIIIB domain, CGS-2, EpCAM, EGFR, HER-2, HER-3, c-Met, FOLR1, FAP, and CEA. The pharmaceutical compositions disclosed herein also include proteins comprising two antigen binding domains that bind to two different target antigens known to be expressed on diseased cells or tissues. Exemplary antigen binding domain pairs include, but are not limited to, EGFR/CEA, EpCAM/CEA, and HER-2/HER-3.
In some embodiments, the targeting polypeptide independently comprises a scFv, a VH domain, a VL domain, a non-Ig domain, or a ligand that specifically binds to a target antigen. In some embodiments, the targeting polypeptide specifically binds to a cell surface molecule. In some embodiments, the targeting polypeptide specifically binds to a tumor antigen. In some embodiments, the targeting polypeptide specifically and independently binds to a tumor antigen selected from at least one of EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR 1. In some embodiments, the targeting polypeptide specifically and independently binds two different antigens, wherein at least one of the antigens is a tumor antigen selected from the group consisting of EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR 1. In some embodiments, the targeting polypeptide serves as a retention domain and is linked to the cytokine through a non-cleavable linker.
As described herein, a cytokine blocking moiety can bind to a cytokine and thereby block activation of the cytokine's cognate receptor.
The application also relates to nucleic acids, e.g., DNA, RNA, mRNA, encoding the conditionally active proteins described herein, and vectors and host cells containing such nucleic acids.
The application also relates to pharmaceutical compositions comprising the conditionally active proteins, nucleic acids encoding the conditionally active proteins, and vectors and host cells comprising such nucleic acids. Typically, the pharmaceutical composition contains one or more physiologically acceptable carriers and/or excipients.
The present application also relates to methods of treatment comprising administering to a subject in need thereof an effective amount of a conditionally active protein, a nucleic acid encoding the conditionally active protein, a vector or host cell containing such a nucleic acid, and a pharmaceutical composition of any of the foregoing. Typically, the subject has or is at risk of developing a proliferative disease, a neoplastic disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, a graft-versus-host disease, or a host-versus-graft disease.
The application also relates to the use of conditionally active proteins, nucleic acids encoding conditionally active proteins, vectors or host cells containing such nucleic acids, and pharmaceutical compositions of any of the foregoing for treating a subject in need thereof. Typically, the subject has or is at risk of developing a proliferative disease, a neoplastic disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, a graft-versus-host disease, or a host-versus-graft disease.
The application also relates to the use of a conditionally active protein, a nucleic acid encoding a conditionally active protein, a vector or a host cell containing such a nucleic acid for the manufacture of a medicament for the treatment of a disease, such as a proliferative disease, a tumorous disease, an inflammatory disease, an immunological disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, a graft-versus-host disease or a host-versus-graft disease.
Drawings
Figure 1A is a schematic diagram showing protease-activated cytokines or chemokines comprising blocking moieties. The blocking moiety may optionally serve as a serum half-life extending domain. The graph to the left of the arrow shows that the cytokine is linked to the blocking moiety through a protease cleavable linker, thereby blocking its ability to bind to the receptor. The figure to the right of the arrow shows that in an inflammatory or tumor environment, the protease cleaves at the protease cleavage site on the linker, thereby releasing the blocking moiety and allowing the cytokine to bind to its receptor.
Fig. 1B is a schematic diagram showing protease-activated cytokines or chemokines, wherein HSA (blocking moiety) binds directly to the target cytokine or chemokine, wherein the protease cleavage site is between HSA and the target cytokine or chemokine. The graph to the left of the arrow shows that the cytokine is linked to the blocking moiety through a protease cleavable linker, thereby blocking its ability to bind to the receptor. The figure to the right of the arrow shows that in an inflammatory or tumor environment, the protease cleaves at the protease cleavage site on the linker, thereby releasing the blocking moiety and allowing the cytokine to bind to its receptor.
Fig. 1C is a schematic diagram showing protease-activated cytokines or chemokines, wherein more than one HSA (blocking moiety) is directly bound to the target molecule. If desired, one or more of HSA can be bound to a cytokine or chemokine through a linker, such as one containing a protease cleavage site. The graph to the left of the arrow shows that the cytokine is linked to the blocking moiety through a protease cleavable linker, thereby blocking its ability to bind to the receptor. The graph to the right of the arrow shows that in an inflammatory or tumor environment, the protease cleaves at the protease cleavage site on the linker, thereby releasing the blocking moiety and allowing the cytokine to bind to the receptor. The cytokine now has similar pK properties (e.g., has a shorter half-life) compared to the native cytokine.
Figure 1D is a schematic diagram showing protease-activated cytokines or chemokines, each bound to a binding domain through a protease-cleavable linker, comprising more than one cytokine of the same type or different types. The graph to the left of the arrow shows that the cytokine is linked to the blocking moiety through a protease cleavable linker, thereby blocking its ability to bind to the receptor. The figure to the right of the arrow shows that in an inflammatory or tumor environment, the protease cleaves at the protease cleavage site on the linker, thereby releasing the blocking moiety and allowing the cytokine to bind to its receptor.
Figure 2 is a schematic diagram showing a protease-activated cytokine or chemokine comprising a cytokine or chemokine polypeptide, a blocking moiety, and a serum half-life extending domain linked by at least one protease-cleavable linker. The graph to the left of the arrow shows that the cytokine is linked to the blocking moiety through a protease cleavable linker, thereby blocking its ability to bind to the receptor. The linker is also conjugated to a separate half-life extending element, which extends the half-life of the serum. The graph to the right of the arrow shows that in an inflammatory or tumor environment, the protease cleaves at the protease cleavage site on the linker, thereby releasing the serum half-life extending element and blocking moiety and allowing the cytokine to bind to its receptor. The cytokine now has similar pK properties (e.g., shorter half-life) compared to the native cytokine.
Figure 3 is a schematic diagram showing a protease-activated cytokine or chemokine comprising a cytokine or chemokine polypeptide, a blocking moiety, and a targeting domain linked by at least one protease-cleavable linker. The graph to the left of the arrow shows that the cytokine is linked to the blocking moiety and targeting domain via a protease cleavable linker, thereby blocking its ability to bind to the receptor. The figure to the right of the arrow shows that in an inflammatory or tumor microenvironment, the protease cleaves at the protease cleavage site in the linker, thereby releasing the targeting domain and blocking moiety and allowing the cytokine to bind to its receptor.
Figure 4A is a schematic diagram showing a protease-activated cytokine or chemokine comprising a cytokine or chemokine polypeptide, a blocking moiety, a targeting domain, and a serum half-life extending domain connected by at least one protease-cleavable linker, wherein the cytokine polypeptide and the targeting domain are connected by a protease-cleavable linker. The graph to the left of the arrow shows that the cytokine is linked to the targeting domain, blocking moiety and half-life extending element via one or more protease cleavable linkers, thereby blocking its ability to bind to the receptor. The figure to the right of the arrow shows that in an inflammatory or tumor environment, the protease is cleaved at the protease cleavage site on one or more linkers, thereby releasing the half-life extending element, targeting domain and blocking moiety and allowing the cytokine to bind to its receptor. The cytokine now has similar pK properties (e.g., shorter half-life) compared to the native cytokine.
Figure 4B is a schematic diagram showing a protease-activated cytokine or chemokine comprising a cytokine or chemokine polypeptide, a blocking moiety, a targeting domain, and a serum half-life extending domain connected by at least one protease-cleavable linker. The graph to the left of the arrow shows that the cytokine is linked to the targeting domain, blocking moiety and half-life extending element via one or more protease cleavable linkers, thereby blocking its ability to bind to the receptor. The graph to the right of the arrow shows that in an inflammatory or tumor environment, the protease is cleaved at the protease cleavage site on one or more linkers, thereby releasing the half-life extending element and blocking moiety and allowing the cytokine to bind to the receptor. The targeting moiety remains bound, thereby maintaining the cytokine in the tumor microenvironment. The cytokine now has similar pK properties (e.g., shorter half-life) compared to the native cytokine.
Figure 5 is a schematic diagram showing the structure of the variable domains of an immunoglobulin molecule. The variable domains of the light and heavy immunoglobulin chains contain three hypervariable loops or Complementarity Determining Regions (CDRs). The three CDRs (CDR1, CDR2, CDR3) of the V domain are clustered at one end of the β -barrel. CDRs are loops connecting beta chains B-C, C '-C' and F-G of the immunoglobulin fold, while the bottom loops connecting beta chains AB, CC ', C' -D and E-F of the immunoglobulin fold and the top loops connecting D-E chains of the immunoglobulin fold are non-CDR loops.
Figure 6 is a schematic diagram showing a protease-activated cytokine or chemokine comprising a cytokine or chemokine polypeptide, a blocking moiety that is a serum albumin binding domain (e.g., dAb), and a protease-cleavable linker. In the illustrated example, non-CDR loops in the serum albumin binding domain (e.g., sdAb) can form the binding site for the cytokine IL-2. In this example, the binding site for serum albumin may be formed by the CDRs of the serum albumin binding domain.
FIGS. 7A-7H are a series of graphs showing the activity of exemplary IL-2 fusion proteins in the cell line CTLL-2 of IL-2 dependent cytotoxic T lymphocytes. Each graph shows a graph obtained by basing(Promega) measurement of cell viability of luminescence the results of the IL-2 proliferation assay quantified. Each proliferation assay was performed with or without HSA (fig. 7B, 7D, 7E, 7G). Each fusion protein comprises an anti-HSA conjugate, and each assay uses the uncleaved and MMP9 protease cleaved forms of the fusion proteins.
FIGS. 8A to 8F are a series of graphs showing the activity of exemplary IL-2 fusion proteins in the cell line CTLL-2 of IL-2 dependent cytotoxic T lymphocytes. Each graph shows the results of an IL-2 proliferation assay quantified by a cell viability assay based on CellTiter-glo (promega) luminescence. Each assay used uncleaved and MMP9 protease cleaved forms of the fusion protein.
FIGS. 9A to 9Z are a series of graphs showing the activity of exemplary IL-2 fusion proteins in the cell line CTLL-2 of IL-2 dependent cytotoxic T lymphocytes. Each graph shows the results of an IL-2 proliferation assay quantified by a cell viability assay based on CellTiter-glo (promega) luminescence. Each assay used uncleaved and MMP9 protease cleaved forms of the fusion protein.
Figure 10 shows the results of the proteolytic assay. The fusion protein ACP16 was run on SDS-PAGE gels in both cleaved and uncleaved forms. As can be seen in the gel, lysis was complete.
FIG. 11 is a graph depicting the results of HEK-Blue IL-12 reporter gene assays performed on human p 40/murine p35 IL12 fusion proteins before and after protease cleavage. Based on the use of reagentsThe secreted alkaline phosphatase (SEAP) activity was quantified and analyzed by (InvivoGen). The results confirmed that the IL12 protein fusion protein had activity.
FIGS. 12A-12F show a series of graphs depicting the results of HEK-blue assays of four IL-12 fusion proteins before and after cleavage by MMP 9. The analysis was carried out on the basis of the quantification of the activity of secreted alkaline phosphatase (SEAP) using the reagent QUANTI-blue (InvivoGen). The data show that activity in cleaved IL12 is greater than in the intact fusion protein. The constructs tested were ACP06 (fig. 12A), ACP07 (fig. 12B), ACP08 (fig. 12C), ACP09 (fig. 12D), ACP10 (fig. 12E), ACP11 (fig. 12F).
Figure 13 shows the results of the proteolytic assay. The fusion protein ACP11 was run on SDS-PAGE gels in both cleaved and uncleaved forms. As can be seen in the gel, lysis was complete.
Figure 14 is a schematic depicting a non-limiting example of an inducible cytokine protein, where the construct is activated upon protease cleavage of the linker connecting the two subunits of the cytokine.
FIGS. 15A-15D are graphs depicting the results of HEK-Blue assays performed on human p 40/murine p35IL12 fusion proteins before and after protease cleavage. And (4) carrying out measurement. The results confirmed that the IL12 protein fusion protein had activity. Each proliferation assay was performed with or without HSA.
Figures 16A-16F are a series of graphs showing the activity of exemplary IFN γ fusion proteins compared to the activity of a mouse IFN γ control using the WEHI 279 cell survival assay. Each assay was performed using medium containing HSA (+ HSA) or without HSA (-HSA). Each fusion protein comprises an anti-HSA conjugate, and each assay uses the uncleaved and MMP9 protease cleaved forms of the fusion proteins.
Fig. 17A-17F are a series of graphs showing the activity of exemplary IFN γ fusion proteins compared to the activity of a mouse IFN γ control using the B16 reporter gene assay. Each assay was performed using medium containing HSA (+ HSA) or without HSA (-HSA). Each fusion protein comprises an anti-HSA conjugate, and each assay uses the uncleaved and MMP9 protease cleaved forms of the fusion proteins.
Fig. 18A and 18B show the results of a protein cleavage assay as described in example 2. Both constructs ACP31(IFN-a fusion protein; 9A) and ACP55(IFN-g fusion protein; 9B) were run in both cleaved and uncleaved forms on SDS-PAGE gels. As can be seen in the gel, lysis was complete.
Fig. 19A and 19B are a series of graphs (11A and 11B) showing the activity of exemplary IFN γ fusion proteins before and after protease cleavage, obtained using the B16 reporter gene assay. Each assay was performed using HSA-containing medium, and each fusion protein included an anti-HSA conjugate. Each assay used uncleaved and MMP9 protease cleaved forms of the fusion protein.
Fig. 20A and 20B are a series of graphs (12A and 12B) showing activity of exemplary IFNa fusion proteins before and after cleavage, obtained using the B16 reporter gene assay. Each assay was performed using HSA-containing medium, and each fusion protein included an anti-HSA conjugate. Each assay used uncleaved and MMP9 protease cleaved forms of the fusion protein.
Fig. 21A-21D are a series of graphs depicting the results of tumor growth studies performed using the MC38 cell line. Fig. 21A to 21C show the effect of IFN γ and IFN γ fusion proteins on tumor growth when injected Intraperitoneally (IP) using different dosing levels and regimens (ug microgram, BID twice daily, BIW twice weekly, QW twice weekly). FIG. 21D shows the effect of Intratumoral (IT) injection of IFN γ and IL-2 on tumor growth.
Fig. 22A and 22B are a series of graphs showing the activity of MMP9 protease cleaved exemplary IFN γ fusion proteins (ACP51, ACP52, and ACP62) compared to the activity of the uncleaved fusion protein using the B16 reporter gene assay. Each fusion protein comprises an anti-HSA conjugate and a tumor targeting domain.
Fig. 23A and 23B are a series of graphs showing the activity of MMP9 protease cleaved exemplary IFN γ fusion proteins (ACP53 and ACP54) compared to the activity of the uncleaved fusion protein using the B16 reporter gene assay. Each fusion protein comprises IFN γ fused directly to albumin.
FIGS. 24A-24D are graphs depicting the results of HEK-Blue IL-2 reporter assays performed on IL-2 fusion proteins and recombinant human IL2(Rec hIL-2). The analysis was carried out on the basis of the quantification of the activity of secreted alkaline phosphatase (SEAP) using the reagent QUANTI-blue (InvivoGen).
Fig. 25A and 25B are two graphs showing analysis of ACP16(25A) and ACP124(25B) in the HEKBlue IL-2 reporter assay in the presence of HSA. Circles depict the activity of uncleaved polypeptide and squares depict the activity of cleaved polypeptide. FIG. 25C is a graph showing the results of CTLL-2 proliferation assay. CTLL2 cells (ATCC) were seeded at a concentration of 500,000 cells/well in medium with or without 40mg/ml Human Serum Albumin (HSA) and at 37 ℃ and 5% CO 2Next, stimulation with serially diluted activatable hIL2 was performed for 72 hours. The activity of uncleaved and lysed activatable ACP16 was tested. By incubation with active MMP9The resulting cleaved activatable hIL 2. Cell activity was assessed using a cell viability assay based on CellTiter-glo (Promega) luminescence. Circles depict the intact fusion protein and squares depict the protease cleaved fusion protein.
Fig. 26A-26C are a series of graphs showing the activity of the fusion proteins in a HEKBlue IL-12 reporter gene assay. FIG. 26A depicts IL-12/STAT4 activation in comparison of ACP11 (human p 40/murine p35 IL12 fusion protein) and ACP04 (negative control). FIG. 26B is a graph showing analysis of ACP91 (chimeric IL-12 fusion protein). Circles depict the activity of the control polypeptide ACP04, squares depict the activity of the uncleaved ACP91 polypeptide, and triangles depict the activity of the cleaved polypeptide (ACP91+ MMP 9). The EC50 values for each polypeptide are shown in the table. FIG. 26C is a graph showing analysis of ACP136 (chimeric IL-12 fusion protein). Circles depict the activity of the control polypeptide ACP04, squares depict the activity of the uncleaved ACP136 polypeptide, and triangles depict the activity of the cleaved polypeptide (ACP136+ MMP 9). The EC50 values for each polypeptide are shown in the inset table.
FIGS. 27A-27F are a series of graphs showing that cleaved IL-12 polypeptide is active in a HEKBlue reporter assay. The upper left panel shows that murine IL-12 is active in this assay (positive control). The bottom left and bottom right panels show activity without cleavage (squares) and with cleavage (triangles), respectively. EC50 values for each antibody are shown in the inset table (upper right panel).
Fig. 28A to 28N are a series of graphs depicting the activity of APC56 (fig. 28A), APC57 (fig. 8B), APC58 (fig. 28C), APC59 (fig. 28D), APC60 (fig. 28E), APC61+ HSA (fig. 28F), ACP30+ HSA (fig. 28G), ACP73 (fig. 28H), ACP70+ HSA (fig. 28I), ACP71 (fig. 28J), ACO 72 (fig. 28K), ACP73 (fig. 28L), ACP74 (fig. 28M), and ACP75 (fig. 28N) in the B16 IFN α reporter gene assay. Each fusion was tested for activity when cleaved (squares) and uncleaved (circles). Analysis of murine IFN γ was included in each graph as a comparison.
Fig. 29A and 29B are two graphs showing the results of analyzing ACP31 (mouse IFN α 1 fusion protein) and ACP11 (human p 40/mouse p35 IL12 fusion protein) in a tumor xenograft model. Figure 29A shows tumor volume over time for mice treated with 30 μ g ACP31 (circles), 110 μ g ACP31 (triangles), 330 μ g ACP31 (diamonds), and 1 μ g murine wild-type IFNa1 (dashed lines, squares) and 10 μ g mfna 1 (dashed lines, small circles) as controls. The large open circles indicate the individual vehicles. The data show that tumor volume decreases dose-dependently over time in mice treated with ACP 31. Fig. 29B shows tumor volumes over time for mice treated with 17.5 μ g ACP11 (squares), 175 μ g ACP31 (triangles), 525 μ g ACP31 (circles), and 2 μ g ACP04 (dashed lines, triangles) and 10 μ g ACP04 (dashed lines, diamonds) as controls. The large open circles indicate the individual vehicles. The data show that tumor volume decreased in a dose-dependent manner over time in mice treated with ACP11 and ACP04 (human p 40/murine p35 IL12 fusion protein).
Fig. 30 is a series of pasta plots showing tumor volume over time in a mouse xenograft tumor model in mice, each treated with vehicle alone (top left), 2 μ g ACP04 (top center), 10 μ g ACP04 (top right), 17.5 μ g ACP11 (bottom left), 175 μ g ACP11 (bottom center), and 525 μ g ACP11 (bottom right). Each line represents a single mouse.
Fig. 31A to 31C are three graphs showing the results of analyzing ACP16, ACP124 in the tumor xenograft model. Figure 31A shows tumor volume over time in mice treated with 4.4 μ g ACP16 (squares), 17 μ g ACP16 (triangles), 70 μ g ACP16 (inverted triangles), 232 μ g ACP16 (black circles), and as a comparison, 12 μ g wild-type IL-2 (dashed lines, triangles), and 36 μ g wild-type IL-2 (dashed lines, diamonds). The large open circles indicate the individual vehicles. The data show that tumor volume decreased in a dose-dependent manner over time in mice treated with higher concentrations of ACP 16. Fig. 31B shows tumor volume over time in mice treated with 17 μ g ACP124 (squares), 70 μ g ACP124 (triangles), 230 μ g ACP124 (inverted triangles), and 700 μ g ACP 124. The large open circles indicate the individual vehicles. Fig. 31C shows tumor volumes over time in mice treated with 17 μ g ACP16 (triangles), 70 μ g ACP16 (circles), 232 μ g ACP16 (black circles), and as a comparison 17 μ g ACP124 (dashed lines, triangles), 70 μ g ACP124 (dashed lines, diamonds), 230 μ g ACP124 (dashed lines, diamonds). The black inverted triangle indicates the vehicle alone. The data show that tumor volume decreased in a dose-dependent manner over time in mice treated with ACP16, but not ACP 124.
Fig. 32A to 32C are a series of pasta plots showing the activity of the fusion protein in the MC38 mouse xenograft model, which corresponds to the data shown in fig. 31. Each line in the figure is a single mouse.
Fig. 33 is a graph showing tumor volume over time in a mouse xenograft model, showing tumor growth in control mice (open circles) and AP 16-treated mice (squares).
Fig. 34A-34D are a series of survival graphs showing survival of mice over time following treatment with cleavable fusion proteins. Figure 34A shows data for mice treated with vehicle alone (grey line), 17 μ g ACP16 (dark line), and 1 μ g ACP124 (dashed line). Figure 34B shows data for mice treated with vehicle alone (grey line), 70 μ g ACP16 (dark line), and 70 μ g ACP124 (dashed line). Figure 34C shows data for mice treated with vehicle alone (grey line), 232 μ g ACP16 (dark line), and 230 μ g ACP124 (dashed line). Figure 34D shows data for mice treated with vehicle alone (grey line), 232 μ g ACP16 (dark line), and 700 μ g ACP124 (dashed line).
Fig. 35 is a series of pasta plots showing the activity of the fusion protein in the MC38 mouse xenograft model. A total of four doses were administered to all mouse groups, except for the highest three doses of APC132, where lethal toxicity was detected after 1 week/2 doses. Vehicle alone (top), 17 μ g, 55 μ g, 70 μ g and 230 μ g ACP16 (top full row), 9 μ g, 38 μ g, 36 μ g and 119 μ g ACP132 (middle full row) and 13 μ g, 42 μ g, 54 μ g and 177 μ g ACP21 (bottom full row) are shown. Each line in the figure represents an individual animal.
Fig. 36-41 show the properties of the TriTac polypeptide, which is used as an exemplary protease cleavable fusion protein.
Detailed Description
Disclosed herein are methods and compositions for engineering constructs comprising inducible cytokines and using the constructs. Cytokines are potent immune agonists, which have led to their recognition as promising tumor therapeutics. However, cytokines have been shown to have a very narrow therapeutic window. Cytokines have short serum half-lives and are also considered to be highly potent. Thus, therapeutic administration of cytokines produces undesirable systemic effects and toxicity. These problems are exacerbated by the large amounts of cytokines that need to be administered in order to achieve the desired cytokine levels at the intended cytokine site (e.g., tumor). Unfortunately, cytokines have not achieved the desired clinical advantages in the treatment of tumors because of their biological properties and the inability to effectively target and control their activity.
Disclosed herein are fusion proteins that overcome the problems of toxicity and short half-life, which severely limit the clinical utility of cytokines in oncology. The fusion protein contains a cytokine polypeptide having receptor agonist activity. However, in the case of fusion proteins, cytokine receptor agonist activity is reduced and the circulating half-life is extended. Fusion proteins comprise a protease cleavage site that is cleaved by a protease associated with a desired cytokine active site (e.g., a tumor), and is typically enriched for or selectively present at the site having the desired activity. Thus, the fusion protein is preferentially (or selectively) and efficiently cleaved at the desired active site to substantially restrict the activity of the cytokine to the desired active site, such as a tumor microenvironment. Cleavage of the protease at the desired active site (such as in the tumor microenvironment) releases a form of the cytokine from the fusion protein that is much more active as a cytokine receptor agonist than the fusion protein (typically at least about 100-fold more active than the fusion protein). The form of cytokine released upon lysis of the fusion protein typically has a short half-life, which is typically substantially similar to that of naturally occurring cytokines, thereby further limiting cytokine activity to the tumor microenvironment. Even though the half-life of the fusion protein is extended, toxicity is significantly reduced or eliminated because the circulating fusion protein is attenuated and the active cytokines target the tumor microenvironment. The fusion proteins described herein for the first time enable the administration of therapeutically effective doses of cytokines to treat tumors, wherein the activity of the cytokines is substantially restricted to the tumor microenvironment and the unwanted systemic effects and toxicity of the cytokines are significantly reduced or eliminated.
Unless defined otherwise, all technical terms, symbols, and other scientific terms used herein are intended to have the meanings commonly understood by those of skill in the art to which this application belongs. In some instances, terms having commonly understood meanings are defined herein for clarity and/or ease of reference, and the inclusion of such definitions herein should not necessarily be construed to represent a distinction from what is commonly understood in the art. The techniques and procedures described or referenced herein are generally well understood by those skilled in the art and are generally applied using conventional methods such as the widely applied Molecular Cloning methods described in Sambrook et al, Molecular Cloning: A Laboratory Manual version 4 (2012) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Suitably, procedures involving the use of commercially available kits and reagents are generally performed according to manufacturer-defined protocols and conditions, unless otherwise specified.
"cytokines" are well known terms of art and refer to any class of immunomodulatory proteins (such as interleukins or interferons) that are secreted by cells, particularly cells of the immune system, and are modulators of the immune system. Cytokine polypeptides that can be used in the fusion proteins disclosed herein include, but are not limited to, transforming growth factors such as TGF-alpha and TGF-beta (e.g., TGF β 1, TGF β 2, TGF β 3); interferons such as interferon- α, interferon- β, interferon- γ, interferon- κ, and interferon- ω; interleukins such as IL-1, IL-1 α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-21, and IL-25; tumor necrosis factors such as tumor necrosis factor alpha and lymphotoxin; chemokines (e.g., the C-X-C motifs chemokine 10(CXCL10), CCL19, CCL20, CCL21), and granulocyte macrophage colony stimulating factor (GM-CS), as well as fragments of such polypeptides that activate cytokine-cognate receptors (i.e., functional fragments of the foregoing). "chemokine" is a term of art and refers to any family of small cytokines that have the ability to induce directional chemotaxis of nearby reactive cells.
It is well known that cytokines have a short serum half-life, often only a few minutes or hours. Even cytokine forms that have altered the amino acid sequence intended to prolong serum half-life but retain receptor agonist activity generally have a shorter serum half-life. As used herein, "half-life cytokine" refers to a cytokine that has a substantially transient half-life cycle in the serum of a subject, such as a serum half-life of less than 10 minutes, less than 15 minutes, less than 30 minutes, less than 60 minutes, less than 90 minutes, less than 120 minutes, less than 240 minutes, or less than 480 minutes. As used herein, a cytokine with a short half-life includes cytokines whose sequence has not been modified to achieve a longer half-life in a subject than the normal half-life, as well as polypeptides that have altered the amino acid sequence intended to extend serum half-life but retain receptor agonist activity. The latter case is not meant to include the addition of heterologous protein domains, such as true half-life extending elements, such as serum albumin.
"sortases" are transpeptidases that modify proteins by recognizing and cleaving carboxy-terminal sorting signals embedded in or terminally attached to a target protein or peptide. Sortase a catalyzes the cleavage of the LPXTG motif (where X is any standard amino acid) between Thr and Gly residues on the target protein, where the Thr residue is transiently linked to the active site Cys residue on the enzyme, thereby forming the enzyme thioacyl intermediate. To accomplish transpeptidation and create a peptide-monomer conjugate, a biomolecule with an N-terminal nucleophilic group (usually an oligoglycine motif) attacks the intermediate, replacing sortase a and linking the two molecules.
As used herein, the term "steric blocker" refers to a polypeptide or polypeptide portion that is covalently bonded, directly or indirectly, to a cytokine polypeptide, but not otherwise, through other moieties such as linkers (e.g., in the form of chimeric polypeptides (fusion proteins)). The steric blocker may be non-covalently bonded to the cytokine polypeptide, for example, by electrostatic bonding, hydrophobic bonding, ionic bonding, or hydrogen bonding. Steric blockers generally inhibit or block the activity of the cytokine moiety due to their proximity and relative size. Steric blockers can also block by recruiting large protein binding partners. Examples of steric blockers are antibodies that bind to serum albumin; while the antibody itself may or may not be large enough to prevent activation or binding by itself, albumin recruitment allows for sufficient steric blockade.
As used and described herein, a "half-life extending element" is a portion of a chimeric polypeptide that increases serum half-life and improves pK, for example, by altering its size (e.g., above the renal filtration limit), shape, hydrodynamic radius, charge, or parameters of absorption, biodistribution, metabolism, and elimination.
As used herein, the terms "activatable", "activating", "inducing" and "inducible" refer to the ability of a protein (i.e., cytokine) that is part of a fusion protein to bind its receptor and achieve activity upon cleavage of other elements from the fusion protein.
As used herein, a "plasmid" or "viral vector" is an agent that transports the disclosed nucleic acids into a cell without degradation, and comprises a promoter that produces expression of the nucleic acid molecule and/or polypeptide in the cell into which it is delivered.
As used herein, the term "peptide," "polypeptide," or "protein" is used broadly to refer to two or more amino acids joined by peptide bonds. Proteins, peptides and polypeptides may also be used interchangeably herein to refer to amino acid sequences. It will be appreciated that the term polypeptide is not used herein to imply a particular size or number of amino acids making up the molecule, and that the peptides of the present application may contain up to a few amino acid residues or more.
As used throughout, a "subject" can be a vertebrate, more specifically a mammal (e.g., human, horse, cat, dog, cow, pig, sheep, goat, mouse, rabbit, rat, and guinea pig), bird, reptile, amphibian, fish, and any other animal. The term does not denote a particular age or gender. Thus, adult and neonatal subjects, whether male or female, are intended to be encompassed.
As used herein, "patient" or "subject" are used interchangeably and may refer to a subject having a disease or disorder (e.g., cancer). The term patient or subject includes human and veterinary subjects.
As used herein, the term "treating" refers to a method of reducing the effects of a disease or condition or the symptoms of a disease or condition. Thus, in the disclosed methods, treatment may refer to at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or substantially complete reduction in the severity of an established disease or condition or symptom of a disease or condition. For example, a method for treating a disease is considered a treatment if one or more symptoms of the disease are reduced by 10% in a subject compared to a control. Thus, the reduction may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percentage reduction between 10% and 100% compared to the native or control level. It is to be understood that treatment does not necessarily refer to curing or completely eliminating a disease, condition, or symptom of a disease or condition.
As used herein, the term "preventing" a disease or disorder refers to the effect of administering a chimeric polypeptide or a nucleic acid sequence encoding a chimeric polypeptide, which inhibits or delays the onset or exacerbation of one or more symptoms of the disease or disorder, e.g., before or about the same time as the subject begins to exhibit one or more symptoms of the disease or disorder.
As used herein, reference to "reduce", "reduce" or "inhibit" includes a change of at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or more as compared to a suitable control level. Such terms may include, but do not necessarily include, complete elimination of a function or property, such as agonist activity.
A "reduced cytokine receptor agonist" is a cytokine receptor agonist having reduced receptor agonist activity compared to a naturally occurring agonist of the cytokine receptor. An attenuated cytokine agonist may have at least about 10-fold, at least about 50-fold, at least about 100-fold, at least about 250-fold, at least about 500-fold, at least about 1000-fold or less agonist activity compared to a naturally occurring agonist of the receptor. When a fusion protein containing a cytokine polypeptide as described herein is described as "attenuated" or having "attenuated activity," it is meant that the fusion protein is an attenuated cytokine receptor agonist.
An "intact fusion protein" is one in which the domains have not been removed, e.g., by protease cleavage. The domain can be removed by protease cleavage or other enzymatic activity, but this does not occur when the fusion protein is "intact".
As used herein, "moiety" refers to a portion of a molecule that has a different function within the molecule, and that function can be performed by that portion in the case of another molecule. The moiety may be a chemical entity having a specific function, or a portion of a biomolecule having a specific function. For example, a "blocking moiety" within a fusion protein is a portion of the fusion protein that is capable of blocking the activity of some or all of the fusion polypeptide. This may be a protein domain such as serum albumin. Blocking can be accomplished by steric blockers or specific blockers. Steric blockers block by size and location rather than based on specific binding; one example is serum albumin. Specific blocking agents block by specific interaction with the moiety to be blocked. Specific blockers must be tailored to specific cytokines or active domains; regardless of the payload, a steric blocker may be used, provided it is sufficiently large.
In general, the therapeutic use of cytokines is strongly limited by their systemic toxicity. For example, TNF was initially found to have the ability to induce hemorrhagic necrosis of some tumors and to have cytotoxic effects in vitro on different tumor cell lines, but it was later demonstrated to have strong pro-inflammatory activity that could have dangerous effects on the human body in the event of overproduction. Since systemic toxicity is a fundamental problem in the use of pharmaceutically active amounts of cytokines in humans, new derivatives and therapeutic strategies are currently being evaluated aimed at reducing the toxic effects of such bioeffectors while maintaining their therapeutic efficacy.
IL-2 plays a stimulating and regulatory role in the immune system and, together with other members of the common gamma chain (yc) cytokine family, plays a crucial role in immune homeostasis. IL-2 mediates its effects by binding to the IL-2 receptor (IL-2R), which consists of the trimeric receptor IL-2 or the dimeric β γ IL-2R (1,3) made up of chains IL-2R α (CD25), IL-2R β (CD122) and IL-2R γ (γ c, CD 132). Both IL-2R variants are capable of signaling upon IL-2 binding. However, trimeric α β γ IL-2R has about 10 to 100 fold higher affinity for IL-2 than dimeric β γ IL-2R (3), suggesting that CD25 confers IL-2 high affinity binding to its receptor, but is not important for signal transduction. Trimeric IL-2R, which are sensitive to IL-2 in vitro and in vivo, were found on activated T cells and CD4+ forkhead box P3(FoxP3) + T regulatory cells (Tregs). In contrast, antigen stimulated (memory) CD8+, CD44 high Memory Phenotype (MP) CD8+, and Natural Killer (NK) cells were endowed with high levels of dimeric β γ IL-2R, and these cells also responded potently to IL-2 in vitro and in vivo.
Expression of high affinity IL-2R is critical to conferring T cell response to low concentrations of IL-2 that are transiently available in vivo. IL-2R α expression is absent on naive and memory T cells, but is induced upon antigen activation. IL-2R β is constitutively expressed by NK, NKT and memory CD8+ T cells, but is also induced on naive T cells after antigen activation. Yc is less tightly regulated and is constitutively expressed by all lymphoid cells. Once antigen induces high affinity IL-2R, IL-2R signaling upregulates IL-2R α expression in part through Stat 5-dependent regulation of Il2ra transcription (Kim et al, 2001). This process represents a mechanism to maintain high affinity IL-2R expression and maintain IL-2 signaling, while still retaining the source of IL-2.
IL-2R α captures IL-2 via a large hydrophobic binding surface surrounded by a polar perimeter, resulting in a relatively weak interaction (Kd 10-8M) and fast switching binding kinetics. However, the IL-2R α -IL-2 binary complex results in very little conformational change in IL-2, thereby facilitating association with IL-2R β through a pronounced polar interaction between IL-2 and IL-2R β. The pseudo-high affinity of the IL2/α/β trimer complex (i.e. Kd about 300pM) clearly indicates that the trimer complex is more stable than IL2 bound to the α chain alone (Kd ═ 10nM) or the β chain alone (Kd ═ 450nM), as shown by the data in Ciardelli. Regardless, the IL2/α/β trimer then recruits the γ chain into a quaternary complex capable of signaling, facilitated by the large complex binding site of the γ chain on the β chain to which IL2 binds.
In other words, the ternary IL-2R α -IL-2R β -IL-2 complex then recruits yc through a weak interaction with IL-2 and a strong interaction with IL-2R β to produce a stable quaternary high affinity IL-2R (Kd 10-11M, i.e., 10 pM). Formation of the high affinity quaternary IL-2-IL-2R complex results in signal transduction by the tyrosine kinases Jak1 and Jak3, which associate with IL-2R β and γ c, respectively (Nelson and Willerford, 1998). Quaternary IL-2-IL-2R complexes are rapidly internalized, with IL-2, IL-2R β and γ c rapidly degrading, but IL-2R α circulating to the cell surface (Bemar et al, 1995; Yu and Malek, 2001). Thus, those functional activities that require sustained IL-2R signaling require a sustained source of IL-2 to engage IL-2R α and form additional IL-2-IL-2R signaling complexes.
Interleukin-15 (IL-15), another member of the 4-alpha-helical bundle family of cytokines, has also emerged as an immunomodulator for the treatment of cancer. IL-15 is initially captured by IL-15 Ra, which is expressed on antigen-presenting dendritic cells, monocytes, and macrophages. IL-15 exhibits a wide range of activity and induces differentiation and proliferation of T cells, B cells and Natural Killer (NK) cells via signaling through IL-15/IL-2-R-beta (CD122) and common gamma chain (CD 132). IL-15 also enhances CD8 +Cytolytic activity of T cells and induction of persistent antigen-stimulated CD8+CD44 memory T cells. IL-15 stimulates B cells to proceedDifferentiation and immunoglobulin synthesis, and induction of dendritic cell maturation. It does not stimulate immunosuppressive T regulatory cells (tregs). Thus, selectively enhancing IL-15 activity in the tumor microenvironment can enhance innate and specific immunity and fight tumors (Waldmann et al, 2012). The ability of IL-15 to stimulate T cell proliferation and signaling through JAK1/JAK3 and STAT3/STAT5 in an IL-2 like manner by co-receptor components (IL-2R/15R β - γ c) was initially identified. Like IL-2, IL-15 has been shown to stimulate proliferation of activated CD4-CD8-, CD4+ CD8+, CD4+ and CD8+ T cells, and to promote induction of cytotoxic T lymphocytes and generation, proliferation and activation of NK cells (Waldmann et al, 1999). However, unlike IL-2, which is required to maintain CD4+ CD25+ Treg cells expressing forkhead box P3(FOXP3) and to retain these cells in the periphery, IL-15 has little effect on tregs (Berger et al, 2009). This is important because CD4+ CD25+ tregs expressing FOXP3 suppress effector T cells, thereby suppressing immune responses, including those against tumors. IL-2 also plays a crucial role in initiating activation-induced cell death (AICD), a process leading to the elimination of autoreactive T cells, whereas IL-15 is an anti-apoptotic factor for T cells (Marks-Konczalik et al, 2000). IL-15 co-delivered with HIV peptide vaccines has been shown to overcome CD4+ T cell deficiency by increasing the lifespan of antigen-specific CD8+ T cells and blocking TRAIL-mediated apoptosis (Oh et al, 2008). In addition, IL-15 promotes long-term maintenance of CD8+ CD44hi memory T cells (Kanegane et al, 1996).
By IL-15R alpha-/-And IL-15-/-The mouse phenotype further highlights the importance of IL-15 and IL-15R α on T cell and NK cell development. Knockout mice showed a reduction in the total number of CD8+ T cells and lack certain subpopulations of memory phenotype CD8+ T cells, NK/T cells and intestinal intraepithelial lymphocytes, indicating that IL-15 provides the essential homeostatic function for these cell subpopulations (Lodolce et al, 1996; Kennedy et al, 1998). Phenotypic similarity of knockout mice of these two strains indicates the importance of IL-15R α in maintaining physiologically relevant IL-15 signaling.
IL-15 is presented in trans via the IL-15 receptor alpha chain to the IL-15 Rbetagammac complex displayed on the surface of T cells and Natural Killer (NK) cells (Han et al, 2011). The IL-15Ra chain functions as a chaperone, stabilizing and increasing the activity of IL-15 (Desbois et al, 2016). It has been shown that exogenous IL-15 may have limited effect on patients with cancer, due to its dependence on IL-15Ra, which is often down-regulated in cancer patients. Thus, a fusion protein RLI consisting of the sushi + domain of IL15Ra coupled to IL-15 via a linker has been proposed as an alternative to IL15 treatment (besnard et al, 2009). Administration of the soluble IL-15/IL-15 Ra complex was found to greatly enhance IL-15 serum half-life and in vivo bioavailability (Stoklasek et al, 2010).
In addition to the effects on T cells and NK cells, IL-15 also has a variety of effects on other components of the immune system. IL-15 protects neutrophils from apoptosis, regulates phagocytosis and stimulates secretion of IL-8 and IL-1R antagonists. IL-15 functions by activating JAK2, p38 and ERK1/2MAPK, Syk kinase, and NF-kB transcription factors (Pelletier et al, 2002). In mast cells, IL-15 may act as a growth factor and an inhibitor of apoptosis. In these cells, IL-15 activates the JAK2/STAT5 pathway without the need for yc binding (Tagaya et al, 1996). IL-15 also induces B-lymphocyte proliferation and differentiation, and increases immunoglobulin secretion (Armitage et al, 1995). IL-15 also prevents Fas-mediated apoptosis and allows the induction of antibody responses partially independent of CD4 help (Demerci et al, 2004; Steel et al, 2010). Monocytes, macrophages and dendritic cells efficiently transcribe and translate IL-15. They also respond to IL-15 stimulation. Macrophages respond by increasing phagocytosis, inducing expression of IL-8, IL-12, and MCP-1, and secreting IL-6, IL-8, and TNF α (Budagian et al, 2006). Dendritic cells incubated with IL-15 showed maturation in which CD83, CD86, CD40 and MHC class II expression were increased also resistant to apoptosis and showed enhanced interferon- γ secretion (Anguille et al, 2009).
IL-15 has also been shown to have effects on non-blood cells, including muscle cells, adipocytes, endothelial cells, and neural cells. IL-15 has anabolic effects on muscle and can support muscle cell differentiation (Quinn et al, 1995). IL-15 stimulates muscle cells and muscle fibers to accumulate contractile proteins and can slow muscle atrophy in rats with cancer-associated cachexia (Figuras et al, 2004). IL-15 has also been shown to stimulate angiogenesis (Angiolillo et al, 1997) and induce microglial cell growth and survival (Hanisch et al, 1997).
Interleukin-7 (IL-7) also belongs to the IL-2/IL-15 family, is a well-characterized pleiotropic cytokine, and is expressed by stromal cells, epithelial cells, endothelial cells, fibroblasts, smooth muscle cells, and keratinocytes, and is scaled by dendritic cells after activation (Alpdogan et al, 2005). Although it was originally described as a growth and differentiation factor for precursor B lymphocytes, subsequent studies have shown that IL-7 is critically involved in the development and differentiation of T lymphocytes. Interleukin-7 signaling is critical for optimal CD 8T cell function, homeostasis, and memory establishment (Schluns et al, 2000); it is required for the survival of most T cell subsets and its expression is thought to be important for regulating T cell numbers.
IL-7 and dimer receptors (including IL-7R alpha and gamma)c) Combine to form a ternary complex that plays a fundamental role in the remodeling, development and homeostasis of the extracellular matrix of T and B cells (mazzuccheli and Durum, 2007). IL-7R α also cross-reacts with Thymic Stromal Lymphopoietin (TSLP) and its receptor (TSLPR) to form a ternary complex and activate the TSLP pathway, leading to human T cell and dendritic cell proliferation and further development of mouse B cells (Leonard, 2002). Therefore, tight regulation of the signaling cascade activated by the complex is critical for normal cellular function. Under-stimulation of the IL-7 pathway by mutations in the extracellular domain of IL-7R α inhibits T-cell and B-cell development, resulting in patients with the Severe Combined Immunodeficiency (SCID) form (Giliani et al, 2005; Puel et al, 1998).
IL-7 has a potential role in enhancing immune reconstitution in cancer patients following cytotoxic chemotherapy. IL-7 treatment enhances immune reconstitution and may enhance even limited thymus function by promoting peripheral expansion of even small amounts of recent thymus grafts (emigrants). Thus, IL-7 treatment could potentially restore the immune system of patients who have been compromised by cytotoxic chemotherapy (Capitini et al, 2010).
Interleukin-12 (IL-12) is a disulfide-linked heterodimer of two separately encoded subunits (p35 and p40) that are covalently linked to produce a so-called biologically active heterodimer (p70) molecule (Lieschke et al, 1997; Jana et al, 2014). In addition to the formation of heterodimers (IL-12 and IL-23), the p40 subunit also functions as a monomer (p40) and homodimer (p40)2) Is secreted out. It is known in the art to synthesize heterodimers as single chains with linkers connecting p35 to the p40 subunit, retaining the full biological activity of the heterodimer. IL-12 plays a key role in the early inflammatory response of infection and the generation of Th1 cells, which favors cell-mediated immunity. It has been found that overproduction of IL-12 can be dangerous to the host as it is involved in the pathogenesis of many autoimmune inflammatory diseases (e.g., MS, arthritis, type 1 diabetes).
The IL-12 receptor (IL-12R) is a heterodimeric complex consisting of chains of IL-12R β 1 and IL-12R β 2 expressed on the surface of activated T cells and natural killer cells (Trinchieri et al, 2003). The IL-12R β 1 chain binds to the IL-12p40 subunit, whereas IL-12p35, which is associated with IL-12R β 2, has intracellular signaling capacity (Benson et al, 2011). Signal transduction by IL-12R induces phosphorylation of Janus kinase (Jak2) and tyrosine kinase (Tyk2), which phosphorylates and activates Signal Transducer and Activator of Transcription (STAT)1, STAT3, STAT4, and STAT 5. The specific cellular role of IL-12 is primarily due to the activation of STAT 4. IL-12 induces natural killer and T cells to produce cytokines, particularly Interferon (IFN) γ, which mediate many of the proinflammatory activities of IL-12, including the differentiation of CD4+ T cells to the Th1 phenotype (Montepaone et al, 2014).
Regulatory T cells actively suppress the activation of the immune system and prevent pathological autoreactions and subsequent autoimmune diseases. The development of drugs and methods to selectively activate regulatory T cells to treat autoimmune diseases is the subject of intense research and has been largely unsuccessful until the development of the present application capable of selectively delivering active interleukins at sites of inflammation. Regulatory T cells (tregs) are a class of CD4+ CD25+ T cells that suppress the activity of other immune cells. Tregs are critical for immune system homeostasis and play a major role in maintaining tolerance to self-antigens and modulating immune responses to foreign antigens. A variety of autoimmune and inflammatory diseases, including type 1 diabetes (T1D), Systemic Lupus Erythematosus (SLE), and Graft Versus Host Disease (GVHD), have been shown to lack Treg cell numbers or Treg function.
Therefore, there is a great interest in developing therapies that enhance Treg cell number and/or function. One therapeutic approach to autoimmune disease that is being investigated is the transplantation of autologous, ex vivo expanded Treg cells (Tang, q. et al, 2013, Cold Spring harb.perfect.med., 3: 1-15). While this approach holds promise in treating animal disease models and in a number of early human clinical trials, it requires personalized treatment using the patient's own T cells, is invasive and technically complex. Another approach is treatment with low doses of interleukin-2 (IL-2). Treg cells characteristically express high constitutive levels of the high affinity IL-2 receptor IL2R α β γ, which consists of subunits IL2R α (CD25), IL2R β (CD122), and IL2R γ (CD132), and have been shown to be dependent on IL-2 for their growth (Malek, t.r. et al, 2010, Immunity,33: 153-65).
Conversely, IL-2 has also been used to achieve immune activation, and recombinant IL-2 has been approvedCan be used for treating certain cancers. High doses of IL-2 are used to treat patients with metastatic melanoma and metastatic renal cell carcinoma, which has a long-term impact on overall survival.
Clinical trials of low doses of IL-2 in patients with chronic GVHD (Koreth, J. et al, 2011, N Engl J med.,365:2055-66) and HCV-associated autoimmune vasculitis (Saadoun, d. et al, 2011, N Engl J med.,365:2067-77) have demonstrated increased levels of Treg and evidence of clinical efficacy. New clinical trials have begun to investigate the efficacy of IL-2 in a variety of other autoimmune and inflammatory diseases. Use ofThe rationale for the so-called low dose of IL-2 is to take advantage of the high IL-2 affinity of the trimeric IL-2 receptor, which is constitutively expressed on tregs, while leaving other T cells, which do not express the high affinity receptor, in an inactive state. Recombinant form of IL-2 Aldesleukin (Aldesleukin) used in these experiments (by Prometheus Laboratories, San Diego, Calif. in order toSold) are associated with high toxicity. High doses of aldesleukin have been approved for the treatment of metastatic melanoma and metastatic renal cancer, but their side effects are so severe that their use in hospitals with intensive care units is only recommended (website: www.proleukin.com/assets/pdf/proleukin.
Clinical trials of IL-2 in autoimmune diseases have used lower doses of IL-2 to target Treg cells, as Treg cells respond to lower concentrations of IL-2 than many other immune cell types by expressing IL2R α (Klatzmann D,2015 Nat Rev Immunol.15: 283-94). However, even these lower doses lead to safety and tolerability issues, and the treatment used employs daily subcutaneous injections for long periods or in 5-day intermittent courses. Thus, there is a need for autoimmune disease therapies that enhance Treg cell number and function, target Treg cells more specifically than IL-2, are safer and more tolerable, and are less frequently administered.
One approach that has been proposed for improving the therapeutic index of autoimmune diseases based on IL-2 therapy is to use IL-2 variants that are selective for Treg cells relative to other immune cells. The IL-2 receptor is expressed on a variety of different immune cells, including T cells, NK cells, eosinophils and monocytes, and this broad pattern of expression may contribute to its pleiotropic effects on the immune system and high systemic toxicity. In particular, activated T effector cells express IL2R α β γ as do lung epithelial cells. However, activating T effector cells is directly opposite the goal of down regulating and controlling immune responses, and activating lung epithelial cells can lead to known dose-limiting side effects of IL-2, including pulmonary edema. In fact, a major side effect of high dose IL-2 immunotherapy is Vascular Leak Syndrome (VLS), which results in the accumulation of intravascular fluids in organs such as the lung and liver, with subsequent pulmonary edema and hepatocellular injury. There is no other method of treating VLS other than IL-2. Low dose IL-2 regimens have been tested in patients to avoid VLS, however, at the cost of suboptimal therapeutic outcomes.
According to the literature, VLS is thought to be caused by the release of pro-inflammatory cytokines by NK cells activated by IL-2. However, there is some evidence that pulmonary edema is caused by the direct binding of IL-2 to lung endothelial cells expressing low to moderate levels of functional α β γ IL-2R. Also, VLS was prevented by blocking binding to CD25 with anti-CD 25 monoclonal antibody (mAb) in CD25 deficient host mice or by eliminating pulmonary edema associated with IL-2 and lung endothelial cell interaction through the use of CD122 specific IL-2/anti-IL-2 mAb (IL-2/mAb) complexes.
Treatment with interleukin cytokines other than IL-2 is more limited. IL-15 exhibits similar immune cell stimulating activity as IL-2, but does not have the same inhibitory effect, thus making it a promising immunotherapeutic candidate. Clinical trials of recombinant human IL-15 for the treatment of metastatic malignant melanoma or renal cell carcinoma showed significant changes in immune cell distribution, proliferation and activation, and suggested potential anti-tumor activity (Conlon et al, 2014). IL-15 is currently in clinical trials to treat various forms of cancer. However, IL-15 treatment is known to be associated with undesirable and toxic effects, such as exacerbation of certain leukemias, graft versus host disease, hypotension, thrombocytopenia, and liver injury. (Mishra A. et al, cancer Cell,2012,22(5): 645-55; Alpdogan O. et al, Blood,2005,105(2): 866-73; Conlon KC et al, J Clin Oncol,2015,33(1): 74-82.)
IL-7 promotes the development of lymphocytes in the thymus and maintains the homeostatic survival of both naive and memory T cells. In addition, it is also important for organogenesis and maintenance of activated T cells recruited into Secondary Lymphoid Organs (SLO) of Lymph Nodes (LN) (Gao et al, 2015). In a clinical trial of IL-7, patients receiving IL-7 showed an increase in both CD4+ and CD8+ T cells, without a significant increase in the number of regulatory T cells monitored by FoxP3 expression (sports et al, 2008). In clinical trials reported in 2006, 2008 and 2010, patients with different types of cancer such as metastatic melanoma or sarcoma were injected subcutaneously with different doses of IL-7. Little toxicity was seen except for transient fever and mild erythema. Circulating levels of CD4+ and CD8+ T cells were significantly increased and the number of tregs was reduced. Following IL-7 treatment, TCR repertoire diversity increases. However, the anti-tumor activity of IL-7 was not well evaluated (Gao et al, 2015). The results indicate that IL-7 treatment can enhance and amplify the immune response.
IL-12 is a pleiotropic cytokine, the role of which has been linked between innate and adaptive immunity. IL-12 was first described as a factor secreted by PMA-induced EBV-transformed B cell lines. According to its role, IL-12 has been assigned to cytotoxic lymphocyte maturation factor and natural killer cell stimulating factor. IL-12 appears to be an ideal candidate for human tumor immunotherapy, since it bridges innate and adaptive immunity and effectively stimulates the production of the cytokine IFN γ, which coordinates natural anti-cancer defense mechanisms. However, the severe side effects associated with systemic administration of IL-12 in clinical studies and the very narrow therapeutic index of this cytokine significantly reduce the enthusiasm for using this cytokine in cancer patients (Lasek et al, 2014). Methods of tumor-targeted cytokine-delivery IL-12 therapy are currently in clinical trials for cancer, which may reduce some of the previous problems with IL-12 therapy.
