IP Library › Granted Patent US 11,274,150
Granted Patent B2
US 11,274,150 · App. 16/683,927 · Granted Mar 15, 2022

Anti-human natural killer cell inhibitory receptor group 2A protein (NKG2A) antibodies

Inventors: Natalie Bezman (Foster City, CA); Alan J. Korman (Piedmont, CA); Shrikant Deshpande (Fremont, CA); Amy D. Jhatakia (Fremont, CA); Richard Y. Huang (Bridgewater, NJ); Guodong Chen (East Brunswick, NJ); Ginger C. Rakestraw (Somerville, MA); Karla Ann Henning (Milpitas, CA); Vangipuram S. Rangan (Pleasant Hill, CA); Christine Bee (San Francisco, CA); Xiang Shao (Milpitas, CA)
Assignee: Bristol-Myers Squibb Company
C07K16/2803A61K39/3955A61K47/6849A61P35/00G01N33/68A61K2039/507C07K2317/21C07K2317/24C07K2317/31C07K2317/33C07K2317/76C07K2317/77C07K2317/92C07K2317/94
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Quick Facts
Patent No.
US 11,274,150
App. No.
16/683,927
Granted
Mar 15, 2022
Kind
B2
Abstract

The present disclosure provides isolated monoclonal antibodies (e.g., humanized and human monoclonal antibodies), or antigen-binding fragments thereof, that specifically bind to human natural killer cell inhibitory receptor group 2A (NKG2A) protein with high affinity and exhibit therapeutically desirable functional properties, such as for the treatment of, for example, cancer. Immunoconjugates, bispecific molecules, and pharmaceutical compositions comprising the anti-NKG2A antibodies of the invention are also provided. Nucleic acid molecules encoding the antibodies, expression vectors, host cells, and methods of treatment of, for example, cancer using the antibodies are further provided. Combination therapy, in which an anti-NKG2A antibody in the present disclosure is co-administered with at least one additional agent such as another antibody (e.g., anti-PD-1, anti-PD-L1, and/or anti-CTLA-4 antibodies), is also provided.

Claims (113)

1. An isolated antibody, or antigen-binding fragment thereof, that binds human natural killer cell inhibitory receptor group 2A protein (NKG2A) wherein said antibody comprises an heavy chain complementarity determining region 1 (HCDR1), an HCDR2 and an HCDR3 of a heavy chain variable region (VH) of the amino acid sequence of SEQ ID NO:8 and a light chain complementary determining region 1 (LCDR1), an LCDR2 and an LCDR3 of a light chain variable region (VL) of the amino acid sequence of SEQ ID NO:9.

2. The isolated antibody, or antigen-binding fragment thereof, of claim 1 wherein the VH consists essentially of the amino acid sequence of SEQ ID NO:8 and the VL consists essentially of the amino acid sequence of SEQ ID NO:9.

3. The isolated antibody, or antigen-binding fragment thereof, of claim 1 wherein the antibody comprises a VH at least 95% identical to the amino acid sequence of SEQ ID NO:8 and a VL at least 95% identical to the amino acid sequence of SEQ ID NO:9.

4. The isolated antibody, or antigen-binding fragment thereof, of claim 1 wherein the antibody comprises a VH at least 98% identical to the amino acid sequence of SEQ ID NO:8 and a VL at least 98% identical to the amino acid sequence of SEQ ID NO:9.

5. The isolated antibody, or antigen-binding fragment thereof, of claim 1 wherein the antibody comprises a VH at least 99% identical to the amino acid sequence of SEQ ID NO:8 and a VL at least 99% identical to the amino acid sequence of SEQ ID NO:9.

6. The antibody, or antigen-binding fragment thereof, of claim 1 wherein the antibody is an antibody fragment.

7. The antigen-binding fragment of claim 6 wherein the antibody fragment is a Fab, Fab′, (Fab′)2, Fv, or scFv fragment.

8. The antibody of claim 1 wherein the antibody is a full-length antibody.

9. The antibody, or antigen-binding fragment thereof, of claim 1 wherein the antibody is an IgG1 antibody.

10. The antibody, or antigen-binding fragment thereof, of claim 1 wherein the antibody is a human, humanized, or chimeric antibody.

