Anti-Tim-3 antibodies and use thereof

1. An antibody capable of binding to human Tim-3, comprising:

(a) a heavy chain variable region (VH) comprising a VH-CDR1 amino acid sequence of SEQ ID NO 3, a VH-CDR2 amino acid sequence of SEQ ID NO 26, a VH-CDR3 amino acid sequence of SEQ ID NO 5; and a light chain variable region (VL) comprising a VL-CDR1 amino acid sequence of SEQ ID NO 6, a VL-CDR2 amino acid sequence of SEQ ID NO 7, and a VL-CDR3 amino acid sequence of SEQ ID NO 27;

(b) a VH comprising a VH-CDR1 amino acid sequence of SEQ ID NO 3, a VH-CDR2 amino acid sequence of SEQ ID NO 4, a VH-CDR3 amino acid sequence of SEQ ID NO 5; and VL comprising a VL-CDR1 amino acid sequence of SEQ ID NO 6, a VL-CDR2 amino acid sequence of SEQ ID NO 7, and a VL-CDR3 amino acid sequence of SEQ ID NO 27;

(c) a VH comprising a VH-CDR1 amino acid sequence of SEQ ID NO 3, a VH-CDR2 amino acid sequence of SEQ ID NO 26, a VH-CDR3 amino acid sequence of SEQ ID NO 5; and VL comprising a VL-CDR1 amino acid sequence of SEQ ID NO 6, a VL-CDR2 amino acid sequence of SEQ ID NO 7, and a VL-CDR3 amino acid sequence of SEQ ID NO 8; or

(d) a VH comprising a VH-CDR1 amino acid sequence of SEQ ID NO 3, a VH-CDR2 amino acid sequence of SEQ ID NO 4, a VH-CDR3 amino acid sequence of SEQ ID NO 5; and VL comprising a VL-CDR1 amino acid sequence of SEQ ID NO 6, a VL-CDR2 amino acid sequence of SEQ ID NO 7, and a VL-CDR3 amino acid sequence of SEQ ID NO 8.

2. The antibody of claim 1 , wherein the antibody comprises:

a heavy chain variable region (VH) comprising a VH-CDR1 amino acid sequence of SEQ ID NO 3, a VH-CDR2 amino acid sequence of SEQ ID NO 26 and a VH-CDR3 amino acid sequence of SEQ ID NO 5; and a light chain variable region (VL) comprising a VL-CDR1 amino acid sequence of SEQ ID NO 6, a VL-CDR2 amino acid sequence of SEQ ID NO 7 and a VL-CDR3 amino acid sequence of SEQ ID NO 27.

3. The antibody of claim 1 , wherein the antibody is a humanized antibody molecule.

4. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NOs 9, 17, 28 or 40.

5. The antibody of claim 1 , wherein the antibody comprises a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NOs 9, 17 or 28.

6. The antibody of claim 1 , wherein the antibody comprises a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 11, 19, 30 or 36.

7. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 9, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 11;

(b) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 9, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 19;

(c) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 9, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 30;

(d) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 9, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 36;

(e) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 17, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 11;

(f) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 17, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 19;

(g) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 17, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 30;

(h) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 17, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 36;

(i) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 28, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 11;

(j) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 28, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 19;

(k) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 28, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 30;

(l) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 28, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 36;

(m) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 40, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 11;

(n) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 40, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 19;

(o) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 40, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 30; or

(p) a heavy chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 40, and a light chain variable domain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 36.

8. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 9, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 11;

(b) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 17, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 19;

(c) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 28, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 30;

(d) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 28, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 36; or

(e) a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO 40, and a light chain variable domain comprising the amino acid sequence of SEQ ID NO 36.

9. The antibody of claim 1 , wherein the antibody comprises a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 13, 22 or 32.

10. The antibody of claim 1 , wherein the antibody comprises a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 15, 24, 34 or 38.

11. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 13, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 15;

(b) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 13, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 24;

(c) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 13, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 34;

(d) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 13, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 38;

(e) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 22, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 15;

(f) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 22, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 24;

(g) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 22, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 34;

(h) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 22, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 38;

(i) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 32, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 15;

(j) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 32, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 24;

(k) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 32, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 34; or

(l) a heavy chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 32, and a light chain having at least 95% sequence identity with the amino acid sequence of SEQ ID NO 38.