Because IL-2 has well documented therapeutic risks, such as its short serum half-life and high toxicity, the direct use of IL-2 as an agonist to bind IL-2R and therapeutically modulate the immune response has been problematic. These risks also limit therapeutic development and use of other cytokines. New forms of cytokines that reduce these risks are needed. Disclosed herein are compositions and methods comprising IL-2 and IL-15 and other cytokines, functional fragments and muteins of cytokines, as well as conditionally active cytokines designed to address these risks and provide desired immunomodulatory therapeutics.
The present application is designed to address the shortcomings of direct IL-2 therapy and therapies using other cytokines, such as the use of cytokine blocking moieties, e.g., steric blocking polypeptides, serum half-life extending polypeptides, targeting polypeptides, linking polypeptides (comprising a protease cleavable linker), and combinations thereof. Cytokines, including interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23), interferons (IFN, including IFN α, IFN β, and IFN γ), tumor necrosis factors (e.g., TNF α, lymphotoxin), transforming growth factors (e.g., TGF β 1, TGF β 2, TGF β 3), chemokines (C-X-C motif chemokine 10(CXCL10), CCL19, CCL20, CCL21), and granulocyte-macrophage colony stimulating factor (GM-CS), have high potency when administered to a patient. As used herein, "chemokine" means a family of small cytokines that have the ability to induce directional chemotaxis in proximally reactive cells. Cytokines can provide potent therapies, but are associated with undesirable effects that are clinically difficult to control and limit clinical use of cytokines. The present application relates to novel forms of cytokines that can be used in patients with reduced or eliminated undesirable effects. In particular, the present application relates to pharmaceutical compositions comprising chimeric polypeptides (fusion proteins), pharmaceutical compositions of nucleic acids encoding fusion proteins, and pharmaceutical preparations thereof, containing a cytokine or an active fragment of a cytokine or a mutein having reduced cytokine receptor activating activity compared to the corresponding cytokine. However, under selected conditions or in a selected biological environment, chimeric polypeptides often activate their cognate receptors with the same or greater potency as the corresponding naturally occurring cytokine. As described herein, this is typically achieved using cytokine blocking moieties that block or inhibit the receptor activation function of cytokines, active fragments thereof, or muteins, such as those present at the desired cytokine active site (e.g., site of inflammation or tumor), under general conditions, but not under selected conditions.
Chimeric polypeptides and nucleic acids encoding chimeric polypeptides can be prepared using any suitable method. For example, a nucleic acid encoding a chimeric polypeptide can be prepared using recombinant DNA techniques, synthetic chemistry, or a combination of these techniques and expressed in a suitable expression system such as CHO cells. Chimeric polypeptides can be similarly prepared, for example, by expressing the appropriate nucleic acid using synthetic or semi-synthetic chemical techniques, and the like. In some embodiments, the blocking moiety may be attached to the cytokine polypeptide by sortase-mediated conjugation. "sortases" are transpeptidases that modify proteins by recognizing and cleaving carboxy-terminal sorting signals embedded in or terminally attached to a target protein or peptide. Sortase a catalyzes the cleavage of the LPXTG motif (SEQ ID No.:193) between Thr and Gly residues on the target protein, where X is any standard amino acid, where the Thr residue is transiently linked to the active site Cys residue on the enzyme, thereby forming an enzyme-sulfuryl intermediate. To accomplish transpeptidation and create a peptide-monomer conjugate, a biomolecule with an N-terminal nucleophilic group (usually an oligoglycine motif) attacks the intermediate, replacing sortase a and linking the two molecules.
To form the cytokine-blocking moiety fusion protein, the cytokine polypeptide is first labeled with a polyglycine sequence at the N-terminus, or alternatively with the LPXTG motif (SEQ ID No.:193) at the C-terminus. The blocking moiety or other element has attached a corresponding peptide that serves as a receptor site for the marker polypeptide. For conjugation to a domain carrying LPXTG (SEQ ID No.:193) receptor peptide linked through its N-terminus, the polypeptide will be labeled with an N-terminal polyglycine stretcher. For conjugation to a domain carrying a polyglycine peptide linked through its C-terminus, the polypeptide will be labeled at its C-terminus with the LPXTG (SEQ ID No.:193) sortase recognition sequence. Recognizing the polyglycine and LPXTG (SEQ ID No.:193) sequences, sortase will form a peptide bond between the polymer polypeptide and the marker polypeptide. The sortase reaction cleaves glycine residues as intermediates and occurs at room temperature.
Various mechanisms can be used to remove or reduce the inhibition caused by the blocking moiety. For example, the pharmaceutical composition can comprise a cytokine moiety having a protease-cleavable linker comprising a protease cleavage site located between or within the cytokine and cytokine blocking moiety, and a blocking moiety, such as a steric blocking moiety. When the protease cleavage site is cleaved, the blocking moiety can dissociate from the cytokine, and the cytokine can then activate the cytokine receptor. The cytokine moiety may also be blocked by a specific blocking moiety (such as an antibody) that binds to an epitope found on the relevant cytokine.
Any suitable linker may be used. For example, the linker may comprise glycine-glycine, a sortase recognition motif, or a sortase recognition motif and a peptide sequence (Gly)4Ser)n(SEQ ID No.:195) or (Gly)3Ser)n(SEQ ID No.:196) wherein n is 1, 2, 3, 4 or 5. Typically, the sortase recognition motif comprises the peptide sequence LPXTG (SEQ ID No.:193), wherein X is any amino acid. In some embodiments, the covalent bond is between a reactive lysine residue attached to the C-terminus of the cytokine polypeptide and a reactive aspartic acid attached to the N-terminus of the blocker or other domain. In other embodiments, the covalent bond is between a reactive aspartic acid residue attached to the N-terminus of the cytokine polypeptide and a reactive lysine residue attached to the C-terminus of the blocker or other domain.
Thus, as described in detail herein, the cytokine blocking moiety used may be a steric blocker. As used herein, "steric blocker" refers to a polypeptide or polypeptide portion that can be covalently bonded to, but not otherwise covalently bonded to, a cytokine polypeptide, either directly or indirectly through other moieties such as linkers (e.g., in the form of chimeric polypeptides (fusion proteins)). The steric blocker may be non-covalently bonded to the cytokine polypeptide, for example, by electrostatic bonding, hydrophobic bonding, ionic bonding, or hydrogen bonding. Steric blockers generally inhibit or block the activity of the cytokine moiety due to their proximity and relative size. The steric inhibition of the cytokine moiety can be removed by spatially separating the cytokine moiety from the steric blocker, such as by enzymatically cleaving a fusion protein comprising the steric blocker and the cytokine polypeptide at a site between the steric blocker and the cytokine polypeptide.
As described in more detail herein, the blocking function may be combined with or due to additional functional components in the pharmaceutical composition, such as targeting domains, serum half-life extending elements, and protease cleavable linking polypeptides. For example, the serum half-life extending polypeptide may also be a steric blocker.
In order to present a brief disclosure of the full scope of the present application, aspects of the present application are described in detail using the cytokine IL-2 as an exemplary cytokine. However, this application and this application are not limited to IL-2. It will be clear to those skilled in the art that the present application, including the disclosed methods, polypeptides and nucleic acids, fully describes and enables the use of other cytokines, fragments and muteins, such as IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23, IFN α, IFN β, IFN γ, TNF α, lymphotoxin, TGF- β 1, TGF β 2, TGF β 3, GM-CSF, CXCL10, CCL19, CCL20, CCL21 and functional fragments or muteins of any of the foregoing.
The various elements ensure preferential delivery and activity of IL-2 at the desired IL-2 active site and severely limit systemic exposure to interleukins through blocking and/or targeting strategies preferentially associated with serum half-life extension strategies. In this serum half-life extension strategy, the blocking version of the interleukin has an extended circulation time (preferably 1 to 2 weeks or more), but the activated version has a typical interleukin serum half-life.
The serum half-life of intravenously administered IL-2 is only about 10 minutes compared to the extended serum half-life version, since it is distributed in the systemic extracellular space, which is large, about 15L in average size adults. Subsequently, IL-2 is metabolized by the kidney with a half-life of about 2.5 hours. (Smith, K. "Interleukin 2 Immunology." Therapeutic Immunology 240 (2001)). By other measurements, IL-2 has a very short plasma half-life, 85 minutes for intravenous administration, and 3.3 hours for subcutaneous administration (Kirchner, G.I. et al, 1998, Br J Clin Pharmacol.46: 5-10). In some embodiments of the present application, the half-life extending element is linked to the interleukin via a linker that is cleaved at the site of action (e.g., by an inflammation-specific or tumor-specific protease), thereby releasing the full activity of the interleukin at the desired site and also separating it from the half-life extension of the uncleaved version. In such embodiments, the fully active and free interleukins will have very different pharmacokinetic (pK) profiles with half-lives of hours rather than weeks. In addition, exposure to active cytokines is limited to the desired site of cytokine activity (e.g., site of inflammation or tumor) and systemic exposure to active cytokines and associated reduction in toxicity and side effects.
Other cytokines contemplated in the present application (e.g., IL-15 reported by Blood 2011117: 4787-.
If desired, IL-2 can be engineered to specifically bind with different affinity to the corresponding wild-type IL-2, typically to the IL-2R complex or one of the three IL-2R subunits, e.g., to selectively activate Tregs or teffs. For example, an IL-2 polypeptide that is believed to have a higher affinity for the trimeric form of the IL-2 receptor relative to the dimeric β/γ form of the IL-2 receptor as compared to wild-type IL-2 may have an amino acid sequence comprising one of the following sets of mutations relative to SEQ ID NO:1 (mature IL-2 protein, which comprises amino acids 21-153 of human IL-2, having Uniprot accession number P60568-1): (a) K64R, V69A and Q74P; (b) V69A, Q74P, and T101A; (c) V69A, Q74P, and I128T; (d) N30D, V69A, Q74P and F103S; (e) K49E, V69A, a73V and K76E; (f) V69A, Q74P, T101A and T133N; (g) N30S, V69A, Q74P and I128A; (h) V69A, Q74P, N88D and S99P; (i) N30S, V69A, Q74P and I128T; (j) K9T, Q11R, K35R, V69A and Q74P; (k) A1T, M46L, K49R, E61D, V69A and H79R; (l) K48E, E68D, N71T, N90H, F103S and I114V; (m) S4P, T10A, Q11R, V69A, Q74P, N88D, and T133A; (N) E15K, N30S Y31H, K35R, K48E, V69A, Q74P, and I92T; (o) N30S, E68D, V69A, N71A, Q74P, S75P, K76R, and N90H; (p) N30S, Y31C, T37A, V69A, a73V, Q74P, H79R, and I128T; (Q) N26D, N29S, N30S, K54R, E67G, V69A, Q74P, and I92T; (r) K8R, Q13R, N26D, N30T, K35R, T37R, V69A, Q74P and I92T; and(s) N29S, Y31H, K35R, T37A, K48E, V69A, N71R, Q74P, N88D, and I89V. This method can also be used to make muteins of other cytokines, including interleukins (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-23), interferons (IFNs, including IFN α, IFN β, and IFN γ), tumor necrosis factors (e.g., TNF α, lymphotoxins), transforming growth factors (e.g., TGF β 1, TGF β 2, TGF β 3), and granulocyte-macrophage colony stimulating factor (GM-CS). For example, muteins having a desired binding affinity for a cognate receptor can be prepared.
As described above, any of the mutant IL-2 polypeptides disclosed herein may comprise the sequence; they may also be limited to the sequences and otherwise identical to SEQ ID NO: 1. In addition, any of the mutant IL-2 polypeptides disclosed herein may optionally comprise a substitution of the cysteine residue at position 125 with another residue (e.g., serine) and/or may optionally comprise a deletion of the alanine residue at position 1 of SEQ ID NO: 1.
Another approach to improve the therapeutic index of IL-2 based therapies is to optimize the pharmacokinetics of the molecule to maximize the activation of Treg cells. Early studies of the effects of IL-2 have shown that IL-2 requires at least 5 to 6 hours of exposure to effective concentrations of IL-2 in vitro to stimulate human T cell proliferation (Cantrell, D.A. et al, 1984, Science,224:1312, 1316). IL-2 has a very short plasma half-life when administered to human patients, 85 minutes for intravenous administration, and 3.3 hours for subcutaneous administration (Kirchner, G.I. et al, 1998, Br J Clin Pharmacol.46: 5-10). Because of the short half-life of IL-2, maintaining circulating IL-2 at or above the levels necessary to stimulate T cell proliferation for the necessary period of time requires high doses to bring the peak level of IL-2 significantly above the EC50 of Treg cells or will require frequent administration. These high peak IL-2 levels can activate IL2R β γ receptor and produce other unexpected or adverse effects, such as VLS as described above. An IL-2 analogue or a multifunctional protein of IL-2 wherein the circulating half-life is longer than IL-2 (wherein IL-2 is linked to a domain capable of binding to the FcRn receptor) may reach the target drug concentration at a lower dose than IL-2 for a specified period of time and at a lower peak level. Therefore, such IL-2 analogs would require lower doses or less frequent administration than IL-2 to effectively stimulate Treg cells. A lower frequency of subcutaneous administration of IL-2 drugs will also make patients more tolerant. Therapeutic agents with these characteristics would translate clinically into improved pharmacological efficacy, reduced toxicity and improved patient compliance with treatment. Alternatively, IL-2 or a mutein of IL-2 (herein "IL-2") may be selectively targeted to the intended site of action (e.g. site of inflammation or tumor). Such targeting can be achieved by one of several strategies, including the addition of a domain to the administered agent comprising the blocking agent for cleaved IL-2 (or mutein), or by targeting the domain, or a combination of both.
In some embodiments, the IL-2 partial agonist may be tailored to bind with higher or lower affinity depending on the desired target; for example, IL-2 may be engineered to bind with enhanced affinity to one of the receptor subunits but not to the other. Unlike full agonists or full antagonists, these types of partial agonists provide the ability to tune the signaling properties to an amplitude that results in a desired functional property, while not meeting the threshold for an undesirable property. Given the differences in partial agonist activity, a range of IL-2 variants can be engineered to exhibit even better unique signaling activities, ranging from almost full agonism to partial agonism to full antagonism.
In some embodiments, IL-2 alters the affinity for IL-2 ra. In some embodiments, IL-2 has a higher affinity for IL-2 ra than wild-type IL-2. In other embodiments, IL-2 alters the affinity for IL-2R β. In one embodiment, IL-2 has enhanced binding affinity for IL-2R β (e.g., N-terminal to IL-2R β), which eliminates the functional requirement for IL-2R α. In another embodiment, the IL-2 generated has increased binding affinity for IL-2R β but exhibits reduced binding to IL-2R γ, and is therefore defective IL-2R β γ heterodimer and signaling.
Blocking moieties, described in further detail below, may also be used to facilitate binding to or activation of one or more receptors. In one embodiment, a blocking moiety is added such that IL-2R β γ binding or activation is blocked, but IL-2R α binding or activation is not altered. In another embodiment, a blocking moiety is added such that IL-2R α binding or activation is reduced. In another embodiment, a blocking moiety is added such that binding to all three receptors and or activation of the receptors is inhibited. Such blockade can be eliminated by removing the blocking moiety in a particular environment, for example, by proteolytic cleavage of a linker that links the blocking moiety or moieties to the cytokine.
Similar approaches can be applied to improve other cytokines, particularly for use as immunostimulants, e.g., for the treatment of cancer. For example, in this aspect, the pharmacokinetics and/or pharmacodynamics of cytokines (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23, IFN α, IFN β and IFN γ, TNF α, lymphotoxin, TGF β 1, TGF β 2, TGF β 3, GM-CSF, CXCL10, CCL19, CCL20, and CCL21) can be adjusted to maximize activation of effector cells (e.g., effector T cells, NK cells) and/or cytotoxic immune response promoting cells (e.g., inducing dendritic cell maturation) at the site of desired activity, such as in a tumor, but preferably not systemically.
Accordingly, pharmaceutical compositions provided herein comprise at least one cytokine polypeptide, such as an interleukin (e.g., IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IL-23), interferon (IFN, including IFN α, IFN β, and IFN γ), tumor necrosis factor (e.g., TNF α, lymphotoxin), transforming growth factor (e.g., TGF β 1, TGF β 2, TGF β 3), chemokine (e.g., CXCL10, CCL19, CCL20, CCL21), and granulocyte-macrophage colony stimulating factor (GM-CS), or a functional fragment or mutein of any of the foregoing. The polypeptide typically further comprises at least one linker amino acid sequence, wherein in certain embodiments the amino acid sequence is capable of being cleaved by an endogenous protease. In one embodiment, the linker comprises an amino acid sequence comprising HSSKLQ (SEQ ID No.:25), GPLGVRG (SEQ ID No.:197), IPVSLRSG (SEQ ID No.:198), vplsysg (SEQ ID No.199), or SGESPAYYTA (SEQ ID No. 200). In other embodiments, the chimeric polypeptide further comprises a blocking moiety, such as a steric blocking polypeptide moiety, capable of blocking the activity of an interleukin polypeptide. For example, the blocking moiety may comprise a Human Serum Albumin (HSA) binding domain or optionally branched or multi-armed polyethylene glycol (PEG). Alternatively, the pharmaceutical composition comprises a first cytokine polypeptide or fragment thereof and a blocking moiety, such as a steric blocking polypeptide moiety, wherein the blocking moiety blocks the activity of the cytokine polypeptide at the cytokine receptor, and wherein in certain embodiments, the blocking moiety comprises a protease cleavable domain. In some embodiments, the blocking and reduction of cytokine activity is achieved only by linking an additional domain with a very short linker to the N-or C-terminus of the interleukin domain. In such embodiments, it is contemplated that blocking is mitigated by protease digestion of the blocking moiety or a short linker linking the blocking agent to the interleukin. Once the domain is sheared or released, it will no longer be able to effect a block in cytokine activity.
Pharmaceutical compositions such as chimeric polypeptides may comprise two or more cytokines, which may be the same cytokine polypeptide or different cytokine polypeptides. For example, two or more different types of cytokines have complementary functions. In some examples, the first cytokine is IL-2 and the second cytokine is IL-12. In some embodiments, each of the two or more different types of cytokine polypeptides has activity in modulating the activity of the other cytokine polypeptide. In some examples of chimeric polypeptides comprising two cytokine polypeptides, the first cytokine polypeptide is T-cell activated and the second cytokine polypeptide is non-T-cell activated. In some examples of chimeric polypeptides comprising two cytokine polypeptides, the first cytokine is a chemotactic agent, e.g., CXCL10, and the second cytokine is an immune cell activator.
Preferably, the cytokine polypeptides (including functional fragments) included in the fusion proteins disclosed herein are not mutated or engineered to alter the properties of naturally occurring cytokines, including receptor binding affinity and specificity or serum half-life. However, alterations in the amino acid sequence of naturally occurring (including wild-type) cytokines may be acceptable, for example, to facilitate cloning and achieve desired levels of expression.
Blocking moiety
The blocking moiety may be any moiety that inhibits the ability of a cytokine to bind to and/or activate its receptor. The blocking moiety may inhibit the ability of the cytokine to bind to and/or activate its receptor, thereby sterically blocking and/or by non-covalent binding to the cytokine. Examples of suitable blocking moieties include full-length or cytokine-binding fragments or muteins of cytokine-cognate receptors. Antibodies and fragments thereof that bind cytokines can also be used, including polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, single chain variable fragments (scfvs), single domain antibodies such as heavy chain variable domains (VH), light chain variable domains (VL), and variable domains of camelid nanobodies (VHH), dabs, and the like. Other suitable antigen binding domains that bind cytokines may also be used, including non-immunoglobulin proteins that mimic antibody binding and/or structure, such as anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, darpins, fynomers, kunitz-type (kunitz) domain polypeptides, monomers (monobodies), and binding domains based on other engineered scaffolds such as SpA, GroEL, fibronectin, liposomes, and CTLA4 scaffold. Other examples of suitable blocking polypeptides include polypeptides that sterically inhibit or block the binding of a cytokine to its cognate receptor. Advantageously, such moieties may also serve as half-life extending elements. For example, peptides modified by conjugation to water soluble polymers such as PEG can sterically inhibit or prevent binding of cytokines to their receptors. Polypeptides with longer serum half-life or fragments thereof, such as serum albumin (human serum albumin), immunoglobulin Fc, transferrin, and the like, as well as fragments and muteins of such polypeptides, may also be used.
Antibodies and antigen binding domains that bind to, for example, proteins with a longer serum half-life (such as HSA, immunoglobulins, or transferrin) or to receptors that circulate to the plasma membrane (such as FcRn or transferrin receptor) can also inhibit cytokines, particularly when bound to their antigens. Examples of such antigen binding polypeptides include single chain variable fragments (scFv), single domain antibodies such as heavy chain variable domains (VH), light chain variable domains (VL) and variable domains of camelid nanobodies (VHH), dabs, and the like. Other suitable antigen binding domains that bind cytokines may also be used, including non-immunoglobulin proteins that mimic antibody binding and/or structure, such as anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, darpins, fynomers, kunitz-type domain polypeptides, monomers, and binding domains based on other engineered scaffolds such as SpA, GroEL, fibronectin, liposomes, and CTLA4 scaffolds.
In illustrative examples, when IL-2 is a cytokine in a chimeric polypeptide, the blocking moiety can be a full length or fragment or mutein of the alpha chain of the IL-2 receptor (IL-2 Ra) or the beta chain of the IL-2 receptor (IL-2 Rbeta) or the gamma chain (IL-2 Rgamma), an anti-IL-2 single domain antibody (dAb) or scFv, a Fab, an anti-CD 25 antibody or fragment thereof, and an anti-HAS dAb or scFv, and the like.
Additional aspects of the present application
1. A fusion protein comprising a cytokine moiety operably linked to a binding moiety, said binding moiety comprising a non-CDR loop and a cleavable linker, wherein said binding moiety is capable of masking the binding of said cytokine to its receptor and/or the activation of said receptor by said cytokine.
2. The fusion protein of aspect 1, wherein the binding moiety is a natural peptide, a synthetic peptide, an engineered scaffold, or an engineered large serum protein.
3. The fusion protein of aspect 1 or 2, wherein the engineered scaffold comprises a sdAb, scFv, Fab, VHH, fibronectin type III domain, immunoglobulin-like scaffold, DARPin, cystine knot peptide, lipocalin, triple helix bundle scaffold, protein G-related albumin binding module, or a DNA or RNA aptamer scaffold.
4. The fusion protein of any one of aspects 1-2, wherein the binding moiety is capable of binding to a large serum protein.
5. The fusion protein of any one of aspects 1-3, wherein the non-CDR loops are from a variable domain, a constant domain, a group C1 domain, a group C2 domain, an I domain, or any combination thereof.
6. The fusion protein of any one of aspects 1-4, wherein the binding moiety further comprises a Complementarity Determining Region (CDR).
7. The fusion protein of aspect 5, wherein the binding moiety is capable of binding to a large serum protein.
8. The fusion protein of aspect 6, wherein the large serum protein is a half-life extending protein.
9. The fusion protein of aspect 6 or 7, wherein the large serum protein is albumin, transferrin, factor XIII, or fibrinogen.
10. The fusion protein of any one of aspects 5-8, wherein the CDR loops provide a binding site specific for a large serum protein or an immunoglobulin light chain, or any combination thereof.
11. The fusion protein of any one of aspects 1-9, wherein the cleavable linker comprises a cleavage site.
12. The fusion protein of aspect 10, wherein the cleavage site is recognized by a protease.
13. The fusion protein of aspect 11, wherein the binding moiety binds to the cytokine.
14. The fusion protein of aspect 11 or 11, wherein the binding moiety is covalently linked to the cytokine.
15. The fusion protein of aspect 11, 11 or 14, wherein the binding moiety is capable of masking the binding of the cytokine to its target by specific intermolecular interactions between the binding moiety and the cytokine.
16. The fusion protein of any one of aspects 11-14, wherein the non-CDR loop provides a binding site specific for binding of the moiety and the cytokine.
17. The fusion protein of any one of aspects 11-15, wherein upon cleavage of the cleavable linker, the binding moiety is separated from the cytokine and the cytokine binds to its target.
18. The fusion protein of any one of aspects 1-16, wherein the cytokine binds a cytokine receptor.
19. The fusion protein of aspect 17, wherein the cytokine receptor comprises a type I cytokine receptor, a type I IL receptor, a type II IL receptor, a chemokine receptor, or a tumor necrosis receptor superfamily receptor.
20. The fusion protein of any one of aspects 1-18, wherein the cleavable linker comprises a cleavage site.
21. The fusion protein of aspect 20, wherein the cleavage site is recognized by a protease.
22. The fusion protein of aspect 21, wherein the protease cleavage site is recognized by a serine protease, a cysteine protease, an aspartic protease, a threonine protease, a glutamic protease, a metalloprotease, a gelatinase, or an asparaginase.
23. The fusion protein of aspect 21, wherein the protease cleavage site is recognized by a protease that is: cathepsin B, cathepsin C, cathepsin D, cathepsin E, cathepsin K, cathepsin L, kallikrein, hK1, hK10, hK15, plasmin (plasmin), collagenase type IV, stromelysin, factor Xa, chymotrypsin-like protease, trypsin-like protease, elastase-like protease, subtilisin-like protease, actinidin, bromelain, calpain, caspase-3, Mir1-CP, papain, HIV-1 protease, HSV protease, CMV protease, rennin, pepsin, proteolytic enzyme, legumain, plasmin (plasmepsin), nepenthesin, metalloaprotinin, metalloendopeptidase, Matrix Metalloproteinase (MMP), MMP1, MMP2, MMP3, MMP8, MMP9, MMP10, MMP3, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, ADAM10, ADAM17, ADAM12, urokinase plasminogen activator (uPA), enterokinase, prostate specific targets (PSA, hK3), interleukin-1 β converting enzyme, thrombin, FAP (FAP- α), dipeptidyl peptidase or dipeptidyl peptidase IV (DPPIV/CD26), transmembrane serine protease type II (TTSP), neutrophil elastase, cathepsin G, protease 3, neutrophil serine protease 4, mast cell chymase, mast cell tryptase, dipeptidyl peptidase and dipeptidyl peptidase IV (DPPIV/CD 26).
24. A conditionally active binding protein, comprising a binding moiety (M) comprising a non-CDR loop, a cytokine and a cleavable linker (L), wherein the non-CDR loop is capable of binding to the cytokine, and wherein the binding moiety is capable of inhibiting the binding of the cytokine to its receptor and/or inhibiting the activation of the receptor by the cytokine.
25. The conditionally active binding protein of aspect 24, wherein the binding moiety is capable of binding to a half-life extending protein.
26. The conditionally active binding protein of aspect 24 or 25, wherein the binding moiety is a natural peptide, a synthetic peptide, an engineered scaffold, or an engineered large serum protein.
27. The conditionally active binding protein of aspect 26, wherein the engineered scaffold comprises a sdAb, scFv, Fab, VHH, fibronectin type III domain, immunoglobulin-like scaffold, DARPin, cystine knot peptide, lipocalin, triple helix bundle scaffold, protein G-related albumin binding module, or a DNA or RNA aptamer scaffold.
28. The conditionally active binding protein of any one of aspects 24 to 27, wherein the non-CDR loop is from a variable domain, a constant domain, a group C1 domain, a group C2 domain, an I domain, or any combination thereof.
29. The conditionally active binding protein of any one of aspects 24 to 28, wherein the binding moiety further comprises a Complementarity Determining Region (CDR).
30. The conditionally active binding protein of any one of aspects 24 to 29, wherein the binding moiety comprises a binding site specific for a large serum protein.
31. The conditionally active binding protein of aspect 30, wherein the large serum protein is albumin, transferrin, factor XIII, or fibrinogen.
32. The conditionally active binding protein of any one of aspects 29 to 31, wherein the CDRs provide a binding site specific for a large serum protein or an immunoglobulin light chain, or any combination thereof.
33. The conditionally active binding protein of any one of aspects 29 to 32, wherein the binding moiety is capable of masking binding of a cytokine to its target by a specific intermolecular interaction between the binding moiety and the cytokine.
34. The conditionally active binding protein of any one of aspects 29 to 33, wherein the non-CDR loop provides a binding site specific for binding of a binding moiety and a cytokine.
35. The conditionally active binding protein of any one of aspects 24 to 34, wherein the cytokine binds to a cytokine receptor.
36. The conditionally active binding protein of aspect 35, wherein the cytokine receptor comprises a type I cytokine receptor, a type I IL receptor, a type II IL receptor, a chemokine receptor, or a tumor necrosis receptor superfamily receptor.
37. The conditionally active binding protein of any one of claims 24 to 36, wherein the cleavable linker comprises a cleavage site.
38. The conditionally active binding protein of aspect 37, wherein the cleavage site is recognized by a protease.
39. The conditionally active binding protein of aspect 38, wherein the protease cleavage site is recognized by a serine protease, a cysteine protease, an aspartic protease, a threonine protease, a glutamine protease, a metalloprotease, a gelatinase, or an asparaginase peptide lyase.
40. The conditionally active binding protein of aspect 38, wherein the protease cleavage site is recognized by a protease that is: cathepsin B, cathepsin C, cathepsin D, cathepsin E, cathepsin K, cathepsin L, kallikrein, hK1, hK10, hK15, plasmin, collagenase type IV, stromelysin, factor Xa, chymotrypsin-like protease, trypsin-like protease, elastase-like protease, subtilisin-like protease, actinidin, bromelain, calpain, caspase-3, Mir1-CP, papain, HIV-1 protease, HSV protease, CMV protease, chymosin, renin, pepsin, proteolytic enzyme, legumain, plasmin, nepenthesin, metalloexopeptidase, metalloendopeptidase, Matrix Metalloproteinase (MMP), MMP1, MMP2, MMP3, MMP8, MMP9, MMP10, MMP11, MMP12, MMP13, MMP14, ADAM10, ADAM17, ADAM12, urokinase plasminogen activator (uPA), enterokinase, prostate specific targets (PSA, hK3), interleukin-1 β converting enzyme, thrombin, FAP (FAP- α), dipeptidyl peptidase or dipeptidyl peptidase IV (DPPIV/CD26), transmembrane serine protease type II (TTSP), neutrophil elastase, cathepsin G, protease 3, neutrophil serine protease 4, mast cell chymase, mast cell tryptase, dipeptidyl peptidase and dipeptidyl peptidase IV (DPPIV/CD 26).
41. The conditionally active binding protein of aspect 24, further comprising a half-life extending domain bound to the binding moiety, wherein the half-life extending domain provides a safety switch for the binding protein, and wherein upon cleavage of the linker, the binding protein is activated by separating the binding moiety and the half-life extending domain from the cytokine, and thereby separating the binding protein from the safety switch.
42. The conditionally active binding protein of aspect 41, wherein cleavage of the linker is located in the tumor microenvironment.
43. A conditionally active binding protein, comprising a binding moiety that binds to a cytokine through a non-CDR loop within the binding moiety, wherein the binding moiety is further linked to a half-life extending domain and comprises a cleavable linker, wherein the binding protein has an extended half-life prior to its activation by cleavage of the linker, and wherein upon activation the binding moiety and the half-life extending domain are separated from the cytokine, and wherein the binding protein does not have an extended half-life in the activated state.
44. The conditionally active binding protein of aspect 43, wherein cleavage of the linker is located in the tumor microenvironment.
In vivo half-life extending element
Preferably, the chimeric polypeptide comprises an in vivo half-life extending element. Increasing the in vivo half-life of therapeutic molecules that naturally have a short half-life allows for more acceptable and manageable dosing regimens without sacrificing effectiveness. As used herein, a "half-life extending element" is a portion of a chimeric polypeptide that increases half-life in vivo and improves pK, for example, by altering its size (e.g., above the renal filtration limit), shape, hydrodynamic radius, charge, or parameters of absorption, biodistribution, metabolism, and elimination. An exemplary way to improve the pK of a polypeptide is by expressing in the polypeptide chain elements that bind to receptors that are recycled to the plasma membrane of the cell rather than being degraded in lysosomes, such as the FcRn receptor and the transferrin receptor on endothelial cells. The residence time of the three types of proteins (e.g., human IgG, HSA (or fragments), and transferrin) in human serum is much longer than predicted by their size alone, which is a function of their ability to bind to receptors that are recycled rather than degraded in lysosomes. These proteins or their fragments that retain FcRn binding are typically linked to other polypeptides to increase their serum half-life. In one embodiment, the half-life extending element is a Human Serum Albumin (HSA) binding domain. HSA (SEQ ID NO:2) can also be bound directly to the pharmaceutical composition or via a short linker. Fragments of HSA may also be used. HSA and fragments thereof can be used as blocking moieties and half-life extending elements. Human IgG and Fc fragments can also perform similar functions.
The serum half-life extending element may also be an antigen binding polypeptide that binds to a protein with a longer serum half-life, such as serum albumin, transferrin, and the like. Examples of such polypeptides include antibodies and fragments thereof, including polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, single chain variable fragments (scfvs), single domain antibodies such as heavy chain variable domains (VH), light chain variable domains (VL), and variable domains of camelid nanobodies (VHH), dabs, and the like. Other suitable antigen binding domains include non-immunoglobulin proteins that mimic antibody binding and/or structure, such as anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, darpins, fynomers, kunitz-type (kunitz) domain polypeptides, monomers, and binding domains based on other engineered scaffolds such as SpA, GroEL, fibronectin, liposomes, and CTLA4 scaffolds. Other examples of antigen-binding polypeptides include ligands for the desired receptor, ligand-binding portions of the receptor, lectins, and peptides that bind to or associate with one or more target antigens.
Some preferred serum half-life extending elements are polypeptides comprising Complementarity Determining Regions (CDRs) and optionally non-CDR loops. Advantageously, such serum half-life extending elements may extend the serum half-life of a cytokine and also act as inhibitors of the cytokine (e.g., by steric blocking, non-covalent interactions, or a combination thereof) and/or as targeting domains. In some cases, the serum half-life extending element is a domain derived from an immunoglobulin molecule (Ig molecule) or an engineered protein scaffold that mimics antibody structure and/or binding activity. Ig can be of any class or subclass (IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM, etc.). The polypeptide chains of Ig molecules fold into a series of parallel β -chains connected by loops. In the variable region, three loops constitute "complementarity determining regions" (CDRs) that determine the antigen binding specificity of the molecule. IgG molecules comprise at least two heavy (H) chains and two light (L) chains, or antigen-binding fragments thereof, interconnected by disulfide bonds. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH 3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises a domain CL. The VH and VL regions can be further subdivided into hypervariable regions, termed Complementarity Determining Regions (CDRs), which are hypervariable in sequence and/or are involved in antigen recognition and/or generally form structurally defined loops interspersed with more conserved regions, termed Framework Regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged amino-terminal to carboxy-terminal in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR 4. In some embodiments of the present application, at least some or all of the amino acid sequences of FR1, FR2, FR3 and FR4 are part of a "non-CDR loop" of a binding moiety described herein. As shown in fig. 5, the variable domain of an immunoglobulin molecule has several beta chains arranged in two strands. The variable domains of the light and heavy immunoglobulin chains contain three hypervariable loops or Complementarity Determining Regions (CDRs). The three CDRs (CDR1, CDR2, CDR3) of the V domain are clustered at one end of the β -barrel. CDRs are loops connecting beta chains B-C, C '-C' and F-G of the immunoglobulin fold, while the bottom loops connecting beta chains AB, CC ', C' -D and E-F of the immunoglobulin fold and the top loops connecting D-E chains of the immunoglobulin fold are non-CDR loops. In some embodiments of the present application, at least some of the amino acid residues of the constant domain, CH1, CH2, or CH3 are part of a "non-CDR loop" of a binding moiety described herein. In some embodiments, the non-CDR loops comprise one or more of the AB, CD, EF, and DE loops of the C1 group domain of an Ig or Ig-like molecule; the AB, CC ', EF, FG, BC and EC' loops of the group C2 domain of an Ig or Ig-like molecule; the DE, BD, GF, A (A1A2) B and EF loops of the group I (middle) domains of Ig or Ig-like molecules.
Within the variable domain, the CDRs are thought to be responsible for antigen recognition and binding, while the FR residues are thought to be the scaffold for the CDRs. However, in some cases, some FR residues play an important role in antigen recognition and binding. Framework region residues that affect Ag binding fall into two classes. The first is the FR residues that are in contact with the antigen, and thus are part of the binding site, and some of these residues are in sequence proximity to the CDRs. Other residues are residues that are far removed from the CDRs in sequence but are immediately adjacent to them in the 3-D structure of the molecule, e.g., loops in the heavy chain. The serum half-life extending domain (e.g., a domain comprising CDRs) can comprise at least one non-CDR loop. In some embodiments, the non-CDR loops provide binding sites for binding cytokines, large serum proteins, or other target antigens.
In addition to or alternatively to containing CDRs, the serum half-life extending element comprises non-CDR loops. In some embodiments, the non-CDR loops are modified to produce antigen binding sites specific for a desired target antigen (such as a large serum protein, such as albumin) or for a cytokine moiety or other targeted antigen. It is contemplated that the non-CDR loops may be modified using various techniques, such as site-directed mutagenesis, random mutagenesis, insertion of at least one amino acid outside of the non-CDR loop amino acid sequence, amino acid substitution. In some examples, the antigenic peptide is inserted into a non-CDR loop. In some examples, the antigenic peptide replaces a non-CDR loop. In some cases, only one non-CDR loop modification is made to create the antigen binding site. In other cases, more than one non-CDR loop is modified. For example, any of the non-CDR loops shown in FIG. 5 (i.e., AB, CC', C "D, EF, and D-E) are modified. In some cases, the DE loop is modified. In other cases, all four of the AB, CC', C "-D, E-F loops were modified.
In some examples, the serum half-life extending element has dual binding specificities and contains CDRs that specifically bind large serum proteins (such as serum albumin) and non-CDR loops that specifically bind and block cytokine domains. In other examples, the serum half-life extending element contains CDRs that specifically bind a target antigen, such as a cytokine domain or other target antigen, and non-CDR loops that specifically bind a large serum protein, such as serum albumin. Preferably, the serum half-life extending element inhibits binding of the cytokine domain to a cognate cytokine receptor, e.g., by spatial occlusion, by specific intermolecular interactions, or a combination of both.
In some embodiments, the serum half-life extending element non-covalently binds directly to a cytokine and inhibits its activity.
In certain examples, the binding moiety binds to a cytokine through one or more of the AB, CC ', C "D, and E-F loops, and to a large serum protein such as albumin through one or more of BC, C' C", and FG. In certain examples, the binding moiety binds to a large serum protein such as albumin through its AB, CC ', C "D or EF loop and to a cytokine through its BC, C' C" or FG loop. In certain examples, the binding moiety binds to a large serum protein such as albumin through its AB, CC ', C "D and EF loops and to a cytokine through its BC, C' C" and FG loops. In certain examples, the binding moiety binds to a large serum protein such as albumin through one or more of the AB, CC ', C "D, and E-F loops, and to a cytokine through one or more of BC, C' C", and FG.
The binding moiety is any kind of polypeptide. For example, in some cases, the binding moiety is a natural peptide, a synthetic peptide, or a fibronectin scaffold or an engineered large serum protein. Large serum proteins include, for example, albumin, fibrinogen, or globulin. In some embodiments, the binding moiety is an engineered scaffold. Engineered scaffolds include, for example, sdabs, scfvs, fabs, VHHs, fibronectin type III domains, immunoglobulin-like scaffolds (as set forth in Halaby et al, 1999 Prot Eng 12(7): 563-571), darpins, cystine knot peptides, lipocalins, triple helix bundle scaffolds, protein G-related albumin binding modules, or DNA or RNA aptamer scaffolds.
In some cases, the serum half-life extending element binds the cytokine domain through its non-CDR loop, and the cytokine domain is further linked to a targeting domain as described herein. In some cases, the serum half-life extending element comprises a binding site for a large serum protein. In some embodiments, the CDRs provide a binding site for large serum proteins. In some examples, the large serum protein is globulin, albumin, transferrin, IgG1, IgG2, IgG4, IgG3, IgA monomers, XIII factor, fibrinogen, IgE, or pentameric IgM. In some embodiments, the CDRs form a binding site for an immunoglobulin light chain (such as an Ig κ free light chain or an Ig λ free light chain).
An exemplary conditionally active protein is shown in figure 6. In the examples shown, a non-CDR loop in a serum albumin binding domain (e.g., a dAb) can form a binding site for the cytokine IL-2. In this example, the binding site for serum albumin may be formed by the CDRs of the serum albumin binding domain.
The serum half-life extending element may be any type of binding domain including, but not limited to, domains from monoclonal antibodies, polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies. In some embodiments, the binding moiety is a single chain variable fragment (scFv), a single domain antibody, such as a heavy chain variable domain (VH), a light chain variable domain (VL), and a variable domain of a camelid-derived nanobody (VHH). In other embodiments, the binding moiety is a non-Ig binding domain, i.e., an antibody mimetic, such as anticalin, affilin, affibody molecules, affimers, affitin, alphabody, avimer, DARPin, fynomer, kunitz-type domain polypeptides and monomers.
In other embodiments, the serum half-life extending element may be a water soluble polymer or a peptide conjugated to a water soluble polymer (such as PEG). As used herein, "PEG," "polyethylene glycol," and "poly (ethylene glycol)" are interchangeable and include any non-peptide water soluble poly (ethylene oxide). The term "PEG" is also intended to mean a PEG containing a majority, i.e., greater than 50%, of-OCH 2CH2-polymers of repeating subunits. With respect to particular forms, PEG can take any number of a variety of molecular weights, as well as structures or geometries that will be described in more detail below, such as "branched," "linear," "forked," "multifunctional," and the like. PEG is not limited to a particular structure, and can be linear (e.g., end-capped, e.g., alkoxy PEG or bifunctional PEG), branched or multi-armed (e.g., forked PEG or PEG attached to a polyol core), dendritic (or star) structures, each with or without one or more degradable linking moieties. In addition, the internal structure of the PEG may be organized in any number of different repeating patterns and may be selected from the group consisting of homopolymers, alternating copolymers, random copolymers, block copolymers, alternating terpolymers, random terpolymers, and block terpolymers. PEG can be conjugated to polypeptides and peptides by any suitable method. Typically, a reactive PEG derivative (such as N-hydroxysuccinimide ester PEG) is reacted with a peptide or polypeptide comprising an amino acid with a side chain containing an amine, thiol, carboxylic acid or hydroxyl functionality, such as cysteine, lysine, asparagine, glutamine, threonine, tyrosine, serine, aspartic acid and glutamic acid.
Targeting and retention domains
For certain applications, it may be desirable to maximize the time that the construct is present at its desired location in the body. This can be achieved by including another domain in the chimeric polypeptide (fusion protein) to influence its movement in vivo. For example, a chimeric nucleic acid can encode a domain that directs a polypeptide to a location in the body (e.g., a tumor cell or site of inflammation); this domain is referred to as a "targeting domain" and/or a domain that encodes a polypeptide that is retained at a location in the body (e.g., a tumor cell or site of inflammation); this domain is called the "retention domain". In some embodiments, domains may be used as targeting domains and retention domains. In some embodiments, the targeting domain and/or the retention domain are specific for a protease-rich environment. In some embodiments, the encoded targeting and/or retention domains are specific for regulatory T cells (tregs), e.g., targeting CCR4 or CD39 receptors. Other suitable targeting and/or retention domains include those with homologous ligands that are overexpressed in inflammatory tissues, such as the IL-1 receptor or IL-6 receptor. In other embodiments, suitable targeting and/or retention domains include those with homologous ligands that are overexpressed in tumor tissue, such as Epcam, CEA, or mesothelin. In some embodiments, the targeting domain is linked to the interleukin through a linker that is cleaved at the site of action (e.g., by an inflammation or cancer specific protease) to release the full activity of the interleukin at the desired site. In some embodiments, the targeting and/or retention domain is linked to the interleukin via a linker that is not cleaved at the site of action (e.g., by an inflammation or cancer specific protease), thereby retaining the cytokine at the desired site.
In some cases, the selected antigen is expressed on the surface of a diseased cell or tissue (e.g., a tumor or cancer cell). Antigens that may be used for tumor targeting and retention include, but are not limited to, EpCAM, EGFR, HER-2, HER-3, c-Met, FOLR1, and CEA. The pharmaceutical compositions disclosed herein also include proteins comprising two targeting and/or retention domains that bind to two different target antigens known to be expressed on diseased cells or tissues. Exemplary antigen binding domain pairs include, but are not limited to, EGFR/CEA, EpCAM/CEA, and HER-2/HER-3.
Suitable targeting and/or retention domains include antigen binding domains such as antibodies and fragments thereof, including polyclonal antibodies, recombinant antibodies, human antibodies, humanized antibodies, single chain variable fragments (scFv), single domain antibodies such as heavy chain variable domains (VH), light chain variable domains (VL) and variable domains of camelid nanobodies (VHH), dabs, and the like. Other suitable antigen binding domains include non-immunoglobulin proteins that mimic antibody binding and/or structure, such as anticalins, affilins, affibody molecules, affimers, affitins, alphabodies, avimers, darpins, fynomers, kunitz-type domain polypeptides, monomers, and binding domains based on other engineered scaffolds such as SpA, GroEL, fibronectin, liposomes, and CTLA4 scaffolds. Other examples of antigen-binding polypeptides include ligands for the desired receptor, ligand-binding portions of the receptor, lectins, and peptides that bind to or associate with one or more target antigens.
In some embodiments, the targeting and/or retention domain specifically binds to a cell surface molecule. In some embodiments, the targeting and/or retention domain specifically binds to a tumor antigen. In some embodiments, the targeting polypeptide specifically and independently binds to a tumor antigen selected from at least one of: fibroblast activation protein alpha (FAPa), trophoblast glycoprotein (5T4), tumor-associated calcium signal transducer 2(Trop2), fibronectin EDB (EDB-FN), fibronectin EIIIB domain, CGS-2, EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR 1. In some embodiments, the targeting polypeptide specifically and independently binds two different antigens, wherein at least one of the antigens is a tumor antigen selected from the group consisting of EpCAM, EGFR, HER-2, HER-3, cMet, CEA, and FOLR 1.
The targeted and/or retained antigen may be a tumor antigen expressed on a tumor cell. Tumor antigens are well known in the art and include, for example, EpCAM, EGFR, HER-2, HER-3, c-Met, FOLR1, PSMA, CD38, BCMA and CEA, 5T4, AFP, B7-H3, cadherin-6, CAIX, CD117, CD123, CD138, CD166, CD19, CD20, CD205, CD22, CD30, CD33, CD352, CD37, CD44, CD 84 52, CD56, CD70, CD71, CD74, CD79B, DLL B, EphA B, FAP, FGFR B, GPC B, FLT-3, gpB, HPV-16E B, ITGA B, SLC 3639A B, MAGE B, mesothelin, SLC B, SLCP B, SLIP B, SLCP B, SLIP B, SLEP B, SLIP B, SLS B, SLIP B, SL.
The targeted and/or retained antigen may be an immune checkpoint protein. Examples of immune checkpoint proteins include, but are not limited to, CD27, CD137, 2B4, TIGIT, CD155, ICOS, HVEM, CD40L, LIGHT, TIM-1, OX40, DNAM-1, PD-L1, PD1, PD-L2, CTLA-4, CD8, CD40, CEACAM1, CD48, CD70, A2AR, CD39, CD73, B7-H3, B7-H4, BTLA, IDO1, IDO2, TDO, KIR, LAG-3, TIM-3, or VITA.
The targeted and/or retained antigen may be a cell surface molecule such as a protein, lipid or polysaccharide. In some embodiments, the targeted and/or retained antigen is on tumor cells, virus-infected cells, bacteria-infected cells, damaged red blood cells, arterial plaque cells, inflamed or fibrotic tissue cells. Targeting and/or retaining an antigen may comprise an immune response modifier. Examples of immune response modifiers include, but are not limited to, granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), interleukin 2(IL-2), interleukin 3(IL-3), interleukin 12(IL-12), interleukin 15(IL-15), B7-1(CD80), B7-2(CD86), GITRL, CD3, or GITR.
The targeted and/or retained antigen may be a cytokine receptor. Examples of cytokine receptors include, but are not limited to, type I cytokine receptors such as GM-CSF receptor, G-CSF receptor, type I IL receptor, Epo receptor, LIF receptor, CNTF receptor, TPO receptor; type II cytokine receptors such as IFN-alpha receptor (IFNAR1, IFNAR2), IFB-beta receptor, IFN-gamma receptor (IFNGR1, IFNGR2), type II IL receptor; chemokine receptors such as CC chemokine receptor, CXC chemokine receptor, CX3C chemokine receptor, XC chemokine receptor; tumor necrosis receptor superfamily receptors such as TNFRSF5/CD40, TNFRSF8/CD30, TNFRSF7/CD27, TNFRSF1A/TNFR1/CD120a, TNFRSF1B/TNFR2/CD120 b; TGF-beta receptors, such as TGF-beta receptor 1, TGF-beta receptor 2; ig superfamily receptors such as IL-1 receptor, CSF-1R, PDGFR (PDGFRA, PDGFRB), SCFR.
Joint
As described above, the pharmaceutical composition comprises one or more linker sequences. Linker sequences are used to provide flexibility between polypeptides such that, for example, blocking moieties can inhibit the activity of cytokine polypeptides. Linker sequences may be located between any or all of the cytokine polypeptide, serum half-life extending element, and/or blocking moiety. As described herein, at least one of the linkers is protease cleavable and contains the cleavage site(s) of the desired protease(s). Preferably, the desired protease is enriched for or selectively expressed at the desired cytokine active site (e.g., tumor microenvironment). Thus, the fusion protein is preferentially or selectively cleaved at the site of the desired cytokine activity.
Suitable linkers can be of varying lengths, such as 1 amino acid (e.g., Gly) to 20 amino acids, 2 amino acids to 15 amino acids, 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and can be 1, 2, 3, 4, 5, 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, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 amino acids.
Orientation of the components of the pharmaceutical composition is largely a matter of design choice, and it has been recognized that a variety of orientations are possible, and all orientations are intended to be encompassed by the present application. For example, the blocking moiety may be located at the C-terminus or N-terminus of the cytokine polypeptide.
Proteases known to be associated with diseased cells or tissues include, but are not limited to, serine proteases, cysteine proteases, aspartic proteases, threonine proteases, glutamic proteases, metalloproteinases, asparaginase lyase, serum proteases, cathepsins, cathepsin B, cathepsin C, cathepsin D, cathepsin E, cathepsin K, cathepsin L, kallikrein, hKl, hK10, hK15, plasmin, collagenase type IV, stromelysin, factor Xa, chymotrypsin-like proteases, trypsin-like proteases, elastase-like proteases, subtilisin-like proteases, actinidin, bromelain, calpain, caspase-3, Mir1-CP, papain, HIV-1 protease, HSV protease, CMV protease, chymosin, renin, pepsin, proteolytic enzymes, legumain, plasmin, nepenthesin, metalloaprotinin, metalloendopeptidase, Matrix Metalloproteinase (MMP), MMP1, MMP2, MMP3, MMP8, MMP9, MMP13, MMP11, MMP14, urokinase plasminogen activator (uPA), enterokinase, prostate specific target (PSA, hK3), interleukin-1 β convertase, thrombin, FAP (FAP-a), dipeptidyl peptidase, transmembrane peptidase, granzyme and dipeptidyl peptidase IV (DPPIV/CD 26). Proteases capable of cleaving the amino acid sequence encoded by the chimeric nucleic acid sequences provided herein can be, for example, selected from the group consisting of: prostate Specific Antigen (PSA), Matrix Metalloproteinases (MMP), bifidobacterium a and metalloproteases (ADAM), plasminogen activators, cathepsins, caspases, tumor cell surface proteases, and elastase. The MMP can be, for example, matrix metalloproteinase 2(MMP2) or matrix metalloproteinase 9(MMP 9).
Table 1 lists proteases that may be used in the methods disclosed herein, and table 1a lists exemplary proteases and their cleavage sites:
TABLE 1 proteases associated with inflammation and cancer
Table 1 a: exemplary proteases and protease recognition sequences
Provided herein are pharmaceutical compositions comprising polypeptide sequences. As with all peptides, polypeptides and proteins (including fragments thereof), it will be understood that additional modifications (amino acid sequence variants) may occur in the amino acid sequence of the chimeric polypeptide, but such modifications do not alter the nature or function of the peptide, polypeptide or protein. Such modifications include conservative amino acid substitutions, and are discussed in more detail below.
The compositions provided herein have the desired functionality. The composition comprises at least a cytokine polypeptide, such as IL-2, IL-7, IL-12, IL-15, IL-18, IL-21, IFNa or IFNg; or chemokines, such as CXCL10, CCL19, CCL20, CCL 21; blocking moieties, such as space-blocking polypeptides; and optionally a serum half-life extending element, and optionally a targeting polypeptide, wherein one or more linkers are attached to each polypeptide in the composition. A first polypeptide (e.g., an IL-2 mutein) is provided as an active agent. Blocking moieties are provided to block interleukin activity. A linker polypeptide, e.g., a protease cleavable polypeptide, is provided to be cleaved by a protease specifically expressed on the intended target of the active agent. Optionally, the blocking moiety blocks the activity of the first polypeptide by binding to an interleukin polypeptide. In some embodiments, the blocking moiety (e.g., steric blocking peptide) is linked to the interleukin via a protease-cleavable linker that is cleaved at the site of action (e.g., by an inflammation-specific or tumor-specific protease), thereby releasing the full activity of the cytokine at the desired site.
The protease cleavage site may be a naturally occurring protease cleavage site or an artificially engineered protease cleavage site. An artificially engineered protease cleavage site may be cleaved by more than one protease specific for the desired environment (e.g., a tumor) in which cleavage will occur. The protease cleavage site may be cleavable by at least one protease, at least two proteases, at least three proteases, or at least four proteases.
