IP Library › Granted Patent US 10,752,687

Granted Patent B2

US 10,752,687 · App. 15/727,456 · Granted Aug 25, 2020

Antibody molecules to PD-1 and uses thereof

Inventors: Gordon James Freeman (Brookline, MA); Arlene Helen Sharpe (Brookline, MA); Walter A. Blattler (Brookline, MA); Jennifer Marie Mataraza (Cambridge, MA); Catherine Anne Sabatos-Peyton (Cambridge, MA); Hwai Wen Chang (Cambridge, MA); Gerhard Johann Frey (San Diego, CA)

Assignees: Novartis AG; DANA-FARBER CANCER INSTITUTE, INC.; PRESIDENT AND FELLOWS OF HARVARD COLLEGE

C07K16/2818 A61K45/06 C07K16/2896 C07K16/30 G01N33/566 G01N33/57484 G01N33/6854 C07K2317/24 C07K2317/31 C07K2317/565 C07K2317/569 C07K2317/74 C07K2317/76 C07K2317/92 G01N2333/70596 Y02A50/58

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Quick Facts

Patent No.: US 10,752,687
App. No.: 15/727,456
Granted: Aug 25, 2020
Kind: B2

External Links

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Abstract

Antibody molecules that specifically bind to PD-1 are disclosed. The anti-PD-1 antibody molecules can be used to treat, prevent and/or diagnose cancerous or infectious conditions and disorders.

Claims (260)

1. A nucleic acid molecule comprising a first nucleotide sequence that encodes a heavy chain variable region (VH), or a second nucleotide sequence that encodes a light chain variable region (VL), or both, of an antibody molecule capable of binding to human Programmed Death-1 (PD-1), wherein the antibody molecule comprises:

(a) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33;

(b) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32;

(c) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33; or

(d) a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.

2. The nucleic acid molecule of claim 1 , wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 1; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.

3. The nucleic acid molecule of claim 1 , wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33.

4. The nucleic acid molecule of claim 1 , wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.

5. A nucleic acid molecule comprising a first nucleotide sequence that encodes a VH, or a second nucleotide sequence that encodes a VL, or both, of a bispecific antibody molecule having a first binding specificity for PD-1 and a second binding specificity for TIM-3, LAG-3, CEACAM-1, CEACAM-5, PD-L1 or PD-L2, wherein the bispecific antibody molecule comprises:

(d) a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 224; a VHCDR2 amino acid sequence of SEQ ID NO: 2; and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 10, a VLCDR2 amino acid sequence of SEQ ID NO: 11, and a VLCDR3 amino acid sequence of SEQ ID NO: 32.

6. The nucleic acid molecule of claim 1 , wherein the first and the second nucleotide sequences are in the same nucleic acid molecule.

7. The nucleic acid molecule of claim 1 , wherein the first and the second nucleotide sequences are in separate nucleic acid molecules.

8. The nucleic acid molecule of claim 5 , wherein the first and the second nucleotide sequences are in the same nucleic acid molecule.

9. The nucleic acid molecule of claim 5 , wherein the first and the second nucleotide sequences are in separate nucleic acid molecules.

10. An expression vector comprising the nucleic acid molecule of claim 1 .

11. An expression vector comprising the nucleic acid molecule of claim 5 .

12. A host cell comprising the nucleic acid molecule of claim 1 .

13. A host cell comprising the nucleic acid molecule of claim 5 .

14. A method of producing an antibody molecule, comprising culturing the host cell of claim 12 under conditions suitable for gene expression.

15. A method of producing an antibody molecule, comprising culturing the host cell of claim 13 under conditions suitable for gene expression.

16. The nucleic acid molecule of claim 1 , wherein the antibody molecule comprises a VH comprising a VHCDR1 amino acid sequence of SEQ ID NO: 4, a VHCDR2 amino acid sequence of SEQ ID NO: 5, and a VHCDR3 amino acid sequence of SEQ ID NO: 3; and a VL comprising a VLCDR1 amino acid sequence of SEQ ID NO: 13, a VLCDR2 amino acid sequence of SEQ ID NO: 14, and a VLCDR3 amino acid sequence of SEQ ID NO: 33.

17. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence encodes a VH comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs: 38, 50, 82, or 86.

18. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence encodes a VH comprising the amino acid sequence of SEQ ID NO: 38, 50, 82, or 86.

19. The nucleic acid molecule of claim 1 , wherein the second nucleotide sequence encodes a VL comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs: 42, 46, 54, 58, 62, 66, 70, 74, or 78.

20. The nucleic acid molecule of claim 1 , wherein the second nucleotide sequence encodes a VL comprising the amino acid sequence of SEQ ID NO: 42, 46, 54, 58, 62, 66, 70, 74, or 78.

21. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence and the second nucleotide sequence encode, respectively:

(a) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 54;

(b) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 42;

(c) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 66;

(d) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 70;

(e) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 70;

(f) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 46;

(g) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 46;

(h) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 54;

(i) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 58;

(j) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 62;

(k) a VH comprising the amino acid sequence of SEQ ID NO: 50 and a VL comprising the amino acid sequence of SEQ ID NO: 66;

(l) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 74;

(m) a VH comprising the amino acid sequence of SEQ ID NO: 38 and a VL comprising the amino acid sequence of SEQ ID NO: 78;

(n) a VH comprising the amino acid sequence of SEQ ID NO: 82 and a VL comprising the amino acid sequence of SEQ ID NO: 70;

(o) a VH comprising the amino acid sequence of SEQ ID NO: 82 and a VL comprising the amino acid sequence of SEQ ID NO: 66; or

(p) a VH comprising the amino acid sequence of SEQ ID NO: 86 and a VL comprising the amino acid sequence of SEQ ID NO: 66.

22. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence comprises a nucleotide sequence at least 85% identical to any of SEQ ID NOs: 39, 51, 83, 87, 90, 95, or 101.

23. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence comprises the nucleotide sequence of SEQ ID NO: 39, 51, 83, 87, 90, 95, or 101.

24. The nucleic acid molecule of claim 1 , wherein the second nucleotide sequence comprises a nucleotide sequence at least 85% identical to any of SEQ ID NOs: 43, 47, 55, 59, 63, 67, 71, 75, 79, 93, 97, 99, 104, or 106.

25. The nucleic acid molecule of claim 1 , wherein the second nucleotide sequence comprises the nucleotide sequence of SEQ ID NO: 43, 47, 55, 59, 63, 67, 71, 75, 79, 93, 97, 99, 104, or 106.

26. The nucleic acid molecule of claim 1 , which comprises:

(a) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 55;

(b) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 43;

(c) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 67;

(d) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of any of SEQ ID NO: 71;

(e) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 51 and a second nucleotide sequence comprising the nucleotide sequence of any of SEQ ID NO: 71;

(f) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 47;

(g) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 51 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 47;

(h) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 51 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 55;

(i) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 59;

(j) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 63;

(k) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 51 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 67;

(l) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 75;

(m) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 39 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 79;

(n) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 83 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 71;

(o) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 83 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 67;

(p) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 87 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 67;

(q) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 90 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 93;

(r) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 95 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 97;

(s) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 90 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 99;

(t) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 101 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 104; or

(u) a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 95 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 106.

27. The nucleic acid molecule of claim 1 , which encodes a heavy chain comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs: 40, 52, 84, 88, 91, or 102.

28. The nucleic acid molecule of claim 1 , which encodes a heavy chain comprising the amino acid sequence of SEQ ID NO: 40, 52, 84, 88, 91, or 102.

29. The nucleic acid molecule of claim 1 , which encodes a light chain comprising an amino acid sequence at least 85% identical to any of SEQ ID NOs: 44, 48, 56, 60, 64, 68, 72, 76, or 80.

30. The nucleic acid molecule of claim 1 , which encodes a light chain comprising the amino acid sequence of SEQ ID NO: 44, 48, 56, 60, 64, 68, 72, 76, or 80.

31. The nucleic acid molecule of claim 1 , which encodes:

(a) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;

(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;

(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;

(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;

(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 102 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;

(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 44;

(g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 48;

(h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 48;

(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;

(j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 56;

(k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 60;

(l) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 64;

(m) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;

(n) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 68;

(o) a heavy chain comprising the amino acid sequence of SEQ ID NO: 52 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;

(p) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;

(q) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 76;

(r) a heavy chain comprising the amino acid sequence of SEQ ID NO: 40 and a light chain comprising the amino acid sequence of SEQ ID NO: 80;

(s) a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 72;

(t) a heavy chain comprising the amino acid sequence of SEQ ID NO: 84 and a light chain comprising the amino acid sequence of SEQ ID NO: 68; or

(u) a heavy chain comprising the amino acid sequence of SEQ ID NO: 88 and a light chain comprising the amino acid sequence of SEQ ID NO: 68.