12. The antibody of claim 1 , wherein the antibody comprises:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO 13, and a light chain comprising the amino acid sequence of SEQ ID NO 15;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO 22, and a light chain comprising the amino acid sequence of SEQ ID NO 24;

(c) a heavy chain comprising the amino acid sequence of SEQ ID NO 32, and a light chain comprising the amino acid sequence of SEQ ID NO 34; or

(d) a heavy chain comprising the amino acid sequence of SEQ ID NO 32, and a light chain comprising the amino acid sequence of SEQ ID NO 38.

13. The antibody of claim 1 , wherein the antibody comprises one or more of:

(a) a light chain with an Aspartic acid to Glutamic acid mutation at position 1 of SEQ ID NO 24;

(b) a light chain with a Leucine to Methionine mutation at position 4 of SEQ ID NO 24;

(c) a light chain with a Valine to Isoleucine mutation at position 62 of SEQ ID NO 24;

(d) a light chain with a Aspartic acid to Glutamic acid mutation at position 74 of SEQ ID NO 24;

(e) a light chain with a Methionine to Leucine mutation at position 96 of SEQ ID NO 24;

(f) a heavy chain with a Phenylalanine to Tyrosine mutation at position 59 of SEQ ID NO 22;

(g) (h) (g) a heavy chain with a Proline to Valine mutation at position 60 of SEQ ID NO 22; a heavy chain with a Serine to Threonine mutation at position 77 of SEQ ID NO 22; or

(i) a heavy chain with a Cysteine to Leucine mutation at position 78 of SEQ ID NO 22.

14. The antibody of claim 1 , wherein the antibody is a Fab, F(ab′)2, Fv, or a single chain Fv (ScFv).

15. The antibody of claim 1 , wherein the antibody comprises a heavy chain constant region of the subclass of IgG1, IgG2, IgG3, or IgG4 or a variant thereof, and a light chain constant region of the type of kappa or lambda or a variant thereof.

16. The antibody of claim 15 , wherein the antibody comprises a variant heavy chain constant region of the subclass of IgG1, IgG2, IgG3, or IgG4, wherein the variant heavy chain constant region provides a reduced or eliminated effector function.

17. The antibody of claim 16 , wherein the effector function is antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

18. The antibody of claim 15 , wherein the antibody comprises a heavy chain constant region of human IgG1 or a variant thereof.

19. The antibody of claim 18 , wherein the variant heavy chain constant region of human IgG1 comprises one or more mutations selected from a group consisting of E 233 P, L 234 A, L 235 A, L 236 Δ and P 329 A.

20. The antibody of claim 19 , wherein the variant human IgG1 heavy chain constant region comprising the amino sequence of SEQ ID NO 21, and a human kappa light chain constant religion.

21. A pharmaceutical composition, comprising the antibody of claim 1 , and a pharmaceutically acceptable excipient.

22. A method of stimulating an immune response in a subject, comprising administrating to a subject in need thereof an antibody of claim 1 in an amount effective to stimulate the immune respond.

23. A method for treating a cancer or a tumor, comprising administrating to a subject in need thereof the antibody of claim 1 in an amount effective to treat the cancer or tumor.

24. The method of claim 23 , wherein the cancer is selected from a lung cancer, a liver cancer, a stomach cancer, a cervical cancer, a melanoma, a renal cancer, a breast cancer, a colorectal cancer, a leukemia, a lymphoma, an ovarian cancer, a head and neck cancer or a metastatic lesion of the cancer.

25. The method of claim 23 , wherein the antibody is administrated in combination with a second therapeutic agent or procedure, wherein the second therapeutic agent or procedure is selected from a chemotherapy, a targeted therapy, an oncolytic drug, a cytotoxic agent, an immune-based therapy, a cytokine, a surgical procedure, a radiation procedure, an activator of a costimulatory molecule, an inhibitor of an inhibitory molecule, a vaccine, or a cellular immunotherapy.

26. The method of claim 23 , wherein the antibody is administered in combination with an inhibitor of an immune checkpoint molecule selected from PD-1, PD-L1, PD-L2, CTLA-4, LAG-3, CEACAM-1, CEACAM-5, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 or TGFR.

27. The method of claim 23 , wherein the antibody is administered in combination with an anti-PD-1 mAb 317-4B6, or 317-4B6/IgG4mt10.

28. A method of treating an infectious disease, comprising administering to a subject in need thereof an antibody of claim 1 in an amount effective to treat the infectious disease.

29. The method of claim 28 , wherein the infectious disease is a chronic viral infection, selected from HIV infection and HCV infection.