In some embodiments, the linker comprises a glycine-glycine, a sortase recognition motif, or a sortase recognition motif and a peptide sequence (Gly)4Ser)n(SEQ ID No.:195) or (Gly)3Ser)n(SEQ ID No.:196) wherein n is 1, 2, 3, 4 or 5. In one embodiment, the sortase recognition motif comprises the peptide sequence LPXTG (SEQ ID No.:193), wherein X is any amino acid. In one embodiment, the covalent bond is between a reactive lysine residue attached to the C-terminus of the cytokine polypeptide and a reactive aspartic acid attached to the N-terminus of the blocking moiety or other moiety. In one embodiment, the covalent bond is between a reactive aspartic acid residue attached to the N-terminus of the cytokine polypeptide and a reactive lysine residue attached to the C-terminus of the blocking moiety or other moiety.
Cleavage and inducibility
As described herein, in the case of fusion proteins, the activity of the cytokine polypeptide is reduced and protease cleavage at the desired active site (such as in the tumor microenvironment) releases a form of the cytokine from the fusion protein that is much more active as a cytokine receptor agonist than the fusion protein. For example, the cytokine-receptor activating (agonist) activity of the fusion polypeptide may be at least about 10-fold, at least about 50-fold, at least about 100-fold, at least about 250-fold, at least about 500-fold, or at least about 1000-fold lower than the cytokine receptor activating activity of the cytokine polypeptide as a separate molecular entity. When a cytokine polypeptide that is part of a fusion protein contains amino acids that are substantially identical to the cytokine polypeptide and contain substantially no additional amino acids and are not associated (by covalent or non-covalent bonds) with other molecules, then it exists as a separate molecular entity. If necessary, the cytokine polypeptide as a separate molecular entity may contain some additional amino acid sequence, such as a tag or short sequence, to aid in expression and/or purification.
In other examples, the cytokine-receptor activating (agonist) activity of the fusion polypeptide is at least about 10-fold, at least about 50-fold, at least about 100-fold, at least about 250-fold, at least about 500-fold, or about 1000-fold lower than the cytokine receptor activating activity of a polypeptide comprising a cytokine polypeptide produced by cleaving a protease-cleavable linker in the fusion protein. In other words, the cytokine receptor activating (agonist) activity of the polypeptide comprising the cytokine polypeptide produced by cleavage of the protease cleavable linker in the fusion protein is at least about 10-fold, at least about 50-fold, at least about 100-fold, at least about 250-fold, at least about 500-fold, or at least about 1000-fold greater than the cytokine receptor activating activity of the fusion protein.
Polypeptide substitutions
The polypeptides described herein can comprise components (e.g., cytokines, blocking moieties) having the same amino acid sequence as the corresponding naturally occurring protein (e.g., IL-2, IL-15, HSA) or can have amino acid sequences different from that of the naturally occurring protein so long as the desired function is maintained. It will be appreciated that one way of defining any known modifications and derivatives, or modifications and derivatives that may occur, to the disclosed proteins and nucleic acids encoding them is by defining sequence variants on the basis of identity to particular known reference sequences. Specifically disclosed polypeptides and nucleic acids are at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identical to the chimeric polypeptides provided herein. For example, a polypeptide or nucleic acid is provided that has at least 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to the sequence of any nucleic acid or polypeptide described herein. One skilled in the art would readily understand how to determine the identity of two polypeptides or two nucleic acids. For example, identity can be calculated after aligning the two sequences so that the identity is at its highest level.
Another way of calculating identity may be performed by published algorithms. Optimal sequence alignment for comparison can be performed by: the local identity algorithm of Smith and Waterman adv.Appl.Math.2:482 (1981); identity alignment algorithms of Needleman and Wunsch, J.mol.biol.48:443 (1970); methods for similarity exploration of Pearson and Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988); computerized implementation of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group,575Science Dr., Madison, Wis.); or inspected.
For nucleic acids, the same type of identity can be determined, for example, by Zuker, Science 244:48-52 (1989); jaeger et al, Proc.Natl.Acad.Sci.USA 86:7706-7710 (1989); obtained by the algorithm disclosed in Jaeger et al, Methods Enzymol.183:281-306(1989), which is incorporated herein by reference for at least the material relevant to nucleic acid alignment. It is understood that any method may be used in general, and that in some cases the results of these various methods may differ, but the skilled artisan understands that if identity is found using at least one of these methods, the sequences can be considered to have that identity and are disclosed herein.
Protein modifications include amino acid sequence modifications. Modifications of amino acid sequences may occur naturally as allelic variations (e.g., due to genetic polymorphisms), may occur due to environmental influences (e.g., by exposure to ultraviolet light), or may result from human intervention (e.g., by mutagenizing cloned DNA sequences), such as induced points, deletions, insertions, and substitution mutants. These modifications may result in changes in the amino acid sequence, provide silent mutations, modify restriction sites or provide other specific mutations. Amino acid sequence modifications typically fall into one or more of three categories: substitution, insertion or deletion modifications. Insertions include amino and/or carboxy terminal fusions as well as intrasequence insertions of single or multiple amino acid residues. Insertions will typically be smaller than those of amino-or carboxy-terminal fusions, e.g., about one to four residues. Deletions are characterized by the removal of one or more amino acid residues from the protein sequence. Typically, no more than about 2 to 6 residues are deleted at any site within the protein molecule. Amino acid substitutions are typically single residues, but may occur at multiple different positions simultaneously; insertions are typically of about 1 to 10 amino acid residues; and deletions range from about 1 to 30 residues. Deletions or insertions are preferably made in adjacent pairs, i.e. 2 residue deletions or 2 residue insertions. Substitutions, deletions, insertions, or any combination thereof may be combined to arrive at the final construct. The mutation will not place the sequence out of reading frame and preferably will not create a complementary region that can give rise to secondary mRNA structure. Substitution modifications are modifications in which at least one residue has been removed and a different residue inserted in its place. Such substitutions are generally made according to table 2 below and are referred to as conservative substitutions.
TABLE 2 exemplary amino acid substitutions
Modifications, including specific amino acid substitutions, are made by known methods. For example, the modification is performed by site-specific mutagenesis of nucleotides in the DNA encoding the polypeptide, thereby producing DNA encoding the modification, and the DNA is subsequently expressed in recombinant cell culture. Techniques for making substitution mutations at predetermined sites in DNA having a known sequence are well known, such as M13 primer mutagenesis and PCR mutagenesis.
Modifications can be selected to optimize binding. For example, affinity maturation techniques can be used to alter scFv binding by introducing random mutations within Complementarity Determining Regions (CDRs). Such random mutations can be introduced using a variety of techniques, including radiation, chemical mutagens, or error-prone PCR. Multiple rounds of mutation and selection can be performed using, for example, phage display.
The present application also relates to nucleic acids encoding the chimeric polypeptides described herein, and to the use of such nucleic acids to produce chimeric polypeptides and for therapeutic purposes. For example, the present application includes DNA and RNA molecules (e.g., mRNA, self-replicating RNA) encoding chimeric polypeptides, and therapeutic uses of such DNA and RNA molecules.
Exemplary compositions
Exemplary fusion proteins of the present application combine the elements described above in a variety of orientations. The orientations described in this section are by way of example only and should not be construed as limiting.
In some embodiments, the fusion protein comprises a cytokine, a blocking moiety, and a half-life extending element. In some embodiments, the cytokine is located between the half-life extending element and the blocking moiety. In some embodiments, the cytokine is located N-terminal to the blocking moiety and half-life extending element. In some such embodiments, the cytokine is proximal to the blocking moiety; in some such embodiments, the cytokine is located proximal to the half-life extending element. In all embodiments it is necessary to include at least one protease cleavable linker so that the cytokine can be active upon cleavage. In some embodiments, the cytokine is located C-terminal to the blocking moiety and half-life extending element. The additional elements may be connected to each other by a cleavable linker, a non-cleavable linker or by direct fusion.
In some embodiments, the blocking domain used is capable of extending half-life, and a cytokine is located between two such blocking domains. In some embodiments, the cytokine is located between two blocking domains, one of which is capable of extending half-life.
In some embodiments, both cytokines are contained in the same construct. In some embodiments, the cytokines are each linked to two blocking domains (a total of three in a molecule), wherein the blocking domains are located between the two cytokine domains. In some embodiments, one or more additional half-life extending domains may be included to optimize pharmacokinetic properties. In some cases, it is beneficial to include two identical cytokines to promote dimerization. An example of a cytokine that acts as a dimer is IFN γ.
In some embodiments, the three cytokines are contained in the same construct. In some embodiments, the third cytokine may act to block the other two cytokines in place of the blocking domain between the other two cytokines.
Preferred half-life extending elements for fusion proteins are Human Serum Albumin (HSA), antibodies or antibody fragments (e.g. scFV, dAb) that bind serum albumin, human or humanized IgG, or fragments of any of the foregoing. In some preferred embodiments, the blocking moiety is Human Serum Albumin (HSA), or an antibody or antibody fragment that binds serum albumin, an antibody that binds a cytokine and prevents binding to activation or cytokine receptor, i.e., activation of another cytokine, or a fragment of any of the foregoing. In preferred embodiments comprising additional targeting domains, the targeting domain is an antibody that binds to a cell surface protein enriched on the surface of cancer cells, such as EpCAM, FOLR1, and fibronectin.
Therapeutic methods and pharmaceutical compositions
Also provided are methods of treating a subject having or at risk of developing a disease or disorder, such as a proliferative disease, a neoplastic disease, an inflammatory disease, an immune disorder, an autoimmune disease, an infectious disease, a viral disease, an allergic reaction, a parasitic reaction, or a graft-versus-host disease. The method administers to a subject in need thereof an effective amount of a fusion protein as disclosed herein, typically as a pharmaceutical composition. In some embodiments, the method further comprises selecting a subject having or at risk of developing such a disease or disorder. The pharmaceutical composition preferably comprises a blocked cytokine, fragment thereof or mutein thereof activated at the site of inflammation or tumor. In one embodiment, the chimeric polypeptide comprises a cytokine polypeptide, a fragment or mutein thereof and a serum half-life extending element. In another embodiment, the chimeric polypeptide comprises a cytokine polypeptide, a fragment thereof, or a mutein thereof and a blocking moiety, such as a steric blocking polypeptide, wherein the steric blocking polypeptide is capable of sterically blocking the activity of the cytokine polypeptide, fragment thereof, or mutein. In another embodiment, the chimeric polypeptide comprises a cytokine polypeptide, a fragment or mutein thereof, a blocking moiety, and a serum half-life extending element.
Inflammation is part of the complex biological response of human tissues to harmful stimuli, such as pathogens, damaged cells, or irritants, and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cellular injury, to clear necrotic cells and tissue damaged during the initial injury and inflammation, and to initiate tissue repair. Inflammation may be caused by infection, occurring as a symptom or disease, such as cancer, atherosclerosis, allergy, myopathy, HIV, obesity, or an autoimmune disease. Autoimmune diseases are chronic conditions caused by an abnormal immune response to self-antigens. Autoimmune diseases that can be treated with the polypeptides disclosed herein include, but are not limited to, lupus, celiac disease, type 1 diabetes, Graves disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.
The pharmaceutical composition may comprise one or more protease cleavable linker sequences. The linker sequence is used to provide flexibility between the polypeptides such that each polypeptide is capable of inhibiting the activity of the first polypeptide. The linker sequence may be located between any or all of the cytokine polypeptide, fragment or mutein thereof, the blocking moiety and the serum half-life extending element. Optionally, the composition comprises two, three, four or five linker sequences. The linker sequences, i.e., two, three or four linker sequences, may be the same or different linker sequences. In one embodiment, the linker sequence comprises GGGGS (SEQ ID NO.:201), GSGSGS (SEQ ID NO.:202) or G (SGGG)2SGGT (SEQ ID NO: 203). In another embodiment, the linker comprises a protease cleavable sequence selected from the group consisting of: HSSKLQ (SEQ ID No.:25), GPLGVRG (SEQ ID No.:197), IPVSLRSG (SEQ ID No.:198), VPLSLYSG (SEQ ID No.:199) and SGESPAYYTA (SEQ ID No.: 200).
In some embodiments, the linker is cleaved by a protease selected from the group consisting of: kallikrein, thrombin, chymotrypsin, carboxypeptidase A, cathepsin G, elastase, PR-3, granzyme M, calpain, Matrix Metalloproteinase (MMP), plasminogen activator, cathepsin, caspase, tryptase, or tumor cell surface protease.
Suitable linkers can be of varying lengths, such as 1 amino acid (e.g., Gly) to 20 amino acids, 2 amino acids to 15 amino acids, 3 amino acids to 12 amino acids, including 4 amino acids to 10 amino acids, 5 amino acids to 9 amino acids, 6 amino acids to 8 amino acids, or 7 amino acids to 8 amino acids, and can be 1, 2, 3, 4, 5, 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, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 amino acids.
Also provided are methods of treating a subject having or at risk of developing cancer. The method comprises administering to a subject in need thereof an effective amount of a chimeric polypeptide (fusion protein) as disclosed herein, typically as a pharmaceutical composition. In some embodiments, the method further comprises selecting a subject having or at risk of developing cancer. The pharmaceutical composition preferably comprises a blocked cytokine, fragment thereof or mutein thereof activated at the tumor site. Preferably, the tumor is a solid tumor. The cancer may be, but is not limited to, colon cancer, lung cancer, melanoma, sarcoma, renal cell carcinoma, and breast cancer.
The methods can further comprise administering one or more additional agents to treat the cancer, such as chemotherapeutic agents (e.g., doxorubicin (Adriamycin), daunorubicin (Cerubidine), Bleomycin (Bleomycin), melphalan (Alkeran), vinblastine (Velban), vincristine (Oncovin), fluorouracil, thiotepa, methotrexate, bisantrene (Noantrone), thioguanine (thiguarine), cytarabine (cytabine), procarbazine (procarbazine)), immunotumoral agents (e.g., anti-PD-L1, anti-CTLA 4, anti-PD-1, anti-CD 47, anti-GD 2), cell therapies (e.g., CAR-T, T cell therapy), oncolytic viruses, and the like.
Provided herein are pharmaceutical formulations or compositions containing a chimeric polypeptide and a pharmaceutically acceptable carrier. The compositions provided herein are suitable for in vitro or in vivo administration. By pharmaceutically acceptable carrier is meant a material that is not biologically or otherwise undesirable, i.e., the material is administered to a subject without causing undesirable biological effects or interacting in a deleterious manner with other components of a pharmaceutical formulation or composition containing the material. The carrier is selected to minimize degradation of the active ingredient and to minimize adverse side effects in the subject.
Suitable carriers and formulations thereof are described in Remington, The Science and Practice of Pharmacy, 21 st edition, eds David B.Troy, Lippicott Williams & Wilkins (2005). Typically, an appropriate amount of a pharmaceutically acceptable salt is used in the formulation to render the formulation isotonic, although the formulation may be hypertonic or hypotonic if desired. Examples of pharmaceutically acceptable carriers include, but are not limited to, sterile water, saline, buffered solutions (e.g., ringer's solution), and dextrose solutions. The pH of the solution is typically from about 5 to about 8 or from about 7 to 7.5. Other carriers include sustained release formulations, such as semipermeable matrices of solid hydrophobic polymers containing the immunogenic polypeptide. The matrix is in the form of a shaped article, such as a membrane, liposome, or microparticle. Certain formulations may be more preferred depending on, for example, the route of administration and the concentration of the composition administered. Carriers are those suitable for administration of the chimeric polypeptide or a nucleic acid sequence encoding the chimeric polypeptide to a human or other subject.
The pharmaceutical formulation or composition is administered in a variety of ways depending on whether local or systemic treatment is desired and the area to be treated. The compositions are administered by any of several routes of administration, including topical, oral, parenteral, intravenous, intraarticular, intraperitoneal, intramuscular, subcutaneous, intracavity, transdermal, intrahepatic, intracranial, nebulization/inhalation, or by installation via bronchoscopy. In some embodiments, the composition is administered locally (non-systemically), including intratumorally, intraarticularly, intrathecally, and the like.
Formulations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Aqueous carriers include water, alcohol/aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, ringer's dextrose, dextrose and sodium chloride, lactated ringer's solution, or fixed oils. Intravenous vehicles include fluid and nutritional supplements, electrolyte supplements (such as those based on ringer's dextrose), and the like. Preservatives and other additives are optionally present such as, for example, antimicrobials, antioxidants, chelating agents, and inert gases and the like.
Formulations for topical administration include ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like are optionally necessary or desirable.
Compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids, or binders are optionally desirable.
Optionally, the chimeric polypeptide or a nucleic acid sequence encoding the chimeric polypeptide is administered from a vector. There are a number of compositions and methods that can be used to deliver nucleic acid molecules and/or polypeptides to cells in vitro or in vivo, for example, via expression vectors. These methods and compositions can be largely divided into two categories: viral-based delivery systems and non-viral-based delivery systems. Such methods are well known in the art and are readily applicable to the compositions and methods described herein. Such compositions and methods can be used to transfect or transduce cells in vitro or in vivo, e.g., to produce cell lines that express and preferably secrete the encoded chimeric polypeptide or to deliver nucleic acids therapeutically to a subject. The components of the chimeric nucleic acids disclosed herein are typically operably linked in frame to encode a fusion protein.
As used herein, a plasmid or viral vector is an agent that transports the disclosed nucleic acids into a cell without degradation, and includes a promoter that causes expression of the nucleic acid molecule and/or polypeptide in the cell into which it is delivered. Viral vectors are, for example, adenoviruses, adeno-associated viruses, herpes viruses, vaccinia viruses, polioviruses, Sindbis (Sindbis) and other RNA viruses, including those having an HIV backbone. It is also preferred that these viruses share the properties of any virus family that makes them suitable for use as vectors. Retroviral vectors are generally described by Coffin et al, Retroviruses, Cold Spring Harbor Laboratory Press (1997), wherein the vectors and methods for their preparation are incorporated herein by reference. The construction of replication-defective adenoviruses has been described (Berkner et al, J.Virol.61:1213-20 (1987); Massie et al, mol.cell.biol.6:2872-83 (1986); Haj-Ahmad et al, J.Virol.57:267-74 (1986); Davidson et al, J.Virol.61:1226-39 (1987); Zhang et al, BioTechniques 15:868-72 (1993)). The benefit and use of these viruses as vectors is that the extent to which they can spread on other cell types is limited because they can replicate within the originally infected cell, but cannot form new infectious viral particles. Recombinant adenoviruses have been shown to achieve high efficiency following direct in vivo delivery to airway epithelium, hepatocytes, vascular endothelium, CNS parenchyma and many other tissue sites. Other useful systems include, for example, replicative and host-restricted non-replicative vaccinia virus vectors.
The provided polypeptides and/or nucleic acid molecules can be delivered by a virus-like particle. Virus-like particles (VLPs) are composed of one or more viral proteins derived from viral structural proteins. Methods for making and using virus-like particles are described, for example, in Garcea and Gissmann, Current Opinion in Biotechnology 15:513-7 (2004).
The provided polypeptides can be delivered by a subviral Densome (DB). DB transports proteins into target cells by membrane fusion. Methods for making and using DB are described, for example, in Pepperl-Klindworth et al, Gene Therapy 10:278-84 (2003).
The provided polypeptides can be delivered through an aggregate of integuments. Methods for making and using the skin aggregates are described in international publication number WO 2006/110728.
Non-viral based delivery methods may include expression vectors comprising a nucleic acid molecule and a nucleic acid sequence encoding a polypeptide, wherein the nucleic acid is operably linked to an expression control sequence. Suitable vector backbones include, for example, those conventionally used in the art, such as plasmids, artificial chromosomes, BAC, YAC, or PAC. Many vectors and expression systems are commercially available from companies such as Novagen (Madison, Wis.), Clonetech (pall Alto, Calif.), Stratagene (La Jolla, Calif.), and Invitrogen/Life Technologies (Carlsbad, Calif.). The vector typically contains one or more regulatory regions. Regulatory regions include, but are not limited to, promoter sequences, enhancer sequences, response elements, protein recognition sites, induction factors, protein binding sequences, 5 'and 3' untranslated regions (UTRs), transcription initiation sites, termination sequences, polyadenylation sequences, and introns. Such vectors may also be used to prepare chimeric polypeptides by expression in suitable host cells such as CHO cells.
Preferred promoters for controlling transcription of vectors in mammalian host cells can be obtained from a variety of sources, for example, the genomes of viruses such as polyoma virus, simian virus 40(SV40), adenovirus, retrovirus, hepatitis b virus, and most preferably Cytomegalovirus (CMV); or from a heterologous mammalian promoter, such as the β -actin promoter or the EF1 α promoter; or from a hybrid or chimeric promoter (e.g., a CMV promoter fused to a β -actin promoter). Of course, promoters from host cells or related species may also be used herein.
Enhancers generally refer to sequences in DNA that function at a fixed distance from the transcription start site, and may be located 5 'or 3' to a transcriptional unit. Furthermore, enhancers can be located within introns as well as within the coding sequence itself. They are typically between 10 and 300 base pairs (bp) in length, and they act in cis. Enhancers generally function to increase transcription from nearby promoters. Enhancers may also contain response elements that mediate the regulation of transcription. Although many enhancer sequences are known from mammalian genes (globin, elastase, albumin, alpha-fetoprotein, and insulin), one will typically use enhancers from eukaryotic cell viruses for general expression. Preferred examples are the SV40 enhancer on the posterior side of the replication origin, the cytomegalovirus early promoter enhancer, the polyoma enhancer on the posterior side of the replication origin, and adenovirus enhancers.
Promoters and/or enhancers may be inducible (e.g., chemically or physically regulated). Chemically regulated promoters and/or enhancers can be regulated, for example, by the presence of an alcohol, tetracycline, steroid, or metal. Physically regulated promoters and/or enhancers can be regulated, for example, by environmental factors such as temperature and light. Optionally, the promoter and/or enhancer region may act as a constitutive promoter and/or enhancer to maximize expression of the region of the transcriptional unit to be transcribed. In certain vectors, promoter and/or enhancer regions may be active in a cell-type specific manner. Optionally, in certain vectors, the promoter and/or enhancer regions may be active in all eukaryotic cells, regardless of cell type. Preferred promoters of this type are the CMV promoter, SV40 promoter, β -actin promoter, EF1 α promoter and retroviral Long Terminal Repeats (LTRs).
The vector may further comprise, for example, an origin of replication and/or a marker. The marker gene may confer a selectable phenotype, such as antibiotic resistance, on the cell. The marker product is used to determine whether the vector has been delivered to the cell and is expressed once delivered. Examples of selectable markers for mammalian cells are dihydrofolate reductase (DHFR), thymidine kinase, neomycin analog G418, hygromycin, puromycin, and blasticidin. When such selectable markers are successfully transferred into mammalian host cells, transformation occurs if placed under selective pressure Can survive. Examples of other markers include, for example, the e.coli (e.coli) lacZ gene, Green Fluorescent Protein (GFP), and luciferase. In addition, the expression vector may include a tag sequence designed to facilitate manipulation or detection (e.g., purification or localization) of the expressed polypeptide. Tag sequences such as GFP, glutathione S-transferase (GST), polyhistidine, c-myc, hemagglutinin or FLAGTMTag (Kodak; New Haven, Conn.) sequences are typically expressed as fusions to the encoded polypeptide. Such tags may be inserted anywhere within the polypeptide, including the carboxy terminus or the amino terminus.
As used herein, the term peptide, polypeptide or protein is used broadly to refer to two or more amino acids linked by peptide bonds. Proteins, peptides and polypeptides may also be used interchangeably herein to refer to amino acid sequences. It will be appreciated that the term polypeptide is not used herein to imply a particular size or number of amino acids making up the molecule, and that the peptides of the present application may contain up to a few amino acid residues or more. As used throughout, a subject may be a vertebrate, more specifically a mammal (e.g., human, horse, cat, dog, cow, pig, sheep, goat, mouse, rabbit, rat, and guinea pig), bird, reptile, amphibian, fish, and any other animal. The term does not denote a particular age or gender. Thus, adult and neonatal subjects, whether male or female, are intended to be encompassed. As used herein, patient or subject is used interchangeably and may refer to a subject suffering from a disease or disorder (e.g., cancer). The term patient or subject includes human and veterinary subjects.
A subject at risk of developing a disease or disorder may be genetically predisposed to the disease or disorder, e.g., having a family history or having a mutation in a gene causing the disease or disorder, or exhibiting early signs or symptoms of the disease or disorder. A subject currently suffering from a disease or disorder has one or more symptoms of the disease or disorder, and may have been diagnosed as suffering from the disease or disorder.
The methods and agents as described herein are useful for prophylactic and therapeutic treatment. For prophylactic use, a therapeutically effective amount of a chimeric polypeptide described herein or a chimeric nucleic acid sequence encoding the chimeric polypeptide is administered to a subject prior to onset (e.g., prior to an apparent sign of cancer or inflammation) or during an early onset (e.g., at the early signs and symptoms of cancer or inflammation). Prophylactic administration can occur several days to several years before symptoms of cancer or inflammation manifest. For example, prophylactic administration can be used to prophylactically treat a subject diagnosed as having a genetic predisposition to cancer. Therapeutic treatment involves administering to a subject a therapeutically effective amount of a chimeric polypeptide described herein or a nucleic acid sequence encoding the chimeric polypeptide after diagnosis or progression to cancer or inflammation (e.g., autoimmune disease). Prophylactic applications may also be used when a patient is receiving treatment (e.g., chemotherapy) that is expected to be inflammatory.
According to the methods taught herein, an effective amount of an agent (e.g., a chimeric polypeptide) is administered to a subject. The terms effective amount and effective dose are used interchangeably. The term effective amount is defined as any amount necessary to produce a desired physiological response. Effective amounts and regimens for administering the agents can be determined empirically, and making such determinations is within the skill of the art. The dosage range administered is one that is sufficiently large to produce the desired effect, wherein one or more symptoms of the disease or disorder are affected (e.g., reduced or delayed). The dosage should not be so large as to cause serious adverse side effects such as unwanted cross-reactions, allergic reactions, and the like. In general, the dosage varies with age, condition, sex, type of disease, extent of disease or disorder, route of administration, or whether other drugs are included in the regimen, and can be determined by one skilled in the art. In the case of any contraindication, the dosage may be adjusted by the individual physician. The dosage may vary, and may be administered in one or more daily dose administrations over one or more days. Guidance may be found in the literature regarding appropriate dosages for a given class of pharmaceutical products.
As used herein, the term treatment refers to a method of reducing the effects of a disease or condition or the symptoms of a disease or condition. Thus, in the disclosed methods, treatment may refer to a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in the severity of an established disease or condition or symptom of a disease or condition. For example, a method for treating a disease is considered a treatment if one or more symptoms of the disease are reduced by 10% in a subject compared to a control. Thus, the reduction may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or any percentage reduction between 10% and 100% compared to the native or control level. It is to be understood that treatment does not necessarily refer to curing or completely eliminating a disease, condition, or symptom of a disease or condition.
As used herein, the terms prevention of a disease or disorder (prevent, preventing, and prevention) refer to the effect of administering a chimeric polypeptide or a nucleic acid sequence encoding a chimeric polypeptide that inhibits or delays the onset or exacerbation of one or more symptoms of a disease or disorder, e.g., before or about the same time as the subject begins to exhibit one or more symptoms of a disease or disorder. As used herein, reference to reduction, or inhibition includes a change of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more, as compared to a control level. Such terms may include, but do not necessarily include, complete elimination.
IL-2 variants selective for IL 2R. alpha. beta. gamma. over IL 2R. beta. gamma have been developed (Shanafelt, A.B. et al, 2000, Nat Biotechnol.18: 1197-202; Cassell, D.J. et al, 2002, Curr Pharm Des.,8: 2171-83). These variants have amino acid substitutions that reduce their affinity for IL2 RB. Since IL-2 has undetectable affinity for IL2RG, these variants have reduced affinity for the IL2R β γ receptor complex and reduced ability to activate IL2R β γ expressing cells, but retain the ability to bind IL2RA and bind and activate the IL2R α β γ receptor complex.
Based on the hypothesis that NK cells expressing IL2R β γ are the major factor responsible for toxicity, one of these variants, IL2/N88R (Bay 50-4798), was clinically tested as a low-toxicity version of IL-2 as an immune system stimulator. Bay 50-4798 has been shown to selectively stimulate proliferation of activated T cells relative to NK cells and is evaluated in phase I/II clinical trials in Cancer patients (Margolin, K. et al, 2007, Clin Cancer Res.,13:3312-9) and HIV patients (Davey, R.T. et al, 2008, J Interferon Cytokine Res.,28: 89-100). These clinical trials indicate that Bay 50-4798 is safer and more tolerant than aldesleukin, and also that it increases the levels of CD4+ CD25+ T cells (a population of Treg-rich cells). Following these experiments, studies in the field more fully established the identity of Treg cells and demonstrated that Treg cells selectively express IL2R α β γ (reviewed in Malek, t.r. et al, 2010, Immunity,33: 153-65).
In addition, mutants can be made that selectively alter the affinity for the CD25 chain relative to native IL-2.
IL-2 can be engineered to produce mutants that bind to the IL-2R complex in general or to the IL-2R α subunit specifically, with an affinity that differs from that of the corresponding wild-type IL-2 or currently available mutants (referred to as C125S, because the cysteine residue at position 125 is replaced by a serine residue).
Accordingly, the application features a mutant interleukin-2 (IL-2) polypeptide that includes an amino acid sequence at least 80% identical (e.g., 85%, 87%, 90%, 95%, 97%, 98%, or 99% identical) to wild-type IL-2 and that binds to an IL-2 trimer receptor higher relative to a dimer IL-2 receptor as compared to WT IL-2. Typically, the mutein will also bind to the IL-2 receptor alpha subunit (IL-2R alpha) with greater affinity than the wild-type IL-2 binds to IL-2R alpha. The amino acid sequence within the mutant IL-2 polypeptide may differ from that of SEQ ID NO:1(UniProtKB accession number P60568) by containing (or containing only) one or more amino acid substitutions (which may be considered conservative or non-conservative substitutions). Non-naturally occurring amino acids may also be incorporated. Alternatively or additionally, the amino acid sequence may differ from SEQ ID NO:1 (which may be considered a "reference" sequence) by virtue of the inclusion and addition and/or deletion of one or more amino acid residues. More specifically, the amino acid sequence may differ from SEQ ID No. 1: 1. 4, 8, 9, 10, 11, 13, 15, 26, 29, 30, 31, 35, 37, 46, 48, 49, 54, 61, 64, 67, 68, 69, 71, 73, 74, 75, 76, 79, 88, 89, 90, 92, 99, 101, 103, 114, 125, 128, or 133 (or a combination thereof). As noted, it is possible that only one of these positions may be changed, and two, three, four, five, six, seven, eight, nine, ten, or 11 or more (including at most all) of the possible positions may be changed. For example, the amino acid sequence may differ from SEQ ID NO. 1 at positions 69 and 74 and further at one or more of positions 30, 35 and 128. The amino acid sequence may also differ from SEQ ID NO:2 at one of the following sets of positions (as disclosed in US 7569215, which is incorporated herein by reference): (a) positions 64, 69 and 74; (b) positions 69, 74 and 101; (c) positions 69, 74 and 128; (d) positions 30, 69, 74 and 103; (e) positions 49, 69, 73 and 76; (f) positions 69, 74, 101, and 133; (g) positions 30, 69, 74 and 128; (h) positions 69, 74, 88, and 99; (i) positions 30, 69, 74 and 128; (j) positions 9, 11, 35, 69 and 74; (k) positions 1, 46, 49, 61, 69 and 79; (1) positions 48, 68, 71, 90, 103 and 114; (m) positions 4, 10, 11, 69, 74, 88 and 133; (n) positions 15, 3031, 35, 48, 69, 74 and 92; (O) positions 30, 68, 69, 71, 74, 75, 76 and 90; (p) positions 30, 31, 37, 69, 73, 74, 79 and 128; (q) positions 26, 29, 30, 54, 67, 69, 74 and 92; (r) positions 8, 13, 26, 30, 35, 37, 69, 74 and 92; and(s) positions 29, 31, 35, 37, 48, 69, 71, 74, 88 and 89. In addition to mutations at these positions, the amino acid sequence of the mutant IL-2 polypeptide may be otherwise identical to SEQ ID NO. 1. With respect to specific substitutions, the amino acid sequence may differ from SEQ ID NO: 1: A1T, S4P, K8P, K9P, T10P, Q11P, Q13P, E15P, N26P, N29P, N30P, Y31P, K35P, T37P, M46P, K48P, K49P, K54P, E61P, K64P, E67P, E68P, V69P, N71P, a 73P, Q74P, S75P, K76P, H79P, N88P, I3689, N90P, I92, S3699, T101, F72, I P, T79P, T36. Our nomenclature is consistent with that of the scientific literature, in which the one letter code for an amino acid in a wild-type or reference sequence is immediately preceded by its position in the sequence, and then by the one letter code for the amino acid that replaces it. Thus, A1T represents the substitution of the alanine residue at position 1 with threonine. Other mutant polypeptides within the scope of the present application include those that include mutant SEQ ID NO. 2 with substitutions at V69 (e.g., A) and Q74 (e.g., P). For example, the amino acid sequence may comprise one of the following sets of mutations relative to SEQ ID NO: 2: (a) K64R, V69A and Q74P; (b) V69A, Q74P, and T101A; (c) V69A, Q74P, and I128T; (d) N30D, V69A, Q74P and F103S; (e) K49E, V69A, a73V and K76E; (f) V69A, Q74P, T101A and T133N; (g) N30S, V69A, Q74P and I128A; (h) V69A, Q74P, N88D and S99P; (i) N30S, V69A, Q74P and I128T; (j) K9T, Q11R, K35R, V69A and Q74P; (k) A1T, M46L, K49R, E61D, V69A and H79R; (l) K48E, E68D, N71T, N90H, F103S and I114V; (m) S4P, T10A, Q11R, V69A, Q74P, N88D, and T133A; (N) E15K, N30S Y31H, K35R, K48E, V69A, Q74P, and I92T; (o) N30S, E68D, V69A, N71A, Q74P, S75P, K76R, and N90H; (p) N30S, Y31C, T37A, V69A, a73V, Q74P, H79R, and I128T; (Q) N26D, N29S, N30S, K54R, E67G, V69A, Q74P, and I92T; (r) K8R, Q13R, N26D, N30T, K35R, T37R, V69A, Q74P and I92T; and(s) N29S, Y31H, K35R, T37A, K48E, V69A, N71R, Q74P, N88D, and I89V. 2 is disclosed in US 7569215 as an exemplary IL-2 polypeptide sequence useful in the present application, which patent is incorporated herein by reference.
As described above, any of the mutant IL-2 polypeptides disclosed herein may comprise the sequence; they may also be limited to the sequences and otherwise identical to SEQ ID NO: 1. In addition, any of the mutant IL-2 polypeptides described herein may optionally comprise a substitution of the cysteine residue at position 125 with another residue (e.g., serine) and/or may optionally comprise a deletion of the alanine residue at position 1 of SEQ ID NO: 1.
The mutant IL-2 polypeptides disclosed herein can bind to K of the IL-2R alpha subunitdLess than about 28nM (e.g., less than about 25 nM; less than about 5 nM; about 1 nM; less than about 500 pM; or less than about 100 pM). More specifically, the mutant IL-2 polypeptide can have an affinity equilibrium constant of less than 1.0nM (e.g., about 0.8nM, 0.6nM, 0.4nM, or 0.2nM). Affinity can also be expressed as the relative rate of dissociation from the IL-2R α subunit or IL-2 receptor complex (e.g., a complex expressed on the surface of a cell or otherwise bound to a membrane). For example, the rate of dissociation of the mutant IL-2 polypeptide from, e.g., IL-2 ra is reduced relative to the wild-type polypeptide or IL-2 based therapeutic agent, e.g., IL-2. Alternatively, affinity may be characterized by the time or average time that the IL-2 polypeptide is present continuously, e.g. on the surface of a cell expressing IL-2R. For example, an IL-2 polypeptide may persist on the receptor at least about 2, 5, 10, 50, 100, or 250 times (or more).
The disclosed materials, compositions, and components can be used for, can be used in conjunction with, can be used to prepare, or are products of the disclosed methods and compositions. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a method is disclosed and discussed and a number of modifications that can be made to a number of molecules (including the method) are discussed, each and every combination and permutation of the method and possible modifications are specifically contemplated unless specifically indicated to the contrary. Likewise, any subset or combination of these is also specifically contemplated and disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific method step or combination of method steps of the disclosed methods, and that each such combination or subset of combinations is contemplated and should be considered disclosed herein.
The publications cited herein and the materials in which they are cited are hereby expressly incorporated by reference in their entirety.
Examples
The following are examples of the methods and compositions of the present application. It is to be understood that various other embodiments may be implemented in view of the general description provided herein.
Example 1: detection of IL-2, IL-2 muteins, IL-2R alpha and IL-2R gamma in fusion proteins by ELISA
IL-2 muteins are detected with commercially available antibodies, such as anti-IL-2 monoclonal antibody (JES6-1A12) (BD Pharmingen; San Jose, Calif.). Positive controls were used to show whether the monoclonal antibody recognizes a cytokine or a mutein. Antibodies to IL-2R α and IL-2R γ chains are also used. The wells of a 96-well plate were coated with antibody in PBS (2.5. mu.g/ml). The content of the active ingredients is 0.2 percentThe wells were blocked with 5% skim milk in PBS (PBS-M-Tw) and the fusion protein was added at 37 ℃ for 1 to 2 hours. After washing, an anti-IL-2 biotin-labeled antibody, such as JES5H4(BD Pharmingen), is added and binding is detected using Streptavidin HRP (Southern Biotechnology Associates; Birmingham, Ala.). By adding 0.04% H at 0.1M citrate pH 4.52O2ELISA plates were developed by adding 50. mu.l of o-phenylenediamine (OPD) (Sigma-Aldrich) and developing by adding 50. mu.l/well 2N H 2SO4The ELISA was stopped and the absorbance read at 490 nm.
Example 2: proteolytic cleavage of fusion proteins by MMP9 protease
One skilled in the art will be familiar with methods for establishing protein cleavage assays. 100ug of protein in 1xPBS pH7.4 was cleaved with 1ug of active MMP9(Sigma Cat. No. SAE0078-50 or Enzo Cat. BML-SE360) and incubated at room temperature for up to 16 hours. The digested protein was then used for functional assays or stored at-80 ℃ prior to testing. The extent of cleavage was monitored by SDS PAGE using methods well known in the art. As shown in fig. 10, 13, 18A, 18B, 24C and 27A, MMP9 protease was seen to completely cleave the fusion protein.
Example 3: CTLL-2 assay
CTLL2 cells (ATCC) were seeded at a concentration of 500,000 cells/well in medium with or without 40mg/ml Human Serum Albumin (HSA) and37 ℃ and 5% CO2Next, the cells were stimulated with serial dilutions of recombinant hIL2 or activatable hIL2 for 72 hours. The activity of active hIL2 was tested both uncleaved and cleaved. Cleaved activatable hIL2 was generated by incubation with active MMP 9. Cell viability was assessed using a cell viability assay based on CellTiter-glo (Promega) luminescence. The results are shown in fig. 8, 9 and 25.
Example 4: proteolytic cleavage of the IL-2/IL-2R α/IL-2R γ chimeric polypeptide results in increased accessibility to antibodies and biologically active IL-2 muteins.
IL-2 mutein fusion proteins were biochemically characterized before and after cleavage with proteases (e.g., PSA). Immunoblot analysis will show that the fusion protein can be cleaved by PSA and that the predicted low molecular weight cleavage product of about 20kDa reacts more strongly with anti-IL-2 antibodies after treatment of the sample with PSA. The extent of lysis depends on the amount of PSA and the incubation time. Interestingly, when the fusion proteins were analyzed by ELISA before and after PSA treatment, it was found that the apparent amount of IL-2 increased after PSA cleavage. In this experiment, the apparent amount of IL-2 detected using this sandwich ELISA was increased by about 2 or 4 fold depending on the construct, indicating that antibody binding was partially blocked in the intact fusion protein. Aliquots of the same samples were also analyzed after PSA treatment using the CTLL-2 cell line (which requires IL-2 for growth and survival), and the viability of the cells can be determined using a colorimetric MTT assay. In this assay, the more supernatant that can be diluted, the more biologically active IL-2 it contains and the increased amount of biologically active IL-2 after PSA lysis. An increase in the amount of IL-2 mutein would indicate that, after PSA cleavage, the predicted low molecular weight cleaved fragment of about 20kDa reactive with anti-IL-2 antibodies is increased, antibody accessibility is increased, and most importantly, the amount of biologically active IL-2 mutein is increased.
Example 5 in vivo delivery of protease-activated fusion proteins results in reduced tumor growth
The chimeric polypeptide is examined to determine whether it can have a biological effect in vivo. For these experiments, a system was used in which intraperitoneally injected tumor cells rapidly and preferentially attach to and begin to grow on opalescent spots, which are a series of organized immune aggregates found on the omentum (Gerber et al, am.j. pathol.169:1739-52 (2006)). This system provides a convenient way to examine the effect of fusion protein therapy on tumor growth, since the fusion protein can be delivered intraperitoneally multiple times and tumor growth can be analyzed by examining dissociated omentum cells. For these experiments, the fast growing tumor cell line colon 38 cell line expressing MMP2 and MMP9 in vitro could be used. Omentum tissue typically expresses relatively small amounts of MMP2 and MMP9, but when colon 38 tumors appear on the omentum, MMP levels are elevated. Using this tumor model, the ability of the IL-2 mutein fusion proteins to influence tumor growth was examined. Colon 38 cells were injected intraperitoneally, allowed to attach and grow for 1 day, and then treated intraperitoneally with the fusion protein daily. On day 7, animals were sacrificed and tumor growth of omentum was examined by colony formation assay using flow cytometry.
Example 6: construction of an exemplary activatable IL2 protein targeting CD20
Generation of activatable IL2 Domain
IL-2 polypeptides capable of binding to a CD20 polypeptide present in a tumor or on tumor cells were generated as follows. Generating a nucleic acid comprising the following nucleic acid sequence: (1) encodes an IFNg polypeptide sequence and (2) one or more polypeptide linkers. The activatable interleukin plasmid construct may have an optional Flag, His, or other affinity tag and be electroporated into HEK293 or other suitable human or mammalian cell line and purified. Validation assays include T cell activation assays using T cells that respond to IFNg stimulation in the presence of proteases.
Generation of scFv CD20 binding Domain
CD20 is one of the cell surface proteins present on B lymphocytes. The CD20 antigen is present in both normal and malignant pre-B and mature B lymphocytes, including those in more than 90% of B cell non-hodgkin's lymphomas (NHLs). Antigens are not present in hematopoietic stem cells, activated B lymphocytes (plasma cells) and normal tissues. Thus, several antibodies have been described which are mainly of murine origin: 1F5, 2B8/C2B8, 2H7 and 1H 4.
Thus, human or humanized anti-CD 20 antibodies are used to generate scFv sequences that activate the CD20 binding domain of the interleukin protein. DNA sequences encoding human or humanized VL and VH domains are obtained and the codons of the construct are optionally optimized for expression in homo sapiens cells. The order in which the VL and VH domains appear in the scFv is varied (i.e.VL-VH or VH-VL orientation) and "G4S" (SEQ ID NO: 201) or "G 4S "(SEQ ID NO: 201) subunit (G)4S)3Three copies of (SEQ ID NO: 204) were joined to the variable domains to create scFv domains. The anti-CD 20 scFv plasmid construct can have an optional Flag, His, or other affinity tag, and be electroporated into HEK293 or other suitable human or mammalian cell line and purified. Validation assays included binding analysis by FACS, kinetic analysis using Proteon, and staining of CD20 expressing cells.
Cloning of DNA expression constructs encoding activatable IL2 protein
The activatable IL2 construct with protease cleavage site domain was used to construct a combination of an activatable interleukin protein with an anti-CD 20 scFv domain and a serum half-life extending element (e.g., HSA binding peptide or VH domain), wherein the organized domains are as shown in figure 11. To express the activatable interleukin protein in CHO cells, the coding sequences for all protein domains were cloned into a mammalian expression vector system. Briefly, the gene sequence encoding the activatable interleukin domain, the serum half-life extender element and the CD20 binding domain, and the peptide linkers L1 and L2 were synthesized separately and subcloned. The resulting constructs were then linked together in the order of CD20 binding domain-L1-IL 2 subunit 1-L2-proteolytic cleavage domain-L3-IL 2 subunit 2-L4-anti-CD 20 scFv-L5-serum half-life extending element to produce the final construct. All expression constructs were designed to contain the coding sequence (SEQ ID No.205) of an N-terminal signal peptide and a C-terminal hexahistidine (6xHis) tag to facilitate protein secretion and purification, respectively.
Expression of activatable IL2 protein in stably transfected CHO cells
Using CHO-K1 ChinaCHO cell expression System (A) (of hamster ovary cells (ATCC, CCL-61) ((C)Life Technologies) (Kao and Puck, Proc. Natl. Acad Sci USA 1968; 60(4):1275-81). Adherent cells were subcultured according to standard cell culture protocols provided by Life Technologies.
To accommodate growth in suspension, cells were separated from the tissue culture flasks and placed in serum-free medium. The suspension-adapted cells were cryopreserved in medium containing 10% DMSO.
Recombinant CHO cell lines stably expressing secreted activatable interleukin proteins were generated by transfection of suspension adapted cells. During selection with the antibiotic hygromycin B, viable cell density was measured twice a week, and cells were centrifuged and fractionated at 0.1x106The maximum density of viable cells/mL is suspended in fresh selection medium. After 2 to 3 weeks of selection, the pool of cells stably expressing the activatable interleukin protein is recovered, at which point the cells are transferred to standard medium in shake flasks. Expression of the recombinant secreted protein was confirmed by performing protein gel electrophoresis or flow cytometry. The stable cell banks were cryopreserved in DMSO-containing medium.
The activatable IL2 protein was produced by secretion into the cell culture supernatant in 10 days batch fed culture of stably transfected CHO cell lines. Cell culture supernatants were harvested after 10 days at typically > 75% culture viability. Samples were collected from the production cultures every other day and cell density and viability were assessed. On the day of harvest, the cell culture supernatant was removed by centrifugation and vacuum filtration before further use.
Protein expression titers and product integrity in cell culture supernatants were analyzed by SDS-PAGE.
Purification of activatable IL2 protein
The activatable IL2 protein was purified from CHO cell culture supernatant in a two-step procedure. The constructs were subjected to affinity chromatography in a first step, followed by preparative Size Exclusion Chromatography (SEC) on Superdex 200 in a second step. Samples were buffer exchanged and concentrated by ultrafiltration to typical concentrations >1 mg/mL. The purity and homogeneity (typically > 90%) of the final samples were assessed by SDS PAGE under reducing and non-reducing conditions, followed by immunoblotting using anti-HSA or anti-idiotype antibodies and by analytical SEC, respectively. The purified protein was stored in aliquots at-80 ℃ until use.
Example 7: determination of antigen affinity by flow cytometry
The activatable interleukin protein of example 1 was tested with human CD20+Cells and cynomolgus monkey CD20+Binding affinity of the cell.
Will CD20+Cells were incubated with 100 μ L of a serial dilution of the activatable interleukin protein of example 1 and at least one protease. After three washes with FACS buffer, the cells were incubated with 0.1mL of mouse monoclonal anti-idiotype antibody at 10. mu.g/mL for 45min on ice in the same buffer. After the second wash cycle, cells were incubated with 0.1mL of 15. mu.g/mL FITC conjugated goat anti-mouse IgG antibody under the same conditions as before. As a control, cells were incubated with anti-His IgG followed by FITC-conjugated goat anti-mouse IgG antibody without activatable IL2 protein. The cells were then washed again and resuspended in 0.2mL FACS buffer containing 2. mu.g/mL Propidium Iodide (PI) to exclude dead cells. 1x10 was measured with a Beckman-Coulter FC500 MPL flow cytometer using MXP software (Beckman-Coulter, Krefeld, Germany) or with a Millipore Guava easy cell flow cytometer using Incyte software (Merck Millipore, Schwalbach, Germany) 4Fluorescence of individual living cells. The mean fluorescence intensity of the cell samples was calculated using CXP software (Beckman-Coulter, Krefeld, Germany) or Incyte software (Merck Millipore, Schwalbach, Germany). After subtracting the fluorescence intensity values of cells stained with only secondary and tertiary reagents, these values were then used to calculate K using the single point binding (hyperbolic) equation of GraphPad Prism (Windows version 6.00, GraphPad software, La Jolla California USA)DThe value is obtained.
Assessment in human CD20+Tumor cellsCD20 binding and cross-reactivity on the lines. Use of K determined on CHO cell lines expressing recombinant human or recombinant cynomolgus monkey antigensDValue calculation of Cross-reactivity KDAnd (4) the ratio.
Example 8: cytotoxicity assays
In vitro evaluation of the activatable interleukin protein of example 1 against CD20+Modulation of the immune response of the target cell.
Fluorescent-labeled CD20+REC-1 cells (mantle cell lymphoma cell line, ATCC CRL-3004) were incubated with isolated PBMCs from random donors or CB 15T cells (standardized T cell line) as effector cells in the presence of the activatable IL2 protein of example 5 and at least one protease. After incubation at 37 ℃ for 4h in a humidified incubator, the release of the fluorescent dye from the target cells into the supernatant was determined in a fluorescence spectrophotometer. Target cells incubated without the activatable IL2 protein of example 1 and target cells that were completely lysed at the end of incubation by the addition of saponin served as negative and positive controls, respectively.
Based on the remaining viable target cells measured, the percentage of specific cell lysis was calculated according to the following formula: [1- (live target)(sample)Number/live target(spontaneous)Number)]X 100%. Calculation of sigmoidal dose-response curves and EC by nonlinear regression/4-parameter logistic fitting using GraphPad software50The value is obtained. The lysis values obtained for a given antibody concentration were used to calculate a sigmoidal dose-response curve by 4-parameter log fit analysis using Prism software.
Example 9: pharmacokinetics capable of activating interleukin protein
The half-life elimination of the activatable interleukin protein of example 5 was evaluated in an animal study.
Activatable IL2 protein was injected in 0.5mg/kg bolus into the saphenous vein for administration to cynomolgus monkeys. Another cynomolgus group received a comparable size IL2 construct but lacked a serum half-life extending element. The third and fourth groups received an IL2 construct with a serum half-life extending element and a cytokine with CD20 and a serum half-life extending element, respectively, and both were comparable in size to the activatable interleukin protein. Each test group consisted of 5 monkeys. Serum samples were taken at the indicated time points, serially diluted, and protein concentrations were determined using a binding ELISA for CD 20.
Pharmacokinetic analysis was performed using plasma concentrations of the test articles. When plotted against time post-dose, the group mean plasma data for each test article followed a multi-exponential curve. The data were fitted through a standard two-compartment model with bolus inputs and first order rate constants for the distribution phase and the elimination phase. The general equation for a best fit of intravenous administration data is: c (t) Ae-αt+Be-βtWhere c (t) is the plasma concentration at time t, A and B are the intercepts on the Y axis, and α and β are the apparent first order rate constants for the distribution and elimination phases, respectively. The β 0 phase is the initial clearance phase and reflects the distribution of protein in all extracellular fluids of the animal, while the second or β 1 phase of the decay curve represents true plasma clearance. Methods for fitting such equations are well known in the art. For example, a ═ D/V (β 2-k21)/(α - β), B ═ D/V (β -k21)/(α - β), and α and β (for α and β)>Beta) is the root r of the quadratic equation2+ (k12+ k21+ k10) r + k21k10 ═ 0, using the following estimated parameters: v-distribution volume, k 10-elimination rate, k 12-transport rate from atrioventricular 1 to atrioventricular 2, k 21-transport rate from atrioventricular 2 to atrioventricular 1, and D-administered dose.
And (3) data analysis: using Kaleidagraph (Kaleidagraph)TMV.3.09 copy 1986 and 1997 Synergy software reading, Pa.) graph of concentration versus time was prepared. Values reported as Less Than Reportable (LTR) are not included in the PK analysis and are not graphically represented. Using WinNonlin software (Professional V.3.1 WinNonlinTMCopyright 1998-1999, Pharsight corporation. mountain View, Calif.) pharmacokinetic parameters were determined by atrioventricular analysis. Pharmacokinetic parameters were calculated as described by Ritschel W A and Kearns G L,1999 Handbook Of Basic pharmacy inclusion Clinical Applications, 5 th edition,as described in American Pharmaceutical assoc, Washington, d.c.
The activatable interleukin protein of example 5 is expected to have improved pharmacokinetic parameters, such as increased elimination half-life, compared to proteins lacking serum half-life extending elements.
Example 10: xenograft tumor model
The activatable IL2 protein of example 5 was evaluated in a xenograft model.
Female immunodeficient NOD/scid mice were sublethally irradiated (2Gy) and subcutaneously inoculated 4X10 on the dorsal right side6And Ramos RA1 cells. When the tumor reaches 100 to 200mm3At times, animals were divided into 3 treatment groups. Group 2 and group 3 (8 animals per group) were injected intraperitoneally with 1.5x10 7Activated human T cells. Three days later, animals of group 3 were subsequently treated with a total of 9 intravenous doses of 50 μ g of the activatable interleukin protein of example 1 (qdx9 d). Groups 1 and 2 used only carrier treatment. Body weight and tumor volume were measured for 30 days.