11. A composition comprising the antibody of claim 1 and pharmaceutically acceptable carrier.

12. The composition of claim 11 , further comprising an additional therapeutic agent.

13. The composition of claim 12 , wherein the additional therapeutic agent is an anti-PD-1 antibody, anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

14. The composition of claim 13 , wherein the anti-PD-1 antibody is nivolumab.

15. The composition of claim 13 , wherein the anti-CTLA-4 antibody is ipilimumab.

16. The composition of claim 12 , wherein the additional therapeutic agent is cetuximab.

17. An isolated antibody, or antigen-binding fragment thereof, that binds human NKG2A wherein said antibody comprises an HCDR1 of the amino acid sequence of SEQ ID NO:10, an HCDR2 of the amino acid sequence of SEQ ID NO:11 and an HCDR3 of the amino acid sequence of SEQ ID NO:12 and an LCDR1 of the amino acid sequence of SEQ ID NO:13, an LCDR2 of the amino acid sequence of SEQ ID NO:14 and an LCDR3 of the amino acid sequence of SEQ ID NO:15.

18. The isolated antibody, or antigen-binding fragment thereof, of claim 17 wherein the antibody comprises a VH region at least 90% identical to the amino acid sequence of SEQ ID NO:8 and a VL region at least 90% identical to the amino acid sequence of SEQ ID NO:9.

19. The isolated antibody, or antigen-binding fragment thereof, of claim 17 wherein the antibody comprises a VH region at least 95% identical to the amino acid sequence of SEQ ID NO:8 and a VL region is at least 95% identical to the amino acid sequence of SEQ ID NO:9.

20. The isolated antibody, or antigen-binding fragment thereof, of claim 17 wherein the antibody comprises a VH region at least 98% identical to the amino acid sequence of SEQ ID NO:8 and a VL region at least 98% identical to the amino acid sequence of SEQ ID NO:9.

21. The isolated antibody, or antigen-binding fragment thereof, of claim 17 wherein the antibody comprises a VH region at least 99% identical to the amino acid sequence of SEQ ID NO:8 and a VL region at least 99% identical to the amino acid sequence of SEQ ID NO:9.

22. The antibody, or antigen-binding fragment thereof, of claim 17 wherein the antibody is an antibody fragment.

23. The antigen-binding fragment of claim 22 wherein the antibody fragment is a Fab, Fab′, (Fab′)2, Fv, or scFv fragment.

24. The antibody of claim 17 wherein the antibody is a full-length antibody.

25. The antibody, or antigen-binding fragment thereof, of claim 17 wherein the antibody is an IgG1 antibody.

26. The antibody, or antigen-binding fragment thereof, of claim 17 wherein the antibody is a human, humanized, or chimeric antibody.

27. A composition comprising the antibody of claim 17 and pharmaceutically acceptable carrier.

28. The composition of claim 27 , further comprising an additional therapeutic agent.

29. The composition of claim 28 , wherein the additional therapeutic agent is an anti-PD-1 antibody, anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

30. The composition of claim 29 , wherein the anti-PD-1 antibody is nivolumab.

31. The composition of claim 29 , wherein the anti-CTLA-4 antibody is ipilimumab.

32. The composition of claim 28 , wherein the additional therapeutic agent is cetuximab.

33. An isolated antibody, or antigen-binding fragment thereof, that binds human NKG2A wherein said antibody comprises a VH of the amino acid sequence of SEQ ID NO:8 and a VL of the amino acid sequence of SEQ ID NO:9.

34. The isolated antibody, or antigen-binding fragment thereof, of claim 33 wherein the antibody comprises a heavy chain (HC) at least 90% identical to an amino acid sequence of SEQ ID NO:7 and a light chain (LC) at least 90% identical to an amino acid sequence of SEQ ID NO:5.

35. The isolated antibody, or antigen-binding fragment thereof, of claim 33 wherein the antibody comprises a HC at least 95% identical to an amino acid sequence of SEQ ID NO:7 and a LC at least 95% identical to an amino acid sequence of SEQ ID NO:5.

