阅读说明：本技术 抗程序性死亡配体1(pd-l1)抗体及其治疗用途 (Anti-programmed death ligand 1(PD-L1) antibodies and therapeutic uses thereof ) 是由 张英 于 2017-02-16 设计创作，主要内容包括：提供了抗程序性死亡配体1(PD-L1)抗体、其使用方法、其治疗组合物,以及其用于上调细胞介导的免疫应答和治疗T细胞功能障碍性病症的用途。也提供了抗PD-L1抗体作为体外诊断剂的用途。(Anti-programmed death ligand 1(PD-L1) antibodies, methods of use thereof, therapeutic compositions thereof, and uses thereof for upregulating cell-mediated immune responses and treating T cell dysfunctional disorders are provided. Also provided is the use of an anti-PD-L1 antibody as an in vitro diagnostic agent.)

1. An anti-PD-L1 antibody or antigen-binding fragment, wherein the antibody comprises SEQ ID NO: 1. SEQ ID NO: 3. SEQ ID NO: 5 and SEQ ID NO: 7.

2. An anti-PD-L1 antibody or antigen-binding fragment, wherein the antibody comprises SEQ ID NO: 2. SEQ ID NO: 4. SEQ ID NO: 6 and SEQ ID NO: 8, or a pharmaceutically acceptable salt thereof.

3. An anti-PD-L1 antibody or antigen-binding fragment, wherein the antibody or fragment comprises a Heavy Chain Variable Region (HCVR) having Complementarity Determining Regions (CDRs) selected from the group consisting of: SEQ ID NO: 9 CDR 1-3; SEQ ID NO: 10 CDR 1-3; SEQ ID NO: 11 CDR 1-3; SEQ ID NO: 15 CDR 1-3; SEQ ID NO: 16 CDR 1-3; SEQ ID NO: 17 CDR 1-3.

4. The anti-PD-L1 antibody or antigen-binding fragment of claim 3, wherein the antibody or fragment comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-11 and 15-17.

5. An anti-PD-L1 antibody or antigen-binding fragment, wherein the antibody or fragment comprises a Light Chain Variable Region (LCVR) having Complementarity Determining Regions (CDRs) selected from the group consisting of: SEQ ID NO: 12 CDR 1-3; SEQ ID NO: 13 CDR 1-3; SEQ ID NO: 14 CDR 1-3; SEQ ID NO: 18 CDR 1-3; SEQ ID NO: 19 CDR 1-3; SEQ ID NO: 20 CDR 1-3.

6. The anti-PD-L1 antibody or antigen-binding fragment of claim 5, wherein the antibody or fragment comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 12-14 and 18-20.

7. The anti-PD-L1 antibody or antigen-binding fragment of any one of claims 1-6, wherein the antibody or fragment comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9-11 and 15-17 and an H-CDR selected from SEQ ID NOs: 12-14 and 18-20.

8. The anti-PD-L1 antibody or antigen-binding fragment of any one of claims 1-7, wherein the antibody comprises H-CDR and L-CDR pairings selected from: has the sequence shown in SEQ ID NO: 9-11 and 15-17 and a HCVR having the sequence shown in SEQ ID NO: 12-14 and 18-20;

each and SEQ ID NOs of M1 to M6: 9-20 matching:

m1) from SEQ ID NO: 9 and the H-CDR of SEQ ID NO: 12, the pairing sequence of the L-CDR;

m2) from SEQ ID NO: 10 and the H-CDR of SEQ ID NO: 13, a pairing sequence of the L-CDR;

m3) from SEQ ID NO: 11 and the H-CDR of SEQ ID NO: 14, the pairing sequence of the L-CDR;

m4) from SEQ ID NO: 15 and the H-CDR of SEQ ID NO: 18, the pairing sequence of the L-CDR;

m5) from SEQ ID NO: 16 and the H-CDR of SEQ ID NO: 19, a pairing sequence of the L-CDR;

m6) from SEQ ID NO: 17 and the H-CDR of SEQ ID NO: 20, and a pairing sequence of the L-CDRs.

9. The antibody of claims 1-8, wherein the antibody comprises:

(a) and SEQ ID NO: 11 has at least 95% sequence identity to the amino acid sequence of VH;

(b) and SEQ ID NO: 14 having at least 95% sequence identity to the amino acid sequence of VL;

(c) the VH sequence in (a) and the VL sequence in (b);

(d) and SEQ ID NO: 17 having at least 95% sequence identity to the amino acid sequence of VH;

(e) and SEQ ID NO: 20 having at least 95% sequence identity to the amino acid sequence of VL;

(f) the VH sequence in (d) and the VL sequence in (e);

10. the antibody of any one of claims 1-9, wherein the antibody is an IgG₁Or IgG of₄。

11. The antibody of any one of claims 1-9, wherein the antibody is an IgG_1λOr IgG_1κ。

12. The antibody of claims 1-11, wherein the antibody fragment is selected from the group consisting of Fab, single chain variable fragment (scFv), Fv, Fab '-SH, F (ab')₂And diabodies.

13. The anti-PD-L1 antibody or antigen-binding fragment of any one of claims 1-12 that specifically binds to an epitope within the extracellular domain of human or mouse PD-L1.

14. A method for producing a PD-L1 antibody that specifically binds human PD-L1, comprising:

(a) providing a starting nucleic acid encoding a variable domain of all components, wherein the variable domain comprises the CDR3 of the CDR3 encoding region to be replaced or deleted;

(b) the coding library is basically combined as shown in SEQ ID NO: 2. SEQ ID NO: 4. SEQ ID NO: 6 and/or SEQ ID NO: 8 or the amino acid sequence shown in SEQ ID NO: 1. SEQ ID NO: 3. SEQ ID NO: 5 and/or SEQ ID NO: 7 such that the donor nucleic acid is inserted into all of the constituents of the CDR3 region to produce a nucleic acid product encoding all of the constituent variable domains;

(c) expressing the pool of nucleic acid products;

(d) selecting an antigen specific for the PD-L1 binding fragment; and

(e) recovering the specific antigen-binding fragment or nucleic acid encoding the binding fragment.

15. The method of claim 14 for producing an antibody.

16. The any one of claims 1-15, wherein the PD-L1 antibody increases T cell proliferation in a Mixed Lymphocyte Reaction (MLR) assay.

17. The any one of claims 1-15, wherein the PD-L1 antibody kills cancer cells in a Cytotoxic T Lymphocyte (CTL) assay.

18. The any one of claims 1-15, wherein the PD-L1 antibody kills cancer cells in an antibody-dependent cell-mediated cytotoxicity (ADCC) assay.

19. The any one of claims 1-15, wherein the PD-L1 antibody kills cancer cells in a Complement Dependent Cytotoxicity (CDC) assay.

20. The any one of claims 1-15, wherein the PD-L1 antibody kills myeloma cancer cells and prolongs survival in NSG mice.

21. The any one of claims 1-15, wherein said PD-L1 antibody in combination with a chemotherapeutic drug lenalidomide kills myeloma cancer cells and prolongs survival in SCID mice.

22. Use of the anti-PD-L1 antibody or antigen-binding fragment of any one of claims 1-15 for detecting PD-L1 in vitro.

23. Use of the anti-PD-L1 antibody or antigen-binding fragment of any one of claims 1-15 as a diagnostic agent in vitro.

24. The anti-PD-L1 antibody or antigen-binding portion according to any one of claims 1-15 or any one of claims 9-21, and methods for the preparation of medicaments for the treatment of T-cell dysfunctional disorders, cancer, most preferably myeloma and lymphoma, autoimmune diseases, inflammatory disease allergies and immune disorders.