Animals treated with the activatable interleukin protein of example 5 were expected to have a statistically significant delay in tumor growth compared to the corresponding vehicle-treated control group.
While preferred embodiments of the present application have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the application. It should be understood that various alternatives to the embodiments of the application described herein may be employed in practicing the application. It is intended that the following claims define the scope of the application and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Example 11: mouse IFNg WEHI cell survival assay
WEHI279 cells (ATCC) were seeded at a concentration of 25,000 cells/well in medium with or without 1.5% Human Serum Albumin (HSA) and at 37 ℃ and 5% CO 2Stimulation with serially diluted recombinant or inducible mIFNgFor 72 hours. Unlysed and lysed inducible mIFNg were tested for activity. Cleavable inducible mffng were generated by incubation with active MMP 9. Cell survival was assessed using a cell viability assay based on CellTiter-glo (Promega) luminescence. The EC50 value of the cleaved inducible mfng molecule is at least 100-fold more efficient than the uncleaved inducible mfng molecule. As shown in fig. 16, greater inducibility was observed in the assay in which the medium contained human serum albumin.
Example 12: mouse IFNg B16 reporter cell assay
B16-Blue IFNg cells (InvivoGen) were seeded at a concentration of 75,000 cells/well in medium with or without 1.5% Human Serum Albumin (HSA) and at 37 ℃ and 5% CO2Next, serial dilutions of recombinant or inducible mffng were used for 24 hours. Unlysed and lysed inducible mIFNg were tested for activity. Cleavable inducible mffng were generated by incubation with active MMP 9. The supernatant was harvested and SEAP activation was assessed by addition of QUANTI-Blue reagent (InvivoGen), incubation at 37 ℃ for 2 hours and measurement of absorbance at 620 nm. The results are shown in fig. 17, 19, 22, 23 and 28. This experiment was repeated using B16-Blue IFNa/B cells for IFNa fusion proteins. The EC50 value of the cleaved inducible mfna molecule is at least 100-fold more efficient than the uncleaved inducible mfna molecule. The results are shown in fig. 12.
Example 13 in vivo delivery of protease-activated fusion proteins results in reduced tumor growth
The chimeric polypeptide is examined to determine whether it can have a biological effect in vivo. For these experiments, a system was used in which intraperitoneally injected tumor cells rapidly and preferentially attach to and begin to grow on opalescent spots, which are a series of organized immune aggregates found on the omentum (Gerber et al, am.j. pathol.169:1739-52 (2006)). This system provides a convenient way to examine the effect of fusion protein therapy on tumor growth, since the fusion protein can be delivered intraperitoneally multiple times and tumor growth can be analyzed by examining dissociated omentum cells. For these experiments, the fast growing tumor cell line colon 38 cell line expressing MMP2 and MMP9 in vitro could be used. Omentum tissue typically expresses relatively small amounts of MMP2 and MMP9, but when colon 38 tumors appear on the omentum, MMP levels are elevated. Using this tumor model, the ability of IFN fusion proteins to affect tumor growth was examined. Colon 38 cells were injected intraperitoneally, allowed to attach and grow for 1 day, and then treated intraperitoneally with the fusion protein daily. On day 7, animals were sacrificed and tumor growth of omentum was examined by colony formation assay using flow cytometry.
Example 13B: the chimeric polypeptide was examined to determine its biological effect in vivo.
A rapidly growing colon adenocarcinoma cell line MC38 cell line expressing MMP9 in vitro was used. Using this tumor model, the ability of IFN γ fusion proteins to affect tumor growth was examined. MC38 cells were injected subcutaneously, allowed to grow for 10 to 14 days, and then treated with fusion protein intraperitoneally twice a week for four doses, the levels of which are shown in figure 21. For comparison, wild-type mfnfn γ was administered twice daily for 2 weeks at the indicated dose levels on a 5 day/2 day off schedule (10 doses total). Tumor growth and body weight were monitored approximately twice weekly for two weeks.
Example 14: construction of an exemplary IFNg protein targeting CD20
Production of activatable cytokine domains
IFNg polypeptides capable of binding to CD20 polypeptides present in tumors or on tumor cells are produced as follows. Generating a nucleic acid comprising the following nucleic acid sequence: (1) encodes an IFNg polypeptide sequence and (2) one or more polypeptide linkers. The activatable IFNg plasmid construct may have an optional Flag, His or other affinity tag and be electroporated into HEK293 or other suitable human or mammalian cell line and purified. Validation assays include T cell activation assays using T cells that respond to IFNg stimulation in the presence of proteases.
Generation of scFv CD20 binding Domain
CD20 is one of the cell surface proteins present on B lymphocytes. The CD20 antigen is present in both normal and malignant pre-B and mature B lymphocytes, including those in more than 90% of B cell non-hodgkin's lymphomas (NHLs). Antigens are not present in hematopoietic stem cells, activated B lymphocytes (plasma cells) and normal tissues. Thus, several antibodies have been described which are mainly of murine origin: 1F5, 2B8/C2B8, 2H7 and 1H 4.
Thus, human or humanized anti-CD 20 antibodies are used to generate scFv sequences that activate the CD20 binding domain of the IFNg protein. DNA sequences encoding human or humanized VL and VH domains are obtained and the codons of the construct are optionally optimized for expression in homo sapiens cells. The order in which the VL and VH domains appear in the scFv is varied (i.e.VL-VH or VH-VL orientation) and "G4S" (SEQ ID NO: 201) or "G4S "(SEQ ID NO: 201) subunit (G)4S)3Three copies of (SEQ ID NO: 204) were joined to the variable domains to create scFv domains. The anti-CD 20 scFv plasmid construct can have an optional Flag, His, or other affinity tag, and be electroporated into HEK293 or other suitable human or mammalian cell line and purified. Validation assays included binding analysis by FACS, kinetic analysis using Proteon, and staining of CD20 expressing cells.
Cloning of DNA expression constructs encoding activatable IFNg proteins
An activatable IFNg construct with a protease cleavage site domain is used to construct a combination of an activatable IFNg protein with an anti-CD 20scFv domain and a serum half-life extending element (e.g., an HSA binding peptide or a VH domain), wherein the organized domains are as shown in figure 14. To express the activatable IFNg protein in CHO cells, the coding sequences for all protein domains were cloned into a mammalian expression vector system. Briefly, the gene sequence encoding the activatable IFNg domain, the serum half-life extender element and the CD20 binding domain, as well as the peptide linkers L1 and L2 were synthesized separately and subcloned. The resulting constructs were then ligated together in the order of CD20 binding domain-L1-IFNg subunit 1-L2-protease cleavage domain-L3-IFNg subunit 2-L4-anti-CD 20 scFv-L5-serum half-life extending element to generate the final construct. All expression constructs were designed to contain the coding sequence of an N-terminal signal peptide and a C-terminal hexahistidine (6xHis) tag (SEQ ID No.:205) to facilitate protein secretion and purification, respectively.
Expression of activatable IFNg protein in stably transfected CHO cell
The CHO cell expression System ((CCL-61)) which is a derivative of CHO-K1 Chinese hamster ovary cells (ATCC, CCL-61)Life Technologies) (Kao and Puck, Proc. Natl. Acad Sci USA 1968; 60(4):1275-81). Adherent cells were subcultured according to standard cell culture protocols provided by Life Technologies.
To accommodate growth in suspension, cells were separated from the tissue culture flasks and placed in serum-free medium. The suspension-adapted cells were cryopreserved in medium containing 10% DMSO.
Recombinant CHO cell lines stably expressing secreted activatable IFNg protein were generated by transfection of suspension adapted cells. During selection with the antibiotic hygromycin B, viable cell density was measured twice a week, and cells were centrifuged and fractionated at 0.1x106The maximum density of viable cells/mL is suspended in fresh selection medium. After 2 to 3 weeks of selection, a pool of cells stably expressing the activatable IFNg protein is recovered, at which point the cells are transferred to standard medium in shake flasks. Expression of the recombinant secreted protein was confirmed by performing protein gel electrophoresis or flow cytometry. The stable cell banks were cryopreserved in DMSO-containing medium.
The activatable IFNg protein was produced by secretion into the cell culture supernatant in 10 days batch feed culture of stably transfected CHO cell lines. Cell culture supernatants were harvested after 10 days at typically > 75% culture viability. Samples were collected from the production cultures every other day and cell density and viability were assessed. On the day of harvest, the cell culture supernatant was removed by centrifugation and vacuum filtration before further use.
Protein expression titers and product integrity in cell culture supernatants were analyzed by SDS-PAGE.
Purification of activatable IFNg protein
The activatable IFNg protein was purified from CHO cell culture supernatant in a two-step procedure. The constructs were subjected to affinity chromatography in a first step, followed by preparative Size Exclusion Chromatography (SEC) on Superdex 200 in a second step. Samples were buffer exchanged and concentrated by ultrafiltration to typical concentrations >1 mg/mL. The purity and homogeneity (typically > 90%) of the final samples were assessed by SDS PAGE under reducing and non-reducing conditions, followed by immunoblotting using anti-HSA or anti-idiotype antibodies and by analytical SEC, respectively. The purified protein was stored in aliquots at-80 ℃ until use.
Example 15: determination of antigen affinity by flow cytometry
The activatable IFNg protein of example 1 was tested with human CD20+Cells and cynomolgus monkey CD20+Binding affinity of the cell.
Will CD20+Cells were incubated with 100 μ L of serial dilutions of the activatable IFNg protein of example 1 and at least one protease. After three washes with FACS buffer, the cells were incubated with 0.1mL of mouse monoclonal anti-idiotype antibody at 10. mu.g/mL for 45min on ice in the same buffer. After the second wash cycle, cells were incubated with 0.1mL of 15. mu.g/mL FITC conjugated goat anti-mouse IgG antibody under the same conditions as before. As a control, cells were incubated with anti-His IgG followed by FITC-conjugated goat anti-mouse IgG antibody without activatable IFNg protein. The cells were then washed again and resuspended in 0.2mL FACS buffer containing 2. mu.g/mL Propidium Iodide (PI) to exclude dead cells. 1x10 was measured with a Beckman-Coulter FC500 MPL flow cytometer using MXP software (Beckman-Coulter, Krefeld, Germany) or with a Millipore Guava easy cell flow cytometer using Incyte software (Merck Millipore, Schwalbach, Germany) 4Fluorescence of individual living cells. The mean fluorescence intensity of the cell samples was calculated using CXP software (Beckman-Coulter, Krefeld, Germany) or Incyte software (Merck Millipore, Schwalbach, Germany). After subtracting the fluorescence intensity values of cells stained with only secondary and tertiary reagents, these values were then used to generate fluorescence spectra using GraphPad Prism (Windows version 6.00, GraphPad software,la Jolla California USA) to calculate KDThe value is obtained.
Assessment in human CD20+CD20 binding and cross-reactivity on tumor cell lines. Use of K determined on CHO cell lines expressing recombinant human or recombinant cynomolgus monkey antigensDValue calculation of Cross-reactivity KDAnd (4) the ratio.
Example 16: cytotoxicity assays
In vitro evaluation of the activatable IFNg protein of example 5 on CD20+Modulation of the immune response of the target cell.
Fluorescent-labeled CD20+REC-1 cells (mantle cell lymphoma cell line, ATCC CRL-3004) were incubated with isolated PBMCs from random donors or CB 15T cells (standardized T cell line) as effector cells in the presence of the activatable IFNg protein of example 5 and at least one protease. After incubation at 37 ℃ for 4h in a humidified incubator, the release of the fluorescent dye from the target cells into the supernatant was determined in a fluorescence spectrophotometer. Target cells incubated without the activatable IFNg protein of example 5 and target cells that were completely lysed at the end of incubation by the addition of saponin served as negative and positive controls, respectively.
Based on the remaining viable target cells measured, the percentage of specific cell lysis was calculated according to the following formula: [1- (live target)(sample)Number/live target(spontaneous)Number)]X 100%. Calculation of sigmoidal dose-response curves and EC by nonlinear regression/4-parameter logistic fitting using GraphPad software50The value is obtained. The lysis values obtained for a given antibody concentration were used to calculate a sigmoidal dose-response curve by 4-parameter log fit analysis using Prism software.
Example 17: pharmacokinetics of activatable IFNg protein
The half-life elimination of the activatable IFNg protein of example 5 was evaluated in an animal study.
Activatable IFNg protein was injected into the saphenous vein at 0.5mg/kg bolus for administration to cynomolgus monkeys. Another cynomolgus monkey group received comparable size cytokines but lacked serum half-life extension elements. The third and fourth groups received cytokines with serum half-life extending elements and cytokines with CD20 and serum half-life extending elements, respectively, and both were comparable in size to the activatable IFNg protein. Each test group consisted of 5 monkeys. Serum samples were taken at the indicated time points, serially diluted, and protein concentrations were determined using a binding ELISA for CD 20.
Pharmacokinetic analysis was performed using plasma concentrations of the test articles. When plotted against time post-dose, the group mean plasma data for each test article followed a multi-exponential curve. The data were fitted through a standard two-compartment model with bolus inputs and first order rate constants for the distribution phase and the elimination phase. The general equation for a best fit of intravenous administration data is: c (t) Ae-αt+Be-βtWhere c (t) is the plasma concentration at time t, A and B are the intercepts on the Y axis, and α and β are the apparent first order rate constants for the distribution and elimination phases, respectively. The β 0 phase is the initial clearance phase and reflects the distribution of protein in all extracellular fluids of the animal, while the second or β 1 phase of the decay curve represents true plasma clearance. Methods for fitting such equations are well known in the art. For example, a ═ D/V (β 2-k21)/(α - β), B ═ D/V (β -k21)/(α - β), and α and β (for α and β)>Beta) is the root r of the quadratic equation2+ (k12+ k21+ k10) r + k21k10 ═ 0, using the following estimated parameters: v-distribution volume, k 10-elimination rate, k 12-transport rate from atrioventricular 1 to atrioventricular 2, k 21-transport rate from atrioventricular 2 to atrioventricular 1, and D-administered dose.
And (3) data analysis: using Kaleidagraph (Kaleidagraph)TMV.3.09 copy 1986 and 1997 Synergy software reading, Pa.) graph of concentration versus time was prepared. Values reported as Less Than Reportable (LTR) are not included in the PK analysis and are not graphically represented. Using WinNonlin software (Professional V.3.1 WinNonlinTMCopyright 1998-1999, Pharsight corporation. mountain View, Calif.) pharmacokinetic parameters were determined by atrioventricular analysis. Medicine actingThe mechanical parameters were calculated as described in Ritschel W A and Kearns G L,1999 Handbook Of Basic Pharmaceutical additives Applications, 5 th edition, American Pharmaceutical Assoc, Washington, D.C.
The activatable IFNg protein of example 5 is expected to have improved pharmacokinetic parameters, such as increased elimination half-life, compared to proteins lacking serum half-life extending elements.
Example 18: xenograft tumor model
The activatable IFNg protein of example 5 was evaluated in a xenograft model.
Female immunodeficient NOD/scid mice were sublethally irradiated (2Gy) and subcutaneously inoculated 4X10 on the dorsal right side6And Ramos RA1 cells. When the tumor reaches 100 to 200mm3At times, animals were divided into 3 treatment groups. Group 2 and group 3 (8 animals per group) were injected intraperitoneally with 1.5x10 7Activated human T cells. Three days later, animals of group 3 were subsequently treated with a total of 9 intravenous doses of 50 μ g of the activatable IFNg protein of example 5 (qdx9 d). Groups 1 and 2 used only carrier treatment. Body weight and tumor volume were measured for 30 days.
Animals treated with the activatable IFNg protein of example 5 are expected to have a statistically significant delay in tumor growth compared to the corresponding vehicle-treated control group.
While preferred embodiments of the present application have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the application. It should be understood that various alternatives to the embodiments of the application described herein may be employed in practicing the application. It is intended that the following claims define the scope of the application and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Example 19: HEK Blue assay
HEK-Blue IL12 cells (InvivoGen) were seeded in a suspension at a concentration of 250,000 cells/well with or without 40mg/ml human serum albumin (HSA) in medium and at 37 ℃ and 5% CO2Next, the cells were stimulated with serial dilutions of recombinant hIL12, chimeric IL12 (mouse p 35/human p40) or activatable hIL12 for 24 hours. The activity of active hIL12 was tested both uncleaved and cleaved. Cleaved inducible hIL12 was generated by incubation with active MMP 9. IL12 activity was assessed by quantifying (i.e.by a colorimetric-based assay) the secreted alkaline phosphatase (SEAP) activity using the reagent QUANTI-blue (InvivoGen). The results are shown in fig. 11, 12, 15, 26 and 27.
HEK-Blue IL2 cells (InvivoGen) were seeded at a suspension concentration of 50,000 cells/well in medium with or without 15mg/ml to 40mg/ml Human Serum Albumin (HSA) at 37 ℃ and 5% CO2Next, the cells were stimulated with serial dilutions of recombinant hIL2 or activatable hIL2 for 24 hours. The activity of active hIL2 was tested both uncleaved and cleaved. Cleaved inducible hIL2 was generated by incubation with active MMP 9. IL12 activity was assessed by quantifying (i.e.by a colorimetric-based assay) the secreted alkaline phosphatase (SEAP) activity using the reagent QUANTI-blue (InvivoGen). The results are shown in fig. 24.
Example 20: splenocyte T-Blast assay
T-Blast was induced from murine splenocytes by 6 days of PHA incubation and 24 hours of recombinant hIL12 incubation. The Tblast suspension at a concentration of 200,000 cells/well was then inoculated in medium with or without 40mg/ml Human Serum Albumin (HSA) and incubated at 37 ℃ and 5% CO 2Next, the cells were stimulated with serial dilutions of recombinant hIL12 or chimeric IL12 (mouse p 35/human p40) or activatable IL12 for 72 hours. Unlysed and cleaved IL12 were tested for activity. Cleaved inducible hIL12 was generated by incubation with active MMP 9. IL12 activity was assessed by quantifying IFN γ production downstream using mfny α LISA.
Example 21: in vivo delivery of protease-activated fusion proteins results in reduced tumor growth
The chimeric polypeptide is examined to determine whether it can have a biological effect in vivo. For these experiments, a system was used in which intraperitoneally injected tumor cells rapidly and preferentially attach to and begin to grow on opalescent spots, which are a series of organized immune aggregates found on the omentum (Gerber et al, am.j. pathol.169:1739-52 (2006)). This system provides a convenient way to examine the effect of fusion protein therapy on tumor growth, since the fusion protein can be delivered intraperitoneally multiple times and tumor growth can be analyzed by examining dissociated omentum cells. For these experiments, the fast growing tumor cell line colon 38 cell line expressing MMP2 and MMP9 in vitro could be used. Omentum tissue typically expresses relatively small amounts of MMP2 and MMP9, but when colon 38 tumors appear on the omentum, MMP levels are elevated. Using this tumor model, the ability of the IL-2 mutein fusion proteins to influence tumor growth was examined. Colon 38 cells were injected intraperitoneally, allowed to attach and grow for 1 day, and then treated intraperitoneally with the fusion protein daily. On day 7, animals were sacrificed and tumor growth of omentum was examined by colony formation assay using flow cytometry.
Example 22: construction of exemplary activatable interleukin proteins targeting CD20
Generation of activatable interleukin domains
The standard sequence of the human IL-12P35 chain is Uniprot accession number P29459. The standard sequence of the human IL-12P40 chain is Uniprot accession number P29460. IL-12p35 and IL-12p40 were cloned into expression constructs. The protease cleavage site is comprised between the IL-12p35 and IL-12p40 domains. IL-12 polypeptides capable of binding to a CD20 polypeptide present in a tumor or on tumor cells are produced as follows. Generating a nucleic acid comprising the following nucleic acid sequence: (1) encodes an IFNg polypeptide sequence and (2) one or more polypeptide linkers. The activatable interleukin plasmid construct may have an optional Flag, His, or other affinity tag and be electroporated into HEK293 or other suitable human or mammalian cell line and purified. Validation assays include T cell activation assays using T cells that respond to IL-12 stimulation in the presence of proteases.
Generation of scFv CD20 binding Domain
CD20 is one of the cell surface proteins present on B lymphocytes. The CD20 antigen is present in both normal and malignant pre-B and mature B lymphocytes, including those in more than 90% of B cell non-hodgkin's lymphomas (NHLs). Antigens are not present in hematopoietic stem cells, activated B lymphocytes (plasma cells) and normal tissues. Thus, several antibodies have been described which are mainly of murine origin: 1F5, 2B8/C2B8, 2H7 and 1H 4.
Thus, human or humanized anti-CD 20 antibodies are used to generate scFv sequences that activate the CD20 binding domain of the interleukin protein. DNA sequences encoding human or humanized VL and VH domains are obtained and the codons of the construct are optionally optimized for expression in homo sapiens cells. The order in which the VL and VH domains appear in the scFv is varied (i.e.VL-VH or VH-VL orientation) and "G4S" (SEQ ID NO: 201) or "G4S "(SEQ ID NO: 201) subunit (G)4S)3Three copies of (SEQ ID NO: 204) were joined to the variable domains to create scFv domains. The anti-CD 20 scFv plasmid construct can have an optional Flag, His, or other affinity tag, and be electroporated into HEK293 or other suitable human or mammalian cell line and purified. Validation assays included binding analysis by FACS, kinetic analysis using Proteon, and staining of CD20 expressing cells.
Cloning of DNA expression constructs encoding activatable Interleukin proteins
Activatable interleukin constructs having protease cleavage site domains are used to construct combinations of activatable interleukin protein with anti-CD 20 scFv domains and serum half-life extending elements (e.g., HSA binding peptides or VH domains). To express the activatable interleukin protein in CHO cells, the coding sequences for all protein domains were cloned into a mammalian expression vector system. Briefly, the gene sequence encoding the activatable interleukin domain, the serum half-life extender element and the CD20 binding domain, and the peptide linkers L1 and L2 were synthesized separately and subcloned. The resulting constructs were then ligated together in the order of CD20 binding domain-L1-IL-12 p 35-L2-proteolytic cleavage domain-L3-IL-12 p 40-L4-anti-CD 20 scFv-L5-serum half-life extending element to generate the final construct. All expression constructs were designed to contain the coding sequence of an N-terminal signal peptide and a C-terminal hexahistidine (6xHis) tag (SEQ ID No.:205) to facilitate protein secretion and purification, respectively.
Expression of activatable interleukin protein in stably transfected CHO cell
The CHO cell expression System ((CCL-61)) which is a derivative of CHO-K1 Chinese hamster ovary cells (ATCC, CCL-61)Life Technologies) (Kao and Puck, Proc. Natl. Acad Sci USA 1968; 60(4):1275-81). Adherent cells were subcultured according to standard cell culture protocols provided by Life Technologies.
To accommodate growth in suspension, cells were separated from the tissue culture flasks and placed in serum-free medium. The suspension-adapted cells were cryopreserved in medium containing 10% DMSO.
Recombinant CHO cell lines stably expressing secreted activatable interleukin proteins were generated by transfection of suspension adapted cells. During selection with the antibiotic hygromycin B, viable cell density was measured twice a week, and cells were centrifuged and fractionated at 0.1x106The maximum density of viable cells/mL is suspended in fresh selection medium. After 2 to 3 weeks of selection, the pool of cells stably expressing the activatable interleukin protein is recovered, at which point the cells are transferred to standard medium in shake flasks. Expression of the recombinant secreted protein was confirmed by performing protein gel electrophoresis or flow cytometry. The stable cell banks were cryopreserved in DMSO-containing medium.
The activatable interleukin protein was produced by secretion into the cell culture supernatant in a 10 day batch fed culture of a stably transfected CHO cell line. Cell culture supernatants were harvested after 10 days at typically > 75% culture viability. Samples were collected from the production cultures every other day and cell density and viability were assessed. On the day of harvest, the cell culture supernatant was removed by centrifugation and vacuum filtration before further use.
Protein expression titers and product integrity in cell culture supernatants were analyzed by SDS-PAGE.
Purification of activatable interleukin proteins
The activatable interleukin protein was purified from CHO cell culture supernatant in a two-step procedure. The constructs were subjected to affinity chromatography in a first step, followed by preparative Size Exclusion Chromatography (SEC) on Superdex 200 in a second step. Samples were buffer exchanged and concentrated by ultrafiltration to typical concentrations >1 mg/mL. The purity and homogeneity (typically > 90%) of the final samples were assessed by SDS PAGE under reducing and non-reducing conditions, followed by immunoblotting using anti-HSA or anti-idiotype antibodies and by analytical SEC, respectively. The purified protein was stored in aliquots at-80 ℃ until use.
Example 23: determination of antigen affinity by flow cytometry
The activatable interleukin protein of example 5 was tested with human CD20+Cells and cynomolgus monkey CD20+Binding affinity of the cell.
Will CD20+Cells were incubated with 100 μ L of a serial dilution of the activatable interleukin protein of example 5 and at least one protease. After three washes with FACS buffer, the cells were incubated with 0.1mL of mouse monoclonal anti-idiotype antibody at 10. mu.g/mL for 45min on ice in the same buffer. After the second wash cycle, cells were incubated with 0.1mL of 15. mu.g/mL FITC conjugated goat anti-mouse IgG antibody under the same conditions as before. As a control, cells were incubated with anti-His IgG followed by FITC conjugated goat anti-mouse IgG antibodies without activatable interleukin protein. The cells were then washed again and resuspended in 0.2mL FACS buffer containing 2. mu.g/mL Propidium Iodide (PI) to exclude dead cells. 1x10 was measured with a Beckman-Coulter FC500 MPL flow cytometer using MXP software (Beckman-Coulter, Krefeld, Germany) or with a Millipore Guava easy cell flow cytometer using Incyte software (Merck Millipore, Schwalbach, Germany) 4Fluorescence of individual living cells. The mean fluorescence intensity of the cell samples was calculated using CXP software (Beckman-Coulter, Krefeld, Germany) or Incyte software (Merck Millipore, Schwalbach, Germany). After subtracting the fluorescence intensity values of cells stained with only secondary and tertiary reagents, these values were then used to utilize GraphPad Prism (Windows version)This 6.00, GraphPad software, La Jolla California USA) single point combination (hyperbolic) equation calculates KDThe value is obtained.
Assessment in human CD20+CD20 binding and cross-reactivity on tumor cell lines. Use of K determined on CHO cell lines expressing recombinant human or recombinant cynomolgus monkey antigensDValue calculation of Cross-reactivity KDAnd (4) the ratio.
Example 24: cytotoxicity assays
In vitro evaluation of the activatable interleukin protein of example 5 on CD20+Modulation of the immune response of the target cell.
Fluorescent-labeled CD20+REC-1 cells (mantle cell lymphoma cell line, ATCC CRL-3004) were incubated with isolated PBMCs from random donors or CB 15T cells (standardized T cell line) as effector cells in the presence of the activatable interleukin protein of example 5 and at least one protease. After incubation at 37 ℃ for 4h in a humidified incubator, the release of the fluorescent dye from the target cells into the supernatant was determined in a fluorescence spectrophotometer. Target cells incubated without the activatable interleukin protein of example 5 and target cells that were completely lysed at the end of incubation by the addition of saponin served as negative and positive controls, respectively.
Based on the remaining viable target cells measured, the percentage of specific cell lysis was calculated according to the following formula: [1- (live target)(sample)Number/live target(spontaneous)Number)]X 100%. Calculation of sigmoidal dose-response curves and EC by nonlinear regression/4-parameter logistic fitting using GraphPad software50The value is obtained. The lysis values obtained for a given antibody concentration were used to calculate a sigmoidal dose-response curve by 4-parameter log fit analysis using Prism software.
Example 25: pharmacokinetics capable of activating interleukin protein
The half-life elimination of the activatable interleukin protein of example 5 was evaluated in an animal study.
The activatable interleukin protein was injected into the saphenous vein at a bolus of 0.5mg/kg for administration to cynomolgus monkeys. Another cynomolgus monkey group received comparable size cytokines but lacked serum half-life extension elements. The third and fourth groups received cytokines with serum half-life extending elements and cytokines with CD20 and serum half-life extending elements, respectively, and both were comparable in size to the activatable interleukin protein. Each test group consisted of 5 monkeys. Serum samples were taken at the indicated time points, serially diluted, and protein concentrations were determined using a binding ELISA for CD 20.
Pharmacokinetic analysis was performed using plasma concentrations of the test articles. When plotted against time post-dose, the group mean plasma data for each test article followed a multi-exponential curve. The data were fitted through a standard two-compartment model with bolus inputs and first order rate constants for the distribution phase and the elimination phase. The general equation for a best fit of intravenous administration data is: c (t) Ae-αt+Be-βtWhere c (t) is the plasma concentration at time t, A and B are the intercepts on the Y axis, and α and β are the apparent first order rate constants for the distribution and elimination phases, respectively. The β 0 phase is the initial clearance phase and reflects the distribution of protein in all extracellular fluids of the animal, while the second or β 1 phase of the decay curve represents true plasma clearance. Methods for fitting such equations are well known in the art. For example, a ═ D/V (β 2-k21)/(α - β), B ═ D/V (β -k21)/(α - β), and α and β (for α and β)>Beta) is the root r of the quadratic equation2+ (k12+ k21+ k10) r + k21k10 ═ 0, using the following estimated parameters: v-distribution volume, k 10-elimination rate, k 12-transport rate from atrioventricular 1 to atrioventricular 2, k 21-transport rate from atrioventricular 2 to atrioventricular 1, and D-administered dose.
And (3) data analysis: using Kaleidagraph (Kaleidagraph)TMV.3.09 copy 1986 and 1997 Synergy software reading, Pa.) graph of concentration versus time was prepared. Values reported as Less Than Reportable (LTR) are not included in the PK analysis and are not graphically represented. Using WinNonlin software (Professional V.3.1WinNonlinTM Copyright 1998-1999.Pharsight Corporation.Mountain View,Calif.) pharmacokinetic parameters were determined by atrioventricular analysis. Pharmacokinetic parameters were calculated as described in Ritschel W A and Kearns G L,1999 Handbook Of Basic Pharmaceutical incorporating Clinical Applications, 5 th edition, American Pharmaceutical Assoc, Washington, D.C.
The activatable interleukin protein of example 5 is expected to have improved pharmacokinetic parameters, such as increased elimination half-life, compared to proteins lacking serum half-life extending elements.
Example 26: xenograft tumor model
The activatable interleukin protein of example 5 was evaluated in a xenograft model.
Female immunodeficient NOD/scid mice were sublethally irradiated (2Gy) and subcutaneously inoculated 4X10 on the dorsal right side6And Ramos RA1 cells. When the tumor reaches 100 to 200mm3At times, animals were divided into 3 treatment groups. Group 2 and group 3 (8 animals per group) were injected intraperitoneally with 1.5x10 7Activated human T cells. Three days later, animals of group 3 were subsequently treated with a total of 9 intravenous doses of 50 μ g of the activatable interleukin protein of example 5 (qdx9 d). Groups 1 and 2 used only carrier treatment. Body weight and tumor volume were measured for 30 days.
Animals treated with the activatable interleukin protein of example 5 were expected to have a statistically significant delay in tumor growth compared to the corresponding vehicle-treated control group.
While preferred embodiments of the present application have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the application. It should be understood that various alternatives to the embodiments of the application described herein may be employed in practicing the application. It is intended that the following claims define the scope of the application and that methods and structures within the scope of these claims and their equivalents be covered thereby.
Example 27: MC38 experiment
A rapidly growing colon adenocarcinoma cell line MC38 cell line expressing MMP9 in vitro was used. Using this tumor model, the ability of the fusion protein to affect tumor growth was examined.
Example 27 a: MC38 IL-2POC
Preparation and treatment:
# control group
Example 27 b: MC38 IL-2
Preparation and treatment:
# control group
The procedure is as follows:
mice were anesthetized with isoflurane to implant cells to reduce ulceration. The flank of 308 CR female C57BL/6 mice were established subcutaneously with 5X10 in 0% Matrigel5And MC38 tumor cells. The cell injection volume was 0.1 mL/mouse. Mice were 8 to 12 weeks of age at the start date. When the average size of the tumor reaches 100-3And when treatment is started, pairing is performed. Body weight was measured at the beginning and then every two weeks until the end. Caliper measurements were taken every two weeks until the end. Any adverse reactions should be reported immediately. Any individual animal with a single observation of weight loss of more than 30% or three consecutive weight losses of more than 25% was euthanized. Average weight loss>20% or mortality>10% of any group were discontinued; this group was not euthanized and allowed to recover. In weight loss>20％In the group (2), the individuals who reached the end point of weight loss were euthanized. If the weight loss associated with group treatment returns to within 10% of the original body weight, dosing resumes at a lower dose or less frequent dosing schedule. Exceptions to non-therapeutic weight% recovery were allowed on a case-by-case basis. The endpoint was Tumor Growth Delay (TGD). Animals were monitored individually. The end point of the experiment was that the tumor volume reached 1500mm 3Or 45 days, the first arrival is the standard. The tracking time of the responder is longer. When the endpoint is reached, the animals will be euthanized.
The results are shown in fig. 31A to 31C and fig. 32A to 32C. Survival curves are shown in fig. 34A to 34D.
Example 27 c: MC38 IFNa and IL-12
Preparation and treatment:
# control group
The procedure is as follows:
mice were anesthetized with isoflurane to implant cells to reduce ulceration. The flank of 308 CR female C57BL/6 mice were established subcutaneously with 5X10 in 0% Matrigel5And MC38 tumor cells. The cell injection volume was 0.1 mL/mouse. Mice were 8 to 12 weeks of age at the start date. When the average size of the tumor reaches 100-3And when treatment is started, pairing is performed. Body weight was measured at the beginning and then every two weeks until the end. Caliper measurements were taken every two weeks until the end. Any adverse reactions should be reported immediately. Any individual animal with a single observation of weight loss of more than 30% or three consecutive weight losses of more than 25% was euthanized. Average weight loss>20% or mortality>10% of any group were discontinued; this group did not perform euthanasia and causedIt recovers. In weight loss>In 20% of the groups, subjects who reached the end of weight loss were euthanized. If the weight loss associated with group treatment returns to within 10% of the original body weight, dosing resumes at a lower dose or less frequent dosing schedule. Exceptions to non-therapeutic weight% recovery were allowed on a case-by-case basis. The endpoint was Tumor Growth Delay (TGD). Animals were monitored individually. The end point of the experiment was that the tumor volume reached 1500mm 3Or 45 days, the first arrival is the standard. The tracking time of the responder is longer. When the endpoint is reached, the animals will be euthanized. The results are shown in fig. 29B, 29C and 30.
Example 27 d: treatment with ACP16, ACP132 and ACP21
Anesthesia of mice with isoflurane for cell engraftment to reduce ulceration lateral ventral subcutaneous establishment of CR female C57BL/6 mice with 5x10 in 0% Matrigel5And MC38 tumor cells. The cell injection volume was 0.1 mL/mouse. Mice were 8 to 12 weeks of age at the start date. When the average size of the tumor reaches 100-3And when treatment is started, pairing is performed. ACP16 was administered at 17, 55, 70, or 230 ug/animal; ACP132 was administered at 9, 28, 36, or 119 ug/animal; ACP21 was administered at 13, 42, 54, or 177 ug/animal. Body weight was measured at the beginning and then every two weeks until the end. Caliper measurements were taken every two weeks until the end. Any adverse reactions should be reported immediately. Any individual animal with a single observation of weight loss of more than 30% or three consecutive weight losses of more than 25% was euthanized. Average weight loss>20% or mortality>10% of any group were discontinued; this group was not euthanized and allowed to recover. In weight loss >In 20% of the groups, subjects who reached the end of weight loss were euthanized. If the weight loss associated with group treatment returns to within 10% of the original body weight, dosing resumes at a lower dose or less frequent dosing schedule. Exceptions to non-therapeutic weight% recovery were allowed on a case-by-case basis. The endpoint was Tumor Growth Delay (TGD). Animals were monitored individually. The end point of the experiment was that the tumor volume reached 1500mm3Or 45 days, the first arrival is the standard. The tracking time of the responder is longer. When the end point is reachedAnimals will be euthanized. The results are shown in fig. 35.
Example 27 e: MC38 Re-excitation
The cured mice of example 27b (treated with ACP 16) were re-challenged by tumor implantation to determine if anti-tumor memory was established from the initial treatment.
Preparation and treatment:
# control group
The procedure is as follows:
this part of the study of anesthetizing mice with isoflurane to implant cells to reduce ulceration began on the day of implantation (day 1). The flank of group 1 consisting of 33 CR female C57BL/6 mice was established subcutaneously with 5X10 in 0% Matrigel5And MC38 tumor cells. The left flank of groups 2 to 6 consisting of 33 CR female C57BL/6 mice was subcutaneously established with 5x10 in 0% Matrigel 5And MC38 tumor cells. The tumors of the previous MC38 experiment (example 27b) were implanted in the right flank of each animal. The cell injection volume was 0.1 mL/mouse. The age of the control mice was 14 to 17 weeks at the beginning. These mice were age matched to mice from a previous MC38 experiment (example 27 b). No active agent administration occurred during the re-challenge period. Body weight was measured every two weeks until the end, as was caliper measurements. Any adverse reactions or deaths were reported immediately. Any individual animal with a single observation of weight loss of more than 30% or three consecutive weight losses of more than 25% was euthanized. The endpoint was Tumor Growth Delay (TGD). Animals were monitored individually. The end point of the experiment was that the tumor volume reached 1000mm3Or 45 days, the first arrival is the standard. The tracking time of the responder is longer, if possible. When the endpoint was reached, animals were euthanized. The results are shown in fig. 33.
Example 28 conditionally active fusion proteins contain a blocking moiety as the binding domain of serum albumin
This example describes the production and activity of fusion proteins, preferably cytokines, having inducible activity (i.e., they are inactive prior to being induced), typically by isolating the blocking moiety from the active moiety after cleavage of the linker between the blocking moiety and the active moiety. The fusion protein contains a single antibody variable domain (dAb) that binds serum albumin via a CDR loop and binds to the active moiety (here an anti-CD 3scFV) via one or more non-CDR loops (e.g. a C-loop). The serum albumin binding blocking moiety is operably linked to the active moiety by a protease cleavable linker, and the active moiety is operably linked to the targeting domain (here an anti-Epidermal Growth Factor Receptor (EGFR) dAb or an anti-Prostate Specific Membrane Antigen (PSMA) dAb) by a non-protease cleavable linker. These fusion proteins can be administered as inactive proteins that are activated upon cleavage of the protease cleavable linker and subsequent release of the inhibitory albumin binding domain. The anti-CD 3scFV in the fusion protein is a desirable cytokine replacement in the fusion proteins described in this application. Similar fusion proteins containing a desired cytokine (e.g., IL-2, IL-12, interferon) or functional fragment or mutein thereof, a targeting domain, and an albumin binding dAb that also binds to and inhibits the cytokine or functional fragment or mutein thereof can be prepared using the methods described and exemplified herein. An anti-serum albumin dAb that binds and inhibits the activity of a desired cytokine or functional fragment or mutein thereof can provide both spatial masking of the cytokine (by access to the serum albumin-binding cytokine) and specific masking of the cytokine (by binding the cytokine via a non-CDR loop (e.g., C-loop)). An anti-serum albumin dAb that binds and inhibits the activity of a desired cytokine or functional fragment or mutein thereof can be obtained using a suitable method, such as by introducing amino acid sequence diversity into the non-CDR loops (e.g., C-loops) of an anti-serum albumin binding dAb and screening for binding to the desired cytokine. Any suitable method may be used for selection, such as phage display. For example, exemplary anti-serum albumin dabs that can be used have the following sequences, and the amino acid sequences in the C-loop (bold underlining) can be diversified (e.g., randomized), and the resulting dabs screened for binding to serum albumin by CDR interactions and to cytokines by non-CDR loop interactions. If desired, the amino acid sequence of a known cytokine-binding peptide can be grafted into the C-loop.
EVQLVESGGGLVQPGNSLRLSCAASGFTFSKFGMSWVRQLEWVSSISGSGRDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSVSSQGTLVTVSS(SEQ ID NO.:194)
A. Protease activation of ProTriTAC leads to significant enhancement of in vitro activity
Purified ProTriTAC (prodrug), non-cleavable ProTriTAC [ prodrug (non-cleavable) ] and recombinant active drug fragments mimicking protease-activated ProTriTAC (active drug) were tested for binding to recombinant human CD3 in ELISA assays, binding to purified human primary T cells in flow cytometry assays, and functional potency in T cell-dependent cytotoxicity assays.
For ELISA, the specified concentrations of soluble protitrac protein were incubated with immobilized recombinant human CD3e (R & D Systems) for 1h at room temperature in PBS supplemented with 15mg/ml human serum albumin. SuperBlock (Thermo Fisher) blocking plates were used, washed with PBS with 0.05% Tween-20, and a non-competitive anti-CD 3 idiotype monoclonal antibody 11D3, followed by detection using peroxidase-labeled secondary antibody and TMB-ELISA substrate solution (Thermo Fisher).
For flow cytometry, the specified concentration of soluble protitac protein was incubated with purified human primary T cells in the presence of PBS with 2% fetal bovine serum and 15mg/ml human serum albumin for 1h at 4 ℃. Plates were washed with PBS with 2% fetal bovine serum, detected using AlexaFluor 647-labeled non-competitive anti-CD 3 idiotypic monoclonal antibody 11D3, and data analyzed using FlowJo 10(FlowJo, LLC).
For functional potency in T-cell dependent cytotoxicity assays, the specified concentrations of soluble protitrac protein were incubated with purified resting human T cells (effector cells) and HCT116 cancer cells (target cells) at an effector to target cell ratio of 10:1 for 48h at 37 ℃. The HCT116 target cell line has been stably transfected with a luciferase reporter gene, allowing measurement of specific T cell mediated cell killing by ONE-glo (promega).
ProTriTAC shows potent protease-dependent antitumor activity in rodent tumor xenograft models
In immunocompromised NCG mice, the in vivo anti-tumor activity of protitac was evaluated in HCT116 subcutaneous xenograft tumors mixed with expanded human T cells. Specifically, 5x106 HCT116 cells per mouse were mixed with 2.5x106 expanded T cells on day 0. From the next day, protitac was administered by intraperitoneal injection on a q.d.x 10 schedule. Tumor volume measurements were determined using caliper measurements and calculated at the indicated times using the formula V ═ length x width)/2.
C. Expression, purification, and stability of exemplary ProTriTAC trispecific molecules protein production
The sequence encoding the inducible fusion protein molecule was cloned into the mammalian expression vector pcDNA 3.4(Invitrogen), preceded by a leader sequence and followed by a 6x histidine tag (SEQ ID No.: 205). Expi293F cells (Life Technologies A14527) were maintained in Optimum Growth Flasks (Thomson) in Expi293 medium at a suspension of between 0.2 and 8x 1e6 cells/ml. Purified plasmid DNA was transfected into Expi293 cells following the protocol of the Expi293 expression system kit (Life Technologies, a14635) and maintained for 4 to 6 days after transfection. Alternatively, the sequence encoding the fusion protein molecule was cloned into the mammalian expression vector pDEF38(CMC ICOS) transfected into CHO-DG44 dhfr-cells, a stable pool was generated and cultured in production medium for up to 12 days prior to purification. The final purity was assessed by SDS-PAGE and analytical SEC using Acquity BEH 2001.7 u 4.6x150mm columns (Waters Corporation) dissolved in aqueous/organic mobile phase with excipients at neutral pH on a 1290LC system and peaks integrated with Chemstation CDS software (Agilent). fusion proteins purified from CHO host cells are shown in SDS-PAGE described below.
Evaluation of stability
Purified fusion proteins from both preparations were aliquoted into sterile tubes and pressure was applied by five freeze-thaw cycles, each cycle consisting of incubation at-80 ℃ and room temperature for more than 1 hour or at 37 ℃ for 1 week. The concentration and turbidity of stressed samples were assessed by UV spectroscopy, SDS-PAGE and analytical SEC using spectra max M2 and SoftMaxPro software (Molecular Devices) using UV clear 96-well plates (Corning 3635) and compared to the same analysis of control non-stressed samples. Overlay of analytical SEC chromatograms of control and stress samples of individual exemplary protrititac molecules purified from 293 host cells are described below.
The result shows that the yield of the ProTriTAC is equivalent to the yield of the conventional TriTAC in a CHO stable library; and the protein was stable after repeated freeze-thawing and 1 week at 37 ℃.
D. Functional masking and stability of ProTriTAC in vivo was demonstrated in a three-week cynomolgus pharmacokinetic study
Active drugs targeting single doses of prottritac of PSMA (SEQ ID C1872), non-cleavable prottritac (SEQ ID No.:187), non-maskable/non-cleavable TriTAC (SEQ ID No.:190) and prottritac mimicking protease activation (SEQ ID No.:188) were injected intravenously into cynomolgus monkeys at a dose of 0.1 mg/kg. Plasma samples were collected at the indicated time points. ProTriTAC concentrations were determined using a ligand binding assay using a sulfo-labeled anti-CD 3 idiotypic antibody clone 11D3 in biotinylated recombinant human PSMA (R & D systems) and MSD assays (Meso Scale Diagnostic, LLC). Pharmacokinetic parameters were estimated using the Phoenix WinNonlin pharmacokinetic software using a non-compartmental approach consistent with the intravenous bolus administration route.
To calculate prodrug conversion in vivo, the active drug concentration in the circulation is estimated by solving the following system of differential equations, where P is the prodrug concentration, A is the active drug concentration, kaIs the rate of prodrug activation in the circulation, kc,PIs the clearance of the prodrug, and kc,AIs the clearance rate of the active drug.
Control of prodrugs, active drug and non-cleavable prodrugs of cynomolgus monkeys (k) was empirically determinedc,NCLV) The clearance rate of (c). To estimate the prodrug activation rate in the circulation, it is assumed that the difference between the clearance of cleavable and non-cleavable prodrugs is due only to non-specific activation in the circulation. Thus, the rate of conversion of a prodrug to an active drug in the circulation is estimated by subtracting the clearance of the cleavable prodrug from the non-cleavable prodrug.
ka＝kc，NCLV-kc，P
The initial concentration of prodrug in the circulation is determined empirically and assumes that the initial concentration of active drug is zero.
Results and discussion
The results of example 28 indicate that fusion proteins can be prepared comprising a polypeptide having a desired therapeutic activity, such as a cytokine or a functional fragment or mutein thereof or an anti-CD 3 scFV, wherein the therapeutic activity is masked by a masking domain that binds serum albumin and the active polypeptide. The masking domain is operably linked to the active domain by a protease-cleavable linker. The results indicate that this type of fusion protein can be administered as an inactivated protein that is activated after cleavage by a protease at the desired therapeutically active site, such as a tumor.
The amino acid sequence of the fusion protein used in example 28 is given in SEQ ID NO 183-190.
The sample fusion protein constructs are detailed in table 3. In table 3, "L" is an abbreviation for "linker" and "clean. The other abbreviation "miffng" indicates mouse interferon gamma (IFNg); "hAllbumin" indicates Human Serum Albumin (HSA); "mAlbumin" indicates mouse serum albumin.
Table 3: construct replacement tables
Sequence listing
Is incorporated by reference
The entire disclosures of all patent and non-patent publications cited herein are each incorporated herein by reference in their entirety for all purposes.
Other embodiments
The disclosure set forth above may encompass a variety of different inventions with independent utility. While each of these inventions has been disclosed in its preferred form or forms, the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense as numerous variations are possible. The subject matter of the present application includes all novel and non-obvious combinations and subcombinations of the various elements, features, functions and/or properties disclosed herein. The following claims particularly point out certain combinations and subcombinations regarded as novel and nonobvious. Inventions embodied in other combinations and subcombinations of features, functions, elements, and/or properties may be claimed in this, a priority application of this or a related application. Such claims, whether directed to a different invention or directed to the same invention as the original claims, and whether broader, narrower, equal, or different in scope to the original claims, also are regarded as included within the subject matter of the inventions of the present disclosure.