36. The isolated antibody, or antigen-binding fragment thereof, of claim 33 wherein the antibody comprises a HC at least 98% identical to an amino acid sequence of SEQ ID NO:7 and a LC at least 98% identical to an amino acid sequence of SEQ ID NO:5.

37. The isolated antibody, or antigen-binding fragment thereof, of claim 33 wherein the antibody comprises a HC at least 99% identical to an amino acid sequence of SEQ ID NO:7 and a LC at least 99% identical to an amino acid sequence of SEQ ID NO:5.

38. The antibody, or antigen-binding fragment thereof, of claim 33 wherein the antibody is an antibody fragment.

39. The antigen-binding fragment of claim 38 wherein the antibody fragment is a Fab, Fab′, (Fab′)2, Fv, or scFv fragment.

40. The antibody of claim 33 wherein the antibody is a full-length antibody.

41. The antibody, or antigen-binding fragment thereof, of claim 33 wherein the antibody is an IgG1 antibody.

42. The antibody, or antigen-binding fragment thereof, of claim 33 wherein the antibody is a human, humanized, or chimeric antibody.

43. A composition comprising the antibody of claim 33 and pharmaceutically acceptable carrier.

44. The composition of claim 43 , further comprising an additional therapeutic agent.

45. The composition of claim 44 , wherein the additional therapeutic agent is an anti-PD-1 antibody, anti-PD-L1 antiboyd, or an anti-CTLA-4 antibody.

46. The composition of claim 45 , wherein the anti-PD-1 antibody is nivolumab.

47. The composition of claim 45 , wherein the anti-CTLA-4 antibody ipilimumab.

48. The composition of claim 44 , wherein the additional therapeutic agent is cetuximab.

49. An isolated antibody that binds human NKG2A wherein said antibody comprises a HC of the amino acid sequence of SEQ ID NO:7 and a LC of the amino acid sequence of SEQ ID NO:5.

50. A composition comprising the antibody of claim 49 and pharmaceutically acceptable carrier.

51. The composition of claim 50 , further comprising an additional therapeutical agent.

52. The composition of claim 51 , wherein the additional therapeutic agent is an anti-PD-1 antibody, anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

53. The composition of claim 52 , wherein the anti-PD-1 antibody is nivolumab.

54. The composition of claim 52 , wherein the anti-CTLA-4 antibody is ipilimumab.

55. The composition of claim 51 , wherein the additional therapeutic agent is cetuximab.

56. An isolated antibody, or antigen-binding fragment thereof, that binds NKG2A wherein said antibody comprises a heavy chain complementarity determining region 1 (HCDR1), an HCDR2 and an HCDR3 of a heavy chain variable region (VH) of the amino acid sequence of SEQ ID NO:8 and a light chain complementary determining region 1 (LCDR1), an LCDR2 and an LCDR3 of a light chain variable region (VL) of the amino acid sequence of SEQ ID NO:164.

57. The isolated antibody, or antigen-binding fragment thereof, of claim 56 wherein the VH consists essentially of the amino acid sequence of SEQ ID NO:8 and the VL consists essentially of the amino acid sequence of SEQ ID NO:164.

58. The isolated antibody, or antigen-binding fragment thereof, of claim 56 wherein the antibody comprises a VH at least 95% identical to the amino acid sequence of SEQ ID NO:8 and a VL at least 95% identical to the amino acid sequence of SEQ ID NO:164.

59. The isolated antibody, or antigen-binding fragment thereof, of claim 56 wherein the antibody comprises a VH at least 98% identical to the amino acid sequence of SEQ ID NO:8 and a VL at least 98% identical to the amino acid sequence of SEQ ID NO:164.

60. The isolated antibody, or antigen-binding fragment thereof, of claim 56 wherein the antibody comprises a VH at least 99% identical to the amino acid sequence of SEQ ID NO:8 and a VL at least 99% identical to the amino acid sequence of SEQ ID NO:164.