32. The nucleic acid molecule of claim 1 , which comprises a heavy chain nucleotide sequence at least 85% identical to any of SEQ ID NOs: 41, 53, 85, 89, 92, 96, or 103.

33. The nucleic acid molecule of claim 1 , which comprises a heavy chain nucleotide sequence of SEQ ID NO: 41, 53, 85, 89, 92, 96, or 103.

34. The nucleic acid molecule of claim 1 , which comprises a light chain nucleotide sequence at least 85% identical to any of SEQ ID NOs: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105, or 107.

35. The nucleic acid molecule of claim 1 , which comprises a light chain nucleotide sequence of SEQ ID NO: 45, 49, 57, 61, 65, 69, 73, 77, 81, 94, 98, 100, 105, or 107.

36. The nucleic acid molecule of claim 1 , which comprises:

(a) a heavy chain nucleotide sequence of SEQ ID NO: 92 and a light chain nucleotide sequence of SEQ ID NO: 94;

(b) a heavy chain nucleotide sequence of SEQ ID NO: 96 and a light chain nucleotide sequence of SEQ ID NO: 98;

(d) a heavy chain nucleotide sequence of SEQ ID NO: 96 and a light chain nucleotide sequence of any of SEQ ID NO: 107;

(e) a heavy chain nucleotide sequence of SEQ ID NO: 103 and a light chain nucleotide sequence of any of SEQ ID NO: 105;

(f) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 45;

(g) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 49;

(h) a heavy chain nucleotide sequence of SEQ ID NO: 53 and a light chain nucleotide sequence of SEQ ID NO: 49;

(i) a heavy chain nucleotide sequence of SEQ ID NO: 53 and a light chain nucleotide sequence of SEQ ID NO: 57;

(j) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 57;

(k) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 61;

(l) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 65;

(m) a heavy chain nucleotide sequence of SEQ ID NO: 53 and a light chain nucleotide sequence of SEQ ID NO: 69;

(n) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 69;

(o) a heavy chain nucleotide sequence of SEQ ID NO: 53 and a light chain nucleotide sequence of any of SEQ ID NO: 73;

(p) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of any of SEQ ID NO: 73;

(q) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 77;

(r) a heavy chain nucleotide sequence of SEQ ID NO: 41 and a light chain nucleotide sequence of SEQ ID NO: 81;

(s) a heavy chain nucleotide sequence of SEQ ID NO: 85 and a light chain nucleotide sequence of any of SEQ ID NO: 73;

(t) a heavy chain nucleotide sequence of SEQ ID NO: 85 and a light chain nucleotide sequence of SEQ ID NO: 69; or

(u) a heavy chain nucleotide sequence of SEQ ID NO: 89 and a light chain nucleotide sequence of SEQ ID NO: 69

(v) a heavy chain nucleotide sequence of SEQ ID NO: 92 and a light chain nucleotide sequence of SEQ ID NO: 94;

(w) a heavy chain nucleotide sequence of SEQ ID NO: 96 and a light chain nucleotide sequence of SEQ ID NO: 98;

(x) a heavy chain nucleotide sequence of SEQ ID NO: 92 and a light chain nucleotide sequence of SEQ ID NO: 100;

(y) a heavy chain nucleotide sequence of SEQ ID NO: 103 and a light chain nucleotide sequence of SEQ ID NO: 105; or

(z) a heavy chain nucleotide sequence of SEQ ID NO: 96 and a light chain nucleotide sequence of SEQ ID NO: 107.

37. The nucleic acid molecule of claim 1 , which encodes a Fab, F(ab′)2, Fv, or a single chain Fv fragment (scFv).

38. The nucleic acid molecule of claim 1 , further comprising a nucleotide sequence encoding a heavy chain constant region of IgG1, IgG2, IgG3, or IgG4.

39. The nucleic acid molecule of claim 1 , further comprising a nucleotide sequence encoding a light chain constant region of kappa or lambda.