Sequence listing
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Met Tyr Arg Met Gln Leu Leu Ser Cys Ile Ala Leu Ser Leu Ala Leu
1 5 10 15
Val Thr Asn Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu
20 25 30
Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile
35 40 45
Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe
50 55 60
Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu
65 70 75 80
Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys
85 90 95
Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile
100 105 110
Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala
115 120 125
Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe
130 135 140
Cys Gln Ser Ile Ile Ser Thr Leu Thr
145 150
<210> 2
<211> 609
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 2
Met Lys Trp Val Thr Phe Ile Ser Leu Leu Phe Leu Phe Ser Ser Ala
1 5 10 15
Tyr Ser Arg Gly Val Phe Arg Arg Asp Ala His Lys Ser Glu Val Ala
20 25 30
His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu Val Leu
35 40 45
Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp His Val
50 55 60
Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val Ala Asp
65 70 75 80
Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
85 90 95
Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu Met Ala
100 105 110
Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln
115 120 125
His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro Glu Val
130 135 140
Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe Leu Lys
145 150 155 160
Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
165 170 175
Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr Glu Cys
180 185 190
Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu Asp Glu
195 200 205
Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Gly Leu Lys Cys
210 215 220
Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val
225 230 235 240
Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu Val Ser
245 250 255
Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys His Gly
260 265 270
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys Tyr Ile
275 280 285
Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys Cys Glu
290 295 300
Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu Asn Asp
305 310 315 320
Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val Gly Ser
325 330 335
Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly
340 345 350
Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser Val Val
355 360 365
Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu Lys Cys
370 375 380
Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe Asp Glu
385 390 395 400
Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln Asn Cys
405 410 415
Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala Leu Leu
420 425 430
Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr Leu Val
435 440 445
Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys Lys His
450 455 460
Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Cys Leu Ser Val Phe
465 470 475 480
Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser Asp Arg
485 490 495
Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Gly Arg Pro Cys Phe
500 505 510
Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Asn Ala
515 520 525
Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu Lys Glu
530 535 540
Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys His Lys
545 550 555 560
Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp Phe Ala
565 570 575
Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr Cys Phe
580 585 590
Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala Leu Gly
595 600 605
Leu
<210> 3
<211> 8
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP7 cleavage domain sequence "
<400> 3
Lys Arg Ala Leu Gly Leu Pro Gly
1 5
<210> 4
<211> 40
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP7 cleavage domain sequence "
<400> 4
Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu Asp Glu
1 5 10 15
Arg Pro Leu Ala Leu Trp Arg Ser Asp Arg Asp Arg Asp Arg Asp Arg
20 25 30
Asp Arg Asp Arg Asp Arg Asp Arg
35 40
<210> 5
<211> 5
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP9 cleavage domain sequence "
<220>
<221> variants
<222> (3)..(3)
<223 >/substitution = "Thr"
<220>
<221> variants
<222> (4)..(4)
<223 >/permutation = "Ile"
<220>
<221> variants
<222> (5)..(5)
<223 >/substitution = "Thr"
<220>
<221> site
<222> (1)..(5)
<223 >/annotation = "residues of variants given in sequence have no preference relative to those in the annotation of variant position"
<400> 5
Pro Arg Ser Leu Ser
1 5
<210> 6
<211> 5
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP9 cleavage domain sequence "
<400> 6
Leu Glu Ala Thr Ala
1 5
<210> 7
<211> 10
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP11 cleavage domain sequence "
<400> 7
Gly Gly Ala Ala Asn Leu Val Arg Gly Gly
1 5 10
<210> 8
<211> 10
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP14 cleavage domain sequence "
<400> 8
Ser Gly Arg Ile Gly Phe Leu Arg Thr Ala
1 5 10
<210> 9
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP cleavage Domain sequence "
<400> 9
Pro Leu Gly Leu Ala Gly
1 5
<210> 10
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP cleavage Domain sequence "
<220>
<221> MOD_RES
<222> (6)..(6)
<223> any amino acid
<400> 10
Pro Leu Gly Leu Ala Xaa
1 5
<210> 11
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP cleavage Domain sequence "
<220>
<221> MOD_RES
<222> (4)..(4)
<223> Cys(me)
<400> 11
Pro Leu Gly Xaa Ala Gly
1 5
<210> 12
<211> 8
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP cleavage Domain sequence "
<400> 12
Glu Ser Pro Ala Tyr Tyr Thr Ala
1 5
<210> 13
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP cleavage Domain sequence "
<400> 13
Arg Leu Gln Leu Lys Leu
1 5
<210> 14
<211> 7
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP cleavage Domain sequence "
<400> 14
Arg Leu Gln Leu Lys Ala Cys
1 5
<210> 15
<211> 7
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
MMP2, MMP9, MMP14 cleavage domain sequences "
<220>
<221> MOD_RES
<222> (3)..(3)
<223> Cit
<220>
<221> MOD_RES
<222> (5)..(5)
<223> Hof
<400> 15
Glu Pro Xaa Gly Xaa Tyr Leu
1 5
<210> 16
<211> 5
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
urokinase plasminogen activator (uPA) cleavage domain sequence "
<400> 16
Ser Gly Arg Ser Ala
1 5
<210> 17
<211> 4
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
urokinase plasminogen activator (uPA) cleavage domain sequence "
<400> 17
Asp Ala Phe Lys
1
<210> 18
<211> 5
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
urokinase plasminogen activator (uPA) cleavage domain sequence "
<400> 18
Gly Gly Gly Arg Arg
1 5
<210> 19
<211> 4
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
lysosomal enzyme cleavage domain sequence "
<400> 19
Gly Phe Leu Gly
1
<210> 20
<211> 4
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
lysosomal enzyme cleavage domain sequence "
<400> 20
Ala Leu Ala Leu
1
<210> 21
<211> 2
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
lysosomal enzyme cleavage domain sequence "
<400> 21
Phe Lys
1
<210> 22
<211> 3
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
cathepsin B cleavage Domain sequence "
<400> 22
Asn Leu Leu
1
<210> 23
<211> 5
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
cathepsin D cleavage Domain sequence "
<220>
<221> MOD_RES
<222> (3)..(3)
<223> Cys(Et)
<400> 23
Pro Ile Xaa Phe Phe
1 5
<210> 24
<211> 8
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
cathepsin K cleavage Domain sequence "
<400> 24
Gly Gly Pro Arg Gly Leu Pro Gly
1 5
<210> 25
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
prostate specific antigen cleavage domain sequence "
<400> 25
His Ser Ser Lys Leu Gln
1 5
<210> 26
<211> 7
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
prostate specific antigen cleavage domain sequence "
<400> 26
His Ser Ser Lys Leu Gln Leu
1 5
<210> 27
<211> 9
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
prostate specific antigen cleavage domain sequence "
<400> 27
His Ser Ser Lys Leu Gln Glu Asp Ala
1 5
<210> 28
<211> 10
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
herpes simplex virus protease cleavage domain sequence "
<400> 28
Leu Val Leu Ala Ser Ser Ser Phe Gly Tyr
1 5 10
<210> 29
<211> 10
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
HIV protease cleavage domain sequence "
<400> 29
Gly Val Ser Gln Asn Tyr Pro Ile Val Gly
1 5 10
<210> 30
<211> 10
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
CMV protease cleavage Domain sequence "
<400> 30
Gly Val Val Gln Ala Ser Cys Arg Leu Ala
1 5 10
<210> 31
<211> 4
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
thrombin cleavage domain sequence "
<220>
<221> MOD_RES
<222> (2)..(2)
<223> 2-carboxypiperidine
<400> 31
Phe Xaa Arg Ser
1
<210> 32
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
thrombin cleavage domain sequence "
<400> 32
Asp Pro Arg Ser Phe Leu
1 5
<210> 33
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
thrombin cleavage domain sequence "
<400> 33
Pro Pro Arg Ser Phe Leu
1 5
<210> 34
<211> 4
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
caspase-3 cleavage domain sequence "
<400> 34
Asp Glu Val Asp
1
<210> 35
<211> 5
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
caspase-3 cleavage domain sequence "
<400> 35
Asp Glu Val Asp Pro
1 5
<210> 36
<211> 8
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
caspase-3 cleavage domain sequence "
<400> 36
Lys Gly Ser Gly Asp Val Glu Gly
1 5
<210> 37
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
cleavage domain sequence of interleukin 1 beta converting enzyme "
<400> 37
Gly Trp Glu His Asp Gly
1 5
<210> 38
<211> 7
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
enterokinase cleavage domain sequence "
<400> 38
Glu Asp Asp Asp Asp Lys Ala
1 5
<210> 39
<211> 9
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
FAP cleavage Domain sequence "
<400> 39
Lys Gln Glu Gln Asn Pro Gly Ser Thr
1 5
<210> 40
<211> 6
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
kallikrein 2 cleavage domain sequence "
<400> 40
Gly Lys Ala Phe Arg Arg
1 5
<210> 41
<211> 4
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
plasmin cleavage domain sequence "
<400> 41
Asp Ala Phe Lys
1
<210> 42
<211> 4
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
plasmin cleavage domain sequence "
<400> 42
Asp Val Leu Lys
1
<210> 43
<211> 4
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
plasmin cleavage domain sequence "
<400> 43
Asp Ala Phe Lys
1
<210> 44
<211> 7
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
TOP cleavage Domain sequences "
<400> 44
Ala Leu Leu Leu Ala Leu Leu
1 5
<210> 45
<211> 652
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 45
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp
20 25 30
Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn
85 90 95
Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
130 135 140
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
145 150 155 160
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro
165 170 175
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
180 185 190
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
195 200 205
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
210 215 220
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
225 230 235 240
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
245 250 255
Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
260 265 270
Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
275 280 285
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
290 295 300
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
305 310 315 320
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu
325 330 335
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
340 345 350
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
405 410 415
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
420 425 430
Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro
435 440 445
Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr
450 455 460
Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn
465 470 475 480
Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
485 490 495
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp
500 505 510
Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly
515 520 525
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
530 535 540
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
545 550 555 560
Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln
565 570 575
Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe
580 585 590
Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
595 600 605
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
610 615 620
Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly
625 630 635 640
Thr Lys Val Glu Ile Lys His His His His His His
645 650
<210> 46
<211> 652
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 46
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp
20 25 30
Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn
85 90 95
Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
145 150 155 160
Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val
180 185 190
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr
225 230 235 240
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
260 265 270
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln
275 280 285
Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala
290 295 300
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro
305 310 315 320
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
325 330 335
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
340 345 350
Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
370 375 380
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
385 390 395 400
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly
405 410 415
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
420 425 430
Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys
435 440 445
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
450 455 460
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
465 470 475 480
Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val
485 490 495
Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
500 505 510
Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
515 520 525
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
530 535 540
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro
545 550 555 560
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
565 570 575
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
580 585 590
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
595 600 605
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
610 615 620
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
625 630 635 640
Ile Ile Ser Thr Leu Thr His His His His His His
645 650
<210> 47
<211> 553
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 47
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 Ser Tyr
20 25 30
Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr 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 Ser Pro Ser Ser Leu Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn
145 150 155 160
Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr
210 215 220
Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly
260 265 270
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser
275 280 285
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp
290 295 300
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
305 310 315 320
Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
325 330 335
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
340 345 350
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
355 360 365
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
370 375 380
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
385 390 395 400
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
405 410 415
Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
420 425 430
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
435 440 445
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
450 455 460
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
465 470 475 480
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
485 490 495
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
500 505 510
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
515 520 525
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
530 535 540
Val Ser Ser His His His His His His
545 550
<210> 48
<211> 553
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 48
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 Ser Tyr
20 25 30
Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr 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 Ser Pro Ser Ser Leu Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn
145 150 155 160
Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr
210 215 220
Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
260 265 270
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
275 280 285
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
290 295 300
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
305 310 315 320
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg
325 330 335
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
340 345 350
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
355 360 365
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
370 375 380
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser
385 390 395 400
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro
405 410 415
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu
420 425 430
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
435 440 445
Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala
450 455 460
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
465 470 475 480
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
485 490 495
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
500 505 510
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
515 520 525
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
530 535 540
Thr Leu Thr His His His His His His
545 550
<210> 49
<211> 553
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 49
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
130 135 140
Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
145 150 155 160
Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
165 170 175
Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly
180 185 190
Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr
195 200 205
Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
210 215 220
Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala
225 230 235 240
Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly
245 250 255
Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
260 265 270
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
275 280 285
Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
290 295 300
Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
305 310 315 320
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
325 330 335
Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly
340 345 350
Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro
355 360 365
Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
370 375 380
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
385 390 395 400
Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly
405 410 415
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
420 425 430
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
435 440 445
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
450 455 460
Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro
465 470 475 480
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser
485 490 495
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
500 505 510
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
515 520 525
Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val
530 535 540
Glu Ile Lys His His His His His His
545 550
<210> 50
<211> 682
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 50
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp
20 25 30
Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn
85 90 95
Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
130 135 140
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
145 150 155 160
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro
165 170 175
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
180 185 190
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
195 200 205
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
210 215 220
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
225 230 235 240
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
245 250 255
Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
260 265 270
Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
275 280 285
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
290 295 300
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
305 310 315 320
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu
325 330 335
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
340 345 350
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
405 410 415
Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
420 425 430
Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
435 440 445
Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
450 455 460
Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys
465 470 475 480
Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser
485 490 495
Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
500 505 510
Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
515 520 525
Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp
530 535 540
Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly
545 550 555 560
Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser
565 570 575
Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys
580 585 590
Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys
595 600 605
Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr
610 615 620
Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
625 630 635 640
Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr
645 650 655
Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys
660 665 670
Val Glu Ile Lys His His His His His His
675 680
<210> 51
<211> 667
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 51
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp
20 25 30
Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn
85 90 95
Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
130 135 140
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
145 150 155 160
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro
165 170 175
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
180 185 190
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
195 200 205
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
210 215 220
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
225 230 235 240
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
245 250 255
Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
260 265 270
Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
275 280 285
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
290 295 300
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
305 310 315 320
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu
325 330 335
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
340 345 350
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
405 410 415
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
420 425 430
Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
435 440 445
Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly
450 455 460
Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr
465 470 475 480
Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
485 490 495
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
500 505 510
Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr
515 520 525
Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Gly Gly Pro Gly
530 535 540
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Asp Ile Gln Met Thr Gln
545 550 555 560
Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
565 570 575
Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln
580 585 590
Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg
595 600 605
Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
610 615 620
Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
625 630 635 640
Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
645 650 655
Lys Val Glu Ile Lys His His His His His His
660 665
<210> 52
<211> 682
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 52
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
130 135 140
Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
165 170 175
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
180 185 190
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
195 200 205
Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
210 215 220
Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr
225 230 235 240
Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu
245 250 255
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
260 265 270
Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly
275 280 285
Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
305 310 315 320
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
325 330 335
Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys
340 345 350
Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val
355 360 365
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
370 375 380
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
385 390 395 400
Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
405 410 415
Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
420 425 430
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
435 440 445
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
450 455 460
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
465 470 475 480
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
485 490 495
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
500 505 510
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
515 520 525
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
530 535 540
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
545 550 555 560
Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala
565 570 575
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser
580 585 590
Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
595 600 605
Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser
610 615 620
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
625 630 635 640
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr
645 650 655
Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val
660 665 670
Thr Val Ser Ser His His His His His His
675 680
<210> 53
<211> 393
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 53
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
130 135 140
Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val
145 150 155 160
Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
165 170 175
Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly
180 185 190
Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro
195 200 205
Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
210 215 220
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
225 230 235 240
Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly
245 250 255
Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
260 265 270
Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro
275 280 285
Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys
290 295 300
Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro
305 310 315 320
Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser
325 330 335
Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
340 345 350
Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
355 360 365
Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val
370 375 380
Glu Ile Lys His His His His His His
385 390
<210> 54
<211> 423
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 54
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
130 135 140
Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
165 170 175
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
180 185 190
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
195 200 205
Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
210 215 220
Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr
225 230 235 240
Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu
245 250 255
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
260 265 270
Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly
275 280 285
Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
305 310 315 320
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
325 330 335
Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys
340 345 350
Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val
355 360 365
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
370 375 380
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
385 390 395 400
Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
405 410 415
Lys His His His His His His
420
<210> 55
<211> 682
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 55
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
130 135 140
Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
165 170 175
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
180 185 190
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
195 200 205
Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
210 215 220
Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr
225 230 235 240
Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu
245 250 255
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
260 265 270
Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly
275 280 285
Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
305 310 315 320
Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser
325 330 335
Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys
340 345 350
Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val
355 360 365
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
370 375 380
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
385 390 395 400
Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile
405 410 415
Lys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
420 425 430
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
435 440 445
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
450 455 460
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
465 470 475 480
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
485 490 495
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
500 505 510
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
515 520 525
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
530 535 540
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
545 550 555 560
Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala
565 570 575
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser
580 585 590
Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
595 600 605
Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser
610 615 620
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
625 630 635 640
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr
645 650 655
Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val
660 665 670
Thr Val Ser Ser His His His His His His
675 680
<210> 56
<211> 682
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 56
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asn Ser
20 25 30
Val Met Ala Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu Phe Val
35 40 45
Ala Ile Ile Asn Ser Val Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Val Cys Asn
85 90 95
Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
145 150 155 160
Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val
180 185 190
Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
195 200 205
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
210 215 220
Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr
225 230 235 240
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu
260 265 270
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln
275 280 285
Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala
290 295 300
Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro
305 310 315 320
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
325 330 335
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr
340 345 350
Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys
355 360 365
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly
385 390 395 400
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln
405 410 415
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
420 425 430
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
435 440 445
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
450 455 460
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg
465 470 475 480
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
485 490 495
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
500 505 510
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
515 520 525
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala
530 535 540
Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu
545 550 555 560
Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn
565 570 575
Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys
580 585 590
Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro
595 600 605
Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg
610 615 620
Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys
625 630 635 640
Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr
645 650 655
Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile
660 665 670
Ser Thr Leu Thr His His His His His His
675 680
<210> 57
<211> 393
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 57
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 Ser Tyr
20 25 30
Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr 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 Ser Pro Ser Ser Leu Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn
145 150 155 160
Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr
210 215 220
Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser
225 230 235 240
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro
245 250 255
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu
260 265 270
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
275 280 285
Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala
290 295 300
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
305 310 315 320
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
325 330 335
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
340 345 350
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
355 360 365
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
370 375 380
Thr Leu Thr His His His His His His
385 390
<210> 58
<211> 423
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 58
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 Ser Tyr
20 25 30
Thr Leu Ala Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala
85 90 95
Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr 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 Ser Pro Ser Ser Leu Ser
130 135 140
Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn
145 150 155 160
Val Gly Thr Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
165 170 175
Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser
180 185 190
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
195 200 205
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr
210 215 220
Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
245 250 255
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly
260 265 270
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser
275 280 285
Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp
290 295 300
Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu
305 310 315 320
Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu
325 330 335
Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu
340 345 350
Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp
355 360 365
Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu
370 375 380
Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu
385 390 395 400
Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu
405 410 415
Thr His His His His His His
420
<210> 59
<211> 669
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 59
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp
20 25 30
Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn
85 90 95
Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
130 135 140
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
145 150 155 160
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro
165 170 175
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
180 185 190
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
195 200 205
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
210 215 220
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
225 230 235 240
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
245 250 255
Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
260 265 270
Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
275 280 285
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
290 295 300
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
305 310 315 320
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu
325 330 335
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
340 345 350
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu
405 410 415
Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Val
420 425 430
Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp
435 440 445
Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Asn
450 455 460
Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala
465 470 475 480
Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser
485 490 495
Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg
500 505 510
Gly Asp Gly Tyr Tyr Ala Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr
515 520 525
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
530 535 540
Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu Ala
545 550 555 560
Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser
565 570 575
Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro
580 585 590
Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser
595 600 605
Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
610 615 620
Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys
625 630 635 640
Gln Gln Ser Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu
645 650 655
Glu Ile Lys His His His His His His Glu Pro Glu Ala
660 665
<210> 60
<211> 669
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 60
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp
20 25 30
Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn
85 90 95
Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu
130 135 140
His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr
145 150 155 160
Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro
165 170 175
Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu
180 185 190
Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His
195 200 205
Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu
210 215 220
Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr
225 230 235 240
Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser
245 250 255
Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
260 265 270
Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
275 280 285
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
290 295 300
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
305 310 315 320
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu
325 330 335
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
340 345 350
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
355 360 365
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val Leu
405 410 415
Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala Thr
420 425 430
Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr
435 440 445
Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile
450 455 460
Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly
465 470 475 480
Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro Val Glu Glu
485 490 495
Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro Tyr
500 505 510
Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Gln
530 535 540
Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Val Ser Cys
545 550 555 560
Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys
565 570 575
Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Asn Pro Gly
580 585 590
Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu
595 600 605
Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu
610 615 620
Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp
625 630 635 640
Gly Tyr Tyr Ala Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr
645 650 655
Val Ser Ser His His His His His His Glu Pro Glu Ala
660 665
<210> 61
<211> 689
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 61
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
130 135 140
Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
165 170 175
Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys
180 185 190
Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Glu
195 200 205
Trp Val Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile
210 215 220
Asn Pro Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys
225 230 235 240
Ala Thr Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu
245 250 255
Ser Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp
260 265 270
Arg Gly Asp Gly Tyr Tyr Ala Tyr Phe Asp Val Trp Gly Ala Gly Thr
275 280 285
Thr Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
290 295 300
Gly Gly Gly Gly Ser Asp Ile Val Leu Thr Gln Ser Pro Ala Ser Leu
305 310 315 320
Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser Gln
325 330 335
Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln Lys
340 345 350
Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu
355 360 365
Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe
370 375 380
Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr Tyr
385 390 395 400
Cys Gln Gln Ser Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr Lys
405 410 415
Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
420 425 430
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
435 440 445
Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
450 455 460
Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
465 470 475 480
Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala
485 490 495
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr
500 505 510
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val
515 520 525
Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr
530 535 540
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
545 550 555 560
Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu
565 570 575
Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
580 585 590
Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys
595 600 605
Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr
610 615 620
Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
625 630 635 640
Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly
645 650 655
Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly
660 665 670
Thr Gln Val Thr Val Ser Ser His His His His His His Glu Pro Glu
675 680 685
Ala
<210> 62
<211> 689
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 62
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
1 5 10 15
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
20 25 30
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
35 40 45
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
50 55 60
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
65 70 75 80
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
85 90 95
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
100 105 110
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
115 120 125
Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
130 135 140
Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
145 150 155 160
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Val
165 170 175
Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg Ala
180 185 190
Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp Ser
195 200 205
Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu
210 215 220
Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe Ser
225 230 235 240
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro Val Glu
245 250 255
Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp Pro
260 265 270
Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Gly Gly Gly Gly
275 280 285
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln
290 295 300
Gln Ser Gly Ala Glu Leu Val Arg Pro Gly Thr Ser Val Lys Val Ser
305 310 315 320
Cys Lys Ala Ser Gly Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp Val
325 330 335
Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Val Ile Asn Pro
340 345 350
Gly Ser Gly Gly Thr Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr
355 360 365
Leu Thr Ala Asp Lys Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser
370 375 380
Leu Thr Ser Asp Asp Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg Gly
385 390 395 400
Asp Gly Tyr Tyr Ala Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val
405 410 415
Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
420 425 430
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
435 440 445
Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
450 455 460
Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
465 470 475 480
Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala
485 490 495
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr
500 505 510
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val
515 520 525
Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr
530 535 540
Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
545 550 555 560
Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu
565 570 575
Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg
580 585 590
Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys
595 600 605
Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr
610 615 620
Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys
625 630 635 640
Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly
645 650 655
Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly
660 665 670
Thr Gln Val Thr Val Ser Ser His His His His His His Glu Pro Glu
675 680 685
Ala
<210> 63
<211> 272
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
sequence of IL2Ra "
<400> 63
Met Asp Ser Tyr Leu Leu Met Trp Gly Leu Leu Thr Phe Ile Met Val
1 5 10 15
Pro Gly Cys Gln Ala Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile Pro
20 25 30
His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu Asn
35 40 45
Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu Tyr
50 55 60
Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln Cys
65 70 75 80
Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr Pro
85 90 95
Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser Pro
100 105 110
Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu Pro
115 120 125
Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val Val
130 135 140
Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu His
145 150 155 160
Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr Arg
165 170 175
Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser Gln
180 185 190
Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro Glu
195 200 205
Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln Thr
210 215 220
Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr Gln
225 230 235 240
Val Ala Val Ala Gly Cys Val Phe Leu Leu Ile Ser Val Leu Leu Leu
245 250 255
Ser Gly Leu Thr Trp Gln Arg Arg Gln Arg Lys Ser Arg Arg Thr Ile
260 265 270
<210> 64
<211> 551
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
sequence of IL2Rb "
<400> 64
Met Ala Ala Pro Ala Leu Ser Trp Arg Leu Pro Leu Leu Ile Leu Leu
1 5 10 15
Leu Pro Leu Ala Thr Ser Trp Ala Ser Ala Ala Val Asn Gly Thr Ser
20 25 30
Gln Phe Thr Cys Phe Tyr Asn Ser Arg Ala Asn Ile Ser Cys Val Trp
35 40 45
Ser Gln Asp Gly Ala Leu Gln Asp Thr Ser Cys Gln Val His Ala Trp
50 55 60
Pro Asp Arg Arg Arg Trp Asn Gln Thr Cys Glu Leu Leu Pro Val Ser
65 70 75 80
Gln Ala Ser Trp Ala Cys Asn Leu Ile Leu Gly Ala Pro Asp Ser Gln
85 90 95
Lys Leu Thr Thr Val Asp Ile Val Thr Leu Arg Val Leu Cys Arg Glu
100 105 110
Gly Val Arg Trp Arg Val Met Ala Ile Gln Asp Phe Lys Pro Phe Glu
115 120 125
Asn Leu Arg Leu Met Ala Pro Ile Ser Leu Gln Val Val His Val Glu
130 135 140
Thr His Arg Cys Asn Ile Ser Trp Glu Ile Ser Gln Ala Ser His Tyr
145 150 155 160
Phe Glu Arg His Leu Glu Phe Glu Ala Arg Thr Leu Ser Pro Gly His
165 170 175
Thr Trp Glu Glu Ala Pro Leu Leu Thr Leu Lys Gln Lys Gln Glu Trp
180 185 190
Ile Cys Leu Glu Thr Leu Thr Pro Asp Thr Gln Tyr Glu Phe Gln Val
195 200 205
Arg Val Lys Pro Leu Gln Gly Glu Phe Thr Thr Trp Ser Pro Trp Ser
210 215 220
Gln Pro Leu Ala Phe Arg Thr Lys Pro Ala Ala Leu Gly Lys Asp Thr
225 230 235 240
Ile Pro Trp Leu Gly His Leu Leu Val Gly Leu Ser Gly Ala Phe Gly
245 250 255
Phe Ile Ile Leu Val Tyr Leu Leu Ile Asn Cys Arg Asn Thr Gly Pro
260 265 270
Trp Leu Lys Lys Val Leu Lys Cys Asn Thr Pro Asp Pro Ser Lys Phe
275 280 285
Phe Ser Gln Leu Ser Ser Glu His Gly Gly Asp Val Gln Lys Trp Leu
290 295 300
Ser Ser Pro Phe Pro Ser Ser Ser Phe Ser Pro Gly Gly Leu Ala Pro
305 310 315 320
Glu Ile Ser Pro Leu Glu Val Leu Glu Arg Asp Lys Val Thr Gln Leu
325 330 335
Leu Leu Gln Gln Asp Lys Val Pro Glu Pro Ala Ser Leu Ser Ser Asn
340 345 350
His Ser Leu Thr Ser Cys Phe Thr Asn Gln Gly Tyr Phe Phe Phe His
355 360 365
Leu Pro Asp Ala Leu Glu Ile Glu Ala Cys Gln Val Tyr Phe Thr Tyr
370 375 380
Asp Pro Tyr Ser Glu Glu Asp Pro Asp Glu Gly Val Ala Gly Ala Pro
385 390 395 400
Thr Gly Ser Ser Pro Gln Pro Leu Gln Pro Leu Ser Gly Glu Asp Asp
405 410 415
Ala Tyr Cys Thr Phe Pro Ser Arg Asp Asp Leu Leu Leu Phe Ser Pro
420 425 430
Ser Leu Leu Gly Gly Pro Ser Pro Pro Ser Thr Ala Pro Gly Gly Ser
435 440 445
Gly Ala Gly Glu Glu Arg Met Pro Pro Ser Leu Gln Glu Arg Val Pro
450 455 460
Arg Asp Trp Asp Pro Gln Pro Leu Gly Pro Pro Thr Pro Gly Val Pro
465 470 475 480
Asp Leu Val Asp Phe Gln Pro Pro Pro Glu Leu Val Leu Arg Glu Ala
485 490 495
Gly Glu Glu Val Pro Asp Ala Gly Pro Arg Glu Gly Val Ser Phe Pro
500 505 510
Trp Ser Arg Pro Pro Gly Gln Gly Glu Phe Arg Ala Leu Asn Ala Arg
515 520 525
Leu Pro Leu Asn Thr Asp Ala Tyr Leu Ser Leu Gln Glu Leu Gln Gly
530 535 540
Gln Asp Pro Thr His Leu Val
545 550
<210> 65
<211> 369
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
sequence of IL2Rg "
<400> 65
Met Leu Lys Pro Ser Leu Pro Phe Thr Ser Leu Leu Phe Leu Gln Leu
1 5 10 15
Pro Leu Leu Gly Val Gly Leu Asn Thr Thr Ile Leu Thr Pro Asn Gly
20 25 30
Asn Glu Asp Thr Thr Ala Asp Phe Phe Leu Thr Thr Met Pro Thr Asp
35 40 45
Ser Leu Ser Val Ser Thr Leu Pro Leu Pro Glu Val Gln Cys Phe Val
50 55 60
Phe Asn Val Glu Tyr Met Asn Cys Thr Trp Asn Ser Ser Ser Glu Pro
65 70 75 80
Gln Pro Thr Asn Leu Thr Leu His Tyr Trp Tyr Lys Asn Ser Asp Asn
85 90 95
Asp Lys Val Gln Lys Cys Ser His Tyr Leu Phe Ser Glu Glu Ile Thr
100 105 110
Ser Gly Cys Gln Leu Gln Lys Lys Glu Ile His Leu Tyr Gln Thr Phe
115 120 125
Val Val Gln Leu Gln Asp Pro Arg Glu Pro Arg Arg Gln Ala Thr Gln
130 135 140
Met Leu Lys Leu Gln Asn Leu Val Ile Pro Trp Ala Pro Glu Asn Leu
145 150 155 160
Thr Leu His Lys Leu Ser Glu Ser Gln Leu Glu Leu Asn Trp Asn Asn
165 170 175
Arg Phe Leu Asn His Cys Leu Glu His Leu Val Gln Tyr Arg Thr Asp
180 185 190
Trp Asp His Ser Trp Thr Glu Gln Ser Val Asp Tyr Arg His Lys Phe
195 200 205
Ser Leu Pro Ser Val Asp Gly Gln Lys Arg Tyr Thr Phe Arg Val Arg
210 215 220
Ser Arg Phe Asn Pro Leu Cys Gly Ser Ala Gln His Trp Ser Glu Trp
225 230 235 240
Ser His Pro Ile His Trp Gly Ser Asn Thr Ser Lys Glu Asn Pro Phe
245 250 255
Leu Phe Ala Leu Glu Ala Val Val Ile Ser Val Gly Ser Met Gly Leu
260 265 270
Ile Ile Ser Leu Leu Cys Val Tyr Phe Trp Leu Glu Arg Thr Met Pro
275 280 285
Arg Ile Pro Thr Leu Lys Asn Leu Glu Asp Leu Val Thr Glu Tyr His
290 295 300
Gly Asn Phe Ser Ala Trp Ser Gly Val Ser Lys Gly Leu Ala Glu Ser
305 310 315 320
Leu Gln Pro Asp Tyr Ser Glu Arg Leu Cys Leu Val Ser Glu Ile Pro
325 330 335
Pro Lys Gly Gly Ala Leu Gly Glu Gly Pro Gly Ala Ser Pro Cys Asn
340 345 350
Gln His Ser Pro Tyr Trp Ala Pro Pro Cys Tyr Thr Leu Lys Pro Glu
355 360 365
Thr
<210> 66
<211> 520
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 66
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser
325 330 335
Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu
340 345 350
Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp
355 360 365
Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu
370 375 380
Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr
385 390 395 400
Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr
405 410 415
Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu
420 425 430
Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile
435 440 445
Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser
450 455 460
Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu
465 470 475 480
Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala
485 490 495
Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser
500 505 510
Ser Ala His His His His His His
515 520
<210> 67
<211> 524
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 67
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Asn Leu Pro Val Ala Thr Pro Asp Pro Gly Met Phe Pro Cys
325 330 335
Leu His His Ser Gln Asn Leu Leu Arg Ala Val Ser Asn Met Leu Gln
340 345 350
Lys Ala Arg Gln Thr Leu Glu Phe Tyr Pro Cys Thr Ser Glu Glu Ile
355 360 365
Asp His Glu Asp Ile Thr Lys Asp Lys Thr Ser Thr Val Glu Ala Cys
370 375 380
Leu Pro Leu Glu Leu Thr Lys Asn Glu Ser Cys Leu Asn Ser Arg Glu
385 390 395 400
Thr Ser Phe Ile Thr Asn Gly Ser Cys Leu Ala Ser Arg Lys Thr Ser
405 410 415
Phe Met Met Ala Leu Cys Leu Ser Ser Ile Tyr Glu Asp Leu Lys Met
420 425 430
Tyr Gln Val Glu Phe Lys Thr Met Asn Ala Lys Leu Leu Met Asp Pro
435 440 445
Lys Arg Gln Ile Phe Leu Asp Gln Asn Met Leu Ala Val Ile Asp Glu
450 455 460
Leu Met Gln Ala Leu Asn Phe Asn Ser Glu Thr Val Pro Gln Lys Ser
465 470 475 480
Ser Leu Glu Glu Pro Asp Phe Tyr Lys Thr Lys Ile Lys Leu Cys Ile
485 490 495
Leu Leu His Ala Phe Arg Ile Arg Ala Val Thr Ile Asp Arg Val Met
500 505 510
Ser Tyr Leu Asn Ala Ser His His His His His His
515 520
<210> 68
<211> 940
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 68
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln
65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg Tyr Thr
85 90 95
His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
115 120 125
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met
145 150 155 160
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Phe
165 170 175
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Lys Thr
210 215 220
His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser
260 265 270
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ile Trp
275 280 285
Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr Pro Asp
290 295 300
Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu Glu Asp
305 310 315 320
Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly Ser Gly
325 330 335
Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly Gln Tyr
340 345 350
Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu Leu Leu
355 360 365
His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys Asp Gln
370 375 380
Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys Asn Tyr
385 390 395 400
Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr Asp Leu
405 410 415
Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln Gly Val
420 425 430
Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly Asp Asn
435 440 445
Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala Cys Pro
450 455 460
Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala Val His
465 470 475 480
Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg Asp Ile
485 490 495
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu Lys Asn
500 505 510
Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp Ser Thr
515 520 525
Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln Gly Lys
530 535 540
Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr Ser Ala
545 550 555 560
Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala Gln Asp
565 570 575
Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro Cys Ser
580 585 590
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg
595 600 605
Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg Asn
610 615 620
Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys Leu
625 630 635 640
Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile Thr
645 650 655
Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu His
660 665 670
Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr Arg
675 680 685
Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu Cys
690 695 700
Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe Gln
705 710 715 720
Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile Leu
725 730 735
Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu Asn
740 745 750
His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala Asp
755 760 765
Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe Ser
770 775 780
Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser Ala
785 790 795 800
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu
805 810 815
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
820 825 830
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly
835 840 845
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
850 855 860
Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys
865 870 875 880
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
885 890 895
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
900 905 910
Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val
915 920 925
Ser Ser His His His His His His Glu Pro Glu Ala
930 935 940
<210> 69
<211> 1069
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 69
Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln
1 5 10 15
Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn
20 25 30
Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45
Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln
65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg Tyr Thr
85 90 95
His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly
100 105 110
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
115 120 125
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu
130 135 140
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met
145 150 155 160
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Phe
165 170 175
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly
180 185 190
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln
195 200 205
Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Lys Thr
210 215 220
His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val Thr Val Ser
225 230 235 240
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser
260 265 270
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ile Trp
275 280 285
Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr Pro Asp
290 295 300
Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu Glu Asp
305 310 315 320
Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly Ser Gly
325 330 335
Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly Gln Tyr
340 345 350
Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu Leu Leu
355 360 365
His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys Asp Gln
370 375 380
Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys Asn Tyr
385 390 395 400
Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr Asp Leu
405 410 415
Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln Gly Val
420 425 430
Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly Asp Asn
435 440 445
Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala Cys Pro
450 455 460
Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala Val His
465 470 475 480
Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg Asp Ile
485 490 495
Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu Lys Asn
500 505 510
Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp Ser Thr
515 520 525
Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln Gly Lys
530 535 540
Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr Ser Ala
545 550 555 560
Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala Gln Asp
565 570 575
Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro Cys Ser
580 585 590
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Arg
595 600 605
Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg Asn
610 615 620
Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys Leu
625 630 635 640
Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile Thr
645 650 655
Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu His
660 665 670
Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr Arg
675 680 685
Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu Cys
690 695 700
Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe Gln
705 710 715 720
Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile Leu
725 730 735
Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu Asn
740 745 750
His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala Asp
755 760 765
Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe Ser
770 775 780
Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser Ala
785 790 795 800
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu
805 810 815
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
820 825 830
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly
835 840 845
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
850 855 860
Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys
865 870 875 880
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
885 890 895
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
900 905 910
Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val
915 920 925
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
930 935 940
Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly
945 950 955 960
Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asn
965 970 975
Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu Phe
980 985 990
Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn Tyr Ala Asp Ser Val
995 1000 1005
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
1010 1015 1020
Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr
1025 1030 1035
Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln Gly Thr
1040 1045 1050
Gln Val Thr Val Ser Ser His His His His His His Glu Pro Glu
1055 1060 1065
Ala
<210> 70
<211> 1069
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 70
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly
1 5 10 15
Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asn Ser
20 25 30
Val Met Ala Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu Phe Val
35 40 45
Ala Ile Ile Asn Ser Val Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Val Cys Asn
85 90 95
Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly
130 135 140
Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser
145 150 155 160
Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
165 170 175
Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe
180 185 190
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
195 200 205
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg Tyr
210 215 220
Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val Thr Val Leu
225 230 235 240
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
245 250 255
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser
260 265 270
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly
275 280 285
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
290 295 300
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
305 310 315 320
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
325 330 335
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Lys
340 345 350
Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val Thr Val
355 360 365
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
370 375 380
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
385 390 395 400
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ile
405 410 415
Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr Pro
420 425 430
Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu Glu
435 440 445
Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly Ser
450 455 460
Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly Gln
465 470 475 480
Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu Leu
485 490 495
Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys Asp
500 505 510
Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys Asn
515 520 525
Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr Asp
530 535 540
Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln Gly
545 550 555 560
Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly Asp
565 570 575
Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala Cys
580 585 590
Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala Val
595 600 605
His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg Asp
610 615 620
Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu Lys
625 630 635 640
Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp Ser
645 650 655
Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln Gly
660 665 670
Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr Ser
675 680 685
Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala Gln
690 695 700
Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro Cys
705 710 715 720
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
725 730 735
Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg
740 745 750
Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys
755 760 765
Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile
770 775 780
Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu
785 790 795 800
His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr
805 810 815
Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu
820 825 830
Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe
835 840 845
Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile
850 855 860
Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu
865 870 875 880
Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala
885 890 895
Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe
900 905 910
Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser
915 920 925
Ala Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
930 935 940
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
945 950 955 960
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
965 970 975
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
980 985 990
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
995 1000 1005
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
1010 1015 1020
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
1025 1030 1035
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr
1040 1045 1050
Leu Val Thr Val Ser Ser His His His His His His Glu Pro Glu
1055 1060 1065
Ala
<210> 71
<211> 940
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 71
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser 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 Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro
130 135 140
Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly
145 150 155 160
Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
165 170 175
Leu Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg
180 185 190
Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
195 200 205
Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg
210 215 220
Tyr Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val Thr Val
225 230 235 240
Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
260 265 270
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
275 280 285
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
290 295 300
Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
305 310 315 320
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
325 330 335
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
340 345 350
Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val Thr
355 360 365
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
385 390 395 400
Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
405 410 415
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
420 425 430
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
435 440 445
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
450 455 460
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
465 470 475 480
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
485 490 495
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
500 505 510
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
515 520 525
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
530 535 540
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
545 550 555 560
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
565 570 575
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
580 585 590
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
595 600 605
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
610 615 620
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
625 630 635 640
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
645 650 655
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
660 665 670
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
675 680 685
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
690 695 700
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
705 710 715 720
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
725 730 735
Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser
740 745 750
Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu
755 760 765
Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp
770 775 780
Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu
785 790 795 800
Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr
805 810 815
Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr
820 825 830
Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu
835 840 845
Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile
850 855 860
Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser
865 870 875 880
Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu
885 890 895
Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala
900 905 910
Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser
915 920 925
Ser Ala His His His His His His Glu Pro Glu Ala
930 935 940
<210> 72
<211> 940
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 72
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
115 120 125
Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp
130 135 140
Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr
145 150 155 160
Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val
165 170 175
Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp
180 185 190
Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser
195 200 205
Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile
210 215 220
Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu
225 230 235 240
Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile
245 250 255
Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp
260 265 270
Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val
275 280 285
Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp
290 295 300
Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val
305 310 315 320
Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe
325 330 335
Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys
340 345 350
Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp
355 360 365
Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln
370 375 380
Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp
385 390 395 400
Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val
405 410 415
Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser
420 425 430
Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
435 440 445
Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser
450 455 460
Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala
465 470 475 480
Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His
485 490 495
Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro
500 505 510
Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser
515 520 525
Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met
530 535 540
Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln
545 550 555 560
Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln
565 570 575
Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met
580 585 590
Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val
595 600 605
Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu
610 615 620
His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr
625 630 635 640
Leu Ser Ser Ala Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu
645 650 655
Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
660 665 670
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
675 680 685
Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly
690 695 700
Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser
705 710 715 720
Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu
725 730 735
Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe
740 745 750
Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu
755 760 765
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg Tyr
770 775 780
Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val Thr Val Leu
785 790 795 800
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
805 810 815
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser
820 825 830
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly
835 840 845
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala
850 855 860
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
865 870 875 880
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu
885 890 895
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Lys
900 905 910
Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val Thr Val
915 920 925
Ser Ser His His His His His His Glu Pro Glu Ala
930 935 940
<210> 73
<211> 940
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 73
Ile Trp Glu Leu Lys Lys Asp Val Tyr Val Val Glu Leu Asp Trp Tyr
1 5 10 15
Pro Asp Ala Pro Gly Glu Met Val Val Leu Thr Cys Asp Thr Pro Glu
20 25 30
Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln Ser Ser Glu Val Leu Gly
35 40 45
Ser Gly Lys Thr Leu Thr Ile Gln Val Lys Glu Phe Gly Asp Ala Gly
50 55 60
Gln Tyr Thr Cys His Lys Gly Gly Glu Val Leu Ser His Ser Leu Leu
65 70 75 80
Leu Leu His Lys Lys Glu Asp Gly Ile Trp Ser Thr Asp Ile Leu Lys
85 90 95
Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe Leu Arg Cys Glu Ala Lys
100 105 110
Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp Leu Thr Thr Ile Ser Thr
115 120 125
Asp Leu Thr Phe Ser Val Lys Ser Ser Arg Gly Ser Ser Asp Pro Gln
130 135 140
Gly Val Thr Cys Gly Ala Ala Thr Leu Ser Ala Glu Arg Val Arg Gly
145 150 155 160
Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu Cys Gln Glu Asp Ser Ala
165 170 175
Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile Glu Val Met Val Asp Ala
180 185 190
Val His Lys Leu Lys Tyr Glu Asn Tyr Thr Ser Ser Phe Phe Ile Arg
195 200 205
Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Leu Lys Pro Leu
210 215 220
Lys Asn Ser Arg Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Thr Trp
225 230 235 240
Ser Thr Pro His Ser Tyr Phe Ser Leu Thr Phe Cys Val Gln Val Gln
245 250 255
Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg Val Phe Thr Asp Lys Thr
260 265 270
Ser Ala Thr Val Ile Cys Arg Lys Asn Ala Ser Ile Ser Val Arg Ala
275 280 285
Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser Glu Trp Ala Ser Val Pro
290 295 300
Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
305 310 315 320
Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser
325 330 335
Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu
340 345 350
Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp
355 360 365
Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu
370 375 380
Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr
385 390 395 400
Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr
405 410 415
Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu
420 425 430
Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile
435 440 445
Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser
450 455 460
Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu
465 470 475 480
Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala
485 490 495
Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser
500 505 510
Ser Ala Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
515 520 525
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
530 535 540
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
545 550 555 560
Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln Arg
565 570 575
Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn Thr
580 585 590
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu Ile
595 600 605
Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser Gly
610 615 620
Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln Ala
625 630 635 640
Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg Tyr Thr His
645 650 655
Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly Gly
660 665 670
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln
675 680 685
Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser Leu Arg
690 695 700
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Gly Met His
705 710 715 720
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Phe Ile
725 730 735
Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys Gly Arg
740 745 750
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met
755 760 765
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Lys Thr His
770 775 780
Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val Thr Val Ser Ser
785 790 795 800
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu
805 810 815
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
820 825 830
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly
835 840 845
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
850 855 860
Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys
865 870 875 880
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
885 890 895
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
900 905 910
Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val
915 920 925
Ser Ser His His His His His His Glu Pro Glu Ala
930 935 940
<210> 74
<211> 328
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 74
Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu
1 5 10 15
Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser
325
<210> 75
<211> 215
<212> PRT
<213> little mouse (Mus musculus)
<400> 75
Met Cys Gln Ser Arg Tyr Leu Leu Phe Leu Ala Thr Leu Ala Leu Leu
1 5 10 15
Asn His Leu Ser Leu Ala Arg Val Ile Pro Val Ser Gly Pro Ala Arg
20 25 30
Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val
35 40 45
Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp
50 55 60
Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr
65 70 75 80
Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg
85 90 95
Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr
100 105 110
Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys
115 120 125
Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His
130 135 140
Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp
145 150 155 160
Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys
165 170 175
Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys
180 185 190
Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val
195 200 205
Met Gly Tyr Leu Ser Ser Ala
210 215
<210> 76
<211> 862
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
IL12Rb-2 sequence "
<400> 76
Met Ala His Thr Phe Arg Gly Cys Ser Leu Ala Phe Met Phe Ile Ile
1 5 10 15
Thr Trp Leu Leu Ile Lys Ala Lys Ile Asp Ala Cys Lys Arg Gly Asp
20 25 30
Val Thr Val Lys Pro Ser His Val Ile Leu Leu Gly Ser Thr Val Asn
35 40 45
Ile Thr Cys Ser Leu Lys Pro Arg Gln Gly Cys Phe His Tyr Ser Arg
50 55 60
Arg Asn Lys Leu Ile Leu Tyr Lys Phe Asp Arg Arg Ile Asn Phe His
65 70 75 80
His Gly His Ser Leu Asn Ser Gln Val Thr Gly Leu Pro Leu Gly Thr
85 90 95
Thr Leu Phe Val Cys Lys Leu Ala Cys Ile Asn Ser Asp Glu Ile Gln
100 105 110
Ile Cys Gly Ala Glu Ile Phe Val Gly Val Ala Pro Glu Gln Pro Gln
115 120 125
Asn Leu Ser Cys Ile Gln Lys Gly Glu Gln Gly Thr Val Ala Cys Thr
130 135 140
Trp Glu Arg Gly Arg Asp Thr His Leu Tyr Thr Glu Tyr Thr Leu Gln
145 150 155 160
Leu Ser Gly Pro Lys Asn Leu Thr Trp Gln Lys Gln Cys Lys Asp Ile
165 170 175
Tyr Cys Asp Tyr Leu Asp Phe Gly Ile Asn Leu Thr Pro Glu Ser Pro
180 185 190
Glu Ser Asn Phe Thr Ala Lys Val Thr Ala Val Asn Ser Leu Gly Ser
195 200 205
Ser Ser Ser Leu Pro Ser Thr Phe Thr Phe Leu Asp Ile Val Arg Pro
210 215 220
Leu Pro Pro Trp Asp Ile Arg Ile Lys Phe Gln Lys Ala Ser Val Ser
225 230 235 240
Arg Cys Thr Leu Tyr Trp Arg Asp Glu Gly Leu Val Leu Leu Asn Arg
245 250 255
Leu Arg Tyr Arg Pro Ser Asn Ser Arg Leu Trp Asn Met Val Asn Val
260 265 270
Thr Lys Ala Lys Gly Arg His Asp Leu Leu Asp Leu Lys Pro Phe Thr
275 280 285
Glu Tyr Glu Phe Gln Ile Ser Ser Lys Leu His Leu Tyr Lys Gly Ser
290 295 300
Trp Ser Asp Trp Ser Glu Ser Leu Arg Ala Gln Thr Pro Glu Glu Glu
305 310 315 320
Pro Thr Gly Met Leu Asp Val Trp Tyr Met Lys Arg His Ile Asp Tyr
325 330 335
Ser Arg Gln Gln Ile Ser Leu Phe Trp Lys Asn Leu Ser Val Ser Glu
340 345 350
Ala Arg Gly Lys Ile Leu His Tyr Gln Val Thr Leu Gln Glu Leu Thr
355 360 365
Gly Gly Lys Ala Met Thr Gln Asn Ile Thr Gly His Thr Ser Trp Thr
370 375 380
Thr Val Ile Pro Arg Thr Gly Asn Trp Ala Val Ala Val Ser Ala Ala
385 390 395 400
Asn Ser Lys Gly Ser Ser Leu Pro Thr Arg Ile Asn Ile Met Asn Leu
405 410 415
Cys Glu Ala Gly Leu Leu Ala Pro Arg Gln Val Ser Ala Asn Ser Glu
420 425 430
Gly Met Asp Asn Ile Leu Val Thr Trp Gln Pro Pro Arg Lys Asp Pro
435 440 445
Ser Ala Val Gln Glu Tyr Val Val Glu Trp Arg Glu Leu His Pro Gly
450 455 460
Gly Asp Thr Gln Val Pro Leu Asn Trp Leu Arg Ser Arg Pro Tyr Asn
465 470 475 480
Val Ser Ala Leu Ile Ser Glu Asn Ile Lys Ser Tyr Ile Cys Tyr Glu
485 490 495
Ile Arg Val Tyr Ala Leu Ser Gly Asp Gln Gly Gly Cys Ser Ser Ile
500 505 510
Leu Gly Asn Ser Lys His Lys Ala Pro Leu Ser Gly Pro His Ile Asn
515 520 525
Ala Ile Thr Glu Glu Lys Gly Ser Ile Leu Ile Ser Trp Asn Ser Ile
530 535 540
Pro Val Gln Glu Gln Met Gly Cys Leu Leu His Tyr Arg Ile Tyr Trp
545 550 555 560
Lys Glu Arg Asp Ser Asn Ser Gln Pro Gln Leu Cys Glu Ile Pro Tyr
565 570 575
Arg Val Ser Gln Asn Ser His Pro Ile Asn Ser Leu Gln Pro Arg Val
580 585 590
Thr Tyr Val Leu Trp Met Thr Ala Leu Thr Ala Ala Gly Glu Ser Ser
595 600 605
His Gly Asn Glu Arg Glu Phe Cys Leu Gln Gly Lys Ala Asn Trp Met
610 615 620
Ala Phe Val Ala Pro Ser Ile Cys Ile Ala Ile Ile Met Val Gly Ile
625 630 635 640
Phe Ser Thr His Tyr Phe Gln Gln Lys Val Phe Val Leu Leu Ala Ala
645 650 655
Leu Arg Pro Gln Trp Cys Ser Arg Glu Ile Pro Asp Pro Ala Asn Ser
660 665 670
Thr Cys Ala Lys Lys Tyr Pro Ile Ala Glu Glu Lys Thr Gln Leu Pro
675 680 685
Leu Asp Arg Leu Leu Ile Asp Trp Pro Thr Pro Glu Asp Pro Glu Pro
690 695 700
Leu Val Ile Ser Glu Val Leu His Gln Val Thr Pro Val Phe Arg His
705 710 715 720
Pro Pro Cys Ser Asn Trp Pro Gln Arg Glu Lys Gly Ile Gln Gly His
725 730 735
Gln Ala Ser Glu Lys Asp Met Met His Ser Ala Ser Ser Pro Pro Pro
740 745 750
Pro Arg Ala Leu Gln Ala Glu Ser Arg Gln Leu Val Asp Leu Tyr Lys
755 760 765
Val Leu Glu Ser Arg Gly Ser Asp Pro Lys Pro Glu Asn Pro Ala Cys
770 775 780
Pro Trp Thr Val Leu Pro Ala Gly Asp Leu Pro Thr His Asp Gly Tyr
785 790 795 800
Leu Pro Ser Asn Ile Asp Asp Leu Pro Ser His Glu Ala Pro Leu Ala
805 810 815
Asp Ser Leu Glu Glu Leu Glu Pro Gln His Ile Ser Leu Ser Val Phe
820 825 830
Pro Ser Ser Ser Leu His Pro Leu Thr Phe Ser Cys Gly Asp Lys Leu
835 840 845
Thr Leu Asp Gln Leu Lys Met Arg Cys Asp Ser Leu Met Leu
850 855 860
<210> 77
<211> 662
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
IL12Rb-1 sequence "
<400> 77
Met Glu Pro Leu Val Thr Trp Val Val Pro Leu Leu Phe Leu Phe Leu
1 5 10 15
Leu Ser Arg Gln Gly Ala Ala Cys Arg Thr Ser Glu Cys Cys Phe Gln
20 25 30
Asp Pro Pro Tyr Pro Asp Ala Asp Ser Gly Ser Ala Ser Gly Pro Arg
35 40 45
Asp Leu Arg Cys Tyr Arg Ile Ser Ser Asp Arg Tyr Glu Cys Ser Trp
50 55 60
Gln Tyr Glu Gly Pro Thr Ala Gly Val Ser His Phe Leu Arg Cys Cys
65 70 75 80
Leu Ser Ser Gly Arg Cys Cys Tyr Phe Ala Ala Gly Ser Ala Thr Arg
85 90 95
Leu Gln Phe Ser Asp Gln Ala Gly Val Ser Val Leu Tyr Thr Val Thr
100 105 110
Leu Trp Val Glu Ser Trp Ala Arg Asn Gln Thr Glu Lys Ser Pro Glu
115 120 125
Val Thr Leu Gln Leu Tyr Asn Ser Val Lys Tyr Glu Pro Pro Leu Gly
130 135 140
Asp Ile Lys Val Ser Lys Leu Ala Gly Gln Leu Arg Met Glu Trp Glu
145 150 155 160
Thr Pro Asp Asn Gln Val Gly Ala Glu Val Gln Phe Arg His Arg Thr
165 170 175
Pro Ser Ser Pro Trp Lys Leu Gly Asp Cys Gly Pro Gln Asp Asp Asp
180 185 190
Thr Glu Ser Cys Leu Cys Pro Leu Glu Met Asn Val Ala Gln Glu Phe
195 200 205
Gln Leu Arg Arg Arg Gln Leu Gly Ser Gln Gly Ser Ser Trp Ser Lys
210 215 220
Trp Ser Ser Pro Val Cys Val Pro Pro Glu Asn Pro Pro Gln Pro Gln
225 230 235 240
Val Arg Phe Ser Val Glu Gln Leu Gly Gln Asp Gly Arg Arg Arg Leu
245 250 255
Thr Leu Lys Glu Gln Pro Thr Gln Leu Glu Leu Pro Glu Gly Cys Gln
260 265 270
Gly Leu Ala Pro Gly Thr Glu Val Thr Tyr Arg Leu Gln Leu His Met
275 280 285
Leu Ser Cys Pro Cys Lys Ala Lys Ala Thr Arg Thr Leu His Leu Gly
290 295 300
Lys Met Pro Tyr Leu Ser Gly Ala Ala Tyr Asn Val Ala Val Ile Ser
305 310 315 320
Ser Asn Gln Phe Gly Pro Gly Leu Asn Gln Thr Trp His Ile Pro Ala
325 330 335
Asp Thr His Thr Glu Pro Val Ala Leu Asn Ile Ser Val Gly Thr Asn
340 345 350
Gly Thr Thr Met Tyr Trp Pro Ala Arg Ala Gln Ser Met Thr Tyr Cys
355 360 365
Ile Glu Trp Gln Pro Val Gly Gln Asp Gly Gly Leu Ala Thr Cys Ser
370 375 380
Leu Thr Ala Pro Gln Asp Pro Asp Pro Ala Gly Met Ala Thr Tyr Ser
385 390 395 400
Trp Ser Arg Glu Ser Gly Ala Met Gly Gln Glu Lys Cys Tyr Tyr Ile
405 410 415
Thr Ile Phe Ala Ser Ala His Pro Glu Lys Leu Thr Leu Trp Ser Thr
420 425 430
Val Leu Ser Thr Tyr His Phe Gly Gly Asn Ala Ser Ala Ala Gly Thr
435 440 445
Pro His His Val Ser Val Lys Asn His Ser Leu Asp Ser Val Ser Val
450 455 460
Asp Trp Ala Pro Ser Leu Leu Ser Thr Cys Pro Gly Val Leu Lys Glu
465 470 475 480
Tyr Val Val Arg Cys Arg Asp Glu Asp Ser Lys Gln Val Ser Glu His
485 490 495
Pro Val Gln Pro Thr Glu Thr Gln Val Thr Leu Ser Gly Leu Arg Ala
500 505 510
Gly Val Ala Tyr Thr Val Gln Val Arg Ala Asp Thr Ala Trp Leu Arg
515 520 525
Gly Val Trp Ser Gln Pro Gln Arg Phe Ser Ile Glu Val Gln Val Ser
530 535 540
Asp Trp Leu Ile Phe Phe Ala Ser Leu Gly Ser Phe Leu Ser Ile Leu
545 550 555 560
Leu Val Gly Val Leu Gly Tyr Leu Gly Leu Asn Arg Ala Ala Arg His
565 570 575
Leu Cys Pro Pro Leu Pro Thr Pro Cys Ala Ser Ser Ala Ile Glu Phe
580 585 590
Pro Gly Gly Lys Glu Thr Trp Gln Trp Ile Asn Pro Val Asp Phe Gln
595 600 605
Glu Glu Ala Ser Leu Gln Glu Ala Leu Val Val Glu Met Ser Trp Asp
610 615 620
Lys Gly Glu Arg Thr Glu Pro Leu Glu Lys Thr Glu Leu Pro Glu Gly
625 630 635 640
Ala Pro Glu Leu Ala Leu Asp Thr Glu Leu Ser Leu Glu Asp Gly Asp
645 650 655
Arg Cys Lys Ala Lys Met
660
<210> 78
<211> 328
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 78
Met Cys His Gln Gln Leu Val Ile Ser Trp Phe Ser Leu Val Phe Leu
1 5 10 15
Ala Ser Pro Leu Val Ala Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser
325
<210> 79
<211> 335
<212> PRT
<213> little mouse (Mus musculus)
<400> 79
Met Cys Pro Gln Lys Leu Thr Ile Ser Trp Phe Ala Ile Val Leu Leu
1 5 10 15
Val Ser Pro Leu Met Ala Met Trp Glu Leu Glu Lys Asp Val Tyr Val
20 25 30
Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln
50 55 60
Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys
65 70 75 80
Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr
85 90 95
Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp
100 105 110
Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys
115 120 125
Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln
130 135 140
Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro
145 150 155 160
Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys
165 170 175
Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln
180 185 190
Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu
195 200 205
Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser
210 215 220
Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln
225 230 235 240
Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro
245 250 255
Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val
260 265 270
Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys
275 280 285
Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln
290 295 300
Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn
305 310 315 320
Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser
325 330 335
<210> 80
<211> 399
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 80
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
115 120 125
Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr
130 135 140
Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp
145 150 155 160
Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser
165 170 175
Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn
180 185 190
Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr
195 200 205
Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile
210 215 220
Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn
225 230 235 240
Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg
245 250 255
Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met
260 265 270
Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
275 280 285
