Anti-PD-L1 antibodies and their use to enhance T cell function

JP2026098928APending Publication Date: 2026-06-17GENENTECH INC
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Patent Information

Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
GENENTECH INC
Filing Date
2026-02-27
Publication Date
2026-06-17

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Abstract

The present invention provides means for enhancing T-cell immunity for the treatment of cancer (e.g., tumor immunity) and infection (including acute and chronic (e.g., persistent) infection). [Solution] The present invention provides an anti-PD-L1 antibody, a nucleic acid encoding the antibody, a therapeutic composition of the antibody, and the use of the antibody for enhancing T cell function, upregulating cell-mediated immune responses, and treating T cell dysfunction disorders (including infections (e.g., acute and chronic) and tumor immunity).
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Claims

1. An isolated heavy chain variable region polypeptide comprising HVR-H1, HVR-H2, and HVR-H3 sequences, wherein: (a) HVR-H1 sequence is GFTFSX １ SWIH (Sequence ID 1); (b) HVR-H2 sequence is AWIX ２ PYGGSX ３ YYADSVKG (Sequence ID 2) is; (c) The HVR-H3 sequence is RHWPGGGFDY (Sequence ID 3); Furthermore, in that: X １ is D or G; X ２ is S or L; X ３ A heavy chain variable region polypeptide in which T or S.

2. X １ is D; X ２ is S, and X ３ is T, the polypeptide according to claim 1.

3. The polypeptide according to claim 1, further comprising a heavy chain variable region framework sequence juxtaposed between HVRs in the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4).

4. The polypeptide according to claim 3, wherein the framework sequence is derived from a human consensus framework sequence.

5. The polypeptide according to claim 4, wherein the framework sequence is a VH subgroup III consensus framework.

6. One or more of the framework arrays are as follows: HC-FR1 is EVQLVESGGGGLVQPGGSLRLSCAAS (Sequence ID 4); HC-FR2 is WVRQAPGKGLEWV (Sequence ID 5); HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (Sequence ID 6); HC-FR4 is WGQGTLVTVSA (Sequence ID 7). The polypeptide according to claim 5.

7. An isolated heavy chain polypeptide according to claim 1, combined with a light chain variable region comprising HVR-L1, HVR-L2, and HVR-L3, wherein (a) HVR-L1 sequence is RASQX ４ X ５ X ６ TX ７ X ８ A (Sequence ID 8); (b) HVR-L2 sequence is SASX ９ LX １０ S (Sequence ID 9) is; (c) HVR-L3 sequence is QQX １１ X １２ X １３ X １４ PX １５ T (sequence number 10) is; furthermore, in it: X ４ is D or V; X ５ is V or I; X ６ is S or N; X ７ is A or F; X ８ is V or L; X ９ is F or T; X １０ is Y or A; X １１ is Y, G, F, or S; X １２ is L, Y, F or W; X １３ is Y, N, A, T, G, F or I; X １４ is H, V, P, T or I; X １５ A heavy chain polypeptide in which is A, W, R, P, or T.

8. X ４ D is X ５ V is X ６ S is X ７ A is X ８ V is X ９ F is X １０ Y is X １１ Y is X １２ L is X １３ Y is X １４ H is X １５ The polypeptide according to claim 7, wherein A.

9. Furthermore, the polypeptide according to claim 7, comprising a light chain variable region framework sequence juxtaposed between HVRs in the following formula: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4).

10. The polypeptide according to claim 9, wherein the framework sequence is derived from a human consensus framework sequence.

11. The polypeptide according to claim 10, wherein the framework sequence is a VL Kappa I consensus framework.

12. One or more of the framework arrays are as follows: LC-FR1 is DIQMTQSPSSLSASVGDRVTITTC (Sequence ID 11); LC-FR2 is WYQQKPGKAPKLLIY (Sequence ID 12); LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (Sequence ID 13); LC-FR4 is FGQGTKVEIKR (Sequence ID 14). The polypeptide according to claim 11.

