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 the 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. An isolated antibody which binds to human glucocorticoid-inducible TNF receptor (GITR), comprising 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, wherein the antibody binds to a cell expressing membrane-bound human GITR.
2. The isolated antibody 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.
3. The isolated antibody of claim 1 , wherein the antibody binds to a cell expressing membrane-bound human GITR with a K D of 1 nM or less as determined by Scatchard analysis.
4. The isolated antibody of claim 1 , wherein the antibody binds to GITR on activated human T cells.
5. The isolated antibody of claim 1 , wherein the antibody binds to GITR on 3A9 cells ectopically expressing human GITR.
6. The isolated antibody of claim 1 , which is a human IgG antibody.
7. The isolated antibody of claim 1 , which is a human IgG1, IgG2, or IgG4 antibody.
8. The isolated antibody of claim 1 , which comprises heavy and light chain variable region sequences set forth in SEQ ID NOs: 13 and 14, respectively.
9. The isolated antibody of claim 8 , which is a human IgG antibody.
10. The isolated antibody of claim 8 , which is a human IgG1, IgG2, or IgG4 antibody.
11. The isolated antibody of claim 1 , which comprises heavy chain and light chain sequences selected from the group consisting of: (a) SEQ ID NOs: 15 and 16, respectively; (b) SEQ ID NOs: 17 and 19, respectively; and (c) SEQ ID NOs: 18 and 19, respectively, wherein the heavy chain sequence in (a) optionally lacks the C-terminal lysine.
12. The isolated antibody of claim 1 , which 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.
13. The isolated antibody of claim 1 , which comprises a heavy chain sequence comprising SEQ ID NO: 17 and a light chain sequence comprising SEQ ID NO: 19.
14. The isolated antibody of claim 1 , which comprises a heavy chain sequence comprising SEQ ID NO: 18 and a light chain sequence comprising SEQ ID NO: 19.
15. A nucleic acid encoding the heavy and/or light chain variable region of the antibody, or antigen binding portion thereof, of claim 1 .
16. A composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
17. A composition comprising the antibody of claim 1 and one or more additional therapeutics.
18. The composition of claim 17 , wherein the one or more additional therapeutics are selected from the group consisting of: an anti-PD1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, an anti-PD-LI antibody and combinations thereof.
19. A nucleic acid encoding the heavy and/or light chain variable region of the antibody of claim 8 .
20. A composition comprising the antibody of claim 8 and a pharmaceutically acceptable carrier.
21. A composition comprising the antibody of claim 8 and one or more additional therapeutics.
22. The composition of claim 21 , wherein the one or more additional therapeutics are selected from the group consisting of: an anti-PD1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, an anti-PD-LI antibody and combinations thereof.
23. A nucleic acid encoding the heavy and/or light chain of the antibody of claim 11 .
24. A composition comprising the antibody of claim 11 and a pharmaceutically acceptable carrier.
25. A composition comprising the antibody of claim 11 and one or more additional therapeutics.
26. The composition of claim 25 , wherein the one or more additional therapeutics are selected from the group consisting of: an anti-PD1 antibody, an anti-LAG-3 antibody, an anti-CTLA-4 antibody, an anti-PD-LI antibody and combinations thereof.
27. An isolated antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 17 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 19.
28. The isolated antibody of claim 27 , wherein the heavy chain consists of the amino acid sequence set forth in SEQ ID NO: 17 and the light chain consists of the amino acid sequence set forth in SEQ ID NO: 19.
29. The isolated antibody of claim 28 , comprising two heavy chains and two light chains, wherein each of the heavy chains consists of the amino acid sequence set forth in SEQ ID NO: 17 and each of the light chains consists of the amino acid sequence set forth in SEQ ID NO: 19.
30. The isolated antibody of claim 29 , comprising intermolecular disulfide bonding between the two heavy chain constant regions.
31. The isolated antibody of claim 27 , which binds to human GITR.
32. The isolated antibody of claim 31 , which binds to a cell expressing membrane-bound human GITR.
33. The isolated antibody of claim 29 , comprising two heavy chains and two light chains, wherein each of the heavy chains consists of the amino acid sequence set forth in SEQ ID NO: 17 and each of the light chains consists of the amino acid sequence set forth in SEQ ID NO: 19, and wherein the antibody binds to a cell expressing membrane-bound human GITR.
34. The isolated antibody of claim 33 , comprising intermolecular disulfide bonding between the two heavy chain constant regions.
35. An isolated antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 18 and the light chain comprises the amino acid sequence set forth in SEQ ID NO: 19.
36. The isolated antibody of claim 35 , wherein the heavy chain consists of the amino acid sequence set forth in SEQ ID NO: 18 and the light chain consists of the amino acid sequence set forth in SEQ ID NO: 19.
37. The isolated antibody of claim 36 , comprising two heavy chains and two light chains, wherein each of the heavy chains consists of the amino acid sequence set forth in SEQ ID NO: 18 and each of the light chains consists of the amino acid sequence set forth in SEQ ID NO: 19.
38. The isolated antibody of claim 37 , comprising intermolecular disulfide bonding between the two heavy chain constant regions.
39. The isolated antibody of claim 35 , which binds to human GITR.
40. The isolated antibody of claim 39 , which binds to a cell expressing membrane-bound human GITR.
41. The isolated antibody of claim 37 , comprising two heavy chains and two light chains, wherein each of the heavy chains consists of the amino acid sequence set forth in SEQ ID NO: 18 and each of the light chains consists of the amino acid sequence set forth in SEQ ID NO: 19, and wherein the antibody binds to a cell expressing membrane-bound human GITR.
42. The isolated antibody of claim 41 , comprising intermolecular disulfide bonding between the two heavy chain constant regions.
43. A composition comprising the antibody of claim 27 and a pharmaceutically acceptable carrier.
44. A composition comprising the antibody of claim 28 and a pharmaceutically acceptable carrier.
45. A composition comprising the antibody of claim 29 and a pharmaceutically acceptable carrier.
46. A composition comprising the antibody of claim 30 and a pharmaceutically acceptable carrier.
47. A composition comprising the antibody of claim 31 and a pharmaceutically acceptable carrier.
48. A composition comprising the antibody of claim 32 and a pharmaceutically acceptable carrier.
49. A composition comprising the antibody of claim 33 and a pharmaceutically acceptable carrier.
50. A composition comprising the antibody of claim 34 and a pharmaceutically acceptable carrier.
51. A composition comprising the antibody of claim 35 and a pharmaceutically acceptable carrier.
52. A composition comprising the antibody of claim 36 and a pharmaceutically acceptable carrier.
53. A composition comprising the antibody of claim 37 and a pharmaceutically acceptable carrier.
54. A composition comprising the antibody of claim 38 and a pharmaceutically acceptable carrier.
55. A composition comprising the antibody of claim 39 and a pharmaceutically acceptable carrier.
56. A composition comprising the antibody of claim 40 and a pharmaceutically acceptable carrier.
57. A composition comprising the antibody of claim 41 and a pharmaceutically acceptable carrier.
58. A composition comprising the antibody of claim 42 and a pharmaceutically acceptable carrier.