61. The isolated antibody, or antigen-binding fragment thereof, of claim 56 wherein the antibody comprises a VH of the amino acid sequence of SEQ ID NO:8 and a VL of the amino acid sequence of SEQ ID NO:164.

62. The antibody, or antigen-binding fragment thereof, of claim 56 wherein the antibody is an antibody fragment.

63. The antigen-binding fragment of claim 62 wherein the antibody fragment is a Fab, Fab′, (Fab′)2, Fv, or scFv fragment.

64. The antibody of claim 56 wherein the antibody is a full-length antibody.

65. The antibody, or antigen-binding fragment thereof, of claim 56 wherein the antibody is an IgG1 antibody.

66. The antibody, or antigen-binding fragment thereof, of claim 56 wherein the antibody is a human, humanized, or chimeric antibody.

67. A composition comprising the antibody of claim 56 and pharmaceutically acceptable carrier.

68. The composition of claim 67 , further comprising an additional therapeutic agent.

69. The composition of claim 68 , wherein the additional therapeutic agent is an anti-PD-1 antibody, anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

70. The composition of claim 69 , wherein the anti-PD-1 antibody is nivolumab.

71. The composition of claim 69 , wherein the anti-CTLA-4 antibody is ipilimumab.

72. The composition of claim 68 , wherein the additional therapeutic agent is cetuximab.

73. An isolated antibody, or antigen-binding fragment thereof, that binds human NKG2A wherein said antibody comprises an HCDR1 of the amino acid sequence of SEQ ID NO:10, an HCDR2 of the amino acid sequence of SEQ ID NO:11 and an HCDR3 of the amino acid sequence of SEQ ID NO:12 and a LCDR1 of the amino acid sequence of SEQ ID NO:154, an LCDR2 of the amino acid sequence of SEQ ID NO:14 and an LCDR3 of the amino acid sequence of SEQ ID NO:15.

74. The isolated antibody, or antigen-binding fragment thereof, of claim 73 wherein the antibody comprises a VH region at least 90% identical to the amino acid sequence of SEQ ID NO:8 and a VL region at least 90% identical to the amino acid sequence of SEQ ID NO:164.

75. The isolated antibody, or antigen-binding fragment thereof, of claim 73 wherein the antibody comprises a VH region at least 95% identical to the amino acid sequence of SEQ ID NO:8 and a VL region is at least 95% identical to the amino acid sequence of SEQ ID NO:164.

76. The isolated antibody, or antigen-binding fragment thereof, of claim 73 wherein the antibody comprises a VH region at least 98% identical to the amino acid sequence of SEQ ID NO:8 and a VL region at least 98% identical to the amino acid sequence of SEQ ID NO:164.

77. The isolated antibody, or antigen-binding fragment thereof, of claim 73 wherein the antibody comprises a VH region at least 99% identical to the amino acid sequence of SEQ ID NO:8 and a VL region at least 99% identical to the amino acid sequence of SEQ ID NO:164.

78. The antibody, or antigen-binding fragment thereof, of claim 73 wherein the antibody is an antibody fragment.

79. The antigen-binding fragment of claim 78 wherein the antibody fragment is a Fab, Fab′, (Fab′)2, Fv, or scFv fragment.

80. The antibody of claim 73 wherein the antibody is a full-length antibody.

81. The antibody, or antigen-binding fragment thereof, of claim 73 wherein the antibody is an IgG1 antibody.

82. The antibody, or antigen-binding fragment thereof, of claim 73 wherein the antibody is a human, humanized, or chimeric antibody.

83. A composition comprising the antibody of claim 73 and pharmaceutically acceptable carrier.

84. The composition of claim 83 , further comprising an additional therapeutic agent.

85. The composition of claim 84 , wherein the additional therapeutic agent is an anti-PD-1 antibody, anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

86. The composition of claim 85 , wherein the anti-PD-1 antibody is nivolumab.

87. The composition of claim 85 , wherein the anti-CTLA-4 antibody is ipilimumab.

88. The composition of claim 84 , wherein the additional therapeutic agent is cetuximab.

89. An isolated antibody, or antigen-binding fragment thereof, that binds human NKG2A wherein said antibody comprises a VH of the amino acid sequence of SEQ ID NO:8 and a VL of the amino acid sequence of SEQ ID NO:164.