13. An isolated anti-PD-L1 antibody or antigen-binding fragment comprising heavy chain and light chain variable region sequences, wherein: (a) The heavy chain comprises HVR-H1, HVR-H2, and HVR-H3, wherein: (i) HVR-H1 sequence is GFTFSX １ SWIH (Sequence ID 1); (ii) HVR-H2 array is AWIX ２ PYGGSX ３ YYADSVKG (Sequence ID 2) is; (iii) The HVR-H3 sequence is RHWPGGGFDY (Sequence ID 3); and (b) The light chain comprises HVR-L1, HVR-L2, and HVR-L3, wherein: (iv) HVR-L1 sequence is RASQX ４ X ５ X ６ TX ７ X ８ A (Sequence ID 8); (v) HVR-L2 sequence is SASX ９ LX １０ S (Sequence ID 9) is; and (vi) HVR-L3 sequence is QQX １１ X １２ X １３ X １４ PX １５ T (Sequence ID 10), In that regard: X １ is D or G; X ２ is S or L; X ３ is T or S; X ４ It may be D or V; X ５ It may be V or I; X ６ It may be S or N; X ７ It may be A or F; X ８ It may be V or L; X ９ It may be F or T; X １０ It may be Y or A; X １１ may be Y, G, F, or S; X １２ may be L, Y, F, or W; X １３ may be Y, N, A, T, G, F, or I; X １４ may be H, V, P, T, or I; X １５ may be A, W, R, P or T This is an anti-PD-L1 antibody or antigen-binding fragment.

14. X １ D is X ２ S is X ３ The antibody or antibody fragment according to claim 13, wherein T is present.

15. X ４ = D, X ５ = V, X ６ = S, X ７ = A and X ８ = V, X ９ = F, and X １０ = Y, X １１ = Y, X １２ = L, X １３ = Y, X １４ = H and X １５ The antibody or antibody fragment according to claim 13, which is = A.

16. X １ = D, X ２ = S and X ３ = T, X ４ = D, X ５ = V, X ６ = S, X ７ = A and X ８ = V, X ９ = F, and X １０ = Y, X １１ = Y, X １２ = L, X １３ = Y, X １４ = H and X １５ The antibody or antibody fragment according to claim 13, which is = A.

17. (a) Formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), a heavy chain variable region framework sequence juxtaposed between HVRs, and (b) Formula: Light chain variable region framework array juxtaposed between HVRs in (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4) The antibody or antibody fragment according to any one of claims 13 to 16, further comprising:

18. The antibody or antibody fragment according to claim 17, wherein the framework sequence is derived from a human consensus framework sequence.

19. The antibody or antibody fragment according to claim 18, wherein the heavy chain variable region framework sequence is a VH subgroup III consensus framework.

20. One or more of the framework arrays are as follows: HC-FR1 is EVQLVESGGGGLVQPGGSLRLSCAAS (Sequence ID 4); HC-FR2 is WVRQAPGKGLEWV (Sequence ID 5); HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (Sequence ID 6); HC-FR4 is WGQGTLVTVSA (Sequence ID 7). The antibody or antibody fragment according to claim 19.

21. The antibody or antibody fragment according to claim 18, wherein the light chain variable region framework sequence is a VL kappa I consensus framework.

22. One or more of the framework arrays are as follows: LC-FR1 is DIQMTQSPSSLSASVGDRVTITTC (Sequence ID 11); LC-FR2 is WYQQKPGKAPKLLIY (Sequence ID 12); LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (Sequence ID 13); and LC-FR4 is FGQGTKVEIKR (Sequence ID 14). The antibody or antibody fragment according to claim 21.

23. (a) The variable heavy chain framework sequence is as follows: (i) HC-FR1 is EVQLVESGGGGLVQPGGSLRLSCAAS (Sequence ID 4); (ii) HC-FR2 is WVRQAPGKGLEWV (Sequence ID 5); (iii) HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (Sequence ID 6); (iv) HC-FR4 is WGQGTLVTVSA (Sequence ID 7); and (b) The variable light chain framework sequence is as follows: (i) LC-FR1 is DIQMTQSPSSLSASVGDRVTITTC (Sequence ID 11); (ii) LC-FR2 is WYQQKPGKAPKLLIY (Sequence ID 12); (iii) LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (Sequence ID 13); (iv) LC-FR4 is FGQGTKVEIKR (Sequence ID 14) The antibody or antibody fragment according to claim 18.

24. The antibody or antibody fragment according to claim 23, further comprising a human constant region.

25. The antibody or antibody fragment according to claim 24, wherein the constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

26. An antibody of the antibody fragment according to claim 25, wherein the constant region is IgG1.

27. The antibody or antibody fragment according to claim 23, further comprising a mouse constant region.

28. The antibody or antibody fragment according to claim 27, wherein the constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, and IgG3.

29. The antibody or antibody fragment according to claim 28, wherein the constant region is IgG2A.

30. The antibody or antibody fragment according to claim 25 or 28, having reduced or minimal effector function.

31. The antibody or antibody fragment according to claim 30, wherein the minimum effector function is due to an effectorless Fc mutation.

32. The antibody or antibody fragment according to claim 31, wherein the effector-free Fc mutation is N297A.

33. The antibody or antibody fragment according to claim 31, wherein the effector-free Fc mutation is D265A / N297A.

34. The antibody or antibody fragment according to claim 30, wherein the minimum effector function is due to non-glycation.

