Antibodies to human programmed death receptor PD-1
Antibodies which block binding of hPD-1 to hPD-L1 or hPD-L2 and their variable region sequences are disclosed. A method of increasing the activity (or reducing downmodulation) of an immune cell through the PD-1 pathway is also disclosed.
1. A method of increasing the activity of an immune cell, comprising contacting the immune cell with a monoclonal antibody which binds to human programmed death receptor 1 (hPD-1), wherein the antibody blocks the binding of human PD-L1 and human PD-L2 to hPD-1 and comprises:
a. three light chain CDRs having the amino acid sequences set forth in SEQ ID NOs: 15, 16 and 17 and
b. three heavy chain CDRs having the amino acid sequences set forth in SEQ ID NOs: 18, 19 and 20.
2. A method of increasing the activity of an immune cell for the treatment of cancer in a human patient in need thereof, comprising administering to the patient a therapeutically effective amount of a monoclonal antibody which binds to human programmed death receptor 1 (hPD-1), wherein the antibody blocks the binding of human PD-L1 and human PD-L2 to hPD-1 and comprises:
a. three light chain CDRs having the amino acid sequences set forth in SEQ ID Nos: 15, 16 and 17 and
b. three heavy chain CDRs having the amino acid sequences set forth in SEQ ID Nos: 18, 19 and 20.
3. The method of claim 2 , wherein the cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, or lymphoma.
4. The method of claim 3 , wherein the cancer is melanoma, non-small cell lung cancer, or squamous cell carcinoma of the head and neck.
5. The method of claim 2 , wherein the antibody is used in combination with an anti-neoplastic agent or immunogenic agent.
6. The method of claim 2 , wherein the antibody is used in combination with chemotherapy, radiotherapy, or surgery.
7. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to VEGF.
8. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to EGFR.
9. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to Her2/neu.
10. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to a VEGF receptor.
11. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to CTLA-4.
12. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to OX-40.
13. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to 4-1BB.
14. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to ICOS.
15. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to CD20.
16. The method of claim 2 , wherein the antibody is used in combination with an antibody that binds to CD40.
17. The method of claim 2 , wherein the antibody blocks binding of human PD-L1 and human PD-L2 to human PD-1 with an IC50 of about 1 nM or lower, wherein the IC50 is measured using an FMAT competition assay.
18. The method of claim 2 , wherein the antibody binds PD-1 with a K D of about 30 pM or lower, wherein the binding is determined using bio-light interferometry.
19. The method of claim 2 , wherein the antibody is an IgG4 isotype.
20. The method of claim 2 , wherein the wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody.
21. The method of claim 2 , wherein the antibody blocks binding of human PD-L1 and human PD-L2 to human PD-1 with an IC50 of about 1 nM or lower, wherein the IC50 is measured using a FACS assay.
22. The method of claim 2 , wherein the antibody comprises a light chain variable region comprising amino acid residues 20 to 130 of SEQ ID NO:32 and a heavy chain variable region comprising amino acid residues 20 to 139 of SEQ ID NO:30.
23. The method of claim 22 , wherein the cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, or lymphoma.
24. The method of claim 23 , wherein the cancer is melanoma, non-small cell lung cancer, or squamous cell carcinoma of the head and neck.
25. The method of claim 22 , wherein the antibody is used in combination with an anti-neoplastic agent or immunogenic agent.
26. The method of claim 22 , wherein the antibody is used in combination with chemotherapy, radiotherapy, or surgery.
27. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to VEGF.
28. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to EGFR.
29. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to Her2/neu.
30. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to a VEGF receptor.
31. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to CTLA-4.
32. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to OX-40.
33. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to 4-1BB.
34. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to ICOS.
35. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to CD20.
36. The method of claim 22 , wherein the antibody is used in combination with an antibody that binds to CD40.
37. The method of claim 22 , wherein the antibody blocks binding of human PD-L1 and human PD-L2 to human PD-1 with an IC50 of about 1 nM or lower, wherein the IC50 is measured using an FMAT competition assay.
38. The method of claim 22 , wherein the antibody binds PD-1 with a K D of about 30 pM or lower, wherein the binding is determined using bio-light interferometry.
39. The method of claim 22 , wherein the antibody is an IgG4 isotype.
40. The method of claim 22 , wherein the wherein the antibody is a human antibody, a humanized antibody or a chimeric antibody.
41. The method of claim 22 , wherein the antibody comprises a light chain comprising amino acid residues 20 to 237 of SEQ ID NO:36 and a heavy chain comprising amino acid residues 20 to 466 of SEQ ID NO:31.
42. The method of claim 41 , wherein the cancer is melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, esophageal cancer, squamous cell carcinoma of the head and neck, liver cancer, ovarian cancer, cervical cancer, thyroid cancer, glioblastoma, or lymphoma.
43. The method of claim 42 , wherein the cancer is melanoma, non-small cell lung cancer, or squamous cell carcinoma of the head and neck.
44. The method of claim 41 , wherein the antibody is used in combination with an anti-neoplastic agent or immunogenic agent.
45. The method of claim 41 , wherein the antibody is used in combination with chemotherapy, radiotherapy, or surgery.
46. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to VEGF.
47. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to EGFR.
48. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to Her2/neu.
49. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to a VEGF receptor.
50. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to CTLA-4.
51. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to OX-40.
52. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to 4-1BB.
53. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to ICOS.
54. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to CD20.
55. The method of claim 41 , wherein the antibody is used in combination with an antibody that binds to CD40.
56. The method of claim 41 , wherein the antibody blocks binding of human PD-L1 and human PD-L2 to human PD-1 with an IC50 of about 1 nM or lower, wherein the IC50 is measured using an FMAT competition assay.
57. The method of claim 41 , wherein the antibody binds PD-1 with a K D of about 30 pM or lower, wherein the binding is determined using bio-light interferometry.