40. The nucleic acid molecule of claim 1 , further comprising a nucleotide sequence encoding a human IgG4 heavy chain constant region with a Serine to Proline mutation at position 108 of SEQ ID NO: 212 or 214, and a nucleotide sequence encoding a kappa light chain constant region.

41. The nucleic acid molecule of claim 1 , further comprising a nucleotide sequence encoding a human IgG1 heavy chain constant region with an Asparagine to Alanine mutation at position 180 of SEQ ID NO: 216, and a nucleotide sequence encoding a kappa light chain constant region.

42. The nucleic acid molecule of claim 1 , further comprising a nucleotide sequence encoding a human IgG1 heavy chain constant region with an Aspartate to Alanine mutation at position 148 and a Proline to Alanine mutation at position 212 of SEQ ID NO: 217, and a nucleotide sequence encoding a kappa light chain constant region.

43. The nucleic acid molecule of claim 1 , further comprising a nucleotide sequence encoding a human IgG1 heavy chain constant region with a Leucine to Alanine mutation at position 117 and a Leucine to Alanine mutation at position 118 of SEQ ID NO: 218, and a nucleotide sequence encoding a kappa light chain constant region.

44. The nucleic acid molecule of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 54.

45. The nucleic acid molecule of claim 1 , wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 70.

46. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence comprises the nucleotide sequence of SEQ ID NO: 95 and the second nucleotide sequence comprises the nucleotide sequence of SEQ ID NO: 97.

47. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence comprises the nucleotide sequence of SEQ ID NO: 95 and the second nucleotide sequence comprises the nucleotide sequence of SEQ ID NO: 106.

48. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence encodes a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and the second nucleotide sequence encodes a light chain comprising the amino acid sequence of SEQ ID NO: 56.

49. The nucleic acid molecule of claim 1 , wherein the first nucleotide sequence encodes a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and the second nucleotide sequence encodes a light chain comprising the amino acid sequence of SEQ ID NO: 72.

50. The nucleic acid molecule of claim 1 , comprising a heavy chain nucleotide sequence of SEQ ID NO: 96 and a light chain nucleotide sequence of SEQ ID NO: 98.

51. The nucleic acid molecule of claim 1 , comprising a heavy chain nucleotide sequence of SEQ ID NO: 96 and a light chain nucleotide sequence of SEQ ID NO: 107.

52. A nucleic acid molecule comprising a first nucleotide sequence encoding a VH and a second nucleotide sequence encoding a VL, of an antibody molecule capable of binding to human PD-1, wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 54.

53. An expression vector comprising the nucleic acid molecule of claim 52 .

54. A host cell comprising the nucleic acid molecule of claim 52 .

55. A method producing an antibody molecule or fragment thereof, comprising culturing the host cell of claim 54 under conditions suitable for gene expression, thereby producing the antibody molecule or fragment thereof.

56. A nucleic acid molecule comprising a first nucleotide sequence encoding a VH and a second nucleotide sequence encoding a VL, of an antibody molecule capable of binding to human PD-1, wherein the VH comprises the amino acid sequence of SEQ ID NO: 38 and the VL comprises the amino acid sequence of SEQ ID NO: 70.

57. An expression vector comprising the nucleic acid molecule of claim 56 .

58. A host cell comprising the nucleic acid molecule of claim 56 .

59. A method producing an antibody molecule or fragment thereof, comprising culturing the host cell of claim 58 under conditions suitable for gene expression, thereby producing the antibody molecule or fragment thereof.

60. A nucleic acid molecule comprising a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 95 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 97.

61. A nucleic acid molecule comprising a first nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 95 and a second nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 106.

62. The nucleic acid molecule of claim 5 , wherein the first nucleotide sequence encodes a VH comprising the amino acid sequence of SEQ ID NO: 38, 50, 82, or 86, or an amino acid sequence at least 85% identical thereto.

63. The nucleic acid molecule of claim 5 , wherein the second nucleotide sequence encodes a VL comprising the amino acid sequence of SEQ ID NO: 42, 46, 54, 58, 62, 66, 70, 74, or 78, or an amino acid sequence at least 85% identical thereto.

64. The nucleic acid molecule of claim 5 , wherein the first nucleotide sequence and the second nucleotide sequence encode, respectively: