Antibodies against glucocorticoid-induced tumor necrosis factor receptor (GITR) and uses thereof
Provided herein are antibodies, or antigen binding portions thereof, that bind to glucocorticoid-inducible TNF receptor (GITR). Also provided are uses of these proteins in therapeutic applications, such as in the treatment of cancer. Further provided are cells that produce antibodies, polynucleotides encoding the heavy and/or light chain variable region of the antibodies, and vectors comprising the polynucleotides encoding the heavy and/or light chain variable region of the antibodies.
1. A method for inhibiting the growth of a tumor in a human subject comprising administering to the subject an effective amount of an antibody which binds to human glucocorticoid-inducible TNF receptor (GITR), wherein the antibody comprises heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively.
2. The method of claim 1 , wherein the antibody comprises a heavy chain variable region sequence comprising SEQ ID NO: 13, and a light chain variable region sequence comprising SEQ ID NO: 14.
3. The method of claim 1 , wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 15 and a light chain sequence comprising SEQ ID NO: 16, wherein the heavy chain sequence optionally lacks the C-terminal lysine.
4. The method of claim 1 , wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 17 and a light chain sequence comprising SEQ ID NO: 19.
5. The method of claim 1 , wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 18 and a light chain sequence comprising SEQ ID NO: 19.
6. The method of claim 1 , wherein the antibody binds to a cell expressing membrane-bound human GITR with a K D of 10 nM or less as determined by Scatchard analysis.
7. The method of claim 1 , wherein the antibody binds to human GITR on activated human T cells.
8. The method of claim 1 , wherein the antibody binds to GITR on 3A9 cells ectopically expressing human GITR.
9. The method of claim 1 , wherein the antibody stimulates a T cell response.
10. The method of claim 1 , wherein the antibody is a human IgG antibody.
11. The method of claim 10 , wherein the antibody is a human IgG1, an IgG2, or an IgG4 antibody.
12. The method of claim 1 , wherein the tumor is from a cancer selected from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.
13. The method of claim 12 , wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.
14. The method of claim 1 , further comprising administering one or more additional therapy.
15. The method of claim 14 , wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.
16. The method of claim 3 , wherein the tumor is from a cancer from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.
17. The method of claim 16 , wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.
18. The method of claim 3 , further comprising administering one or more additional therapy.
19. The method of claim 18 , wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.
20. The method of claim 18 , wherein the one or more additional therapy comprises an anti-PD1 antagonist antibody.
21. The method of claim 18 , wherein the one or more additional therapy comprises an anti-LAG-3 antagonist antibody.
22. The method of claim 18 , wherein the one or more additional therapy comprises an anti-CTLA-4 antagonist antibody.
23. The method of claim 18 , wherein the one or more additional therapy comprises an anti-PD-L1 antagonist antibody.
24. The method of claim 4 , wherein the tumor is from a cancer selected from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.
25. The method of claim 24 , wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.
26. The method of claim 4 , further comprising administering one or more additional therapy.
27. The method of claim 26 , wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.
28. The method of claim 26 , wherein the one or more additional therapy comprises an anti-PD1 antagonist antibody.
29. The method of claim 26 , wherein the one or more additional therapy comprises an anti-LAG-3 antagonist antibody.
30. The method of claim 26 , wherein the one or more additional therapy comprises an anti-CTLA-4 antagonist antibody.
31. The method of claim 26 , wherein the one or more additional therapy comprises an anti-PD-L1 antagonist antibody.
32. The method of claim 5 , wherein the tumor is from a cancer from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.
33. The method of claim 32 , wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.
34. The method of claim 5 , further comprising administering one or more additional therapy.
35. The method of claim 34 , wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.
36. The method of claim 34 , wherein the one or more additional therapy comprises an anti-PD1 antagonist antibody.
37. The method of claim 34 , wherein the one or more additional therapy comprises an anti-LAG-3 antagonist antibody.
38. The method of claim 34 , wherein the one or more additional therapy comprises an anti-CTLA-4 antagonist antibody.
39. The method of claim 34 , wherein the one or more additional therapy comprises an anti-PD-L1 antagonist antibody.
40. A method of treating cancer comprising administering to a human subject in need thereof a therapeutically effective amount of an antibody which binds to human glucocorticoid-inducible TNF receptor (GITR), wherein the antibody comprises heavy chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 20, 21, and 22, respectively, and light chain CDR1, CDR2, and CDR3 sequences comprising SEQ ID NOs: 23, 24, and 25, respectively.
41. The method of claim 40 , wherein the antibody comprises a heavy chain variable region sequence comprising SEQ ID NO: 13, and a light chain variable region sequence comprising SEQ ID NO: 14.
42. The method of claim 40 , wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 15 and a light chain sequence comprising SEQ ID NO: 16, wherein the heavy chain sequence optionally lacks the C-terminal lysine.
43. The method of claim 40 , wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 17 and a light chain sequence comprising SEQ ID NO: 19.
44. The method of claim 40 , wherein the antibody comprises a heavy chain sequence comprising SEQ ID NO: 18 and a light chain sequence comprising SEQ ID NO: 19.
45. The method of claim 40 , wherein the antibody binds to a cell expressing membrane-bound human GITR with a K D of 10 nM or less as determined by Scatchard analysis.
46. The method of claim 40 , wherein the antibody binds to human GITR on activated human T cells.
47. The method of claim 40 , wherein the antibody binds to GITR on 3A9 cells ectopically expressing human GITR.
48. The method of claim 40 , wherein the antibody stimulates a T cell response.
49. The method of claim 40 , wherein the antibody is a human IgG antibody.
50. The method of claim 49 , wherein the antibody is a human IgG1, an IgG2, or an IgG4 antibody.
51. The method of claim 40 , wherein the cancer is selected from the group consisting of: bladder cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, prostate cancer, testicular cancer, esophageal cancer, gastrointestinal cancer, pancreatic cancer, colorectal cancer, colon cancer, kidney cancer, head and neck cancer, lung cancer, stomach cancer, germ cell cancer, bone cancer, liver cancer, thyroid cancer, skin cancer, neoplasm of the central nervous system, lymphoma, leukemia, myeloma, sarcoma, and virus-related cancer.
52. The method of claim 51 , wherein the cancer is a metastatic cancer, refractory cancer, or recurrent cancer.
53. The method of claim 40 , further comprising administering one or more additional therapy.
54. The method of claim 53 , wherein the one or more additional therapy is an anti-PD1 antagonist antibody, an anti-LAG-3 antagonist antibody, an anti-CTLA-4 antagonist antibody, an anti-PD-L1 antagonist antibody, or combinations thereof.
55. The method of claim 53 , wherein the one or more additional therapy comprises an anti-PD1 antagonist antibody.
56. The method of claim 53 , wherein the one or more additional therapy comprises an anti-LAG-3 antagonist antibody.
57. The method of claim 53 , wherein the one or more additional therapy comprises an anti-CTLA-4 antagonist antibody.
58. The method of claim 53 , wherein the one or more additional therapy comprises an anti-PD-L1 antagonist antibody.