35. An antibody or antigen-binding fragment comprising heavy chain and light chain variable region sequences, wherein: (a) The heavy chain comprises HVR-H1, HVR-H2, and HVR-H3 sequences having at least 85% total sequence identity with GFTFSDSWIH (SEQ ID NO: 15), AWISPYGGSTYYADSVKG (SEQ ID NO: 16), and RHWPGGGFDY (SEQ ID NO: 3), and (b) The light chain comprises HVR-L1, HVR-L2, and HVR-L3 sequences having at least 85% total sequence identity with RASQDVSTAVA (SEQ ID NO: 17), SASFLYS (SEQ ID NO: 18), and QQYLYHPAT (SEQ ID NO: 19), respectively. Antibody or antigen-binding fragment.

36. The antibody or antibody fragment according to claim 35, wherein the sequence identity is at least 90%.

37. (a) Formula: A heavy chain variable region (VH) framework sequence juxtaposed between HVRs in (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and (b) Formula: Light chain variable region (VL) framework sequence juxtaposed between HVRs in (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4) The antibody or antibody fragment according to claim 36, further comprising:

38. The antibody or antibody fragment according to claim 37, further comprising VH and VL framework regions derived from a human consensus sequence.

39. The antibody or antibody fragment according to claim 38, wherein the VH framework sequence is derived from a Kabat subgroup I, II, or III sequence.

40. The antibody or antibody fragment according to claim 39, wherein the VH framework sequence is a Kabat subgroup III consensus framework sequence.

41. The VH framework array is as follows: HC-FR1 is EVQLVESGGGGLVQPGGSLRLSCAAS (Sequence ID 4); HC-FR2 is WVRQAPGKGLEWV (Sequence ID 5); HC-FR3 is RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (Sequence ID 6); HC-FR4 is WGQGTLVTVSA (Sequence ID 7). The antibody or antibody fragment according to claim 40.

42. The antibody or antibody fragment according to claim 38, wherein the VL framework sequence is derived from the Kabat kappa I, II, III, or IV subgroup sequence.

43. The antibody or antibody fragment according to claim 42, wherein the VL framework sequence is the Kabat Kappa I consensus framework sequence.

44. The VL framework array is as follows: LC-FR1 is DIQMTQSPSSLSASVGDRVTITTC (Sequence ID 11); LC-FR2 is WYQQKPGKAPKLLIY (Sequence ID 12); LC-FR3 is GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (Sequence ID 13); LC-FR4 is FGQGTKVEIKR (Sequence ID 14). The antibody or antibody fragment according to claim 43.

45. An isolated anti-PD-L1 antibody or antigen-binding fragment comprising heavy chain and light chain variable region sequences, wherein: (a) The heavy chain is as follows: It has at least 85% sequence identity with the heavy chain sequence of EVQLVESGGGLLVQPGGSLRLSCAASGFTFSDSWWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISAADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO: 20), and (b) The light chain is as follows: The light chain sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSSTAVAAWYQQKPGKAPKLLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO: 21) has at least 85% sequence identity. Anti-PD-L1 antibody or antigen-binding fragment.

46. The antibody or antigen-binding fragment according to claim 45, wherein the sequence identity is at least 90%.

47. An isolated anti-PD-L1 antibody or antigen-binding fragment comprising heavy chain and light chain variable region sequences, wherein: (a) The heavy chain is as follows: The sequence includes EVQLVESGGGLLVQPGGSLRLSCAASGFTFSDSWWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISAADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (Sequence ID 20), and (b) The light chain is as follows: Includes the sequence DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (Sequence ID 21) Anti-PD-L1 antibody or antigen-binding fragment.

48. A composition comprising an anti-PD-L1 antibody or antigen-binding fragment according to any one of claims 13 to 47 and at least one pharmaceutically acceptable carrier.

49. An isolated nucleic acid encoding a polypeptide according to any one of claims 1 to 11.

50. An isolated nucleic acid encoding a light chain or heavy chain variable sequence of an anti-PD-L1 antibody or antigen-binding fragment, wherein: (a) The heavy chain further comprises HVR-H1, HVR-H2, and HVR-H3 sequences having at least 85% sequence identity with GFTFSDSWIH (SEQ ID NO: 15), AWISPYGGSTYYADSVKG (SEQ ID NO: 16), and RHWPGGGFDY (SEQ ID NO: 3), respectively, or (b) Isolated nucleic acids, wherein the light chain further comprises HVR-L1, HVR-L2, and HVR-L3 sequences having at least 85% sequence identity with RASQDVSTAVA (SEQ ID NO: 17), SASFLYS (SEQ ID NO: 18), and QQYLYHPAT (SEQ ID NO: 19), respectively.

