COMBINATION THERAPY COMPRISING OX40 BINDING AGONISTS AND PD-1 AXIS BINDING ANTAGONISTS

• US 20150190506A1
• Filed: 12/17/2014
• Published: 07/09/2015
• Est. Priority Date: 12/17/2013
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: CHEUNG, Jeanne, KIM, Jeong
• Application Number:
  US14/574,365
• Publication Number:
  US 20150190506A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2039/55 characterised by the host/recipient, e.g. newborn with maternal antibodies
• CPC Class Codes: A61K 38/16 Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof enzyme inhibitors A61K38/005
• CPC Class Codes: A61K 39/39558 against tumor tissues, cells, antigens
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/2878 against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• CPC Class Codes: C07K 2317/75 Agonist effect on antigen
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Abstract

The invention provides compositions and methods for treating cancers. The method comprises administering a PD-1 axis binding antagonist and an OX40 binding agonist.

Claims

1. A method for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a human PD-1 axis binding antagonist and an OX40 binding agonist.

2. The method of claim 1, wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PDL1 binding antagonist and a PDL2 binding antagonist.

3. The method of claim 2, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

4. The method of claim 3, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to its ligand binding partners.

5. The method of claim 3, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PDL1.

6. The method of claim 3, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PDL2.

7. The method of claim 3, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to both PDL1 and PDL2.

8. The method of claim 3, wherein the PD-1 binding antagonist is an antibody.

9. The method of claim 3, wherein the PD-1 binding antagonist is nivolumab.

10. The method of claim 3, wherein the PD-1 binding antagonist is pembrolizumab.

11. The method of claim 3, wherein the PD-1 binding antagonist is CT-011.

12. The method of claim 3, wherein the PD-1 binding antagonist is AMP-224.

13. The method of claim 2, wherein the PD-1 axis binding antagonist is a PDL1 binding antagonist.

14. The method of claim 13, wherein the PDL1 binding antagonist inhibits the binding of PDL1 to PD-1.

15. The method of claim 13, wherein the PDL1 binding antagonist inhibits the binding of PDL1 to B7-1.

16. The method of claim 13, wherein the PDL1 binding antagonist inhibits the binding of PDL1 to both PD-1 and B7-1.

17. The method of claim 13, wherein the PDL1 binding antagonist is an anti-PDL1 antibody.

18. The method of claim 17, wherein the anti-PDL1 antibody is a monoclonal antibody.

19. The method of claim 17, wherein the anti-PDL1 antibody is an antibody fragment selected from the group consisting of Fab, Fab′

-SH, Fv, scFv, and (Fab′

)₂ fragments.

20. The method of claim 17, wherein the anti-PDL1 antibody is a humanized antibody or a human antibody.

21. The method of claim 13, wherein the PDL1 binding antagonist is selected from the group consisting of:

YW243.55.S70, MPDL3280A, MDX-1105, and MEDI4736.

22. The method of claim 17, wherein the antibody comprises a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:

1), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO;

2), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO;

3); and

a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO;

4), HVR-L2 sequence of SASFLYS (SEQ ID NO;

5), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO;

6).

23. The method of claim 17, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYY ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:

7) or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWI SPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQ GTLVTVSSASTK (SEQ ID NO;

8) and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASF LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO;

9).

24. The method of claim 2, wherein the PD-1 axis binding antagonist is a PDL2 binding antagonist.

25. The method of claim 24, wherein the PDL2 binding antagonist is an antibody.

26. The method of claim 24, wherein the PDL2 binding antagonist is an immunoadhesin.

27. The method of claim 17, wherein the antibody is a human IgG1 having Asn to Ala substitution at position 297 according to EU numbering.

28. The method of claim 1, wherein the OX40 binding agonist is selected from the group consisting of an OX40 agonist antibody, an OX40L agonist fragment, an OX40 oligomeric receptor, and an OX40 immunoadhesin.

29. The method of claim 1, wherein the OX40 binding agonist is an OX40 agonist antibody that binds human OX40.

30. The method of claim 29, wherein the OX40 agonist antibody is MEDI6469, MEDI0562, or MEDI6383.

31. The method of claim 29, wherein the OX40 agonist antibody is a full-length human IgG1 antibody.

32. The method of claim 1, wherein the OX40 binding agonist is a trimeric OX40L-Fc protein.

33. The method of claim 1, wherein the OX40 binding agonist is an OX40L agonist fragment comprising one or more extracellular domains of OX40L.

34. The method of claim 1, wherein the cancer is breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, prostate cancer, colorectal cancer, glioblastoma, neuroblastoma, or hepatocellular carcinoma.

35. The method of claim 1, wherein the individual has cancer or has been diagnosed with cancer.

36. The method of claim 1, wherein the treatment results in a sustained response in the individual after cessation of the treatment.

37. The method of claim 1, wherein the OX40 binding agonist is administered before the PD-1 axis binding antagonist, simultaneous with the PD-1 axis binding antagonist, or after the PD-1 axis binding antagonist.

38. The method of claim 1, wherein the individual is a human.

82. The method of claim 1, wherein the PD-1 axis binding antagonist and/or the OX40 binding agonist are administered intravenously, intramuscularly, subcutaneously, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally.

83. The method of claim 1, further comprising administering a chemotherapeutic agent for treating or delaying progression of cancer.

39. A method of enhancing immune function in an individual having cancer comprising administering an effective amount of a PD-1 axis binding antagonist and an OX40 binding agonist.