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
290 295 300
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
305 310 315 320
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
325 330 335
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
340 345 350
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
355 360 365
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
370 375 380
Gln Gly Thr Leu Val Thr Val Ser Ser His His His His His His
385 390 395
<210> 81
<211> 547
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 81
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
115 120 125
Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr
130 135 140
Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp
145 150 155 160
Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser
165 170 175
Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn
180 185 190
Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr
195 200 205
Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile
210 215 220
Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn
225 230 235 240
Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg
245 250 255
Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met
260 265 270
Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser
275 280 285
Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser
290 295 300
Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys
305 310 315 320
Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val
325 330 335
Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser
340 345 350
His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala
355 360 365
Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg
370 375 380
Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu
385 390 395 400
Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly
405 410 415
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
420 425 430
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
435 440 445
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
450 455 460
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
465 470 475 480
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
485 490 495
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
500 505 510
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
515 520 525
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His
530 535 540
His His His
545
<210> 82
<211> 547
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 82
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
115 120 125
Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr
130 135 140
Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp
145 150 155 160
Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser
165 170 175
Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn
180 185 190
Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr
195 200 205
Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile
210 215 220
Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn
225 230 235 240
Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg
245 250 255
Lys Arg Lys Arg Ser Arg Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly
260 265 270
Ser Gly Gly Gly Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser
275 280 285
Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser
290 295 300
Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys
305 310 315 320
Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val
325 330 335
Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser
340 345 350
His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala
355 360 365
Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg
370 375 380
Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu
385 390 395 400
Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly
405 410 415
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
420 425 430
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
435 440 445
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
450 455 460
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
465 470 475 480
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
485 490 495
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
500 505 510
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
515 520 525
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His
530 535 540
His His His
545
<210> 83
<211> 166
<212> PRT
<213> Intelligent (Homo sapiens)
<400> 83
Met Lys Tyr Thr Ser Tyr Ile Leu Ala Phe Gln Leu Cys Ile Val Leu
1 5 10 15
Gly Ser Leu Gly Cys Tyr Cys Gln Asp Pro Tyr Val Lys Glu Ala Glu
20 25 30
Asn Leu Lys Lys Tyr Phe Asn Ala Gly His Ser Asp Val Ala Asp Asn
35 40 45
Gly Thr Leu Phe Leu Gly Ile Leu Lys Asn Trp Lys Glu Glu Ser Asp
50 55 60
Arg Lys Ile Met Gln Ser Gln Ile Val Ser Phe Tyr Phe Lys Leu Phe
65 70 75 80
Lys Asn Phe Lys Asp Asp Gln Ser Ile Gln Lys Ser Val Glu Thr Ile
85 90 95
Lys Glu Asp Met Asn Val Lys Phe Phe Asn Ser Asn Lys Lys Lys Arg
100 105 110
Asp Asp Phe Glu Lys Leu Thr Asn Tyr Ser Val Thr Asp Leu Asn Val
115 120 125
Gln Arg Lys Ala Ile His Glu Leu Ile Gln Val Met Ala Glu Leu Ser
130 135 140
Pro Ala Ala Lys Thr Gly Lys Arg Lys Arg Ser Gln Met Leu Phe Arg
145 150 155 160
Gly Arg Arg Ala Ser Gln
165
<210> 84
<211> 155
<212> PRT
<213> little mouse (Mus musculus)
<400> 84
Met Asn Ala Thr His Cys Ile Leu Ala Leu Gln Leu Phe Leu Met Ala
1 5 10 15
Val Ser Gly Cys Tyr Cys His Gly Thr Val Ile Glu Ser Leu Glu Ser
20 25 30
Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser
35 40 45
Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys
50 55 60
Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val
65 70 75 80
Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser
85 90 95
His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala
100 105 110
Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg
115 120 125
Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu
130 135 140
Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys
145 150 155
<210> 85
<211> 699
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 85
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu
290 295 300
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
305 310 315 320
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
325 330 335
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
340 345 350
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe
355 360 365
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
370 375 380
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
385 390 395 400
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser
405 410 415
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly
420 425 430
Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser
435 440 445
Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn
450 455 460
Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser
465 470 475 480
Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser
485 490 495
Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser
500 505 510
Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu
515 520 525
Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg
530 535 540
Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg
545 550 555 560
Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
565 570 575
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
580 585 590
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
595 600 605
Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
610 615 620
Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu
625 630 635 640
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
645 650 655
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
660 665 670
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu
675 680 685
Val Thr Val Ser Ser His His His His His His
690 695
<210> 86
<211> 436
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 86
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
115 120 125
Gly Ser Cys Asp Leu Pro Gln Thr His Asn Leu Arg Asn Lys Arg Ala
130 135 140
Leu Thr Leu Leu Val Gln Met Arg Arg Leu Ser Pro Leu Ser Cys Leu
145 150 155 160
Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln Glu Lys Val Asp Ala Gln
165 170 175
Gln Ile Lys Lys Ala Gln Ala Ile Pro Val Leu Ser Glu Leu Thr Gln
180 185 190
Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp Ser Ser Ala Ala Trp Asn
195 200 205
Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp Leu His Gln Gln Leu Asn
210 215 220
Asp Leu Gln Gly Cys Leu Met Gln Gln Val Gly Val Gln Glu Phe Pro
225 230 235 240
Leu Thr Gln Glu Asp Ala Leu Leu Ala Val Arg Lys Tyr Phe His Arg
245 250 255
Ile Thr Val Tyr Leu Arg Glu Lys Lys His Ser Pro Cys Ala Trp Glu
260 265 270
Val Val Arg Ala Glu Val Trp Arg Ala Leu Ser Ser Ser Ala Asn Val
275 280 285
Leu Gly Arg Leu Arg Glu Glu Lys Ser Gly Gly Pro Gly Pro Ala Gly
290 295 300
Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
305 310 315 320
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
325 330 335
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
340 345 350
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
355 360 365
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
370 375 380
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
385 390 395 400
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
405 410 415
Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His His His His
420 425 430
Glu Pro Glu Ala
435
<210> 87
<211> 428
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 87
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
115 120 125
Gly Ser Cys Asp Leu Pro Gln Thr His Asn Leu Arg Asn Lys Arg Ala
130 135 140
Leu Thr Leu Leu Val Gln Met Arg Arg Leu Ser Pro Leu Ser Cys Leu
145 150 155 160
Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln Glu Lys Val Asp Ala Gln
165 170 175
Gln Ile Lys Lys Ala Gln Ala Ile Pro Val Leu Ser Glu Leu Thr Gln
180 185 190
Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp Ser Ser Ala Ala Trp Asn
195 200 205
Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp Leu His Gln Gln Leu Asn
210 215 220
Asp Leu Gln Gly Cys Leu Met Gln Gln Val Gly Val Gln Glu Phe Pro
225 230 235 240
Leu Thr Gln Glu Asp Ala Leu Leu Ala Val Arg Lys Tyr Phe His Arg
245 250 255
Ile Thr Val Tyr Leu Arg Glu Lys Lys His Ser Pro Cys Ala Trp Glu
260 265 270
Val Val Arg Ala Glu Val Trp Arg Ala Leu Ser Ser Ser Ala Asn Val
275 280 285
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu
290 295 300
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser
305 310 315 320
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly
325 330 335
Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser
340 345 350
Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys
355 360 365
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu
370 375 380
Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr
385 390 395 400
Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val
405 410 415
Ser Ser His His His His His His Glu Pro Glu Ala
420 425
<210> 88
<211> 489
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
IFNgR1 sequence "
<400> 88
Met Ala Leu Leu Phe Leu Leu Pro Leu Val Met Gln Gly Val Ser Arg
1 5 10 15
Ala Glu Met Gly Thr Ala Asp Leu Gly Pro Ser Ser Val Pro Thr Pro
20 25 30
Thr Asn Val Thr Ile Glu Ser Tyr Asn Met Asn Pro Ile Val Tyr Trp
35 40 45
Glu Tyr Gln Ile Met Pro Gln Val Pro Val Phe Thr Val Glu Val Lys
50 55 60
Asn Tyr Gly Val Lys Asn Ser Glu Trp Ile Asp Ala Cys Ile Asn Ile
65 70 75 80
Ser His His Tyr Cys Asn Ile Ser Asp His Val Gly Asp Pro Ser Asn
85 90 95
Ser Leu Trp Val Arg Val Lys Ala Arg Val Gly Gln Lys Glu Ser Ala
100 105 110
Tyr Ala Lys Ser Glu Glu Phe Ala Val Cys Arg Asp Gly Lys Ile Gly
115 120 125
Pro Pro Lys Leu Asp Ile Arg Lys Glu Glu Lys Gln Ile Met Ile Asp
130 135 140
Ile Phe His Pro Ser Val Phe Val Asn Gly Asp Glu Gln Glu Val Asp
145 150 155 160
Tyr Asp Pro Glu Thr Thr Cys Tyr Ile Arg Val Tyr Asn Val Tyr Val
165 170 175
Arg Met Asn Gly Ser Glu Ile Gln Tyr Lys Ile Leu Thr Gln Lys Glu
180 185 190
Asp Asp Cys Asp Glu Ile Gln Cys Gln Leu Ala Ile Pro Val Ser Ser
195 200 205
Leu Asn Ser Gln Tyr Cys Val Ser Ala Glu Gly Val Leu His Val Trp
210 215 220
Gly Val Thr Thr Glu Lys Ser Lys Glu Val Cys Ile Thr Ile Phe Asn
225 230 235 240
Ser Ser Ile Lys Gly Ser Leu Trp Ile Pro Val Val Ala Ala Leu Leu
245 250 255
Leu Phe Leu Val Leu Ser Leu Val Phe Ile Cys Phe Tyr Ile Lys Lys
260 265 270
Ile Asn Pro Leu Lys Glu Lys Ser Ile Ile Leu Pro Lys Ser Leu Ile
275 280 285
Ser Val Val Arg Ser Ala Thr Leu Glu Thr Lys Pro Glu Ser Lys Tyr
290 295 300
Val Ser Leu Ile Thr Ser Tyr Gln Pro Phe Ser Leu Glu Lys Glu Val
305 310 315 320
Val Cys Glu Glu Pro Leu Ser Pro Ala Thr Val Pro Gly Met His Thr
325 330 335
Glu Asp Asn Pro Gly Lys Val Glu His Thr Glu Glu Leu Ser Ser Ile
340 345 350
Thr Glu Val Val Thr Thr Glu Glu Asn Ile Pro Asp Val Val Pro Gly
355 360 365
Ser His Leu Thr Pro Ile Glu Arg Glu Ser Ser Ser Pro Leu Ser Ser
370 375 380
Asn Gln Ser Glu Pro Gly Ser Ile Ala Leu Asn Ser Tyr His Ser Arg
385 390 395 400
Asn Cys Ser Glu Ser Asp His Ser Arg Asn Gly Phe Asp Thr Asp Ser
405 410 415
Ser Cys Leu Glu Ser His Ser Ser Leu Ser Asp Ser Glu Phe Pro Pro
420 425 430
Asn Asn Lys Gly Glu Ile Lys Thr Glu Gly Gln Glu Leu Ile Thr Val
435 440 445
Ile Lys Ala Pro Thr Ser Phe Gly Tyr Asp Lys Pro His Val Leu Val
450 455 460
Asp Leu Leu Val Asp Asp Ser Gly Lys Glu Ser Leu Ile Gly Tyr Arg
465 470 475 480
Pro Thr Glu Asp Ser Lys Glu Phe Ser
485
<210> 89
<211> 337
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
IFNgR2 sequence "
<400> 89
Met Arg Pro Thr Leu Leu Trp Ser Leu Leu Leu Leu Leu Gly Val Phe
1 5 10 15
Ala Ala Ala Ala Ala Ala Pro Pro Asp Pro Leu Ser Gln Leu Pro Ala
20 25 30
Pro Gln His Pro Lys Ile Arg Leu Tyr Asn Ala Glu Gln Val Leu Ser
35 40 45
Trp Glu Pro Val Ala Leu Ser Asn Ser Thr Arg Pro Val Val Tyr Gln
50 55 60
Val Gln Phe Lys Tyr Thr Asp Ser Lys Trp Phe Thr Ala Asp Ile Met
65 70 75 80
Ser Ile Gly Val Asn Cys Thr Gln Ile Thr Ala Thr Glu Cys Asp Phe
85 90 95
Thr Ala Ala Ser Pro Ser Ala Gly Phe Pro Met Asp Phe Asn Val Thr
100 105 110
Leu Arg Leu Arg Ala Glu Leu Gly Ala Leu His Ser Ala Trp Val Thr
115 120 125
Met Pro Trp Phe Gln His Tyr Arg Asn Val Thr Val Gly Pro Pro Glu
130 135 140
Asn Ile Glu Val Thr Pro Gly Glu Gly Ser Leu Ile Ile Arg Phe Ser
145 150 155 160
Ser Pro Phe Asp Ile Ala Asp Thr Ser Thr Ala Phe Phe Cys Tyr Tyr
165 170 175
Val His Tyr Trp Glu Lys Gly Gly Ile Gln Gln Val Lys Gly Pro Phe
180 185 190
Arg Ser Asn Ser Ile Ser Leu Asp Asn Leu Lys Pro Ser Arg Val Tyr
195 200 205
Cys Leu Gln Val Gln Ala Gln Leu Leu Trp Asn Lys Ser Asn Ile Phe
210 215 220
Arg Val Gly His Leu Ser Asn Ile Ser Cys Tyr Glu Thr Met Ala Asp
225 230 235 240
Ala Ser Thr Glu Leu Gln Gln Val Ile Leu Ile Ser Val Gly Thr Phe
245 250 255
Ser Leu Leu Ser Val Leu Ala Gly Ala Cys Phe Phe Leu Val Leu Lys
260 265 270
Tyr Arg Gly Leu Ile Lys Tyr Trp Phe His Thr Pro Pro Ser Ile Pro
275 280 285
Leu Gln Ile Glu Glu Tyr Leu Lys Asp Pro Thr Gln Pro Ile Leu Glu
290 295 300
Ala Leu Asp Lys Asp Ser Ser Pro Lys Asp Asp Val Trp Asp Ser Val
305 310 315 320
Ser Ile Ile Ser Phe Pro Glu Lys Glu Gln Glu Asp Val Leu Gln Thr
325 330 335
Leu
<210> 90
<211> 528
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 90
Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp
20 25 30
Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val
35 40 45
Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn
85 90 95
Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val
100 105 110
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
115 120 125
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
130 135 140
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys
145 150 155 160
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
165 170 175
Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser
180 185 190
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
195 200 205
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
210 215 220
Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val
225 230 235 240
Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu
245 250 255
Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn
260 265 270
Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu
275 280 285
Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln
290 295 300
Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp
305 310 315 320
Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile
325 330 335
Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser
340 345 350
Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe
355 360 365
Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu Ser Ser Leu
370 375 380
Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly
385 390 395 400
Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
405 410 415
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
420 425 430
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
435 440 445
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
450 455 460
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
465 470 475 480
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
485 490 495
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
500 505 510
Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His His His His
515 520 525
<210> 91
<211> 658
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 91
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
115 120 125
Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr
130 135 140
Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp
145 150 155 160
Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser
165 170 175
Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn
180 185 190
Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr
195 200 205
Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile
210 215 220
Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn
225 230 235 240
Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg
245 250 255
Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met
260 265 270
Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
275 280 285
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
290 295 300
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
305 310 315 320
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
325 330 335
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
340 345 350
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
355 360 365
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
370 375 380
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
385 390 395 400
Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly
405 410 415
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
420 425 430
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
435 440 445
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
450 455 460
Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
465 470 475 480
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
485 490 495
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
500 505 510
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
515 520 525
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
530 535 540
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
545 550 555 560
Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg
565 570 575
Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly
580 585 590
Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
595 600 605
Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys
610 615 620
Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp
625 630 635 640
Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser His His His His
645 650 655
His His
<210> 92
<211> 1337
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 92
Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu
1 5 10 15
Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
20 25 30
Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr Asp
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu
65 70 75 80
Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu
100 105 110
Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys
115 120 125
Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln
145 150 155 160
Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser
165 170 175
Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser
180 185 190
Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro
210 215 220
Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys
225 230 235 240
Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser
260 265 270
Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His
275 280 285
Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala
290 295 300
Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys
340 345 350
Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala
355 360 365
Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro
370 375 380
Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu
385 390 395 400
Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg
420 425 430
Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys
435 440 445
Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His
450 455 460
Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser
465 470 475 480
Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp
500 505 510
Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu
530 535 540
Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys
545 550 555 560
Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val
565 570 575
Thr Arg Cys Lys Asp Ala Leu Ala Ser Gly Gly Pro Gly Pro Ala Gly
580 585 590
Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu
595 600 605
Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys
610 615 620
Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met
625 630 635 640
Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu
645 650 655
Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu
660 665 670
Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp
675 680 685
Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln
690 695 700
Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro
705 710 715 720
Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro
725 730 735
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Ala His Lys Ser
740 745 750
Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly
755 760 765
Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp
770 775 780
Glu His Ala Lys Leu Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys
785 790 795 800
Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu
805 810 815
Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly
820 825 830
Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys
835 840 845
Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg
850 855 860
Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr
865 870 875 880
Phe Met Gly His Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe
885 890 895
Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu
900 905 910
Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys
915 920 925
Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg
930 935 940
Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala
945 950 955 960
Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala
965 970 975
Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys
980 985 990
Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala
995 1000 1005
Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln
1010 1015 1020
Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His Cys Leu Ser
1025 1030 1035
Glu Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala Ile Ala
1040 1045 1050
Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala Glu
1055 1060 1065
Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg
1070 1075 1080
Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys
1085 1090 1095
Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro
1100 1105 1110
Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val
1115 1120 1125
Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu
1130 1135 1140
Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr
1145 1150 1155
Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala
1160 1165 1170
Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro
1175 1180 1185
Glu Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile
1190 1195 1200
Leu Asn Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu
1205 1210 1215
His Val Thr Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro
1220 1225 1230
Cys Phe Ser Ala Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu
1235 1240 1245
Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp Ile Cys Thr Leu
1250 1255 1260
Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu
1265 1270 1275
Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu Lys Thr
1280 1285 1290
Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys Ala
1295 1300 1305
Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val
1310 1315 1320
Thr Arg Cys Lys Asp Ala Leu Ala His His His His His His
1325 1330 1335
<210> 93
<211> 1485
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 93
Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu
1 5 10 15
Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
20 25 30
Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr Asp
35 40 45
Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys
50 55 60
Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu
65 70 75 80
Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro
85 90 95
Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu
100 105 110
Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys
115 120 125
Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala Arg
130 135 140
Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln
145 150 155 160
Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser
165 170 175
Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser
180 185 190
Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu
195 200 205
Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro
210 215 220
Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys
225 230 235 240
Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
245 250 255
Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser
260 265 270
Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His
275 280 285
Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala
290 295 300
Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala
305 310 315 320
Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg
325 330 335
Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys
340 345 350
Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala
355 360 365
Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro
370 375 380
Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu
385 390 395 400
Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro
405 410 415
Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg
420 425 430
Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys
435 440 445
Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His
450 455 460
Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser
465 470 475 480
Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr
485 490 495
Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp
500 505 510
Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala
515 520 525
Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu
530 535 540
Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys
545 550 555 560
Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val
565 570 575
Thr Arg Cys Lys Asp Ala Leu Ala Ser Gly Gly Pro Gly Pro Ala Gly
580 585 590
Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu
595 600 605
Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys
610 615 620
Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met
625 630 635 640
Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu
645 650 655
Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu
660 665 670
Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp
675 680 685
Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln
690 695 700
Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro
705 710 715 720
Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Gly Gly Gly Gly
725 730 735
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser His Gly Thr Val Ile
740 745 750
Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp
755 760 765
Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys
770 775 780
Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu
785 790 795 800
Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile
805 810 815
Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys
820 825 830
Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn
835 840 845
Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His
850 855 860
Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys
865 870 875 880
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu
885 890 895
Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu Gln
900 905 910
His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln Lys
915 920 925
Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr Asp Phe
930 935 940
Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys Ser
945 950 955 960
Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu Arg
965 970 975
Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro Glu
980 985 990
Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu Pro
995 1000 1005
Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys
1010 1015 1020
Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala
1025 1030 1035
Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala
1040 1045 1050
Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp
1055 1060 1065
Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys
1070 1075 1080
Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met
1085 1090 1095
Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
1100 1105 1110
Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys
1115 1120 1125
Leu Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly
1130 1135 1140
Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr
1145 1150 1155
Met Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys
1160 1165 1170
Cys Asp Lys Pro Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val
1175 1180 1185
Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp
1190 1195 1200
Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys
1205 1210 1215
Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His
1220 1225 1230
Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys Tyr
1235 1240 1245
Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala
1250 1255 1260
Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu
1265 1270 1275
Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu
1280 1285 1290
Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln
1295 1300 1305
Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg
1310 1315 1320
Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp
1325 1330 1335
Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn
1340 1345 1350
Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val
1355 1360 1365
Thr Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe
1370 1375 1380
Ser Ala Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys
1385 1390 1395
Ala Glu Thr Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu
1400 1405 1410
Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val
1415 1420 1425
Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu Lys Thr Val Met
1430 1435 1440
Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys Ala Ala Asp
1445 1450 1455
Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val Thr Arg
1460 1465 1470
Cys Lys Asp Ala Leu Ala His His His His His His
1475 1480 1485
<210> 94
<211> 698
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 94
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser
275 280 285
Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu
290 295 300
Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly
305 310 315 320
Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu
325 330 335
Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val
340 345 350
Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys
355 360 365
Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln
370 375 380
Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu
385 390 395 400
Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser His Gly Thr
420 425 430
Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly
435 440 445
Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp
450 455 460
Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe
465 470 475 480
Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn
485 490 495
Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn
500 505 510
Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val
515 520 525
Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val
530 535 540
Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser
545 550 555 560
Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
565 570 575
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
580 585 590
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys
595 600 605
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
610 615 620
Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser
625 630 635 640
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
645 650 655
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
660 665 670
Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val
675 680 685
Thr Val Ser Ser His His His His His His
690 695
<210> 95
<211> 699
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 95
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu
290 295 300
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
305 310 315 320
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
325 330 335
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
340 345 350
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe
355 360 365
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
370 375 380
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
385 390 395 400
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser
405 410 415
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly
420 425 430
Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser
435 440 445
Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn
450 455 460
Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser
465 470 475 480
Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser
485 490 495
Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser
500 505 510
Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu
515 520 525
Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg
530 535 540
Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg
545 550 555 560
Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
565 570 575
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
580 585 590
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
595 600 605
Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
610 615 620
Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu
625 630 635 640
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
645 650 655
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
660 665 670
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu
675 680 685
Val Thr Val Ser Ser His His His His His His
690 695
<210> 96
<211> 554
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 96
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser
275 280 285
Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu
290 295 300
Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly
305 310 315 320
Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu
325 330 335
Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val
340 345 350
Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys
355 360 365
Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln
370 375 380
Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu
385 390 395 400
Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly
405 410 415
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln
420 425 430
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
435 440 445
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
450 455 460
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
465 470 475 480
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg
485 490 495
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
500 505 510
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
515 520 525
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
530 535 540
His His His His His His Glu Pro Glu Ala
545 550
<210> 97
<211> 554
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 97
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu
290 295 300
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
305 310 315 320
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
325 330 335
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
340 345 350
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe
355 360 365
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
370 375 380
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
385 390 395 400
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly
405 410 415
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val
420 425 430
Gln Leu Gln Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu
435 440 445
Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asn Ser Val Met
450 455 460
Ala Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu Phe Val Ala Ile
465 470 475 480
Ile Asn Ser Val Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg
485 490 495
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met
500 505 510
Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Val Cys Asn Arg Asn
515 520 525
Phe Asp Arg Ile Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser
530 535 540
His His His His His His Glu Pro Glu Ala
545 550
<210> 98
<211> 702
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 98
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val
290 295 300
Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile
305 310 315 320
Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln
325 330 335
Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr
340 345 350
Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn
355 360 365
Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser
370 375 380
Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn
385 390 395 400
Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val
405 410 415
His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg
420 425 430
Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
435 440 445
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
450 455 460
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
465 470 475 480
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
485 490 495
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
500 505 510
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
515 520 525
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
530 535 540
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
545 550 555 560
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala
580 585 590
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser
595 600 605
Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
610 615 620
Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser
625 630 635 640
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
645 650 655
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr
660 665 670
Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val
675 680 685
Thr Val Ser Ser His His His His His His Glu Pro Glu Ala
690 695 700
<210> 99
<211> 702
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 99
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser
275 280 285
Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu
290 295 300
Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly
305 310 315 320
Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu
325 330 335
Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val
340 345 350
Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys
355 360 365
Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln
370 375 380
Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu
385 390 395 400
Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly
405 410 415
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr
420 425 430
Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly
435 440 445
Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp
450 455 460
Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe
465 470 475 480
Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn
485 490 495
Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn
500 505 510
Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val
515 520 525
Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val
530 535 540
Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser
545 550 555 560
Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
565 570 575
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
580 585 590
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys
595 600 605
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
610 615 620
Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser
625 630 635 640
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
645 650 655
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
660 665 670
Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val
675 680 685
Thr Val Ser Ser His His His His His His Glu Pro Glu Ala
690 695 700
<210> 100
<211> 702
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 100
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val
290 295 300
Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile
305 310 315 320
Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln
325 330 335
Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr
340 345 350
Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn
355 360 365
Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser
370 375 380
Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn
385 390 395 400
Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val
405 410 415
His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg
420 425 430
Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
435 440 445
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
450 455 460
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
465 470 475 480
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
485 490 495
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
500 505 510
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
515 520 525
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
530 535 540
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
545 550 555 560
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Ala Gln Ala
580 585 590
Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser
595 600 605
Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu
610 615 620
Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn Tyr Ala Asp Ser
625 630 635 640
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
645 650 655
Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Val
660 665 670
Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln Gly Thr Gln Val
675 680 685
Thr Val Ser Ser His His His His His His Glu Pro Glu Ala
690 695 700
<210> 101
<211> 832
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 101
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val
290 295 300
Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile
305 310 315 320
Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln
325 330 335
Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr
340 345 350
Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn
355 360 365
Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser
370 375 380
Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn
385 390 395 400
Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val
405 410 415
His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg
420 425 430
Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
435 440 445
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
450 455 460
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
465 470 475 480
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
485 490 495
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
500 505 510
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
515 520 525
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
530 535 540
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
545 550 555 560
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
580 585 590
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
595 600 605
Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
610 615 620
Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp
625 630 635 640
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
645 650 655
Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
660 665 670
Tyr Cys Ala Arg Gly Val Gly Ala Phe Arg Pro Tyr Arg Lys His Glu
675 680 685
Trp Gly Gln Gly Thr Leu Val Thr Val Ser Arg Gly Gly Gly Gly Ser
690 695 700
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ser Glu Leu Thr Gln
705 710 715 720
Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val Arg Ile Thr Cys
725 730 735
Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp Tyr Gln Gln Lys
740 745 750
Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys Asn Asn Arg Pro
755 760 765
Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser Gly Asn Thr Ala
770 775 780
Ser Leu Thr Thr Thr Gly Ala Gln Ala Glu Asp Glu Ala Asp Tyr Tyr
785 790 795 800
Cys Asn Ser Ser Pro Phe Glu His Asn Leu Val Val Phe Gly Gly Gly
805 810 815
Thr Lys Leu Thr Val Leu His His His His His His Glu Pro Glu Ala
820 825 830
<210> 102
<211> 276
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 102
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys 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
Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr
65 70 75 80
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Gly Val Gly Ala Phe Arg Pro Tyr
115 120 125
Arg Lys His Glu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Arg Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ser
145 150 155 160
Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val
165 170 175
Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp
180 185 190
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys
195 200 205
Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser
210 215 220
Gly Asn Thr Ala Ser Leu Thr Thr Thr Gly Ala Gln Ala Glu Asp Glu
225 230 235 240
Ala Asp Tyr Tyr Cys Asn Ser Ser Pro Phe Glu His Asn Leu Val Val
245 250 255
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
260 265 270
Glu Pro Glu Ala
275
<210> 103
<211> 573
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 103
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu
290 295 300
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
305 310 315 320
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
325 330 335
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
340 345 350
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe
355 360 365
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
370 375 380
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
385 390 395 400
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser
405 410 415
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly
420 425 430
Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser
435 440 445
Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn
450 455 460
Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser
465 470 475 480
Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser
485 490 495
Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser
500 505 510
Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu
515 520 525
Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg
530 535 540
Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg
545 550 555 560
Ser Arg Cys His His His His His His Glu Pro Glu Ala
565 570
<210> 104
<211> 573
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 104
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys His Gly Thr Val Ile Glu Ser Leu Glu Ser
20 25 30
Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser
35 40 45
Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys
50 55 60
Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val
65 70 75 80
Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser
85 90 95
His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala
100 105 110
Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg
115 120 125
Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu
130 135 140
Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
210 215 220
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
225 230 235 240
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
245 250 255
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
260 265 270
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val
290 295 300
Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile
305 310 315 320
Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln
325 330 335
Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr
340 345 350
Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn
355 360 365
Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser
370 375 380
Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn
385 390 395 400
Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val
405 410 415
His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg
420 425 430
Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
435 440 445
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
450 455 460
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
465 470 475 480
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
485 490 495
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
500 505 510
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
515 520 525
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
530 535 540
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
545 550 555 560
Val Ser Ser His His His His His His Glu Pro Glu Ala
565 570
<210> 105
<211> 1511
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 105
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys His Gly Thr Val Ile Glu Ser Leu Glu Ser
20 25 30
Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser
35 40 45
Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys
50 55 60
Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val
65 70 75 80
Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser
85 90 95
His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala
100 105 110
Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg
115 120 125
Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu
130 135 140
Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Ala His Lys Ser Glu
165 170 175
Ile Ala His Arg Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu
180 185 190
Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu
195 200 205
His Ala Lys Leu Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val
210 215 220
Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe
225 230 235 240
Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu
245 250 255
Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe
260 265 270
Leu Gln His Lys Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro
275 280 285
Glu Ala Glu Ala Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe
290 295 300
Met Gly His Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr
305 310 315 320
Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr
325 330 335
Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu
340 345 350
Asp Gly Val Lys Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met
355 360 365
Lys Cys Ser Ser Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp
370 375 380
Ala Val Ala Arg Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu
385 390 395 400
Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys
405 410 415
His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys
420 425 430
Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys
435 440 445
Cys Asp Lys Pro Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu
450 455 460
His Asp Thr Met Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val
465 470 475 480
Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe
485 490 495
Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser
500 505 510
Val Ser Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu
515 520 525
Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu
530 535 540
Ala Glu Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr
545 550 555 560
Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala
565 570 575
Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr
580 585 590
Leu Val Glu Ala Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys
595 600 605
Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser
610 615 620
Ala Ile Leu Asn Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser
625 630 635 640
Glu His Val Thr Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro
645 650 655
Cys Phe Ser Ala Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe
660 665 670
Lys Ala Glu Thr Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu
675 680 685
Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys
690 695 700
His Lys Pro Lys Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp
705 710 715 720
Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr
725 730 735
Cys Phe Ser Thr Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala
740 745 750
Leu Ala Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
755 760 765
Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe
770 775 780
Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile
785 790 795 800
Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln
805 810 815
Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln
820 825 830
Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr
835 840 845
Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala
850 855 860
Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu
865 870 875 880
Leu Ile Arg Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys
885 890 895
Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
900 905 910
Gly Leu Pro Gly Ser Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr
915 920 925
Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe
930 935 940
Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val
945 950 955 960
Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala
965 970 975
Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys
980 985 990
Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys
995 1000 1005
Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
1010 1015 1020
Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu
1025 1030 1035
Ala Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly
1040 1045 1050
His Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala
1055 1060 1065
Pro Glu Leu Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr
1070 1075 1080
Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys
1085 1090 1095
Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser Ser Val Arg Gln
1100 1105 1110
Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu Arg Ala Phe
1115 1120 1125
Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro Asn Ala
1130 1135 1140
Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys Val
1145 1150 1155
Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp
1160 1165 1170
Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile
1175 1180 1185
Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys
1190 1195 1200
Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp
1205 1210 1215
Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys
1220 1225 1230
Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu
1235 1240 1245
Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu
1250 1255 1260
Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys
1265 1270 1275
Ala Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu
1280 1285 1290
Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn
1295 1300 1305
Cys Asp Leu Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala
1310 1315 1320
Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro
1325 1330 1335
Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg Val Gly Thr Lys
1340 1345 1350
Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys Val Glu Asp
1355 1360 1365
Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His Glu Lys
1370 1375 1380
Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser Leu
1385 1390 1395
Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr
1400 1405 1410
Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser
1415 1420 1425
Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln
1430 1435 1440
Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala
1445 1450 1455
Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp
1460 1465 1470
Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu
1475 1480 1485
Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala His His
1490 1495 1500
His His His His Glu Pro Glu Ala
1505 1510
<210> 106
<211> 1511
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 106
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Ala His Lys Ser Glu Ile Ala His Arg
20 25 30
Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala
35 40 45
Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu
50 55 60
Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
65 70 75 80
Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
85 90 95
Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys
100 105 110
Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
115 120 125
Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala
130 135 140
Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr
145 150 155 160
Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
165 170 175
Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala
180 185 190
Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys
195 200 205
Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser
210 215 220
Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
225 230 235 240
Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu
245 250 255
Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu
260 265 270
Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu
275 280 285
Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro
290 295 300
Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met
305 310 315 320
Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu
325 330 335
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe
340 345 350
Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu
355 360 365
Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala
370 375 380
Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln
385 390 395 400
Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu
405 410 415
Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg
420 425 430
Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala
435 440 445
Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu
450 455 460
Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn
465 470 475 480
Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr
485 490 495
Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala
500 505 510
Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr
515 520 525
Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln
530 535 540
Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys
545 550 555 560
Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe
565 570 575
Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr
580 585 590
Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala Ser Gly
595 600 605
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr
610 615 620
Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly
625 630 635 640
Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp
645 650 655
Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe
660 665 670
Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn
675 680 685
Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn
690 695 700
Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val
705 710 715 720
Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val
725 730 735
Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser
740 745 750
Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
755 760 765
Ser Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly
770 775 780
Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu
785 790 795 800
Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr
805 810 815
Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp
820 825 830
Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn
835 840 845
Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu
850 855 860
Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser
865 870 875 880
Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe
885 890 895
Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala
900 905 910
Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu
915 920 925
Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu
930 935 940
Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val
945 950 955 960
Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly
965 970 975
Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe
980 985 990
Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr
995 1000 1005
Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala
1010 1015 1020
Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala
1025 1030 1035
Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu
1040 1045 1050
Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met Pro
1055 1060 1065
Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu
1070 1075 1080
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr
1085 1090 1095
Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser
1100 1105 1110
Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys
1115 1120 1125
Cys Cys Ala Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu
1130 1135 1140
Ala Glu Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys
1145 1150 1155
Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln
1160 1165 1170
Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser
1175 1180 1185
Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg Val Gly
1190 1195 1200
Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys Val
1205 1210 1215
Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His
1220 1225 1230
Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly
1235 1240 1245
Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp
1250 1255 1260
Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe
1265 1270 1275
His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys
1280 1285 1290
Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala
1295 1300 1305
Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe
1310 1315 1320
Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser
1325 1330 1335
Thr Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala
1340 1345 1350
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
1355 1360 1365
His Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe
1370 1375 1380
Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp
1385 1390 1395
Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln
1400 1405 1410
Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys
1415 1420 1425
Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser His
1430 1435 1440
Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala
1445 1450 1455
Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln
1460 1465 1470
Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
1475 1480 1485
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys His His
1490 1495 1500
His His His His Glu Pro Glu Ala
1505 1510
<210> 107
<211> 2110
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 107
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Ala His Lys Ser Glu Ile Ala His Arg
20 25 30
Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala
35 40 45
Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu
50 55 60
Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
65 70 75 80
Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
85 90 95
Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys
100 105 110
Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
115 120 125
Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala
130 135 140
Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr
145 150 155 160
Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
165 170 175
Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala
180 185 190
Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys
195 200 205
Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser
210 215 220
Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
225 230 235 240
Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu
245 250 255
Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu
260 265 270
Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu
275 280 285
Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro
290 295 300
Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met
305 310 315 320
Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu
325 330 335
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe
340 345 350
Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu
355 360 365
Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala
370 375 380
Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln
385 390 395 400
Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu
405 410 415
Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg
420 425 430
Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala
435 440 445
Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu
450 455 460
Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn
465 470 475 480
Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr
485 490 495
Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala
500 505 510
Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr
515 520 525
Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln
530 535 540
Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys
545 550 555 560
Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe
565 570 575
Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr
580 585 590
Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala Ser Gly
595 600 605
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr
610 615 620
Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly
625 630 635 640
Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp
645 650 655
Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe
660 665 670
Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn
675 680 685
Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn
690 695 700
Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val
705 710 715 720
Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val
725 730 735
Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser
740 745 750
Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
755 760 765
Ser Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly
770 775 780
Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu
785 790 795 800
Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr
805 810 815
Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp
820 825 830
Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn
835 840 845
Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu
850 855 860
Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser
865 870 875 880
Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe
885 890 895
Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val Ala
900 905 910
Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu
915 920 925
Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu
930 935 940
Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val
945 950 955 960
Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly
965 970 975
Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe
980 985 990
Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr
995 1000 1005
Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala
1010 1015 1020
Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala
1025 1030 1035
Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu
1040 1045 1050
Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met Pro
1055 1060 1065
Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu
1070 1075 1080
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr
1085 1090 1095
Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser
1100 1105 1110
Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys
1115 1120 1125
Cys Cys Ala Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu
1130 1135 1140
Ala Glu Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys
1145 1150 1155
Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln
1160 1165 1170
Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser
1175 1180 1185
Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg Val Gly
1190 1195 1200
Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys Val
1205 1210 1215
Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His
1220 1225 1230
Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly
1235 1240 1245
Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp
1250 1255 1260
Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe
1265 1270 1275
His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys
1280 1285 1290
Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala
1295 1300 1305
Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe
1310 1315 1320
Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser
1325 1330 1335
Thr Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala
1340 1345 1350
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
1355 1360 1365
His Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe
1370 1375 1380
Asn Ser Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp
1385 1390 1395
Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln
1400 1405 1410
Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys
1415 1420 1425
Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile Glu Ser His
1430 1435 1440
Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala
1445 1450 1455
Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val Gln
1460 1465 1470
Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
1475 1480 1485
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly
1490 1495 1500
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Ala
1505 1510 1515
His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu Gln
1520 1525 1530
His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln
1535 1540 1545
Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val Thr
1550 1555 1560
Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys
1565 1570 1575
Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile
1580 1585 1590
Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr
1595 1600 1605
Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp
1610 1615 1620
Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala
1625 1630 1635
Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His
1640 1645 1650
Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro
1655 1660 1665
Glu Leu Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln
1670 1675 1680
Cys Cys Ala Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu
1685 1690 1695
Asp Gly Val Lys Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg
1700 1705 1710
Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu Arg Ala Phe Lys
1715 1720 1725
Ala Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro Asn Ala Asp
1730 1735 1740
Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys Val Asn
1745 1750 1755
Lys Glu Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg
1760 1765 1770
Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser
1775 1780 1785
Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala
1790 1795 1800
His Cys Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp Leu
1805 1810 1815
Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys
1820 1825 1830
Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr
1835 1840 1845
Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu
1850 1855 1860
Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala
1865 1870 1875
Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe
1880 1885 1890
Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys
1895 1900 1905
Asp Leu Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile
1910 1915 1920
Leu Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr
1925 1930 1935
Leu Val Glu Ala Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys
1940 1945 1950
Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr
1955 1960 1965
Leu Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His Glu Lys Thr
1970 1975 1980
Pro Val Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser Leu Val
1985 1990 1995
Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr Tyr
2000 2005 2010
Val Pro Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp
2015 2020 2025
Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr
2030 2035 2040
Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu
2045 2050 2055
Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr
2060 2065 2070
Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly
2075 2080 2085
Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala His His His
2090 2095 2100
His His His Glu Pro Glu Ala
2105 2110
<210> 108
<211> 2120
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 108
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Ala His Lys Ser Glu Ile Ala His Arg
20 25 30
Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala
35 40 45
Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu
50 55 60
Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
65 70 75 80
Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
85 90 95
Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys
100 105 110
Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
115 120 125
Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala
130 135 140
Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr
145 150 155 160
Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
165 170 175
Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala
180 185 190
Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys
195 200 205
Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser
210 215 220
Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
225 230 235 240
Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu
245 250 255
Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu
260 265 270
Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu
275 280 285
Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro
290 295 300
Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met
305 310 315 320
Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu
325 330 335
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe
340 345 350
Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu
355 360 365
Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala
370 375 380
Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln
385 390 395 400
Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu
405 410 415
Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg
420 425 430
Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala
435 440 445
Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu
450 455 460
Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn
465 470 475 480
Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr
485 490 495
Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala
500 505 510
Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr
515 520 525
Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln
530 535 540
Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys
545 550 555 560
Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe
565 570 575
Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr
580 585 590
Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala Ser Gly
595 600 605
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr
610 615 620
Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly
625 630 635 640
Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp
645 650 655
Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe
660 665 670
Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn
675 680 685
Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn
690 695 700
Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val
705 710 715 720
Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val
725 730 735
Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser
740 745 750
Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
755 760 765
Ser Gly Gly Gly Gly Ser Glu Ala His Lys Ser Glu Ile Ala His Arg
770 775 780
Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala
785 790 795 800
Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu
805 810 815
Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
820 825 830
Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
835 840 845
Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys
850 855 860
Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
865 870 875 880
Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala
885 890 895
Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr
900 905 910
Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
915 920 925
Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala
930 935 940
Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys
945 950 955 960
Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser
965 970 975
Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
980 985 990
Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu
995 1000 1005
Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp
1010 1015 1020
Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met
1025 1030 1035
Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys
1040 1045 1050
Asp Lys Pro Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu
1055 1060 1065
His Asp Thr Met Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe
1070 1075 1080
Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp
1085 1090 1095
Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro
1100 1105 1110
Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu
1115 1120 1125
Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala Cys
1130 1135 1140
Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro
1145 1150 1155
Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly
1160 1165 1170
Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys
1175 1180 1185
Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn
1190 1195 1200
Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln
1205 1210 1215
Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg
1220 1225 1230
Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr
1235 1240 1245
Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser
1250 1255 1260
Ala Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala
1265 1270 1275
Glu Thr Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys
1280 1285 1290
Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys
1295 1300 1305
His Lys Pro Lys Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp
1310 1315 1320
Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys
1325 1330 1335
Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val Thr Arg Cys
1340 1345 1350
Lys Asp Ala Leu Ala Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly
1355 1360 1365
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile
1370 1375 1380
Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile
1385 1390 1395
Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp
1400 1405 1410
Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser
1415 1420 1425
Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile
1430 1435 1440
Ser Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe
1445 1450 1455
Phe Ser Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala
1460 1465 1470
Lys Phe Glu Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn
1475 1480 1485
Glu Leu Ile Arg Val Val His Gln Leu Leu Pro Glu Ser Ser Leu
1490 1495 1500
Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala
1505 1510 1515
Gly Met Lys Gly Leu Pro Gly Ser Glu Ala His Lys Ser Glu Ile
1520 1525 1530
Ala His Arg Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu
1535 1540 1545
Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp
1550 1555 1560
Glu His Ala Lys Leu Val Gln Glu Val Thr Asp Phe Ala Lys Thr
1565 1570 1575
Cys Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys Ser Leu His
1580 1585 1590
Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu Arg Glu
1595 1600 1605
Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro Glu
1610 1615 1620
Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu
1625 1630 1635
Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser Phe
1640 1645 1650
Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val
1655 1660 1665
Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr
1670 1675 1680
Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala
1685 1690 1695
Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu
1700 1705 1710
Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser
1715 1720 1725
Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala
1730 1735 1740
Arg Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr
1745 1750 1755
Lys Leu Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His
1760 1765 1770
Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys
1775 1780 1785
Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr
1790 1795 1800
Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His Cys Leu Ser Glu
1805 1810 1815
Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala Ile Ala Ala
1820 1825 1830
Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala Glu Ala
1835 1840 1845
Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg Arg
1850 1855 1860
His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys
1865 1870 1875
Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro
1880 1885 1890
Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu
1895 1900 1905
Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys
1910 1915 1920
Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr
1925 1930 1935
Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala
1940 1945 1950
Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu
1955 1960 1965
Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu
1970 1975 1980
Asn Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His
1985 1990 1995
Val Thr Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys
2000 2005 2010
Phe Ser Ala Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe
2015 2020 2025
Lys Ala Glu Thr Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro
2030 2035 2040
Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu
2045 2050 2055
Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu Lys Thr Val
2060 2065 2070
Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys Ala Ala
2075 2080 2085
Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val Thr
2090 2095 2100
Arg Cys Lys Asp Ala Leu Ala His His His His His His Glu Pro
2105 2110 2115
Glu Ala
2120
<210> 109
<211> 2130
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 109
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Ala His Lys Ser Glu Ile Ala His Arg
20 25 30
Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala
35 40 45
Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu
50 55 60
Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
65 70 75 80
Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
85 90 95
Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys
100 105 110
Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
115 120 125
Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala
130 135 140
Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr
145 150 155 160
Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
165 170 175
Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala
180 185 190
Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys
195 200 205
Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser
210 215 220
Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
225 230 235 240
Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu
245 250 255
Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu
260 265 270
Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu
275 280 285
Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro
290 295 300
Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met
305 310 315 320
Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu
325 330 335
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe
340 345 350
Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu
355 360 365
Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala
370 375 380
Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln
385 390 395 400
Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu
405 410 415
Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg
420 425 430
Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala
435 440 445
Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu
450 455 460
Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn
465 470 475 480
Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr
485 490 495
Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala
500 505 510
Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr
515 520 525
Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln
530 535 540
Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys
545 550 555 560
Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe
565 570 575
Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr
580 585 590
Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala Ser Gly
595 600 605
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr
610 615 620
Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly
625 630 635 640
Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp
645 650 655
Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe
660 665 670
Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn
675 680 685
Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn
690 695 700
Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val
705 710 715 720
Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val
725 730 735
Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser
740 745 750
Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
755 760 765
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Ala His Lys Ser
770 775 780
Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly
785 790 795 800
Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp
805 810 815
Glu His Ala Lys Leu Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys
820 825 830
Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu
835 840 845
Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly
850 855 860
Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys
865 870 875 880
Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg
885 890 895
Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr
900 905 910
Phe Met Gly His Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe
915 920 925
Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu
930 935 940
Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys
945 950 955 960
Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg
965 970 975
Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala
980 985 990
Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala
995 1000 1005
Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys Val Asn Lys Glu
1010 1015 1020
Cys Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu
1025 1030 1035
Leu Ala Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys
1040 1045 1050
Leu Gln Thr Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His Cys
1055 1060 1065
Leu Ser Glu Val Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala
1070 1075 1080
Ile Ala Ala Asp Phe Val Glu Asp Gln Glu Val Cys Lys Asn Tyr
1085 1090 1095
Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe Leu Tyr Glu Tyr
1100 1105 1110
Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu Leu Arg Leu
1115 1120 1125
Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala Glu Ala
1130 1135 1140
Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln Pro
1145 1150 1155
Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu
1160 1165 1170
Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val
1175 1180 1185
Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val
1190 1195 1200
Glu Ala Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr
1205 1210 1215
Leu Pro Glu Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser
1220 1225 1230
Ala Ile Leu Asn Arg Val Cys Leu Leu His Glu Lys Thr Pro Val
1235 1240 1245
Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser Leu Val Glu Arg
1250 1255 1260
Arg Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr Tyr Val Pro
1265 1270 1275
Lys Glu Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp Ile Cys
1280 1285 1290
Thr Leu Pro Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu
1295 1300 1305
Ala Glu Leu Val Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu
1310 1315 1320
Lys Thr Val Met Asp Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys
1325 1330 1335
Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr Glu Gly Pro Asn
1340 1345 1350
Leu Val Thr Arg Cys Lys Asp Ala Leu Ala Gly Gly Gly Gly Ser
1355 1360 1365
Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
1370 1375 1380
Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu Glu Ser
1385 1390 1395
Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu Lys
1400 1405 1410
Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
1415 1420 1425
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu
1430 1435 1440
Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser
1445 1450 1455
Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys
1460 1465 1470
Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn
1475 1480 1485
Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val
1490 1495 1500
Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg
1505 1510 1515
Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu
1520 1525 1530
Pro Gly Ser Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn
1535 1540 1545
Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe
1550 1555 1560
Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu
1565 1570 1575
Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu
1580 1585 1590
Ser Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp
1595 1600 1605
Lys Leu Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu
1610 1615 1620
Ala Asp Cys Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe
1625 1630 1635
Leu Gln His Lys Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg
1640 1645 1650
Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys Glu Asn Pro Thr
1655 1660 1665
Thr Phe Met Gly His Tyr Leu His Glu Val Ala Arg Arg His Pro
1670 1675 1680
Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln Tyr Asn
1685 1690 1695
Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser Cys
1700 1705 1710
Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser
1715 1720 1725
Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe Gly
1730 1735 1740
Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln Thr
1745 1750 1755
Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr Asp
1760 1765 1770
Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu Glu
1775 1780 1785
Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu Asn
1790 1795 1800
Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro
1805 1810 1815
Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr
1820 1825 1830
Met Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp
1835 1840 1845
Gln Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu
1850 1855 1860
Gly Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser
1865 1870 1875
Val Ser Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu
1880 1885 1890
Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr
1895 1900 1905
Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu
1910 1915 1920
Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu Tyr Gly
1925 1930 1935
Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro Gln
1940 1945 1950
Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg
1955 1960 1965
Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro
1970 1975 1980
Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys Leu
1985 1990 1995
Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys Cys
2000 2005 2010
Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu Thr
2015 2020 2025
Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr Phe
2030 2035 2040
Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln
2045 2050 2055
Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro
2060 2065 2070
Lys Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala
2075 2080 2085
Gln Phe Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys
2090 2095 2100
Phe Ser Thr Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala
2105 2110 2115
Leu Ala His His His His His His Glu Pro Glu Ala
2120 2125 2130
<210> 110
<211> 703
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 110
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Gly Gly Gly
275 280 285
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
290 295 300
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
305 310 315 320
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
325 330 335
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
340 345 350
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe
355 360 365
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
370 375 380
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
385 390 395 400
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly
405 410 415
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser His Gly
420 425 430
Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser
435 440 445
Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn
450 455 460
Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser
465 470 475 480
Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser
485 490 495
Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser
500 505 510
Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu
515 520 525
Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg
530 535 540
Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg
545 550 555 560
Ser Arg Cys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
565 570 575
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
580 585 590
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
595 600 605
Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
610 615 620
Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu
625 630 635 640
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
645 650 655
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
660 665 670
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu
675 680 685
Val Thr Val Ser Ser His His His His His His Glu Pro Glu Ala
690 695 700
<210> 111
<211> 832
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 111
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser Leu
145 150 155 160
Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu Glu
165 170 175
Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly Asp
180 185 190
Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu Phe
195 200 205
Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val Ile
210 215 220
Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys Lys
225 230 235 240
Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln Val
245 250 255
Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu Leu
260 265 270
Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu
290 295 300
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
305 310 315 320
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
325 330 335
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
340 345 350
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe
355 360 365
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
370 375 380
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
385 390 395 400
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser
405 410 415
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly
420 425 430
Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser
435 440 445
Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn
450 455 460
Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser
465 470 475 480
Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser
485 490 495
Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser
500 505 510
Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu
515 520 525
Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg
530 535 540
Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg
545 550 555 560
Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
565 570 575
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
580 585 590
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
595 600 605
Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
610 615 620
Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu
625 630 635 640
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
645 650 655
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
660 665 670
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu
675 680 685
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
690 695 700
Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Ala
705 710 715 720
Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr
725 730 735
Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly Lys Gln
740 745 750
Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn Tyr Ala
755 760 765
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
770 775 780
Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val
785 790 795 800
Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln Gly Thr
805 810 815
Gln Val Thr Val Ser Ser His His His His His His Glu Pro Glu Ala
820 825 830
<210> 112
<211> 832
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 112
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser His Gly Thr Val Ile Glu Ser
275 280 285
Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser Ser Gly Ile Asp Val Glu
290 295 300
Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg Asn Trp Gln Lys Asp Gly
305 310 315 320
Asp Met Lys Ile Leu Gln Ser Gln Ile Ile Ser Phe Tyr Leu Arg Leu
325 330 335
Phe Glu Val Leu Lys Asp Asn Gln Ala Ile Ser Asn Asn Ile Ser Val
340 345 350
Ile Glu Ser His Leu Ile Thr Thr Phe Phe Ser Asn Ser Lys Ala Lys
355 360 365
Lys Asp Ala Phe Met Ser Ile Ala Lys Phe Glu Val Asn Asn Pro Gln
370 375 380
Val Gln Arg Gln Ala Phe Asn Glu Leu Ile Arg Val Val His Gln Leu
385 390 395 400
Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys Arg Ser Arg Cys Ser Gly
405 410 415
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln
420 425 430
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
435 440 445
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
450 455 460
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
465 470 475 480
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg
485 490 495
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
500 505 510
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
515 520 525
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
530 535 540
Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser His
545 550 555 560
Gly Thr Val Ile Glu Ser Leu Glu Ser Leu Asn Asn Tyr Phe Asn Ser
565 570 575
Ser Gly Ile Asp Val Glu Glu Lys Ser Leu Phe Leu Asp Ile Trp Arg
580 585 590
Asn Trp Gln Lys Asp Gly Asp Met Lys Ile Leu Gln Ser Gln Ile Ile
595 600 605
Ser Phe Tyr Leu Arg Leu Phe Glu Val Leu Lys Asp Asn Gln Ala Ile
610 615 620
Ser Asn Asn Ile Ser Val Ile Glu Ser His Leu Ile Thr Thr Phe Phe
625 630 635 640
Ser Asn Ser Lys Ala Lys Lys Asp Ala Phe Met Ser Ile Ala Lys Phe
645 650 655
Glu Val Asn Asn Pro Gln Val Gln Arg Gln Ala Phe Asn Glu Leu Ile
660 665 670
Arg Val Val His Gln Leu Leu Pro Glu Ser Ser Leu Arg Lys Arg Lys
675 680 685
Arg Ser Arg Cys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu
690 695 700
Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
705 710 715 720
Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
725 730 735
Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
740 745 750
Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala
755 760 765
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr
770 775 780
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val
785 790 795 800
Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr
805 810 815
Leu Val Thr Val Ser Ser His His His His His His Glu Pro Glu Ala
820 825 830
<210> 113
<211> 549
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 113
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Arg Val Ile Pro Val Ser Gly Pro Ala Arg
20 25 30
Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val
35 40 45
Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp
50 55 60
Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr
65 70 75 80
Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg
85 90 95
Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr
100 105 110
Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys
115 120 125
Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His
130 135 140
Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp
145 150 155 160
Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys
165 170 175
Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys
180 185 190
Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val
195 200 205
Met Gly Tyr Leu Ser Ser Ala Ser Gly Gly Pro Gly Pro Ala Gly Met
210 215 220
Lys Gly Leu Pro Gly Ser Met Trp Glu Leu Glu Lys Asp Val Tyr Val
225 230 235 240
Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu
245 250 255
Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln
260 265 270
Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys
275 280 285
Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr
290 295 300
Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp
305 310 315 320
Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys
325 330 335
Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln
340 345 350
Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro
355 360 365
Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys
370 375 380
Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln
385 390 395 400
Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu
405 410 415
Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser
420 425 430
Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln
435 440 445
Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro
450 455 460
Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val
465 470 475 480
Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys
485 490 495
Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln
500 505 510
Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn
515 520 525
Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser His
530 535 540
His His His His His
545
<210> 114
<211> 579
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 114
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Arg Val Ile Pro Val Ser Gly Pro Ala Arg
20 25 30
Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val
35 40 45
Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp
50 55 60
Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr
65 70 75 80
Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg
85 90 95
Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr
100 105 110
Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys
115 120 125
Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His
130 135 140
Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp
145 150 155 160
Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys
165 170 175
Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys
180 185 190
Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val
195 200 205
Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly Gly
210 215 220
Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
225 230 235 240
Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
245 250 255
Gly Gly Gly Ser Met Trp Glu Leu Glu Lys Asp Val Tyr Val Val Glu
260 265 270
Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val Asn Leu Thr Cys
275 280 285
Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser Asp Gln Arg His
290 295 300
Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr Val Lys Glu Phe
305 310 315 320
Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Thr Leu Ser
325 330 335
His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly Ile Trp Ser Thr
340 345 350
Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu Lys Cys Glu Ala
355 360 365
Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu Val Gln Arg Asn
370 375 380
Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser Ser Pro Asp Ser
385 390 395 400
Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala Glu Lys Val Thr
405 410 415
Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser Cys Gln Glu Asp
420 425 430
Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile Glu Leu Ala Leu
435 440 445
Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser Thr Ser Phe Phe
450 455 460
Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn Leu Gln Met Lys
465 470 475 480
Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu Tyr Pro Asp Ser
485 490 495
Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe Phe Val Arg Ile
500 505 510
Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu Gly Cys Asn Gln
515 520 525
Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu Val Gln Cys Lys
530 535 540
Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr Tyr Asn Ser Ser
545 550 555 560
Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg Ser His His His
565 570 575
His His His
<210> 115
<211> 809
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 115
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser Met Trp Glu Leu Glu Lys Asp Val
145 150 155 160
Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val
165 170 175
Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser
180 185 190
Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr
195 200 205
Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly
210 215 220
Glu Thr Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly
225 230 235 240
Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu
245 250 255
Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu
260 265 270
Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser
275 280 285
Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala
290 295 300
Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser
305 310 315 320
Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile
325 330 335
Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser
340 345 350
Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
355 360 365
Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu
370 375 380
Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe
385 390 395 400
Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu
405 410 415
Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu
420 425 430
Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr
435 440 445
Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg
485 490 495
Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys
500 505 510
Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile
515 520 525
Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu
530 535 540
His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr
545 550 555 560
Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu
565 570 575
Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe
580 585 590
Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile
595 600 605
Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu
610 615 620
Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala
625 630 635 640
Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe
645 650 655
Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser
660 665 670
Ala Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
675 680 685
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
690 695 700
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
705 710 715 720
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
725 730 735
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
740 745 750
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
755 760 765
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
770 775 780
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
785 790 795 800
Val Ser Ser His His His His His His
805
<210> 116
<211> 938
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 116
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser Met Trp Glu Leu Glu Lys Asp
275 280 285
Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr
290 295 300
Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr
305 310 315 320
Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile
325 330 335
Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly
340 345 350
Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn
355 360 365
Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe
370 375 380
Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp
385 390 395 400
Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser
405 410 415
Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser
420 425 430
Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val
435 440 445
Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro
450 455 460
Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr
465 470 475 480
Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys
485 490 495
Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp
500 505 510
Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys
515 520 525
Phe Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu
530 535 540
Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr
545 550 555 560
Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg
565 570 575
Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val
580 585 590
Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
595 600 605
Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser
610 615 620
Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu
625 630 635 640
Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp
645 650 655
Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu
660 665 670
Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr
675 680 685
Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr
690 695 700
Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu
705 710 715 720
Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile
725 730 735
Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser
740 745 750
Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu
755 760 765
Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala
770 775 780
Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser
785 790 795 800
Ser Ala Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
805 810 815
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
820 825 830
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys
835 840 845
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
850 855 860
Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser
865 870 875 880
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
885 890 895
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
900 905 910
Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val
915 920 925
Thr Val Ser Ser His His His His His His
930 935
<210> 117
<211> 938
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 117
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser Met Trp Glu Leu Glu Lys Asp
275 280 285
Val Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr
290 295 300
Val Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr
305 310 315 320
Ser Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile
325 330 335
Thr Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly
340 345 350
Gly Glu Thr Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn
355 360 365
Gly Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe
370 375 380
Leu Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp
385 390 395 400
Leu Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser
405 410 415
Ser Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser
420 425 430
Ala Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val
435 440 445
Ser Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro
450 455 460
Ile Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr
465 470 475 480
Ser Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys
485 490 495
Asn Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp
500 505 510
Glu Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys
515 520 525
Phe Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu
530 535 540
Glu Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr
545 550 555 560
Glu Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg
565 570 575
Tyr Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val
580 585 590
Arg Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
595 600 605
Ser Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser
610 615 620
Arg Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu
625 630 635 640
Lys Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp
645 650 655
Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu
660 665 670
Leu His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr
675 680 685
Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr
690 695 700
Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu
705 710 715 720
Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile
725 730 735
Ile Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser
740 745 750
Leu Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu
755 760 765
Ala Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala
770 775 780
Phe Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser
785 790 795 800
Ser Ala Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly
805 810 815
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
820 825 830
Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys
835 840 845
Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
850 855 860
Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser
865 870 875 880
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu
885 890 895
Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr
900 905 910
Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val
915 920 925
Thr Val Ser Ser His His His His His His
930 935
<210> 118
<211> 938
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 118
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser Met Trp Glu Leu Glu Lys Asp Val
145 150 155 160
Tyr Val Val Glu Val Asp Trp Thr Pro Asp Ala Pro Gly Glu Thr Val
165 170 175
Asn Leu Thr Cys Asp Thr Pro Glu Glu Asp Asp Ile Thr Trp Thr Ser
180 185 190
Asp Gln Arg His Gly Val Ile Gly Ser Gly Lys Thr Leu Thr Ile Thr
195 200 205
Val Lys Glu Phe Leu Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly
210 215 220
Glu Thr Leu Ser His Ser His Leu Leu Leu His Lys Lys Glu Asn Gly
225 230 235 240
Ile Trp Ser Thr Glu Ile Leu Lys Asn Phe Lys Asn Lys Thr Phe Leu
245 250 255
Lys Cys Glu Ala Pro Asn Tyr Ser Gly Arg Phe Thr Cys Ser Trp Leu
260 265 270
Val Gln Arg Asn Met Asp Leu Lys Phe Asn Ile Lys Ser Ser Ser Ser
275 280 285
Ser Pro Asp Ser Arg Ala Val Thr Cys Gly Met Ala Ser Leu Ser Ala
290 295 300
Glu Lys Val Thr Leu Asp Gln Arg Asp Tyr Glu Lys Tyr Ser Val Ser
305 310 315 320
Cys Gln Glu Asp Val Thr Cys Pro Thr Ala Glu Glu Thr Leu Pro Ile
325 330 335
Glu Leu Ala Leu Glu Ala Arg Gln Gln Asn Lys Tyr Glu Asn Tyr Ser
340 345 350
Thr Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
355 360 365
Leu Gln Met Lys Pro Leu Lys Asn Ser Gln Val Glu Val Ser Trp Glu
370 375 380
Tyr Pro Asp Ser Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Lys Phe
385 390 395 400
Phe Val Arg Ile Gln Arg Lys Lys Glu Lys Met Lys Glu Thr Glu Glu
405 410 415
Gly Cys Asn Gln Lys Gly Ala Phe Leu Val Glu Lys Thr Ser Thr Glu
420 425 430
Val Gln Cys Lys Gly Gly Asn Val Cys Val Gln Ala Gln Asp Arg Tyr
435 440 445
Tyr Asn Ser Ser Cys Ser Lys Trp Ala Cys Val Pro Cys Arg Val Arg
450 455 460
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
465 470 475 480
Arg Val Ile Pro Val Ser Gly Pro Ala Arg Cys Leu Ser Gln Ser Arg
485 490 495
Asn Leu Leu Lys Thr Thr Asp Asp Met Val Lys Thr Ala Arg Glu Lys
500 505 510
Leu Lys His Tyr Ser Cys Thr Ala Glu Asp Ile Asp His Glu Asp Ile
515 520 525
Thr Arg Asp Gln Thr Ser Thr Leu Lys Thr Cys Leu Pro Leu Glu Leu
530 535 540
His Lys Asn Glu Ser Cys Leu Ala Thr Arg Glu Thr Ser Ser Thr Thr
545 550 555 560
Arg Gly Ser Cys Leu Pro Pro Gln Lys Thr Ser Leu Met Met Thr Leu
565 570 575
Cys Leu Gly Ser Ile Tyr Glu Asp Leu Lys Met Tyr Gln Thr Glu Phe
580 585 590
Gln Ala Ile Asn Ala Ala Leu Gln Asn His Asn His Gln Gln Ile Ile
595 600 605
Leu Asp Lys Gly Met Leu Val Ala Ile Asp Glu Leu Met Gln Ser Leu
610 615 620
Asn His Asn Gly Glu Thr Leu Arg Gln Lys Pro Pro Val Gly Glu Ala
625 630 635 640
Asp Pro Tyr Arg Val Lys Met Lys Leu Cys Ile Leu Leu His Ala Phe
645 650 655
Ser Thr Arg Val Val Thr Ile Asn Arg Val Met Gly Tyr Leu Ser Ser
660 665 670
Ala Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
675 680 685
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
690 695 700
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
705 710 715 720
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
725 730 735
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val
740 745 750
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
755 760 765
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
770 775 780
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
785 790 795 800
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
805 810 815
Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Val Gln Ala
820 825 830
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Arg Ile Phe Ser
835 840 845
Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly Lys Gln Arg Glu
850 855 860
Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser Tyr Asp Asp Ser
865 870 875 880
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val
885 890 895
Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Gly Val Tyr Tyr
900 905 910
Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys Gly Thr Gln Val
915 920 925
Thr Val Ser Ser His His His His His His
930 935
<210> 119
<211> 962
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 119
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly
325 330 335
Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala
340 345 350
Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met
355 360 365
Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu
370 375 380
Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys
385 390 395 400
Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr
405 410 415
Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys
420 425 430
Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu
435 440 445
Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn
450 455 460
His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile
465 470 475 480
Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln
485 490 495
Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu
500 505 510
Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg
515 520 525
Val Met Gly Tyr Leu Ser Ser Ala Gly Gly Gly Gly Ser Gly Gly Gly
530 535 540
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
545 550 555 560
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser
580 585 590
Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser
595 600 605
Asn Ile Gly Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr
610 615 620
Ala Pro Lys Leu Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val
625 630 635 640
Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala
645 650 655
Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser
660 665 670
Tyr Asp Arg Tyr Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys
675 680 685
Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
690 695 700
Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
705 710 715 720
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
725 730 735
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
740 745 750
Glu Trp Val Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
755 760 765
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
770 775 780
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
785 790 795 800
Tyr Tyr Cys Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr
805 810 815
Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
820 825 830
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
835 840 845
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
850 855 860
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
865 870 875 880
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu
885 890 895
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
900 905 910
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
915 920 925
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln
930 935 940
Gly Thr Leu Val Thr Val Ser Ser His His His His His His Glu Pro
945 950 955 960
Glu Ala
<210> 120
<211> 832
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 120
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly
325 330 335
Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala
340 345 350
Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met
355 360 365
Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu
370 375 380
Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys
385 390 395 400
Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr
405 410 415
Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys
420 425 430
Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu
435 440 445
Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn
450 455 460
His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile
465 470 475 480
Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln
485 490 495
Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu
500 505 510
Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg
515 520 525
Val Met Gly Tyr Leu Ser Ser Ala Ser Gly Gly Pro Gly Pro Ala Gly
530 535 540
Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
545 550 555 560
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser
580 585 590
Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser
595 600 605
Asn Ile Gly Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr
610 615 620
Ala Pro Lys Leu Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val
625 630 635 640
Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala
645 650 655
Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser
660 665 670
Tyr Asp Arg Tyr Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys
675 680 685
Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
690 695 700
Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
705 710 715 720
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
725 730 735
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
740 745 750
Glu Trp Val Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
755 760 765
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
770 775 780
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
785 790 795 800
Tyr Tyr Cys Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr
805 810 815
Met Val Thr Val Ser Ser His His His His His His Glu Pro Glu Ala
820 825 830
<210> 121
<211> 1091
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 121
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ile Trp Glu Leu Lys Lys Asp Val Tyr Val
20 25 30
Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val Leu
35 40 45
Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp Gln
50 55 60
Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val Lys
65 70 75 80
Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu Val
85 90 95
Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile Trp
100 105 110
Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr Phe
115 120 125
Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp Trp
130 135 140
Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser Arg
145 150 155 160
Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu Ser
165 170 175
Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val Glu
180 185 190
Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro Ile
195 200 205
Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr Thr
210 215 220
Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys Asn
225 230 235 240
Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser Trp
245 250 255
Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu Thr
260 265 270
Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp Arg
275 280 285
Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn Ala
290 295 300
Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp Ser
305 310 315 320
Glu Trp Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly Gly
325 330 335
Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro Ala
340 345 350
Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp Met
355 360 365
Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala Glu
370 375 380
Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu Lys
385 390 395 400
Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala Thr
405 410 415
Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln Lys
420 425 430
Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp Leu
435 440 445
Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln Asn
450 455 460
His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala Ile
465 470 475 480
Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg Gln
485 490 495
Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys Leu
500 505 510
Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn Arg
515 520 525
Val Met Gly Tyr Leu Ser Ser Ala Ser Gly Gly Pro Gly Pro Ala Gly
530 535 540
Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
545 550 555 560
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val Ser
580 585 590
Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser
595 600 605
Asn Ile Gly Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr
610 615 620
Ala Pro Lys Leu Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val
625 630 635 640
Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala
645 650 655
Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser
660 665 670
Tyr Asp Arg Tyr Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys
675 680 685
Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
690 695 700
Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
705 710 715 720
Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
725 730 735
Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
740 745 750
Glu Trp Val Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
755 760 765
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
770 775 780
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
785 790 795 800
Tyr Tyr Cys Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr
805 810 815
Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
820 825 830
Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
835 840 845
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
850 855 860
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
865 870 875 880
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu
885 890 895
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
900 905 910
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
915 920 925
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln
930 935 940
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
945 950 955 960
Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly Gly
965 970 975
Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser
980 985 990
Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro
995 1000 1005
Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser
1010 1015 1020
Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
1025 1030 1035
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys
1040 1045 1050
Pro Glu Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg
1055 1060 1065
Ile Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His
1070 1075 1080
His His His His Glu Pro Glu Ala
1085 1090
<210> 122
<211> 1091
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 122
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr
145 150 155 160
Val Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val
165 170 175
Leu Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp
180 185 190
Gln Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val
195 200 205
Lys Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu
210 215 220
Val Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile
225 230 235 240
Trp Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr
245 250 255
Phe Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp
260 265 270
Trp Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser
275 280 285
Arg Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu
290 295 300
Ser Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val
305 310 315 320
Glu Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro
325 330 335
Ile Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr
340 345 350
Thr Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys
355 360 365
Asn Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser
370 375 380
Trp Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu
385 390 395 400
Thr Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp
405 410 415
Arg Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn
420 425 430
Ala Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp
435 440 445
Ser Glu Trp Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly
450 455 460
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
465 470 475 480
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
485 490 495
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
500 505 510
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
515 520 525
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
530 535 540
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
545 550 555 560
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
565 570 575
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
580 585 590
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
595 600 605
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
610 615 620
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
625 630 635 640
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
645 650 655
Arg Val Met Gly Tyr Leu Ser Ser Ala Ser Gly Gly Pro Gly Pro Ala
660 665 670
Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
675 680 685
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
690 695 700
Ser Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val
705 710 715 720
Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg
725 730 735
Ser Asn Ile Gly Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly
740 745 750
Thr Ala Pro Lys Leu Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly
755 760 765
Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu
770 775 780
Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln
785 790 795 800
Ser Tyr Asp Arg Tyr Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr
805 810 815
Lys Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
820 825 830
Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
835 840 845
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
850 855 860
Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly
865 870 875 880
Leu Glu Trp Val Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr
885 890 895
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
900 905 910
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
915 920 925
Val Tyr Tyr Cys Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
930 935 940
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
945 950 955 960
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
965 970 975
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
980 985 990
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
995 1000 1005
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
1010 1015 1020
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
1025 1030 1035
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
1040 1045 1050
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
1055 1060 1065
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His
1070 1075 1080
His His His His Glu Pro Glu Ala
1085 1090
<210> 123
<211> 1091
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 123
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly
130 135 140
Met Lys Gly Leu Pro Gly Ser Ile Trp Glu Leu Lys Lys Asp Val Tyr
145 150 155 160
Val Val Glu Leu Asp Trp Tyr Pro Asp Ala Pro Gly Glu Met Val Val
165 170 175
Leu Thr Cys Asp Thr Pro Glu Glu Asp Gly Ile Thr Trp Thr Leu Asp
180 185 190
Gln Ser Ser Glu Val Leu Gly Ser Gly Lys Thr Leu Thr Ile Gln Val
195 200 205
Lys Glu Phe Gly Asp Ala Gly Gln Tyr Thr Cys His Lys Gly Gly Glu
210 215 220
Val Leu Ser His Ser Leu Leu Leu Leu His Lys Lys Glu Asp Gly Ile
225 230 235 240
Trp Ser Thr Asp Ile Leu Lys Asp Gln Lys Glu Pro Lys Asn Lys Thr
245 250 255
Phe Leu Arg Cys Glu Ala Lys Asn Tyr Ser Gly Arg Phe Thr Cys Trp
260 265 270
Trp Leu Thr Thr Ile Ser Thr Asp Leu Thr Phe Ser Val Lys Ser Ser
275 280 285
Arg Gly Ser Ser Asp Pro Gln Gly Val Thr Cys Gly Ala Ala Thr Leu
290 295 300
Ser Ala Glu Arg Val Arg Gly Asp Asn Lys Glu Tyr Glu Tyr Ser Val
305 310 315 320
Glu Cys Gln Glu Asp Ser Ala Cys Pro Ala Ala Glu Glu Ser Leu Pro
325 330 335
Ile Glu Val Met Val Asp Ala Val His Lys Leu Lys Tyr Glu Asn Tyr
340 345 350
Thr Ser Ser Phe Phe Ile Arg Asp Ile Ile Lys Pro Asp Pro Pro Lys
355 360 365
Asn Leu Gln Leu Lys Pro Leu Lys Asn Ser Arg Gln Val Glu Val Ser
370 375 380
Trp Glu Tyr Pro Asp Thr Trp Ser Thr Pro His Ser Tyr Phe Ser Leu
385 390 395 400
Thr Phe Cys Val Gln Val Gln Gly Lys Ser Lys Arg Glu Lys Lys Asp
405 410 415
Arg Val Phe Thr Asp Lys Thr Ser Ala Thr Val Ile Cys Arg Lys Asn
420 425 430
Ala Ser Ile Ser Val Arg Ala Gln Asp Arg Tyr Tyr Ser Ser Ser Trp
435 440 445
Ser Glu Trp Ala Ser Val Pro Cys Ser Gly Gly Gly Gly Ser Gly Gly
450 455 460
Gly Gly Ser Gly Gly Gly Gly Ser Arg Val Ile Pro Val Ser Gly Pro
465 470 475 480
Ala Arg Cys Leu Ser Gln Ser Arg Asn Leu Leu Lys Thr Thr Asp Asp
485 490 495
Met Val Lys Thr Ala Arg Glu Lys Leu Lys His Tyr Ser Cys Thr Ala
500 505 510
Glu Asp Ile Asp His Glu Asp Ile Thr Arg Asp Gln Thr Ser Thr Leu
515 520 525
Lys Thr Cys Leu Pro Leu Glu Leu His Lys Asn Glu Ser Cys Leu Ala
530 535 540
Thr Arg Glu Thr Ser Ser Thr Thr Arg Gly Ser Cys Leu Pro Pro Gln
545 550 555 560
Lys Thr Ser Leu Met Met Thr Leu Cys Leu Gly Ser Ile Tyr Glu Asp
565 570 575
Leu Lys Met Tyr Gln Thr Glu Phe Gln Ala Ile Asn Ala Ala Leu Gln
580 585 590
Asn His Asn His Gln Gln Ile Ile Leu Asp Lys Gly Met Leu Val Ala
595 600 605
Ile Asp Glu Leu Met Gln Ser Leu Asn His Asn Gly Glu Thr Leu Arg
610 615 620
Gln Lys Pro Pro Val Gly Glu Ala Asp Pro Tyr Arg Val Lys Met Lys
625 630 635 640
Leu Cys Ile Leu Leu His Ala Phe Ser Thr Arg Val Val Thr Ile Asn
645 650 655
Arg Val Met Gly Tyr Leu Ser Ser Ala Ser Gly Gly Pro Gly Pro Ala
660 665 670
Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
675 680 685
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
690 695 700
Ser Gly Gly Gly Gly Ser Gln Ser Val Leu Thr Gln Pro Pro Ser Val
705 710 715 720
Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg
725 730 735
Ser Asn Ile Gly Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly
740 745 750
Thr Ala Pro Lys Leu Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly
755 760 765
Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu
770 775 780
Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln
785 790 795 800
Ser Tyr Asp Arg Tyr Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr
805 810 815
Lys Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
820 825 830
Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
835 840 845
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
850 855 860
Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly
865 870 875 880
Leu Glu Trp Val Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr
885 890 895
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
900 905 910
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
915 920 925
Val Tyr Tyr Cys Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
930 935 940
Thr Met Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
945 950 955 960
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
965 970 975
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
980 985 990
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
995 1000 1005
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
1010 1015 1020
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
1025 1030 1035
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
1040 1045 1050
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
1055 1060 1065
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His
1070 1075 1080
His His His His Glu Pro Glu Ala
1085 1090
<210> 124
<211> 674
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 124
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser
210 215 220
Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser
225 230 235 240
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
245 250 255
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp
260 265 270
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
275 280 285
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
290 295 300
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
305 310 315 320
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly
325 330 335
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
340 345 350
Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
355 360 365
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
370 375 380
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe
385 390 395 400
Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
420 425 430
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
435 440 445
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
450 455 460
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
465 470 475 480
Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
485 490 495
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
500 505 510
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
515 520 525
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser
530 535 540
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu
545 550 555 560
Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys
565 570 575
Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg
580 585 590
Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly
595 600 605
Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
610 615 620
Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys
625 630 635 640
Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp
645 650 655
Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser His His His His
660 665 670
His His
<210> 125
<211> 674
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 125
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly
130 135 140
Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser
275 280 285
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
290 295 300
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln
305 310 315 320
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser
325 330 335
Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg
340 345 350
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
355 360 365
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala
370 375 380
Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly
385 390 395 400
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
405 410 415
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
420 425 430
Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp
435 440 445
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala
450 455 460
Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
465 470 475 480
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
485 490 495
Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly
500 505 510
Gly Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Pro Gly Pro Ala Gly
515 520 525
Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
530 535 540
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
545 550 555 560
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
565 570 575
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
580 585 590
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
595 600 605
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
610 615 620
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
625 630 635 640
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
645 650 655
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His
660 665 670
His His
<210> 126
<211> 425
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 126
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Leu Cys Asp Asp Asp Pro Pro Glu Ile
20 25 30
Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr Met Leu
35 40 45
Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly Ser Leu
50 55 60
Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp Asn Gln
65 70 75 80
Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln Val Thr
85 90 95
Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met Gln Ser
100 105 110
Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys Arg Glu
115 120 125
Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His Phe Val
130 135 140
Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg Ala Leu
145 150 155 160
His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly Lys Thr
165 170 175
Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu Thr Ser
180 185 190
Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly Arg Pro
195 200 205
Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln Ile Gln
210 215 220
Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr Glu Tyr
225 230 235 240
Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser
260 265 270
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro
275 280 285
Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu
290 295 300
Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro
305 310 315 320
Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala
325 330 335
Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu
340 345 350
Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro
355 360 365
Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly
370 375 380
Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile
385 390 395 400
Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser
405 410 415
Thr Leu Thr His His His His His His
420 425
<210> 127
<211> 425
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 127
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly
165 170 175
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
180 185 190
Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Cys Asp Asp Asp Pro Pro
195 200 205
Glu Ile Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr
210 215 220
Met Leu Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly
225 230 235 240
Ser Leu Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp
245 250 255
Asn Gln Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln
260 265 270
Val Thr Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met
275 280 285
Gln Ser Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys
290 295 300
Arg Glu Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His
305 310 315 320
Phe Val Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg
325 330 335
Ala Leu His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly
340 345 350
Lys Thr Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu
355 360 365
Thr Ser Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly
370 375 380
Arg Pro Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln
385 390 395 400
Ile Gln Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr
405 410 415
Glu Tyr Gln His His His His His His
420 425
<210> 128
<211> 555
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 128
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Cys Asp Asp Asp Pro Pro
145 150 155 160
Glu Ile Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr
165 170 175
Met Leu Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly
180 185 190
Ser Leu Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp
195 200 205
Asn Gln Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln
210 215 220
Val Thr Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met
225 230 235 240
Gln Ser Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys
245 250 255
Arg Glu Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His
260 265 270
Phe Val Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg
275 280 285
Ala Leu His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly
290 295 300
Lys Thr Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu
305 310 315 320
Thr Ser Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly
325 330 335
Arg Pro Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln
340 345 350
Ile Gln Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr
355 360 365
Glu Tyr Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
370 375 380
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
385 390 395 400
Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser
405 410 415
Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His
420 425 430
Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys
435 440 445
Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys
450 455 460
Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys
465 470 475 480
Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu
485 490 495
Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu
500 505 510
Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala
515 520 525
Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile
530 535 540
Ile Ser Thr Leu Thr His His His His His His
545 550 555
<210> 129
<211> 555
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 129
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly
165 170 175
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
180 185 190
Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Cys Asp Asp Asp Pro Pro
195 200 205
Glu Ile Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr
210 215 220
Met Leu Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly
225 230 235 240
Ser Leu Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp
245 250 255
Asn Gln Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln
260 265 270
Val Thr Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met
275 280 285
Gln Ser Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys
290 295 300
Arg Glu Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His
305 310 315 320
Phe Val Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg
325 330 335
Ala Leu His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly
340 345 350
Lys Thr Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu
355 360 365
Thr Ser Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly
370 375 380
Arg Pro Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln
385 390 395 400
Ile Gln Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr
405 410 415
Glu Tyr Gln Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
420 425 430
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
435 440 445
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
450 455 460
Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
465 470 475 480
Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu
485 490 495
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
500 505 510
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
515 520 525
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu
530 535 540
Val Thr Val Ser Ser His His His His His His
545 550 555
<210> 130
<211> 555
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 130
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly
165 170 175
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
180 185 190
Gly Gly Ser Gly Gly Gly Gly Ser Glu Leu Cys Asp Asp Asp Pro Pro
195 200 205
Glu Ile Pro His Ala Thr Phe Lys Ala Met Ala Tyr Lys Glu Gly Thr
210 215 220
Met Leu Asn Cys Glu Cys Lys Arg Gly Phe Arg Arg Ile Lys Ser Gly
225 230 235 240
Ser Leu Tyr Met Leu Cys Thr Gly Asn Ser Ser His Ser Ser Trp Asp
245 250 255
Asn Gln Cys Gln Cys Thr Ser Ser Ala Thr Arg Asn Thr Thr Lys Gln
260 265 270
Val Thr Pro Gln Pro Glu Glu Gln Lys Glu Arg Lys Thr Thr Glu Met
275 280 285
Gln Ser Pro Met Gln Pro Val Asp Gln Ala Ser Leu Pro Gly His Cys
290 295 300
Arg Glu Pro Pro Pro Trp Glu Asn Glu Ala Thr Glu Arg Ile Tyr His
305 310 315 320
Phe Val Val Gly Gln Met Val Tyr Tyr Gln Cys Val Gln Gly Tyr Arg
325 330 335
Ala Leu His Arg Gly Pro Ala Glu Ser Val Cys Lys Met Thr His Gly
340 345 350
Lys Thr Arg Trp Thr Gln Pro Gln Leu Ile Cys Thr Gly Glu Met Glu
355 360 365
Thr Ser Gln Phe Pro Gly Glu Glu Lys Pro Gln Ala Ser Pro Glu Gly
370 375 380
Arg Pro Glu Ser Glu Thr Ser Cys Leu Val Thr Thr Thr Asp Phe Gln
385 390 395 400
Ile Gln Thr Glu Met Ala Ala Thr Met Glu Thr Ser Ile Phe Thr Thr
405 410 415
Glu Tyr Gln Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
420 425 430
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
435 440 445
Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
450 455 460
Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
465 470 475 480
Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu
485 490 495
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr
500 505 510
Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr
515 520 525
Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu
530 535 540
Val Thr Val Ser Ser His His His His His His
545 550 555
<210> 131
<211> 575
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 131
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly
145 150 155 160
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
165 170 175
Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala
180 185 190
Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr
195 200 205
Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu
245 250 255
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
260 265 270
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
275 280 285
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
290 295 300
Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr
305 310 315 320
Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser
325 330 335
Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
340 345 350
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
355 360 365
Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly
370 375 380
Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
385 390 395 400
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
405 410 415
Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
420 425 430
Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu
435 440 445
Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile
450 455 460
Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe
465 470 475 480
Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu
485 490 495
Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys
500 505 510
Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile
515 520 525
Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala
530 535 540
Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe
545 550 555 560
Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His His His
565 570 575
<210> 132
<211> 704
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 132
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly
165 170 175
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
180 185 190
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
195 200 205
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
210 215 220
Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala
225 230 235 240
Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr
245 250 255
Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp
260 265 270
Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
275 280 285
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu
290 295 300
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Ser Gly Gly
305 310 315 320
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Asp Ile Gln Met
325 330 335
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
340 345 350
Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr
355 360 365
Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser
370 375 380
Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
385 390 395 400
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
405 410 415
Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly
420 425 430
Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
450 455 460
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
465 470 475 480
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
485 490 495
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
500 505 510
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
515 520 525
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
530 535 540
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
545 550 555 560
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
580 585 590
Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
595 600 605
Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala
610 615 620
Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr
625 630 635 640
Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
645 650 655
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu
660 665 670
Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp
675 680 685
Gly Lys Gly Thr Gln Val Thr Val Ser Ser His His His His His His
690 695 700
<210> 133
<211> 689
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 133
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
340 345 350
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
355 360 365
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
370 375 380
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
385 390 395 400
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
420 425 430
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
435 440 445
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
450 455 460
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp
465 470 475 480
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp
485 490 495
Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr
500 505 510
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser
515 520 525
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn
530 535 540
Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
545 550 555 560
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
580 585 590
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
595 600 605
Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
610 615 620
Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
625 630 635 640
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
645 650 655
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr
660 665 670
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His
675 680 685
His
<210> 134
<211> 545
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 134
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser
210 215 220
Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser
225 230 235 240
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
245 250 255
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp
260 265 270
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
275 280 285
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
290 295 300
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
305 310 315 320
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly
325 330 335
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
340 345 350
Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
355 360 365
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
370 375 380
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe
385 390 395 400
Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
420 425 430
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
435 440 445
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
450 455 460
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
465 470 475 480
Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
485 490 495
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
500 505 510
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
515 520 525
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His His His
530 535 540
His
545
<210> 135
<211> 575
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 135
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly
165 170 175
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
180 185 190
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
195 200 205
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
210 215 220
Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala
225 230 235 240
Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr
245 250 255
Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp
260 265 270
Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
275 280 285
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu
290 295 300
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
305 310 315 320
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
325 330 335
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
340 345 350
Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr
355 360 365
Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser
370 375 380
Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
385 390 395 400
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
405 410 415
Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly
420 425 430
Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
450 455 460
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
465 470 475 480
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
485 490 495
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
500 505 510
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
515 520 525
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
530 535 540
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
545 550 555 560
Gln Gly Thr Leu Val Thr Val Ser Ser His His His His His His
565 570 575
<210> 136
<211> 421
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 136
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys
145 150 155 160
Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile
165 170 175
Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu
180 185 190
Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu
195 200 205
Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu
210 215 220
Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn
225 230 235 240
Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met
245 250 255
Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg
260 265 270
Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly
275 280 285
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu
290 295 300
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
305 310 315 320
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
325 330 335
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
340 345 350
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe
355 360 365
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
370 375 380
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
385 390 395 400
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His
405 410 415
His His His His His
420
<210> 137
<211> 806
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 137
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly Ser
130 135 140
Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Val Glu Ser Gly
145 150 155 160
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
165 170 175
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
180 185 190
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
195 200 205
Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
210 215 220
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
225 230 235 240
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
245 250 255
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Gly Ser Gly
260 265 270
Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gln Val Gln Leu Gln
275 280 285
Glu Ser Gly Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser
290 295 300
Cys Ala Ala Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr
305 310 315 320
Arg Gln Ala Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg
325 330 335
Gly Gly Thr Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile
340 345 350
Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu
355 360 365
Lys Pro Glu Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr
370 375 380
Asp Tyr Trp Gly Lys Gly Thr Gln Val Thr Val Ser Ser Gly Ser Gly
385 390 395 400
Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln
405 410 415
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
420 425 430
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala
435 440 445
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile
450 455 460
Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe
465 470 475 480
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn
485 490 495
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser
500 505 510
Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
515 520 525
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
530 535 540
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
545 550 555 560
Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr
565 570 575
Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu
580 585 590
Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser
595 600 605
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
610 615 620
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro
625 630 635 640
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Pro
645 650 655
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser
660 665 670
Ser Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu
675 680 685
Gln Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr
690 695 700
Arg Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu
705 710 715 720
Lys His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val
725 730 735
Leu Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu
740 745 750
Ile Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr
755 760 765
Thr Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe
770 775 780
Leu Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr
785 790 795 800
His His His His His His
805
<210> 138
<211> 676
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 138
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly Ser
130 135 140
Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Val Glu Ser Gly
145 150 155 160
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
165 170 175
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
180 185 190
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
195 200 205
Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
210 215 220
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
225 230 235 240
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
245 250 255
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Ser Gly Ser Gly
260 265 270
Ser Gly Ser Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Val
275 280 285
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
290 295 300
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val
305 310 315 320
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser
325 330 335
Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile
340 345 350
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
355 360 365
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp
370 375 380
Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
385 390 395 400
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
405 410 415
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
420 425 430
Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val
435 440 445
Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr
450 455 460
Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
465 470 475 480
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
485 490 495
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr
500 505 510
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Ser Gly Gly Pro Gly Pro
515 520 525
Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr
530 535 540
Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met
545 550 555 560
Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met
565 570 575
Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His
580 585 590
Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn
595 600 605
Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser
610 615 620
Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe
625 630 635 640
Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn
645 650 655
Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His
660 665 670
His His His His
675
<210> 139
<211> 421
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 139
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Ser Gly Ser Gly Ser Gly Ser
130 135 140
Gly Ser Gly Ser Gly Ser Gly Ser Glu Val Gln Leu Val Glu Ser Gly
145 150 155 160
Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala
165 170 175
Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala
180 185 190
Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg
195 200 205
Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
210 215 220
Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro
225 230 235 240
Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val
245 250 255
Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly
260 265 270
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser
275 280 285
Thr Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln
290 295 300
Met Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg
305 310 315 320
Met Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys
325 330 335
His Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu
340 345 350
Asn Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile
355 360 365
Ser Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr
370 375 380
Phe Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu
385 390 395 400
Asn Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His
405 410 415
His His His His His
420
<210> 140
<211> 420
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 140
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly
130 135 140
Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
340 345 350
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
355 360 365
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
370 375 380
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
385 390 395 400
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His
405 410 415
His His His His
420
<210> 141
<211> 550
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 141
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr
275 280 285
Lys Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met
290 295 300
Ile Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met
305 310 315 320
Leu Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His
325 330 335
Leu Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn
340 345 350
Leu Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser
355 360 365
Asn Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe
370 375 380
Met Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn
385 390 395 400
Arg Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly
405 410 415
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln
420 425 430
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
435 440 445
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
450 455 460
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
465 470 475 480
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg
485 490 495
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
500 505 510
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
515 520 525
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
530 535 540
His His His His His His
545 550
<210> 142
<211> 420
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 142
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
340 345 350
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
355 360 365
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
370 375 380
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
385 390 395 400
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His
405 410 415
His His His His
420
<210> 143
<211> 290
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 143
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His
275 280 285
His His
290
<210> 144
<211> 291
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 144
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
210 215 220
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
225 230 235 240
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
245 250 255
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
260 265 270
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His
275 280 285
His His His
290
<210> 145
<211> 689
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 145
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly
130 135 140
Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
340 345 350
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
355 360 365
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
370 375 380
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
385 390 395 400
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
420 425 430
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu
435 440 445
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
450 455 460
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp
465 470 475 480
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp
485 490 495
Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr
500 505 510
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser
515 520 525
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn
530 535 540
Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
545 550 555 560
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
565 570 575
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
580 585 590
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
595 600 605
Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
610 615 620
Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
625 630 635 640
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
645 650 655
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr
660 665 670
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His
675 680 685
His
<210> 146
<211> 704
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 146
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Gly Gly Gly Gly Ser Gly
165 170 175
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
180 185 190
Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
195 200 205
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
210 215 220
Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala
225 230 235 240
Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr
245 250 255
Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp
260 265 270
Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
275 280 285
Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu
290 295 300
Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly
305 310 315 320
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met
325 330 335
Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr
340 345 350
Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr
355 360 365
Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser
370 375 380
Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly
385 390 395 400
Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
405 410 415
Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly
420 425 430
Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly
435 440 445
Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
450 455 460
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
465 470 475 480
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
485 490 495
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
500 505 510
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
515 520 525
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
530 535 540
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
545 550 555 560
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
580 585 590
Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala
595 600 605
Ser Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr
610 615 620
Pro Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser
625 630 635 640
Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
645 650 655
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu
660 665 670
Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp
675 680 685
Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His His His His
690 695 700
<210> 147
<211> 674
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 147
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Ala Pro Thr Ser Ser Ser Thr Lys
130 135 140
Lys Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile
145 150 155 160
Leu Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu
165 170 175
Thr Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu
180 185 190
Gln Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu
195 200 205
Ala Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn
210 215 220
Ile Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met
225 230 235 240
Cys Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg
245 250 255
Trp Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly
260 265 270
Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu
275 280 285
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
290 295 300
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
305 310 315 320
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
325 330 335
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe
340 345 350
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
355 360 365
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
370 375 380
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly
385 390 395 400
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
420 425 430
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg
435 440 445
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala
450 455 460
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile
465 470 475 480
Asp Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe
485 490 495
Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn
500 505 510
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser
515 520 525
Asn Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val
530 535 540
Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
545 550 555 560
Ser Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val
565 570 575
Gly Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr
580 585 590
Asn Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu
595 600 605
Ile Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser
610 615 620
Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln
625 630 635 640
Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro
645 650 655
Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His
660 665 670
His His
<210> 148
<211> 704
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 148
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys 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
Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr
65 70 75 80
Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Thr 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 Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln
180 185 190
Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg
195 200 205
Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 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 Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
245 250 255
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
260 265 270
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
275 280 285
Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
290 295 300
Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln Leu Gln Leu
305 310 315 320
Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly Ile Asn Asn
325 330 335
Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys Phe Tyr Met
340 345 350
Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu Glu Glu Glu
355 360 365
Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser Lys Asn Phe
370 375 380
His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val Ile Val Leu
385 390 395 400
Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr Ala Asp Glu
405 410 415
Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr Phe Cys Gln
420 425 430
Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly Pro Ala Gly Met
435 440 445
Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
450 455 460
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
465 470 475 480
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
485 490 495
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
500 505 510
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
515 520 525
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
530 535 540
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
545 550 555 560
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
580 585 590
Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala
595 600 605
Ser Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr
610 615 620
Pro Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser
625 630 635 640
Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
645 650 655
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu
660 665 670
Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp
675 680 685
Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His His His His
690 695 700
<210> 149
<211> 704
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 149
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser
275 280 285
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala
290 295 300
Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln
305 310 315 320
Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser
325 330 335
Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg
340 345 350
Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala
355 360 365
Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala
370 375 380
Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly
385 390 395 400
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln
405 410 415
Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val
420 425 430
Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp
435 440 445
Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala
450 455 460
Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser
465 470 475 480
Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe
485 490 495
Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly
500 505 510
Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly
515 520 525
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
530 535 540
Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
545 550 555 560
Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln
565 570 575
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
580 585 590
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys
595 600 605
Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