51. The nucleic acid according to claim 50, wherein the sequence identity is 90%.

52. The nucleic acid according to claim 50, wherein the anti-PD-L1 antibody further comprises VL and VH framework regions derived from a human consensus sequence.

53. The nucleic acid according to claim 52, wherein the VH sequence is derived from a Kabat subgroup I, II, or III sequence.

54. The nucleic acid according to claim 52, wherein the VL sequence is derived from a Kabat kappa I, II, III, or IV subgroup sequence.

55. The nucleic acid according to claim 50, wherein the anti-PD-L1 antibody comprises a constant region derived from a mouse antibody.

56. The nucleic acid according to claim 50, wherein the anti-PD-L1 antibody includes a constant region derived from a human antibody.

57. The nucleic acid according to claim 56, wherein the constant region is IgG1.

58. The nucleic acid according to claim 57, having reduced or minimal effector function.

59. The nucleic acid according to claim 58, wherein the minimum effector function is due to an effector-free Fc mutation.

60. The nucleic acid according to claim 59, wherein the effector-free Fc mutation is N297A.

61. A vector comprising the nucleic acid according to any one of claims 49 to 60.

62. A host cell comprising the vector according to claim 61.

63. The host cell according to claim 62, which is a eukaryote.

64. The host cell according to claim 63, which is a mammal.

65. The host cell according to claim 64, which is a Chinese hamster ovary (CHO) cell.

66. The host cell according to claim 62, which is a prokaryote.

67. The host cell according to claim 66, which is E. coli.

68. A process for producing an anti-PD-L1 antibody, comprising culturing host cells according to any one of claims 62 to 67 under conditions suitable for the expression of a vector encoding an anti-PD-L1 antibody or antigen-binding fragment, and recovering the antibody or fragment.

69. A product comprising the composition according to claim 48 and at least one BNCA molecule.

70. A product comprising the composition according to claim 48 and at least one chemotherapeutic agent.

71. The manufactured product according to claim 70, wherein the chemotherapeutic agent is gemcitabine.

72. A product comprising the composition according to claim 48 and at least one agonist for a positive co-stimulating molecule.

73. The article according to claim 72, further comprising a BNCA antagonist.

74. A product comprising the composition according to claim 48 and at least one antibiotic.

75. The manufactured product according to claim 74, wherein the antibiotic is an antiviral agent.

76. The manufactured product according to claim 75, wherein the antiviral agent is a reverse transcriptase inhibitor.

77. The manufactured product according to claim 76, wherein the reverse transcriptase inhibitor is a polymerase inhibitor.

78. The manufactured product according to claim 75, wherein the antiviral agent is a protease inhibitor.

79. A manufactured product comprising the composition according to claim 48 and at least one vaccine.

80. A method for enhancing T cell function, comprising administering an effective amount of the composition according to claim 48 to dysfunctional T cells.

81. A method for treating T-cell dysfunction, comprising administering a therapeutically effective amount of the composition according to claim 48 to a patient suffering from T-cell dysfunction.

82. The method according to claim 81, wherein the T-cell dysfunction is an infection.

83. The method according to claim 82, wherein the infection is chronic.

84. The method according to claim 81, wherein the T-cell dysfunction is tumor immunity.

85. The method according to claim 83, wherein the chronic infection is persistent.

86. The method according to claim 83, wherein chronic infection is potential.

87. The method according to claim 83, wherein the chronic infection is gradual.

88. The method according to claim 82, wherein the infection is caused by a pathogen selected from the group consisting of bacteria, viruses, fungi, and protozoa.

89. The method according to claim 88, wherein the pathogen is a bacterium, and the method further comprises the administration of an antimicrobial agent.

90. The method according to claim 88, wherein the pathogen is a virus, and the method further comprises the administration of an antiviral agent.

91. The method according to claim 88, wherein the pathogen is a fungus, and the method further comprises the administration of an antifungal agent.

92. The method according to claim 88, wherein the pathogen is a protozoan, and the method further comprises the administration of an antiparasitic agent.

93. The method according to claim 88, further comprising administering a vaccine.

94. The method according to claim 84, further comprising the application of a treatment plan selected from the group consisting of radiotherapy, chemotherapy, targeted therapy, immunotherapy, hormone therapy, angiogenesis inhibition, and palliative care.

95. The method according to claim 84, wherein the tumor immunity is due to a cancer selected from the group consisting of breast, lung, colon, ovarian, melanoma, bladder, kidney, liver, salivary, stomach, glioma, thyroid, thymus, epithelial, head and neck cancer, gastric cancer, and pancreatic cancer.