90. The isolated antibody, or antigen-binding fragment thereof, of claim 89 wherein the antibody comprises a HC at least 90% identical to the amino acid sequence of SEQ ID NO:7 and a LC at least 90% identical to the amino acid sequence of SEQ ID NO:19.

91. The isolated antibody, or antigen-binding fragment thereof, of claim 89 wherein the antibody comprises a HC at least 95% identical to the amino acid sequence of SEQ ID NO:7 and a LC at least 95% identical to the amino acid sequence of SEQ ID NO:19.

92. The isolated antibody, or antigen-binding fragment thereof, of claim 89 wherein the antibody comprises a HC at least 98% identical to the amino acid sequence of SEQ ID NO:7 and a LC at least 98% identical to the amino acid sequence of SEQ ID NO:19.

93. The isolated antibody, or antigen-binding fragment thereof, of claim 77 wherein the antibody comprises a HC at least 99% identical to the amino acid sequence of SEQ ID NO:7 and a LC at least 99% identical to the amino acid sequence of SEQ ID NO:19.

94. The antibody, or antigen-binding fragment thereof, of claim 89 wherein the antibody is an antibody fragment.

95. The antigen-binding fragment of claim 94 wherein the antibody fragment is a Fab, Fab′, (Fab′)2, Fv, or scFv fragment.

96. The antibody of claim 89 wherein the antibody is a full-length antibody.

97. The antibody, or antigen-binding fragment thereof, of claim 89 wherein the antibody is an IgG1 antibody.

98. The antibody, or antigen-binding fragment thereof, of claim 89 wherein the antibody is a human, humanized, or chimeric antibody.

99. A composition comprising the antibody of claim 89 and pharmaceutically acceptable carrier.

100. The composition of claim 99 , further comprising an additional therapeutic agent.

101. The composition of claim 100 , wherein the additional therapeutica agent is an anti-PD-1 antibody, anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

102. The composition of claim 101 , wherein the anti-PD-1 antibody is nivolumab.

103. The composition of claim 101 , wherein the anti-CTLA-4 antibody is ipilimumab.

104. The composition of claim 100 , wherein the additional therapeutic agent is cetuximab.

105. An isolated antibody that binds human NKG2A wherein said antibody comprises a HC of the amino acid sequence of SEQ ID NO:7 and a LC of the amino acid sequence of SEQ ID NO:19.

106. A composition comprising the antibody of claim 105 and pharmaceutically acceptable carrier.

107. The composition of claim 106 , further comprising an additional therapeutic agent.

108. The composition of claim 107 , wherein the additional therapeutic agent is an anti-PD-1 antibody, anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

109. The composition of claim 108 , wherein the anti-PD-1 antibody is nivolumab.

110. The composition of claim 108 , wherein the anti-CTLA-4 antibody is ipilimumab.

111. The composition of claim 107 , wherein the additional therapeutic agent is cetuximab.

112. The isolated antibody of claim 49 wherein said antibody consists of a HC of the amino acid sequence of SEQ ID NO:7 and a LC of the amino acid sequence of SEQ ID NO:5.

113. The isolated antibody of claim 105 wherein said antibody consists of a HC of the amino acid sequence of SEQ ID NO:7 and a LC of the amino acid sequence of SEQ ID NO:10.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 3, 2020
From: BEZMAN, NATALIE; KORMAN, ALAN J.; DESHPANDE, SHRIKANT; JHATAKIA, AMY D.; HUANG, RICHARD Y.; CHEN, GUODONG; RAKESTRAW, GINGER C.; HENNING, KARLA A.; RANGAN, VANGIPURAM S.; BEE, CHRISTINE; SHAO, XIANG
To: BRISTOL-MYERS SQUIBB COMPANY
Reel/Frame 051992/0556 →
Continuity (3)
Provisional Application 62927211 · Oct 29, 2019
Provisional Application 62768471 · Nov 16, 2018
Related Publication 20200199226A1 · Jun 25, 2020