610 615 620
Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
625 630 635 640
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val
645 650 655
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
660 665 670
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
675 680 685
Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His His His
690 695 700
<210> 150
<211> 689
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 150
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys 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
Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr
65 70 75 80
Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Thr 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 Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln
180 185 190
Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg
195 200 205
Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 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 Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
245 250 255
Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
260 265 270
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
275 280 285
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
290 295 300
Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
305 310 315 320
Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
325 330 335
Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala
340 345 350
Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr
355 360 365
Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val
370 375 380
Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr
385 390 395 400
Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
405 410 415
Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr Gln
420 425 430
Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn Gly
435 440 445
Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe Lys
450 455 460
Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys Leu
465 470 475 480
Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln Ser
485 490 495
Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn Val
500 505 510
Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu Tyr
515 520 525
Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile Thr
530 535 540
Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser Gly
545 550 555 560
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser
565 570 575
Gly Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala
580 585 590
Ala Ser Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln
595 600 605
Thr Pro Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly
610 615 620
Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
625 630 635 640
Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro
645 650 655
Glu Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr
660 665 670
Trp Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His His His
675 680 685
His
<210> 151
<211> 700
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 151
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Arg Gly Glu Thr Gly
290 295 300
Pro Ala Ala Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly
305 310 315 320
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
325 330 335
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
340 345 350
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
355 360 365
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
370 375 380
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
385 390 395 400
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
405 410 415
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
420 425 430
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
435 440 445
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
450 455 460
Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
465 470 475 480
Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro
485 490 495
Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr
500 505 510
Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn
515 520 525
Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
530 535 540
Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp
545 550 555 560
Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly Gly Gly Gly
565 570 575
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile Gln Met Thr
580 585 590
Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile
595 600 605
Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln
610 615 620
Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe
625 630 635 640
Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr
645 650 655
Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
660 665 670
Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly
675 680 685
Thr Lys Val Glu Ile Lys His His His His His His
690 695 700
<210> 152
<211> 276
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 152
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys 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
Phe Thr Phe Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr
65 70 75 80
Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Ala Arg Gly Val Gly Ala Phe Arg Pro Tyr
115 120 125
Arg Lys His Glu Trp Gly Gln Gly Thr Leu Val Thr Val Ser Arg Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Ser
145 150 155 160
Glu Leu Thr Gln Asp Pro Ala Val Ser Val Ala Leu Gly Gln Thr Val
165 170 175
Arg Ile Thr Cys Gln Gly Asp Ser Leu Arg Ser Tyr Tyr Ala Ser Trp
180 185 190
Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr Gly Lys
195 200 205
Asn Asn Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser Gly Ser Ser Ser
210 215 220
Gly Asn Thr Ala Ser Leu Thr Thr Thr Gly Ala Gln Ala Glu Asp Glu
225 230 235 240
Ala Asp Tyr Tyr Cys Asn Ser Ser Pro Phe Glu His Asn Leu Val Val
245 250 255
Phe Gly Gly Gly Thr Lys Leu Thr Val Leu His His His His His His
260 265 270
Glu Pro Glu Ala
275
<210> 153
<211> 279
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 153
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Gln Ser Gly Ala Glu
20 25 30
Leu Val Arg Pro Gly Thr Ser Val Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys Gln Arg Pro Gly
50 55 60
Gln Gly Leu Glu Trp Ile Gly Val Ile Asn Pro Gly Ser Gly Gly Thr
65 70 75 80
Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys
85 90 95
Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp
100 105 110
Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp Gly Tyr Tyr Ala
115 120 125
Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Gly
130 135 140
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg
165 170 175
Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp
180 185 190
Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
195 200 205
Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe
210 215 220
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro Val
225 230 235 240
Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp
245 250 255
Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys His His His
260 265 270
His His His Glu Pro Glu Ala
275
<210> 154
<211> 279
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 154
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Gln Ser Gly Ala Glu
20 25 30
Leu Val Arg Pro Gly Thr Ser Val Lys Val Ser Cys Lys Ala Ser Gly
35 40 45
Tyr Ala Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys Gln Arg Pro Gly
50 55 60
Gln Gly Leu Glu Trp Ile Gly Val Ile Asn Pro Gly Ser Gly Gly Thr
65 70 75 80
Asn Tyr Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys
85 90 95
Ser Ser Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp
100 105 110
Ser Ala Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp Gly Tyr Tyr Ala
115 120 125
Tyr Phe Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser Ser
130 135 140
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Asp Ile
145 150 155 160
Val Leu Thr Gln Ser Pro Ala Ser Leu Ala Val Ser Leu Gly Gln Arg
165 170 175
Ala Thr Ile Ser Cys Lys Ala Ser Gln Ser Val Asp Tyr Asp Gly Asp
180 185 190
Ser Tyr Met Asn Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu
195 200 205
Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Ile Pro Ala Arg Phe
210 215 220
Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Asn Ile His Pro Val
225 230 235 240
Glu Glu Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Ser Asn Glu Asp
245 250 255
Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys His His His
260 265 270
His His His Glu Pro Glu Ala
275
<210> 155
<211> 279
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 155
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser
20 25 30
Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser
35 40 45
Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu
65 70 75 80
Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr
100 105 110
Tyr Cys Gln Gln Ser Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Leu Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val
145 150 155 160
Arg Pro Gly Thr Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala
165 170 175
Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys Gln Arg Pro Gly Gln Gly
180 185 190
Leu Glu Trp Ile Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr
195 200 205
Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser
210 215 220
Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala
225 230 235 240
Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp Gly Tyr Tyr Ala Tyr Phe
245 250 255
Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser His His His
260 265 270
His His His Glu Pro Glu Ala
275
<210> 156
<211> 279
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 156
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Val Leu Thr Gln Ser Pro Ala Ser
20 25 30
Leu Ala Val Ser Leu Gly Gln Arg Ala Thr Ile Ser Cys Lys Ala Ser
35 40 45
Gln Ser Val Asp Tyr Asp Gly Asp Ser Tyr Met Asn Trp Tyr Gln Gln
50 55 60
Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu
65 70 75 80
Glu Ser Gly Ile Pro Ala Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp
85 90 95
Phe Thr Leu Asn Ile His Pro Val Glu Glu Glu Asp Ala Ala Thr Tyr
100 105 110
Tyr Cys Gln Gln Ser Asn Glu Asp Pro Tyr Thr Phe Gly Gly Gly Thr
115 120 125
Lys Leu Glu Ile Lys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly
130 135 140
Leu Pro Gly Ser Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val
145 150 155 160
Arg Pro Gly Thr Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala
165 170 175
Phe Thr Asn Tyr Leu Ile Glu Trp Val Lys Gln Arg Pro Gly Gln Gly
180 185 190
Leu Glu Trp Ile Gly Val Ile Asn Pro Gly Ser Gly Gly Thr Asn Tyr
195 200 205
Asn Glu Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser
210 215 220
Ser Thr Ala Tyr Met Gln Leu Ser Ser Leu Thr Ser Asp Asp Ser Ala
225 230 235 240
Val Tyr Phe Cys Ala Arg Trp Arg Gly Asp Gly Tyr Tyr Ala Tyr Phe
245 250 255
Asp Val Trp Gly Ala Gly Thr Thr Val Thr Val Ser Ser His His His
260 265 270
His His His Glu Pro Glu Ala
275
<210> 157
<211> 295
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 157
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser
145 150 155 160
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
210 215 220
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
225 230 235 240
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
245 250 255
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
260 265 270
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His His
275 280 285
His His His Glu Pro Glu Ala
290 295
<210> 158
<211> 765
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 158
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser
145 150 155 160
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ala His Lys Ser Glu
165 170 175
Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu
180 185 190
Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp
195 200 205
His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val
210 215 220
Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe
225 230 235 240
Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu
245 250 255
Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe
260 265 270
Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro
275 280 285
Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe
290 295 300
Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr
305 310 315 320
Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr
325 330 335
Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu
340 345 350
Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu
355 360 365
Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp
370 375 380
Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu
385 390 395 400
Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys
405 410 415
His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys
420 425 430
Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys
435 440 445
Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu
450 455 460
Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val
465 470 475 480
Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe
485 490 495
Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser
500 505 510
Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu
515 520 525
Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe
530 535 540
Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln
545 550 555 560
Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala
565 570 575
Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr
580 585 590
Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys
595 600 605
Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser
610 615 620
Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser
625 630 635 640
Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro
645 650 655
Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe
660 665 670
Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu
675 680 685
Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys
690 695 700
His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp
705 710 715 720
Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr
725 730 735
Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala
740 745 750
Leu Gly Leu His His His His His His Glu Pro Glu Ala
755 760 765
<210> 159
<211> 765
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 159
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Gly Gly Gly Gly Ser
145 150 155 160
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ala His Lys Ser Glu
165 170 175
Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu
180 185 190
Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp
195 200 205
His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val
210 215 220
Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe
225 230 235 240
Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu
245 250 255
Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe
260 265 270
Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro
275 280 285
Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe
290 295 300
Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr
305 310 315 320
Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr
325 330 335
Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu
340 345 350
Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu
355 360 365
Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp
370 375 380
Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu
385 390 395 400
Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys
405 410 415
His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys
420 425 430
Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys
435 440 445
Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu
450 455 460
Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val
465 470 475 480
Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe
485 490 495
Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser
500 505 510
Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu
515 520 525
Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe
530 535 540
Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln
545 550 555 560
Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala
565 570 575
Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr
580 585 590
Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys
595 600 605
Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser
610 615 620
Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser
625 630 635 640
Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro
645 650 655
Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe
660 665 670
Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu
675 680 685
Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys
690 695 700
His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp
705 710 715 720
Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr
725 730 735
Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala
740 745 750
Leu Gly Leu His His His His His His Glu Pro Glu Ala
755 760 765
<210> 160
<211> 765
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 160
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Asp Ala His Lys Ser Glu
165 170 175
Val Ala His Arg Phe Lys Asp Leu Gly Glu Glu Asn Phe Lys Ala Leu
180 185 190
Val Leu Ile Ala Phe Ala Gln Tyr Leu Gln Gln Cys Pro Phe Glu Asp
195 200 205
His Val Lys Leu Val Asn Glu Val Thr Glu Phe Ala Lys Thr Cys Val
210 215 220
Ala Asp Glu Ser Ala Glu Asn Cys Asp Lys Ser Leu His Thr Leu Phe
225 230 235 240
Gly Asp Lys Leu Cys Thr Val Ala Thr Leu Arg Glu Thr Tyr Gly Glu
245 250 255
Met Ala Asp Cys Cys Ala Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe
260 265 270
Leu Gln His Lys Asp Asp Asn Pro Asn Leu Pro Arg Leu Val Arg Pro
275 280 285
Glu Val Asp Val Met Cys Thr Ala Phe His Asp Asn Glu Glu Thr Phe
290 295 300
Leu Lys Lys Tyr Leu Tyr Glu Ile Ala Arg Arg His Pro Tyr Phe Tyr
305 310 315 320
Ala Pro Glu Leu Leu Phe Phe Ala Lys Arg Tyr Lys Ala Ala Phe Thr
325 330 335
Glu Cys Cys Gln Ala Ala Asp Lys Ala Ala Cys Leu Leu Pro Lys Leu
340 345 350
Asp Glu Leu Arg Asp Glu Gly Lys Ala Ser Ser Ala Lys Gln Arg Leu
355 360 365
Lys Cys Ala Ser Leu Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp
370 375 380
Ala Val Ala Arg Leu Ser Gln Arg Phe Pro Lys Ala Glu Phe Ala Glu
385 390 395 400
Val Ser Lys Leu Val Thr Asp Leu Thr Lys Val His Thr Glu Cys Cys
405 410 415
His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Asp Leu Ala Lys
420 425 430
Tyr Ile Cys Glu Asn Gln Asp Ser Ile Ser Ser Lys Leu Lys Glu Cys
435 440 445
Cys Glu Lys Pro Leu Leu Glu Lys Ser His Cys Ile Ala Glu Val Glu
450 455 460
Asn Asp Glu Met Pro Ala Asp Leu Pro Ser Leu Ala Ala Asp Phe Val
465 470 475 480
Glu Ser Lys Asp Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe
485 490 495
Leu Gly Met Phe Leu Tyr Glu Tyr Ala Arg Arg His Pro Asp Tyr Ser
500 505 510
Val Val Leu Leu Leu Arg Leu Ala Lys Thr Tyr Glu Thr Thr Leu Glu
515 520 525
Lys Cys Cys Ala Ala Ala Asp Pro His Glu Cys Tyr Ala Lys Val Phe
530 535 540
Asp Glu Phe Lys Pro Leu Val Glu Glu Pro Gln Asn Leu Ile Lys Gln
545 550 555 560
Asn Cys Glu Leu Phe Glu Gln Leu Gly Glu Tyr Lys Phe Gln Asn Ala
565 570 575
Leu Leu Val Arg Tyr Thr Lys Lys Val Pro Gln Val Ser Thr Pro Thr
580 585 590
Leu Val Glu Val Ser Arg Asn Leu Gly Lys Val Gly Ser Lys Cys Cys
595 600 605
Lys His Pro Glu Ala Lys Arg Met Pro Cys Ala Glu Asp Tyr Leu Ser
610 615 620
Val Val Leu Asn Gln Leu Cys Val Leu His Glu Lys Thr Pro Val Ser
625 630 635 640
Asp Arg Val Thr Lys Cys Cys Thr Glu Ser Leu Val Asn Arg Arg Pro
645 650 655
Cys Phe Ser Ala Leu Glu Val Asp Glu Thr Tyr Val Pro Lys Glu Phe
660 665 670
Asn Ala Glu Thr Phe Thr Phe His Ala Asp Ile Cys Thr Leu Ser Glu
675 680 685
Lys Glu Arg Gln Ile Lys Lys Gln Thr Ala Leu Val Glu Leu Val Lys
690 695 700
His Lys Pro Lys Ala Thr Lys Glu Gln Leu Lys Ala Val Met Asp Asp
705 710 715 720
Phe Ala Ala Phe Val Glu Lys Cys Cys Lys Ala Asp Asp Lys Glu Thr
725 730 735
Cys Phe Ala Glu Glu Gly Lys Lys Leu Val Ala Ala Ser Gln Ala Ala
740 745 750
Leu Gly Leu His His His His His His Glu Pro Glu Ala
755 760 765
<210> 161
<211> 708
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 161
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
210 215 220
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
225 230 235 240
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
245 250 255
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
260 265 270
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
275 280 285
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly
305 310 315 320
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
325 330 335
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
340 345 350
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg
355 360 365
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser
370 375 380
Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser
385 390 395 400
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
405 410 415
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp
420 425 430
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
450 455 460
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
465 470 475 480
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly
485 490 495
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
500 505 510
Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
515 520 525
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
530 535 540
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe
545 550 555 560
Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
580 585 590
Gly Gly Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala
595 600 605
Ser Gly Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr
610 615 620
Pro Gly Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser
625 630 635 640
Thr Asn Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
645 650 655
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu
660 665 670
Asp Thr Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp
675 680 685
Gly Gln Gly Thr Gln Val Thr Val Ser Ser His His His His His His
690 695 700
Glu Pro Glu Ala
705
<210> 162
<211> 708
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 162
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
340 345 350
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
355 360 365
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
370 375 380
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
385 390 395 400
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
420 425 430
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro
435 440 445
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
450 455 460
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
465 470 475 480
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val
485 490 495
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser
500 505 510
Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile
515 520 525
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
530 535 540
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp
545 550 555 560
Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
580 585 590
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
595 600 605
Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val
610 615 620
Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr
625 630 635 640
Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
645 650 655
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
660 665 670
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr
675 680 685
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His
690 695 700
Glu Pro Glu Ala
705
<210> 163
<211> 708
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 163
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly
130 135 140
Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
340 345 350
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
355 360 365
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
370 375 380
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
385 390 395 400
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
420 425 430
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro
435 440 445
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
450 455 460
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
465 470 475 480
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val
485 490 495
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser
500 505 510
Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile
515 520 525
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
530 535 540
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp
545 550 555 560
Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
580 585 590
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
595 600 605
Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val
610 615 620
Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr
625 630 635 640
Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
645 650 655
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
660 665 670
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr
675 680 685
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His
690 695 700
Glu Pro Glu Ala
705
<210> 164
<211> 161
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 164
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr His His His His His
145 150 155 160
His
<210> 165
<211> 708
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 165
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
210 215 220
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
225 230 235 240
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
245 250 255
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
260 265 270
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
275 280 285
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly
305 310 315 320
Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu
325 330 335
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
340 345 350
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg
355 360 365
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser
370 375 380
Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser
385 390 395 400
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
405 410 415
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp
420 425 430
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
450 455 460
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
465 470 475 480
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly
485 490 495
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
500 505 510
Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
515 520 525
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
530 535 540
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe
545 550 555 560
Gly Gly Gly Thr Lys Val Glu Ile Lys Gly Gly Gly Gly Ser Gly Gly
565 570 575
Gly Gly Ser Gly Gly Gly Gly Ser Gln Val Gln Leu Gln Glu Ser Gly
580 585 590
Gly Gly Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala
595 600 605
Ser Gly Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala
610 615 620
Pro Gly Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr
625 630 635 640
Ile Ser Tyr Asp Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
645 650 655
Asn Ala Lys Asn Thr Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu
660 665 670
Asp Thr Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp
675 680 685
Gly Lys Gly Thr Gln Val Thr Val Ser Ser His His His His His His
690 695 700
Glu Pro Glu Ala
705
<210> 166
<211> 708
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 166
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
340 345 350
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
355 360 365
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
370 375 380
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
385 390 395 400
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
420 425 430
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro
435 440 445
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
450 455 460
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
465 470 475 480
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val
485 490 495
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser
500 505 510
Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile
515 520 525
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
530 535 540
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp
545 550 555 560
Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
580 585 590
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
595 600 605
Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val
610 615 620
Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr
625 630 635 640
Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
645 650 655
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
660 665 670
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr
675 680 685
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His
690 695 700
Glu Pro Glu Ala
705
<210> 167
<211> 708
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 167
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Ala Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Arg Ile Phe Ser Ile Asp Ile Met Ser Trp Tyr Arg Gln Ala Pro Gly
50 55 60
Lys Gln Arg Glu Leu Val Ala Arg Ile Thr Arg Gly Gly Thr Ile Ser
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 Val Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr
100 105 110
Gly Val Tyr Tyr Cys Asn Ala Leu Tyr Gly Thr Asp Tyr Trp Gly Lys
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala Gly
130 135 140
Met Lys Gly Leu Pro Gly Ser Ala Pro Thr Ser Ser Ser Thr Lys Lys
145 150 155 160
Thr Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu
165 170 175
Asn Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr
180 185 190
Phe Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln
195 200 205
Cys Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala
210 215 220
Gln Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile
225 230 235 240
Asn Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys
245 250 255
Glu Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp
260 265 270
Ile Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro
275 280 285
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
290 295 300
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
305 310 315 320
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
325 330 335
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
340 345 350
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
355 360 365
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
370 375 380
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
385 390 395 400
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
405 410 415
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
420 425 430
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro
435 440 445
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
450 455 460
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser
465 470 475 480
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val
485 490 495
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser
500 505 510
Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile
515 520 525
Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu
530 535 540
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp
545 550 555 560
Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser
565 570 575
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp
580 585 590
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp
595 600 605
Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val
610 615 620
Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr
625 630 635 640
Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser
645 650 655
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu
660 665 670
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr
675 680 685
Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His
690 695 700
Glu Pro Glu Ala
705
<210> 168
<211> 450
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 168
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser Cys Asp Leu Pro Gln Thr His Asn
145 150 155 160
Leu Arg Asn Lys Arg Ala Leu Thr Leu Leu Val Gln Met Arg Arg Leu
165 170 175
Ser Pro Leu Ser Cys Leu Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln
180 185 190
Glu Lys Val Asp Ala Gln Gln Ile Lys Lys Ala Gln Ala Ile Pro Val
195 200 205
Leu Ser Glu Leu Thr Gln Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp
210 215 220
Ser Ser Ala Ala Trp Asn Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp
225 230 235 240
Leu His Gln Gln Leu Asn Asp Leu Gln Gly Cys Leu Met Gln Gln Val
245 250 255
Gly Val Gln Glu Phe Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala Val
260 265 270
Arg Lys Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys His
275 280 285
Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala Leu
290 295 300
Ser Ser Ser Ala Asn Val Ser Gly Gly Pro Gly Pro Ala Gly Met Lys
305 310 315 320
Gly Leu Pro Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
325 330 335
Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
340 345 350
Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys
355 360 365
Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu
370 375 380
Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
385 390 395 400
Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr
405 410 415
Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln
420 425 430
Gly Thr Leu Val Thr Val Ser Ser His His His His His His Glu Pro
435 440 445
Glu Ala
450
<210> 169
<211> 198
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 169
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Cys Asp Leu Pro Gln Thr His Asn Leu Arg
20 25 30
Asn Lys Arg Ala Leu Thr Leu Leu Val Gln Met Arg Arg Leu Ser Pro
35 40 45
Leu Ser Cys Leu Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln Glu Lys
50 55 60
Val Asp Ala Gln Gln Ile Lys Lys Ala Gln Ala Ile Pro Val Leu Ser
65 70 75 80
Glu Leu Thr Gln Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp Ser Ser
85 90 95
Ala Ala Trp Asn Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp Leu His
100 105 110
Gln Gln Leu Asn Asp Leu Gln Gly Cys Leu Met Gln Gln Val Gly Val
115 120 125
Gln Glu Phe Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala Val Arg Lys
130 135 140
Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys His Ser Pro
145 150 155 160
Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala Leu Ser Ser
165 170 175
Ser Ala Asn Val Leu Gly Arg Leu Arg Glu Glu Lys His His His His
180 185 190
His His Glu Pro Glu Ala
195
<210> 170
<211> 328
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 170
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser Cys Asp Leu Pro Gln Thr His Asn
145 150 155 160
Leu Arg Asn Lys Arg Ala Leu Thr Leu Leu Val Gln Met Arg Arg Leu
165 170 175
Ser Pro Leu Ser Cys Leu Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln
180 185 190
Glu Lys Val Asp Ala Gln Gln Ile Lys Lys Ala Gln Ala Ile Pro Val
195 200 205
Leu Ser Glu Leu Thr Gln Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp
210 215 220
Ser Ser Ala Ala Trp Asn Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp
225 230 235 240
Leu His Gln Gln Leu Asn Asp Leu Gln Gly Cys Leu Met Gln Gln Val
245 250 255
Gly Val Gln Glu Phe Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala Val
260 265 270
Arg Lys Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys His
275 280 285
Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala Leu
290 295 300
Ser Ser Ser Ala Asn Val Leu Gly Arg Leu Arg Glu Glu Lys His His
305 310 315 320
His His His His Glu Pro Glu Ala
325
<210> 171
<211> 328
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 171
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Cys Asp Leu Pro Gln Thr His Asn Leu Arg
20 25 30
Asn Lys Arg Ala Leu Thr Leu Leu Val Gln Met Arg Arg Leu Ser Pro
35 40 45
Leu Ser Cys Leu Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln Glu Lys
50 55 60
Val Asp Ala Gln Gln Ile Lys Lys Ala Gln Ala Ile Pro Val Leu Ser
65 70 75 80
Glu Leu Thr Gln Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp Ser Ser
85 90 95
Ala Ala Trp Asn Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp Leu His
100 105 110
Gln Gln Leu Asn Asp Leu Gln Gly Cys Leu Met Gln Gln Val Gly Val
115 120 125
Gln Glu Phe Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala Val Arg Lys
130 135 140
Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys His Ser Pro
145 150 155 160
Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala Leu Ser Ser
165 170 175
Ser Ala Asn Val Leu Gly Arg Leu Arg Glu Glu Lys Ser Gly Gly Pro
180 185 190
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln Leu Val
195 200 205
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
210 215 220
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
225 230 235 240
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
245 250 255
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
260 265 270
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
275 280 285
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
290 295 300
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser His His
305 310 315 320
His His His His Glu Pro Glu Ala
325
<210> 172
<211> 1396
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 172
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Ala His Lys Ser Glu Ile Ala His Arg
20 25 30
Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala
35 40 45
Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu
50 55 60
Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
65 70 75 80
Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
85 90 95
Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys
100 105 110
Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
115 120 125
Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala
130 135 140
Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr
145 150 155 160
Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
165 170 175
Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala
180 185 190
Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys
195 200 205
Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser
210 215 220
Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
225 230 235 240
Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu
245 250 255
Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu
260 265 270
Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu
275 280 285
Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro
290 295 300
Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met
305 310 315 320
Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu
325 330 335
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe
340 345 350
Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu
355 360 365
Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala
370 375 380
Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln
385 390 395 400
Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu
405 410 415
Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg
420 425 430
Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala
435 440 445
Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu
450 455 460
Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn
465 470 475 480
Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr
485 490 495
Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala
500 505 510
Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr
515 520 525
Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln
530 535 540
Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys
545 550 555 560
Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe
565 570 575
Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr
580 585 590
Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala Ser Gly
595 600 605
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Cys Asp Leu
610 615 620
Pro Gln Thr His Asn Leu Arg Asn Lys Arg Ala Leu Thr Leu Leu Val
625 630 635 640
Gln Met Arg Arg Leu Ser Pro Leu Ser Cys Leu Lys Asp Arg Lys Asp
645 650 655
Phe Gly Phe Pro Gln Glu Lys Val Asp Ala Gln Gln Ile Lys Lys Ala
660 665 670
Gln Ala Ile Pro Val Leu Ser Glu Leu Thr Gln Gln Ile Leu Asn Ile
675 680 685
Phe Thr Ser Lys Asp Ser Ser Ala Ala Trp Asn Thr Thr Leu Leu Asp
690 695 700
Ser Phe Cys Asn Asp Leu His Gln Gln Leu Asn Asp Leu Gln Gly Cys
705 710 715 720
Leu Met Gln Gln Val Gly Val Gln Glu Phe Pro Leu Thr Gln Glu Asp
725 730 735
Ala Leu Leu Ala Val Arg Lys Tyr Phe His Arg Ile Thr Val Tyr Leu
740 745 750
Arg Glu Lys Lys His Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu
755 760 765
Val Trp Arg Ala Leu Ser Ser Ser Ala Asn Val Leu Gly Arg Leu Arg
770 775 780
Glu Glu Lys Ser Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro
785 790 795 800
Gly Ser Glu Ala His Lys Ser Glu Ile Ala His Arg Tyr Asn Asp Leu
805 810 815
Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala Phe Ser Gln Tyr
820 825 830
Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu Val Gln Glu Val
835 840 845
Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser Ala Ala Asn Cys
850 855 860
Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu Cys Ala Ile Pro
865 870 875 880
Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys Cys Thr Lys Gln
885 890 895
Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys Asp Asp Asn Pro
900 905 910
Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala Met Cys Thr Ser
915 920 925
Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr Leu His Glu Val
930 935 940
Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala
945 950 955 960
Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala Glu Ala Asp Lys
965 970 975
Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys Glu Lys Ala Leu
980 985 990
Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser Met Gln Lys Phe
995 1000 1005
Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg Leu Ser Gln
1010 1015 1020
Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu Ala Thr
1025 1030 1035
Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu Leu
1040 1045 1050
Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu
1055 1060 1065
Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys
1070 1075 1080
Pro Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp
1085 1090 1095
Thr Met Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu
1100 1105 1110
Asp Gln Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe
1115 1120 1125
Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr
1130 1135 1140
Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr
1145 1150 1155
Leu Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala Cys Tyr Gly
1160 1165 1170
Thr Val Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro Lys Asn
1175 1180 1185
Leu Val Lys Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu Tyr
1190 1195 1200
Gly Phe Gln Asn Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro
1205 1210 1215
Gln Val Ser Thr Pro Thr Leu Val Glu Ala Ala Arg Asn Leu Gly
1220 1225 1230
Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu Asp Gln Arg Leu
1235 1240 1245
Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn Arg Val Cys
1250 1255 1260
Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr Lys Cys
1265 1270 1275
Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala Leu
1280 1285 1290
Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr
1295 1300 1305
Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys
1310 1315 1320
Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys
1325 1330 1335
Pro Lys Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe
1340 1345 1350
Ala Gln Phe Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr
1355 1360 1365
Cys Phe Ser Thr Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp
1370 1375 1380
Ala Leu Ala His His His His His His Glu Pro Glu Ala
1385 1390 1395
<210> 173
<211> 797
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 173
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Ala His Lys Ser Glu Ile Ala His Arg
20 25 30
Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly Leu Val Leu Ile Ala
35 40 45
Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp Glu His Ala Lys Leu
50 55 60
Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys Val Ala Asp Glu Ser
65 70 75 80
Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu Phe Gly Asp Lys Leu
85 90 95
Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly Glu Leu Ala Asp Cys
100 105 110
Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys Phe Leu Gln His Lys
115 120 125
Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg Pro Glu Ala Glu Ala
130 135 140
Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr Phe Met Gly His Tyr
145 150 155 160
Leu His Glu Val Ala Arg Arg His Pro Tyr Phe Tyr Ala Pro Glu Leu
165 170 175
Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu Thr Gln Cys Cys Ala
180 185 190
Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys Leu Asp Gly Val Lys
195 200 205
Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg Met Lys Cys Ser Ser
210 215 220
Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala Trp Ala Val Ala Arg
225 230 235 240
Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala Glu Ile Thr Lys Leu
245 250 255
Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys Cys His Gly Asp Leu
260 265 270
Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala Lys Tyr Met Cys Glu
275 280 285
Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr Cys Cys Asp Lys Pro
290 295 300
Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val Glu His Asp Thr Met
305 310 315 320
Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe Val Glu Asp Gln Glu
325 330 335
Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val Phe Leu Gly Thr Phe
340 345 350
Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr Ser Val Ser Leu Leu
355 360 365
Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu Glu Lys Cys Cys Ala
370 375 380
Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val Leu Ala Glu Phe Gln
385 390 395 400
Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys Thr Asn Cys Asp Leu
405 410 415
Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn Ala Ile Leu Val Arg
420 425 430
Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro Thr Leu Val Glu Ala
435 440 445
Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys Cys Thr Leu Pro Glu
450 455 460
Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu Ser Ala Ile Leu Asn
465 470 475 480
Arg Val Cys Leu Leu His Glu Lys Thr Pro Val Ser Glu His Val Thr
485 490 495
Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg Pro Cys Phe Ser Ala
500 505 510
Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu Phe Lys Ala Glu Thr
515 520 525
Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro Glu Lys Glu Lys Gln
530 535 540
Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val Lys His Lys Pro Lys
545 550 555 560
Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp Asp Phe Ala Gln Phe
565 570 575
Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp Thr Cys Phe Ser Thr
580 585 590
Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp Ala Leu Ala Ser Gly
595 600 605
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Cys Asp Leu
610 615 620
Pro Gln Thr His Asn Leu Arg Asn Lys Arg Ala Leu Thr Leu Leu Val
625 630 635 640
Gln Met Arg Arg Leu Ser Pro Leu Ser Cys Leu Lys Asp Arg Lys Asp
645 650 655
Phe Gly Phe Pro Gln Glu Lys Val Asp Ala Gln Gln Ile Lys Lys Ala
660 665 670
Gln Ala Ile Pro Val Leu Ser Glu Leu Thr Gln Gln Ile Leu Asn Ile
675 680 685
Phe Thr Ser Lys Asp Ser Ser Ala Ala Trp Asn Thr Thr Leu Leu Asp
690 695 700
Ser Phe Cys Asn Asp Leu His Gln Gln Leu Asn Asp Leu Gln Gly Cys
705 710 715 720
Leu Met Gln Gln Val Gly Val Gln Glu Phe Pro Leu Thr Gln Glu Asp
725 730 735
Ala Leu Leu Ala Val Arg Lys Tyr Phe His Arg Ile Thr Val Tyr Leu
740 745 750
Arg Glu Lys Lys His Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu
755 760 765
Val Trp Arg Ala Leu Ser Ser Ser Ala Asn Val Leu Gly Arg Leu Arg
770 775 780
Glu Glu Lys His His His His His His Glu Pro Glu Ala
785 790 795
<210> 174
<211> 797
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 174
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Cys Asp Leu Pro Gln Thr His Asn Leu Arg
20 25 30
Asn Lys Arg Ala Leu Thr Leu Leu Val Gln Met Arg Arg Leu Ser Pro
35 40 45
Leu Ser Cys Leu Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln Glu Lys
50 55 60
Val Asp Ala Gln Gln Ile Lys Lys Ala Gln Ala Ile Pro Val Leu Ser
65 70 75 80
Glu Leu Thr Gln Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp Ser Ser
85 90 95
Ala Ala Trp Asn Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp Leu His
100 105 110
Gln Gln Leu Asn Asp Leu Gln Gly Cys Leu Met Gln Gln Val Gly Val
115 120 125
Gln Glu Phe Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala Val Arg Lys
130 135 140
Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys His Ser Pro
145 150 155 160
Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala Leu Ser Ser
165 170 175
Ser Ala Asn Val Leu Gly Arg Leu Arg Glu Glu Lys Ser Gly Gly Pro
180 185 190
Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Ala His Lys Ser
195 200 205
Glu Ile Ala His Arg Tyr Asn Asp Leu Gly Glu Gln His Phe Lys Gly
210 215 220
Leu Val Leu Ile Ala Phe Ser Gln Tyr Leu Gln Lys Cys Ser Tyr Asp
225 230 235 240
Glu His Ala Lys Leu Val Gln Glu Val Thr Asp Phe Ala Lys Thr Cys
245 250 255
Val Ala Asp Glu Ser Ala Ala Asn Cys Asp Lys Ser Leu His Thr Leu
260 265 270
Phe Gly Asp Lys Leu Cys Ala Ile Pro Asn Leu Arg Glu Asn Tyr Gly
275 280 285
Glu Leu Ala Asp Cys Cys Thr Lys Gln Glu Pro Glu Arg Asn Glu Cys
290 295 300
Phe Leu Gln His Lys Asp Asp Asn Pro Ser Leu Pro Pro Phe Glu Arg
305 310 315 320
Pro Glu Ala Glu Ala Met Cys Thr Ser Phe Lys Glu Asn Pro Thr Thr
325 330 335
Phe Met Gly His Tyr Leu His Glu Val Ala Arg Arg His Pro Tyr Phe
340 345 350
Tyr Ala Pro Glu Leu Leu Tyr Tyr Ala Glu Gln Tyr Asn Glu Ile Leu
355 360 365
Thr Gln Cys Cys Ala Glu Ala Asp Lys Glu Ser Cys Leu Thr Pro Lys
370 375 380
Leu Asp Gly Val Lys Glu Lys Ala Leu Val Ser Ser Val Arg Gln Arg
385 390 395 400
Met Lys Cys Ser Ser Met Gln Lys Phe Gly Glu Arg Ala Phe Lys Ala
405 410 415
Trp Ala Val Ala Arg Leu Ser Gln Thr Phe Pro Asn Ala Asp Phe Ala
420 425 430
Glu Ile Thr Lys Leu Ala Thr Asp Leu Thr Lys Val Asn Lys Glu Cys
435 440 445
Cys His Gly Asp Leu Leu Glu Cys Ala Asp Asp Arg Ala Glu Leu Ala
450 455 460
Lys Tyr Met Cys Glu Asn Gln Ala Thr Ile Ser Ser Lys Leu Gln Thr
465 470 475 480
Cys Cys Asp Lys Pro Leu Leu Lys Lys Ala His Cys Leu Ser Glu Val
485 490 495
Glu His Asp Thr Met Pro Ala Asp Leu Pro Ala Ile Ala Ala Asp Phe
500 505 510
Val Glu Asp Gln Glu Val Cys Lys Asn Tyr Ala Glu Ala Lys Asp Val
515 520 525
Phe Leu Gly Thr Phe Leu Tyr Glu Tyr Ser Arg Arg His Pro Asp Tyr
530 535 540
Ser Val Ser Leu Leu Leu Arg Leu Ala Lys Lys Tyr Glu Ala Thr Leu
545 550 555 560
Glu Lys Cys Cys Ala Glu Ala Asn Pro Pro Ala Cys Tyr Gly Thr Val
565 570 575
Leu Ala Glu Phe Gln Pro Leu Val Glu Glu Pro Lys Asn Leu Val Lys
580 585 590
Thr Asn Cys Asp Leu Tyr Glu Lys Leu Gly Glu Tyr Gly Phe Gln Asn
595 600 605
Ala Ile Leu Val Arg Tyr Thr Gln Lys Ala Pro Gln Val Ser Thr Pro
610 615 620
Thr Leu Val Glu Ala Ala Arg Asn Leu Gly Arg Val Gly Thr Lys Cys
625 630 635 640
Cys Thr Leu Pro Glu Asp Gln Arg Leu Pro Cys Val Glu Asp Tyr Leu
645 650 655
Ser Ala Ile Leu Asn Arg Val Cys Leu Leu His Glu Lys Thr Pro Val
660 665 670
Ser Glu His Val Thr Lys Cys Cys Ser Gly Ser Leu Val Glu Arg Arg
675 680 685
Pro Cys Phe Ser Ala Leu Thr Val Asp Glu Thr Tyr Val Pro Lys Glu
690 695 700
Phe Lys Ala Glu Thr Phe Thr Phe His Ser Asp Ile Cys Thr Leu Pro
705 710 715 720
Glu Lys Glu Lys Gln Ile Lys Lys Gln Thr Ala Leu Ala Glu Leu Val
725 730 735
Lys His Lys Pro Lys Ala Thr Ala Glu Gln Leu Lys Thr Val Met Asp
740 745 750
Asp Phe Ala Gln Phe Leu Asp Thr Cys Cys Lys Ala Ala Asp Lys Asp
755 760 765
Thr Cys Phe Ser Thr Glu Gly Pro Asn Leu Val Thr Arg Cys Lys Asp
770 775 780
Ala Leu Ala His His His His His His Glu Pro Glu Ala
785 790 795
<210> 175
<211> 587
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 175
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Val Gln Leu Gln Glu Ser Gly Gly Gly
20 25 30
Leu Ala Gln Ala Gly Gly Ser Leu Ser Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Val Ser Asn Ser Val Met Ala Trp Tyr Arg Gln Thr Pro Gly
50 55 60
Lys Gln Arg Glu Phe Val Ala Ile Ile Asn Ser Val Gly Ser Thr Asn
65 70 75 80
Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Thr Val Tyr Leu Gln Met Asn Asn Leu Lys Pro Glu Asp Thr
100 105 110
Ala Val Tyr Val Cys Asn Arg Asn Phe Asp Arg Ile Tyr Trp Gly Gln
115 120 125
Gly Thr Gln Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
130 135 140
Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly
145 150 155 160
Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser
165 170 175
Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro
180 185 190
Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp
195 200 205
Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
210 215 220
Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu
225 230 235 240
Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser
245 250 255
Ser Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro
260 265 270
Ala Gly Met Lys Gly Leu Pro Gly Ser Cys Asp Leu Pro Gln Thr His
275 280 285
Asn Leu Arg Asn Lys Arg Ala Leu Thr Leu Leu Val Gln Met Arg Arg
290 295 300
Leu Ser Pro Leu Ser Cys Leu Lys Asp Arg Lys Asp Phe Gly Phe Pro
305 310 315 320
Gln Glu Lys Val Asp Ala Gln Gln Ile Lys Lys Ala Gln Ala Ile Pro
325 330 335
Val Leu Ser Glu Leu Thr Gln Gln Ile Leu Asn Ile Phe Thr Ser Lys
340 345 350
Asp Ser Ser Ala Ala Trp Asn Thr Thr Leu Leu Asp Ser Phe Cys Asn
355 360 365
Asp Leu His Gln Gln Leu Asn Asp Leu Gln Gly Cys Leu Met Gln Gln
370 375 380
Val Gly Val Gln Glu Phe Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala
385 390 395 400
Val Arg Lys Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys
405 410 415
His Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala
420 425 430
Leu Ser Ser Ser Ala Asn Val Leu Gly Arg Leu Arg Glu Glu Lys Ser
435 440 445
Gly Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val
450 455 460
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu
465 470 475 480
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met
485 490 495
Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser
500 505 510
Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly
515 520 525
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln
530 535 540
Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile
545 550 555 560
Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser
565 570 575
Ser His His His His His His Glu Pro Glu Ala
580 585
<210> 176
<211> 587
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 176
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Ser Gly Gly Pro Gly Pro Ala
130 135 140
Gly Met Lys Gly Leu Pro Gly Ser Cys Asp Leu Pro Gln Thr His Asn
145 150 155 160
Leu Arg Asn Lys Arg Ala Leu Thr Leu Leu Val Gln Met Arg Arg Leu
165 170 175
Ser Pro Leu Ser Cys Leu Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln
180 185 190
Glu Lys Val Asp Ala Gln Gln Ile Lys Lys Ala Gln Ala Ile Pro Val
195 200 205
Leu Ser Glu Leu Thr Gln Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp
210 215 220
Ser Ser Ala Ala Trp Asn Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp
225 230 235 240
Leu His Gln Gln Leu Asn Asp Leu Gln Gly Cys Leu Met Gln Gln Val
245 250 255
Gly Val Gln Glu Phe Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala Val
260 265 270
Arg Lys Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys His
275 280 285
Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala Leu
290 295 300
Ser Ser Ser Ala Asn Val Leu Gly Arg Leu Arg Glu Glu Lys Ser Gly
305 310 315 320
Gly Pro Gly Pro Ala Gly Met Lys Gly Leu Pro Gly Ser Glu Val Gln
325 330 335
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
340 345 350
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
355 360 365
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
370 375 380
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg
385 390 395 400
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
405 410 415
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
420 425 430
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
435 440 445
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gln
450 455 460
Val Gln Leu Gln Glu Ser Gly Gly Gly Leu Ala Gln Ala Gly Gly Ser
465 470 475 480
Leu Ser Leu Ser Cys Ala Ala Ser Gly Phe Thr Val Ser Asn Ser Val
485 490 495
Met Ala Trp Tyr Arg Gln Thr Pro Gly Lys Gln Arg Glu Phe Val Ala
500 505 510
Ile Ile Asn Ser Val Gly Ser Thr Asn Tyr Ala Asp Ser Val Lys Gly
515 520 525
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Val Tyr Leu Gln
530 535 540
Met Asn Asn Leu Lys Pro Glu Asp Thr Ala Val Tyr Val Cys Asn Arg
545 550 555 560
Asn Phe Asp Arg Ile Tyr Trp Gly Gln Gly Thr Gln Val Thr Val Ser
565 570 575
Ser His His His His His His Glu Pro Glu Ala
580 585
<210> 177
<211> 458
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 177
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly
20 25 30
Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly
35 40 45
Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr
65 70 75 80
Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
85 90 95
Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Pro Glu Asp
100 105 110
Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser Val Ser Ser
115 120 125
Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly
130 135 140
Gly Gly Ser Gly Gly Gly Gly Ser Cys Asp Leu Pro Gln Thr His Asn
145 150 155 160
Leu Arg Asn Lys Arg Ala Leu Thr Leu Leu Val Gln Met Arg Arg Leu
165 170 175
Ser Pro Leu Ser Cys Leu Lys Asp Arg Lys Asp Phe Gly Phe Pro Gln
180 185 190
Glu Lys Val Asp Ala Gln Gln Ile Lys Lys Ala Gln Ala Ile Pro Val
195 200 205
Leu Ser Glu Leu Thr Gln Gln Ile Leu Asn Ile Phe Thr Ser Lys Asp
210 215 220
Ser Ser Ala Ala Trp Asn Thr Thr Leu Leu Asp Ser Phe Cys Asn Asp
225 230 235 240
Leu His Gln Gln Leu Asn Asp Leu Gln Gly Cys Leu Met Gln Gln Val
245 250 255
Gly Val Gln Glu Phe Pro Leu Thr Gln Glu Asp Ala Leu Leu Ala Val
260 265 270
Arg Lys Tyr Phe His Arg Ile Thr Val Tyr Leu Arg Glu Lys Lys His
275 280 285
Ser Pro Cys Ala Trp Glu Val Val Arg Ala Glu Val Trp Arg Ala Leu
290 295 300
Ser Ser Ser Ala Asn Val Leu Gly Arg Leu Arg Glu Glu Lys Gly Gly
305 310 315 320
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln
325 330 335
Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg
340 345 350
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser
355 360 365
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile
370 375 380
Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg
385 390 395 400
Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met
405 410 415
Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly
420 425 430
Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
435 440 445
His His His His His His Glu Pro Glu Ala
450 455
<210> 178
<211> 579
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 178
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Gly
145 150 155 160
Pro Ala Gly Leu Tyr Ala Gln Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
210 215 220
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
225 230 235 240
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
245 250 255
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
260 265 270
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
275 280 285
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Gly
305 310 315 320
Pro Ala Gly Leu Tyr Ala Gln Pro Gly Ser Glu Val Gln Leu Val Glu
325 330 335
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
340 345 350
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg
355 360 365
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser
370 375 380
Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser
385 390 395 400
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
405 410 415
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp
420 425 430
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
450 455 460
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
465 470 475 480
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly
485 490 495
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
500 505 510
Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
515 520 525
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
530 535 540
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe
545 550 555 560
Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His Glu
565 570 575
Pro Glu Ala
<210> 179
<211> 579
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 179
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Pro
145 150 155 160
Gly Gly Pro Ala Gly Ile Gly Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
210 215 220
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
225 230 235 240
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
245 250 255
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
260 265 270
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
275 280 285
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Pro
305 310 315 320
Gly Gly Pro Ala Gly Ile Gly Pro Gly Ser Glu Val Gln Leu Val Glu
325 330 335
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
340 345 350
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg
355 360 365
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser
370 375 380
Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser
385 390 395 400
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
405 410 415
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp
420 425 430
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
450 455 460
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
465 470 475 480
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly
485 490 495
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
500 505 510
Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
515 520 525
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
530 535 540
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe
545 550 555 560
Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His Glu
565 570 575
Pro Glu Ala
<210> 180
<211> 579
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 180
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Ala
145 150 155 160
Leu Phe Lys Ser Ser Phe Pro Pro Gly Ser Glu Val Gln Leu Val Glu
165 170 175
Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser Cys
180 185 190
Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val Arg
195 200 205
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser
210 215 220
Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile
225 230 235 240
Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu
245 250 255
Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu
260 265 270
Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly
275 280 285
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly
290 295 300
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro Ala
305 310 315 320
Leu Phe Lys Ser Ser Phe Pro Pro Gly Ser Glu Val Gln Leu Val Glu
325 330 335
Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu Ser Cys
340 345 350
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg
355 360 365
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser
370 375 380
Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser
385 390 395 400
Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
405 410 415
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp
420 425 430
Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser Ser Gly
435 440 445
Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Asp Ile
450 455 460
Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly Asp Arg
465 470 475 480
Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly
485 490 495
Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser
500 505 510
Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly
515 520 525
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp
530 535 540
Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr Thr Phe
545 550 555 560
Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His His Glu
565 570 575
Pro Glu Ala
<210> 181
<211> 581
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 181
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Pro
145 150 155 160
Leu Ala Gln Lys Leu Lys Ser Ser Pro Gly Ser Glu Val Gln Leu Val
165 170 175
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
180 185 190
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
195 200 205
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
210 215 220
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
225 230 235 240
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
245 250 255
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
260 265 270
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
275 280 285
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
290 295 300
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro
305 310 315 320
Pro Leu Ala Gln Lys Leu Lys Ser Ser Pro Gly Ser Glu Val Gln Leu
325 330 335
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
340 345 350
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp
355 360 365
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp
370 375 380
Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr
385 390 395 400
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser
405 410 415
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn
420 425 430
Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
435 440 445
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
450 455 460
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
465 470 475 480
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
485 490 495
Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
500 505 510
Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
515 520 525
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
530 535 540
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr
545 550 555 560
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His
565 570 575
His Glu Pro Glu Ala
580
<210> 182
<211> 613
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 182
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Ala Pro Thr Ser Ser Ser Thr Lys Lys Thr
20 25 30
Gln Leu Gln Leu Glu His Leu Leu Leu Asp Leu Gln Met Ile Leu Asn
35 40 45
Gly Ile Asn Asn Tyr Lys Asn Pro Lys Leu Thr Arg Met Leu Thr Phe
50 55 60
Lys Phe Tyr Met Pro Lys Lys Ala Thr Glu Leu Lys His Leu Gln Cys
65 70 75 80
Leu Glu Glu Glu Leu Lys Pro Leu Glu Glu Val Leu Asn Leu Ala Gln
85 90 95
Ser Lys Asn Phe His Leu Arg Pro Arg Asp Leu Ile Ser Asn Ile Asn
100 105 110
Val Ile Val Leu Glu Leu Lys Gly Ser Glu Thr Thr Phe Met Cys Glu
115 120 125
Tyr Ala Asp Glu Thr Ala Thr Ile Val Glu Phe Leu Asn Arg Trp Ile
130 135 140
Thr Phe Cys Gln Ser Ile Ile Ser Thr Leu Thr Ser Gly Gly Pro Pro
145 150 155 160
Gly Gly Pro Ala Gly Ile Gly Ala Leu Phe Lys Ser Ser Phe Pro Pro
165 170 175
Leu Ala Gln Lys Leu Lys Ser Ser Pro Gly Ser Glu Val Gln Leu Val
180 185 190
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu Ser
195 200 205
Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp Val
210 215 220
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser Gly
225 230 235 240
Ser Gly Arg Asp Thr Leu Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr
245 250 255
Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser
260 265 270
Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser
275 280 285
Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly
290 295 300
Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
305 310 315 320
Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Ser Gly Gly Pro
325 330 335
Pro Gly Gly Pro Ala Gly Ile Gly Ala Leu Phe Lys Ser Ser Phe Pro
340 345 350
Pro Leu Ala Gln Lys Leu Lys Ser Ser Pro Gly Ser Glu Val Gln Leu
355 360 365
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Arg Leu
370 375 380
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp
385 390 395 400
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Ala Ile Asp
405 410 415
Ser Ser Ser Tyr Thr Tyr Ser Pro Asp Thr Val Arg Gly Arg Phe Thr
420 425 430
Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser
435 440 445
Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn
450 455 460
Trp Asp Ala Leu Asp Tyr Trp Gly Gln Gly Thr Thr Val Thr Val Ser
465 470 475 480
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
485 490 495
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
500 505 510
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Asn Val Gly Thr Asn
515 520 525
Val Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile
530 535 540
Tyr Ser Ala Ser Phe Arg Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly
545 550 555 560
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
565 570 575
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Tyr Thr Tyr Pro Tyr
580 585 590
Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys His His His His His
595 600 605
His Glu Pro Glu Ala
610
<210> 183
<211> 534
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 183
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn
35 40 45
Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly
50 55 60
Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
65 70 75 80
Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
85 90 95
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser
100 105 110
Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Lys Pro Leu Gly Leu Gln Ala Arg Val Val Gly Gly Gly Gly Thr Gln
130 135 140
Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr
145 150 155 160
Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn
165 170 175
Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu
180 185 190
Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe Ser
195 200 205
Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln
210 215 220
Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg
225 230 235 240
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
260 265 270
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
275 280 285
Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val
290 295 300
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
305 310 315 320
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg
325 330 335
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
340 345 350
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
355 360 365
Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
405 410 415
Gly Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser
420 425 430
Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
435 440 445
Val Val Ala Ile Asn Trp Ala Ser Gly Ser Thr Tyr Tyr Ala Asp Ser
450 455 460
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
465 470 475 480
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
485 490 495
Cys Ala Ala Gly Tyr Gln Ile Asn Ser Gly Asn Tyr Asn Phe Lys Asp
500 505 510
Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
515 520 525
His His His His His His
530
<210> 184
<211> 534
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 184
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn
35 40 45
Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly
50 55 60
Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
65 70 75 80
Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
85 90 95
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser
100 105 110
Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Val Val Gly Gly Gly Gly Thr Gln
130 135 140
Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr
145 150 155 160
Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn
165 170 175
Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu
180 185 190
Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe Ser
195 200 205
Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln
210 215 220
Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg
225 230 235 240
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
260 265 270
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
275 280 285
Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val
290 295 300
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
305 310 315 320
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg
325 330 335
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
340 345 350
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
355 360 365
Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
405 410 415
Gly Ser Leu Thr Leu Ser Cys Ala Ala Ser Gly Arg Thr Phe Ser Ser
420 425 430
Tyr Ala Met Gly Trp Phe Arg Gln Ala Pro Gly Lys Glu Arg Glu Phe
435 440 445
Val Val Ala Ile Asn Trp Ala Ser Gly Ser Thr Tyr Tyr Ala Asp Ser
450 455 460
Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
465 470 475 480
Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
485 490 495
Cys Ala Ala Gly Tyr Gln Ile Asn Ser Gly Asn Tyr Asn Phe Lys Asp
500 505 510
Tyr Glu Tyr Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
515 520 525
His His His His His His
530
<210> 185
<211> 398
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 185
Val Val Gly Gly Gly Gly Thr Gln Thr Val Val Thr Gln Glu Pro Ser
1 5 10 15
Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser
20 25 30
Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys
35 40 45
Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val
50 55 60
Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala
65 70 75 80
Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr
85 90 95
Cys Thr Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys
100 105 110
Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
145 150 155 160
Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
165 170 175
Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr
180 185 190
Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
195 200 205
Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr Ile
225 230 235 240
Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Thr Leu Ser Cys Ala
275 280 285
Ala Ser Gly Arg Thr Phe Ser Ser Tyr Ala Met Gly Trp Phe Arg Gln
290 295 300
Ala Pro Gly Lys Glu Arg Glu Phe Val Val Ala Ile Asn Trp Ala Ser
305 310 315 320
Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
325 330 335
Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
340 345 350
Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Ala Gly Tyr Gln Ile Asn
355 360 365
Ser Gly Asn Tyr Asn Phe Lys Asp Tyr Glu Tyr Asp Tyr Trp Gly Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser His His His His His His
385 390 395
<210> 186
<211> 518
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 186
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn
35 40 45
Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly
50 55 60
Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
65 70 75 80
Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
85 90 95
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser
100 105 110
Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Lys Pro Leu Gly Leu Gln Ala Arg Val Val Gly Gly Gly Gly Thr Gln
130 135 140
Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr
145 150 155 160
Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn
165 170 175
Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu
180 185 190
Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe Ser
195 200 205
Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln
210 215 220
Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg
225 230 235 240
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
260 265 270
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
275 280 285
Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val
290 295 300
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
305 310 315 320
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg
325 330 335
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
340 345 350
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
355 360 365
Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
405 410 415
Gly Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu
420 425 430
Tyr His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
435 440 445
Val Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val
450 455 460
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
465 470 475 480
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
485 490 495
Asp Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
500 505 510
His His His His His His
515
<210> 187
<211> 518
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 187
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn
35 40 45
Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly
50 55 60
Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
65 70 75 80
Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
85 90 95
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser
100 105 110
Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly
115 120 125
Ser Gly Gly Gly Gly Ser Gly Gly Val Val Gly Gly Gly Gly Thr Gln
130 135 140
Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val Ser Pro Gly Gly Thr
145 150 155 160
Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala Val Thr Ser Gly Asn
165 170 175
Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln Ala Pro Arg Gly Leu
180 185 190
Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr Pro Ala Arg Phe Ser
195 200 205
Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr Leu Ser Gly Val Gln
210 215 220
Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu Trp Tyr Ser Asn Arg
225 230 235 240
Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gly Gly Gly
245 250 255
Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Glu Val Gln Leu Val
260 265 270
Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser
275 280 285
Cys Ala Ala Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val
290 295 300
Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser
305 310 315 320
Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg
325 330 335
Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met
340 345 350
Asn Asn Leu Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His
355 360 365
Ala Asn Phe Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln
370 375 380
Gly Thr Leu Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly
385 390 395 400
Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly
405 410 415
Gly Ser Leu Thr Leu Ser Cys Ala Ala Ser Arg Phe Met Ile Ser Glu
420 425 430
Tyr His Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
435 440 445
Val Ser Thr Ile Asn Pro Ala Gly Thr Thr Asp Tyr Ala Glu Ser Val
450 455 460
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr
465 470 475 480
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
485 490 495
Asp Ser Tyr Gly Tyr Arg Gly Gln Gly Thr Gln Val Thr Val Ser Ser
500 505 510
His His His His His His
515
<210> 188
<211> 382
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 188
Val Val Gly Gly Gly Gly Thr Gln Thr Val Val Thr Gln Glu Pro Ser
1 5 10 15
Leu Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser
20 25 30
Thr Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys
35 40 45
Pro Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val
50 55 60
Pro Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala
65 70 75 80
Ala Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr
85 90 95
Cys Thr Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys
100 105 110
Leu Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly
115 120 125
Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
130 135 140
Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
145 150 155 160
Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
165 170 175
Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr
180 185 190
Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser
195 200 205
Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr
210 215 220
Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr Ile
225 230 235 240
Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
245 250 255
Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser
260 265 270
Gly Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Thr Leu Ser Cys Ala
275 280 285
Ala Ser Arg Phe Met Ile Ser Glu Tyr His Met His Trp Val Arg Gln
290 295 300
Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Asn Pro Ala Gly
305 310 315 320
Thr Thr Asp Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
325 330 335
Asp Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro
340 345 350
Glu Asp Thr Ala Val Tyr Tyr Cys Asp Ser Tyr Gly Tyr Arg Gly Gln
355 360 365
Gly Thr Gln Val Thr Val Ser Ser His His His His His His
370 375 380
<210> 189
<211> 503
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 189
Gln Val Gln Leu Val Glu Ser Gly Gly Ala Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Pro Val Asn Arg Tyr
20 25 30
Ser Met Arg Trp Tyr Arg Gln Ala Pro Gly Lys Glu Arg Glu Trp Val
35 40 45
Ala Gly Met Ser Ser Ala Gly Asp Arg Ser Ser Tyr Glu Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Arg Asn Thr Val Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Lys Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Asn Val Asn Val Gly Phe Glu Tyr Trp Gly Gln Gly Thr Gln Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu
115 120 125
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn Ser Leu Arg Leu
130 135 140
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe Gly Met Ser Trp
145 150 155 160
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ser Ile Ser
165 170 175
Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe
180 185 190
Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn
195 200 205
Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly
210 215 220
Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser Gly
225 230 235 240
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
245 250 255
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala
260 265 270
Ser Gly Phe Thr Phe Asn Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala
275 280 285
Pro Gly Lys Gly Leu Glu Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn
290 295 300
Asn Tyr Ala Thr Tyr Tyr Ala Asp Gln Val Lys Asp Arg Phe Thr Ile
305 310 315 320
Ser Arg Asp Asp Ser Lys Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu
325 330 335
Lys Thr Glu Asp Thr Ala Val Tyr Tyr Cys Val Arg His Ala Asn Phe
340 345 350
Gly Asn Ser Tyr Ile Ser Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu
355 360 365
Val Thr Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
370 375 380
Gly Gly Gly Ser Gln Thr Val Val Thr Gln Glu Pro Ser Leu Thr Val
385 390 395 400
Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser Thr Gly Ala
405 410 415
Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro Gly Gln
420 425 430
Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val Pro Gly Thr
435 440 445
Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala Leu Thr
450 455 460
Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys Thr Leu
465 470 475 480
Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu Thr Val
485 490 495
Leu His His His His His His
500
<210> 190
<211> 509
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 190
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Ser Ile Ser Gly Ser Gly Arg Asp Thr Leu Tyr Ala Asp Ser Val
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Thr Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Pro Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Ile Gly Gly Ser Leu Ser Val Ser Ser Gln Gly Thr Leu Val Thr
100 105 110
Val Ser Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Val
115 120 125
Val Gly Gly Gly Gly Thr Gln Thr Val Val Thr Gln Glu Pro Ser Leu
130 135 140
Thr Val Ser Pro Gly Gly Thr Val Thr Leu Thr Cys Ala Ser Ser Thr
145 150 155 160
Gly Ala Val Thr Ser Gly Asn Tyr Pro Asn Trp Val Gln Gln Lys Pro
165 170 175
Gly Gln Ala Pro Arg Gly Leu Ile Gly Gly Thr Lys Phe Leu Val Pro
180 185 190
Gly Thr Pro Ala Arg Phe Ser Gly Ser Leu Leu Gly Gly Lys Ala Ala
195 200 205
Leu Thr Leu Ser Gly Val Gln Pro Glu Asp Glu Ala Glu Tyr Tyr Cys
210 215 220
Thr Leu Trp Tyr Ser Asn Arg Trp Val Phe Gly Gly Gly Thr Lys Leu
225 230 235 240
Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly
245 250 255
Gly Ser Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro
260 265 270
Gly Gly Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asn
275 280 285
Lys Tyr Ala Ile Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
290 295 300
Trp Val Ala Arg Ile Arg Ser Lys Tyr Asn Asn Tyr Ala Thr Tyr Tyr
305 310 315 320
Ala Asp Gln Val Lys Asp Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys
325 330 335
Asn Thr Ala Tyr Leu Gln Met Asn Asn Leu Lys Thr Glu Asp Thr Ala
340 345 350
Val Tyr Tyr Cys Val Arg His Ala Asn Phe Gly Asn Ser Tyr Ile Ser
355 360 365
Tyr Trp Ala Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Gly
370 375 380
Gly Gly Gly Ser Gly Gly Gly Ser Glu Val Gln Leu Val Glu Ser Gly
385 390 395 400
Gly Gly Leu Val Gln Pro Gly Gly Ser Leu Thr Leu Ser Cys Ala Ala
405 410 415
Ser Arg Phe Met Ile Ser Glu Tyr His Met His Trp Val Arg Gln Ala
420 425 430
Pro Gly Lys Gly Leu Glu Trp Val Ser Thr Ile Asn Pro Ala Gly Thr
435 440 445
Thr Asp Tyr Ala Glu Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
450 455 460
Asn Ala Lys Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Lys Pro Glu
465 470 475 480
Asp Thr Ala Val Tyr Tyr Cys Asp Ser Tyr Gly Tyr Arg Gly Gln Gly
485 490 495
Thr Gln Val Thr Val Ser Ser His His His His His His
500 505
<210> 191
<211> 267
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 191
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys 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
Phe Thr Phe Ser Ser Tyr Thr Leu Ala Trp Val Arg Gln Ala Pro Gly
50 55 60
Lys Gly Leu Glu Trp Val Ala Ala Ile Asp Ser Ser Ser Tyr Thr Tyr
65 70 75 80
Ser Pro Asp Thr Val Arg Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
85 90 95
Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
100 105 110
Ala Val Tyr Tyr Cys Ala Arg Asp Ser Asn Trp Asp Ala Leu Asp Tyr
115 120 125
Trp Gly Gln Gly Thr Thr 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 Lys Ala Ser Gln Asn Val Gly Thr Asn Val Gly Trp Tyr Gln Gln
180 185 190
Lys Pro Gly Lys Ala Pro Lys Ala Leu Ile Tyr Ser Ala Ser Phe Arg
195 200 205
Tyr Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly 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 Tyr Tyr Thr Tyr Pro Tyr Thr Phe Gly Gly Gly Thr
245 250 255
Lys Val Glu Ile Lys His His His His His His
260 265
<210> 192
<211> 269
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 192
Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15
Leu Arg Gly Ala Arg Cys Gln Ser Val Leu Thr Gln Pro Pro Ser Val
20 25 30
Ser Gly Ala Pro Gly Gln Arg Val Thr Ile Ser Cys Ser Gly Ser Arg
35 40 45
Ser Asn Ile Gly Ser Asn Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly
50 55 60
Thr Ala Pro Lys Leu Leu Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly
65 70 75 80
Val Pro Asp Arg Phe Ser Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu
85 90 95
Ala Ile Thr Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln
100 105 110
Ser Tyr Asp Arg Tyr Thr His Pro Ala Leu Leu Phe Gly Thr Gly Thr
115 120 125
Lys Val Thr Val Leu Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly
130 135 140
Gly Gly Gly Ser Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val
145 150 155 160
Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
165 170 175
Phe Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly
180 185 190
Leu Glu Trp Val Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr
195 200 205
Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
210 215 220
Asn Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
225 230 235 240
Val Tyr Tyr Cys Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
245 250 255
Thr Met Val Thr Val Ser Ser His His His His His His
260 265
<210> 193
<211> 5
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
segrenase A cleavage site "
<220>
<221> MOD_RES
<222> (3)..(3)
<223> any amino acid
<400> 193
Leu Pro Xaa Thr Gly
1 5
<210> 194
<211> 124
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 194
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Asn
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Lys Phe
20 25 30
Gly Met Ser Trp Val Arg Gln Gly Gly Gly Gly Gly Leu Asp Gly Asn
35 40 45
Glu Glu Pro Gly Gly Leu Glu Trp Val Ser Ser Ile Ser Gly Ser Gly
50 55 60
Arg Asp Thr Leu Tyr Ala Asp Ser Val Lys Gly Arg Phe Thr Ile Ser
65 70 75 80
Arg Asp Asn Ala Lys Thr Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
85 90 95
Pro Glu Asp Thr Ala Val Tyr Tyr Cys Thr Ile Gly Gly Ser Leu Ser
100 105 110
Val Ser Ser Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 195
<211> 25
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<220>
<221> site
<222> (1)..(25)
<223 >/Note = "this sequence may contain 1-5 'Gly Gly Gly Gly Ser' repeat unit"
<400> 195
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> 196
<211> 20
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<220>
<221> site
<222> (1)..(20)
<223 >/Note = "this sequence may contain 1-5 'Gly Gly Gly Ser' repeat unit"
<400> 196
Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser
1 5 10 15
Gly Gly Gly Ser
20
<210> 197
<211> 7
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
protease cleavage sequence "
<400> 197
Gly Pro Leu Gly Val Arg Gly
1 5
<210> 198
<211> 8
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
protease cleavage sequence "
<400> 198
Ile Pro Val Ser Leu Arg Ser Gly
1 5
<210> 199
<211> 8
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
protease cleavage sequence "
<400> 199
Val Pro Leu Ser Leu Tyr Ser Gly
1 5
<210> 200
<211> 10
<212> PRT
<213> Unknown (Unknown)
<220>
<221> sources
<223 >/comment = "unknown description:
protease cleavage sequence "
<400> 200
Ser Gly Glu Ser Pro Ala Tyr Tyr Thr Ala
1 5 10
<210> 201
<211> 5
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 201
Gly Gly Gly Gly Ser
1 5
<210> 202
<211> 6
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 202
Gly Ser Gly Ser Gly Ser
1 5
<210> 203
<211> 13
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 203
Gly Ser Gly Gly Gly Ser Gly Gly Gly Ser Gly Gly Thr
1 5 10
<210> 204
<211> 15
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthetic polypeptide "
<400> 204
Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser
1 5 10 15
<210> 205
<211> 6
<212> PRT
<213> Artificial Sequence (Artificial Sequence)
<220>
<221> sources
<223 >/comment = "artificial sequence description: synthesis of 6XHis tag "
<400> 205
His His His His His His
1 5
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