Anti-TIM-3 antibodies and methods of use thereof
The instant disclosure provides antibodies that specifically bind to TIM-3 (e.g., human TIM-3) and antagonize TIM-3 function. Also provided are pharmaceutical compositions comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies.
1. An isolated antibody that specifically binds to human TIM-3, the antibody comprising a heavy chain variable region comprising complementarity determining regions CDRH1, CDRH2 and CDRH3 and a light chain variable region comprising complementarity determining regions CDRL1, CDRL2 and CDRL3, wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 14, 21, and 22; 4, 2, 3, 14, 21, and 22; 5, 2, 3, 14, 21, and 22; 6, 2, 3, 14, 21, and 22; 7, 2, 3, 14, 21, and 22; 8, 2, 3, 14, 21, and 22; 9, 2, 3, 14, 21, and 22; 10, 2, 3, 14, 21, and 22; 11, 2, 3, 14, 21, and 22; 12, 2, 3, 14, 21, and 22; or 1, 2, 3, 15, 18, and 22, respectively.
2. The isolated antibody of claim 1 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 comprise the amino acid sequences set forth in SEQ ID NOs: 5, 2, 3, 14, 21, and 22, respectively.
3. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 55.
4. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-27 and 29-35.
5. The isolated antibody of claim 1 , wherein the heavy chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 24-27 and 29-35.
6. The isolated antibody of claim 1 , wherein the antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 56.
7. The isolated antibody of claim 1 , wherein the antibody comprises a light chain variable region comprising an amino acid sequence which is at least 75%, 80%, 85%, 90%, 95%, or 100% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs: 36-45 and 47.
8. The isolated antibody of claim 1 , wherein the light chain variable region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 36-45 and 47.
9. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 58 or 65.
10. The isolated antibody of claim 1 , wherein the heavy chain variable region and the light chain variable region, respectively, comprise the amino acid sequences set forth in SEQ ID NOs: 24 and 36; 24 and 38; 26 and 42; 24 and 42; 24 and 46; 24 and 43; 26 and 43; 26 and 46; 26 and 41; 24 and 41; 25 and 39; 24 and 47; 25 and 40; 26 and 47; 25 and 37; 25 and 45; 25 and 44; 25 and 46; 25 and 42; 25 and 41; 25 and 43; 25 and 47; 27 and 46; 29 and 46; 30 and 46; 31 and 46; 32 and 46; 33 and 46; 34 and 46; or 35 and 46.
11. The isolated antibody of claim 10 , wherein the amino acid sequences of the heavy chain variable region and the light chain variable region, respectively, consist of the amino acid sequences set forth in SEQ ID NOs: 24 and 36; 24 and 38; 26 and 42; 24 and 42; 24 and 46; 24 and 43; 26 and 43; 26 and 46; 26 and 41; 24 and 41; 25 and 39; 24 and 47; 25 and 40; 26 and 47; 25 and 37; 25 and 45; 25 and 44; 25 and 46; 25 and 42; 25 and 41; 25 and 43; 25 and 47; 27 and 46; 29 and 46; 30 and 46; 31 and 46; 32 and 46; 33 and 46; 34 and 46; or 35 and 46.
12. The isolated antibody of claim 1 , comprising a heavy chain and a light chain, wherein the heavy chain and the light chain, respectively, comprise the amino acid sequences set forth in SEQ ID NOs: 58 and 69; or 65 and 69.
13. The isolated antibody of claim 12 , wherein the amino acid sequences of the heavy chain and the light chain, respectively, consist of the amino acid sequences set forth in SEQ ID NOs: 58 and 69; or 65 and 69.
14. The isolated antibody of any claim 1 , wherein the antibody is internalized upon binding to cells expressing human TIM-3.
15. The isolated antibody of claim 1 , wherein the antibody comprises a heavy chain constant region selected from the group consisting of human IgG 1 , IgG 2 , IgG 3 , IgG 4 , IgA 1 , and IgA 2 .
16. The isolated antibody of claim 15 , wherein the heavy chain constant region is an IgG 1 heavy chain constant region.
17. The isolated antibody of claim 16 , wherein the amino acid sequence of the IgG 1 heavy chain constant region comprises a N297A mutation, numbered according to the EU numbering system.
18. The isolated antibody of claim 17 , wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 72.
19. The isolated antibody of claim 16 , wherein the amino acid sequence of the IgG 1 heavy chain constant region comprises a N297Q mutation, numbered according to the EU numbering system.
20. The isolated antibody of claim 16 , wherein the IgG 1 heavy chain constant region is non-fucosylated.
21. The isolated antibody of claim 15 , wherein the heavy chain constant region is an IgG 4 heavy chain constant region.
22. The isolated antibody of claim 21 , wherein the amino acid sequence of the IgG 4 heavy chain constant region comprises a S228P mutation, numbered according to the EU numbering system.
23. The isolated antibody of claim 22 , wherein the antibody comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 74.
24. The isolated antibody of claim 1 , wherein the antibody comprises a human kappa or human lamda light chain constant region.
25. The isolated antibody of claim 24 , wherein the light chain constant region is a human kappa light chain constant region.
26. The isolated antibody of claim 25 , wherein the antibody comprises a light chain constant region comprising the amino acid sequence of SEQ ID NO: 76.
27. The isolated antibody of claim 1 , wherein the antibody is a human antibody.
28. The isolated antibody of claim 1 , wherein the antibody is antagonistic to human TIM-3.
29. The isolated antibody of claim 1 , wherein the antibody deactivates, reduces, or inhibits an activity of human TIM-3.
30. The isolated antibody of claim 1 , wherein the antibody inhibits binding of human TIM-3 to phosphatidylserine.
31. The isolated antibody of claim 1 conjugated to a cytotoxic agent, cytostatic agent, toxin, radionuclide, or detectable label.
32. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier or excipient.