40. The method of claim 39, wherein CD8 T cells in the individual have enhanced priming, activation, proliferation and/or cytolytic activity relative to prior to the administration of the PD-1 axis binding antagonist and the OX40 binding agonist.

41. The method of claim 39, wherein the number of CD8 T cells is elevated relative to prior to administration of the combination.

42. The method of claim 41, wherein the CD8 T cell is an antigen-specific CD8 T cell.

43. The method of claim 39, wherein Treg function is suppressed relative to prior to the administration of the combination.

44. The method of claim 39, wherein T cell exhaustion is decreased relative to prior to the administration of the combination.

45. The method of claim 39, wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PDL1 binding antagonist and a PDL2 binding antagonist.

46. The method of claim 45, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

47. The method of claim 46, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to its ligand binding partners.

48. The method of claim 46, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PDL1.

49. The method of claim 46, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PDL2.

50. The method of claim 46, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to both PDL1 and PDL2.

51. The method of claim 46, wherein the PD-1 binding antagonist is an antibody.

52. The method of claim 46, wherein the PD-1 binding antagonist is nivolumab.

53. The method of claim 46, wherein the PD-1 binding antagonist is pembrolizumab.

54. The method of claim 46, wherein the PD-1 binding antagonist is CT-011.

55. The method of claim 46, wherein the PD-1 binding antagonist is AMP-224.

56. The method of claim 45, wherein the PD-1 axis binding antagonist is a PDL1 binding antagonist.

57. The method of claim 56, wherein the PDL1 binding antagonist inhibits the binding of PDL1 to PD-1.

58. The method of claim 56, wherein the PDL1 binding antagonist inhibits the binding of PDL1 to B7-1.

59. The method of claim 56, wherein the PDL1 binding antagonist inhibits the binding of PDL1 to both PD-1 and B7-1.

60. The method of claim 56, wherein the PDL1 binding antagonist is an anti-PDL1 antibody.

61. The method of claim 60, wherein the anti-PDL1 antibody is a monoclonal antibody.

62. The method of claim 60, wherein the anti-PDL1 antibody is an antibody fragment selected from the group consisting of Fab, Fab′

-SH, Fv, scFv, and (Fab′

)₂ fragments.

63. The method of claim 60, wherein the anti-PDL1 antibody is a humanized antibody or a human antibody.

64. The method of claim 56, wherein the PDL1 binding antagonist is selected from the group consisting of:

YW243.55.S70, MPDL3280A, MDX-1105, and MEDI4736.

65. The method of claim 60, wherein the anti-PDL1 antibody comprises a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:

1), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO;

2), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO;

3); and

a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO;

4), HVR-L2 sequence of SASFLYS (SEQ ID NO;

5), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO;

6).

66. The method of claim 60, wherein the anti-PDL1 antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYY ADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:

7) or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWI SPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQ GTLVTVSSASTK (SEQ ID NO;

8) and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIY SASF LYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO;

9).

67. The method of claim 60, wherein the antibody is a human IgG1 having Asn to Ala substitution at position 297 according to EU numbering.

68. The method of claim 45, wherein the PD-1 axis binding antagonist is a PDL2 binding antagonist.

69. The method of claim 68, wherein the PDL2 binding antagonist is an antibody.

70. The method of claim 68, wherein the PDL2 binding antagonist is an immunoadhesin.

71. The method of claim 39, wherein the OX40 binding agonist is selected from the group consisting of an OX40 agonist antibody, an OX40L agonist fragment, an OX40 oligomeric receptor, and an OX40 immunoadhesin.

72. The method of claim 71, wherein the OX40 binding agonist is an OX40 agonist antibody that binds human OX40.

73. The method of claim 72, wherein the OX40 agonist antibody is MEDI6469, MEDI0562, or MEDI6383.

74. The method of claim 72, wherein the OX40 agonist antibody is a full-length IgG1 antibody.

75. The method of claim 39, wherein the OX40 binding agonist is a trimeric OX40L-Fc protein.

76. The method of claim 39, wherein the OX40 binding agonist is an OX40L agonist fragment comprising one or more extracellular domains of OX40L.

77. The method of claim 39, wherein the cancer is breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, prostate cancer, colorectal cancer, glioblastoma, neuroblastoma, or hepatocellular carcinoma.

78. The method of claim 39, wherein the individual has been diagnosed with cancer.

79. The method of claim 39, wherein the treatment results in a sustained response in the individual after cessation of the treatment.

80. The method of claim 39, wherein the OX40 binding agonist is administered before the PD-1 axis binding antagonist, simultaneous with the PD-1 axis binding antagonist, or after the PD-1 axis binding antagonist.

81. The method of claim 39, wherein the individual is a human.

84-87. -87. (canceled)

88. A kit comprising a medicament comprising a PD-1 axis binding antagonist and an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration of the medicament in combination with a composition comprising an OX40 binding agonist and an optional pharmaceutically acceptable carrier for treating or delaying progression of cancer in an individual.

89. A kit comprising a first medicament comprising a PD-1 axis binding antagonist and an optional pharmaceutically acceptable carrier, and a second medicament comprising an OX40 binding agonist and an optional pharmaceutically acceptable carrier.

90. The kit of claim 89, wherein the kit further comprises a package insert comprising instructions for administration of the first medicament and the second medicament for treating or delaying progression of cancer in an individual.

91. A kit comprising a medicament comprising an OX40 binding agonist and an optional pharmaceutically acceptable carrier, and a package insert comprising instructions for administration of the medicament in combination with a composition comprising a PD-1 axis binding antagonist and an optional pharmaceutically acceptable carrier for treating or delaying progression of cancer in an individual.