METHODS OF TREATING HER2-POSITIVE CANCERS USING PD-1 AXIS BINDING ANTAGONISTS AND ANTI-HER2 ANTIBODIES

• US 20170008971A1
• Filed: 06/16/2016
• Published: 01/12/2017
• Est. Priority Date: 12/17/2013
• Status: Abandoned Application

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: EBENS, Allen, IRVING, Bryan, JUNTTILA, Teemu T., LI, Ji, DENNIS, Mark S.
• Application Number:
  US15/184,966
• Publication Number:
  US 20170008971A1
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/282 Platinum compounds
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 39/395 Antibodies agglutinins A61K38/36 ; as drug carriers A61K47/50; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• 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: A61K 47/643 Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 16/2818 against CD28 or CD152
• CPC Class Codes: C07K 16/2827 against B7 molecules, e.g. CD80, CD86
• CPC Class Codes: C07K 16/30 from tumour cells
• CPC Class Codes: C07K 16/3015 Breast
• CPC Class Codes: C07K 16/3023 : Lung
• CPC Class Codes: C07K 16/303 : Liver or Pancreas
• CPC Class Codes: C07K 16/3038 : Kidney, bladder
• CPC Class Codes: C07K 16/3069 : Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 16/32 : against translation products of oncogenes
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/524 : CH2 domain
• CPC Class Codes: C07K 2317/526 : CH3 domain
• CPC Class Codes: C07K 2317/73 : Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The invention provides compositions and methods for treating HER2-postitive cancers. The method comprising administering a PD-1 axis binding antagonist and an antibody that targets HER2.

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 anti-HER2 antibody.

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 PD-L1 binding antagonist and a PD-L2 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 4, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1.

6. The method of claim 4, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2.

7. The method of claim 4, wherein the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2.

8. The method of claim 4, wherein the PD-1 binding antagonist is an antibody.

9. The method of claim 4, wherein the PD-1 binding antagonist is selected from the group consisting of MDX-1106 (nivolumab), MK-3475 (lambrolizumab), CT-011 (pidilizumab), and AMP-224.

10. The method of claim 2, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

11. The method of claim 10, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1.

12. The method of claim 10, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1.

13. The method of claim 10, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1.

14. The method of claim 11, wherein the PD-L1 binding antagonist is an antibody.

15. The method of claim 10, wherein the PD-L1 binding antagonist is selected from the group consisting of:

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

16. The method of claim 14, wherein the antibody comprises a heavy chain comprising HVR-H1 sequence of SEQ ID NO:

19, HVR-H2 sequence of SEQ ID NO;

20, and HVR-H3 sequence of SEQ ID NO;

21; and

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

22, HVR-L2 sequence of SEQ ID NO;

23, and HVR-L3 sequence of SEQ ID NO;

24.

17. The method of claim 14, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

25 or 26 and a light chain variable region comprising the amino acid sequence of SEQ ID NO;

4.

18. The method of claim 2, wherein the PD-1 axis binding antagonist is a PD-L2 binding antagonist.

19. The method of claim 18, wherein the PD-L2 binding antagonist is an antibody.

20. The method of claim 18, wherein the PD-L2 binding antagonist is an immunoadhesin.

21. The method of claim 1, wherein the anti-HER2 antibody is trastuzumab or pertuzumab.

22. The method of claim 1, wherein the anti-HER2 antibody comprises a heavy chain variable region comprising HVR-H1 sequence of SEQ ID NO:

38, HVR-H2 sequence of SEQ ID NO;

50, and HVR-H3 sequence of SEQ ID NO;

40; and

/or a light chain variable region comprising HVR-L1 sequence of SEQ ID NO;

41, HVR-L2 sequence of SEQ ID NO;

42, and HVR-L3 sequence of SEQ ID NO;

43.

23. The method of claim 1, wherein the anti-HER2 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:

34 and/or a light chain variable region comprising the amino acid sequence of SEQ ID NO;

35.

24. The method of claim 1, wherein the anti-HER2 antibody is a multispecific antibody.

25. The method of claim 1, wherein the anti-HER2 antibody is a bispecific antibody.

26. The method of claim 25, wherein the bispecific antibody comprises a first antigen binding domain that binds to HER2, and a second antigen binding domain that binds to CD3.

27. The method of claim 26, wherein the first antigen binding domain comprises a heavy chain variable region (V_HHER2) and a light chain variable region (V_LHER2), and the second antigen binding domain comprises a heavy chain variable region (V_HCD3) and a light chain variable region (V_LCD3).

28. The method of claim 27, wherein the first antigen binding domain comprises a heavy chain variable region (V_HHER2) comprising HVR-H1 sequence of SEQ ID NO:

38, HVR-H2 sequence of SEQ ID NO;

50, and HVR-H3 sequence of SEQ ID NO;

40; and

/or a light chain variable region (V_LHER2) comprising HVR-L1 sequence of SEQ ID NO;

41, HVR-L2 sequence of SEQ ID NO;

42, and HVR-L3 sequence of SEQ ID NO;

43.

29. The method of claim 28, wherein the heavy chain variable region (V_HHER2) comprises the amino acid sequence of SEQ ID NO:

34 and/or a light chain variable region (V_LHER2) comprises the amino acid sequence of SEQ ID NO;

35.

30. The method of claim 26, wherein the second antigen binding domain binds to a human CD3 polypeptide.

31. The method of claim 30, wherein the CD3 polypeptide is a human CD3c polypeptide or a human CD3γ

polypeptide.

32. The method of claim 31, wherein the second antigen binding domain binds to a human CD3c polypeptide or a human CD3γ

polypeptide in a native T-cell receptor (TCR) complex in association with other TCR subunits.

33. The method of claim 25, wherein the bispecific antibody is a single-chain bispecific antibody comprising the first antigen binding domain and the second antigen binding domain.

34. The method of claim 33, wherein the single-chain bispecific antibody comprises variable regions, as arranged from N-terminus to C-terminus, selected from the group consisting of (1) V_HHER2-V_LHER2-V_HCD3-V_LCD3, (2) V_HCD3-V_LCD3-V_HHER2-V_LHER2, (3) V_HCD3-V_LCD3-V_LHER2-V_HHER2, (4) V_HHER2-V_LHER2-V_LCD3-V_HCD3, (5) V_LHER2-V_HHER2-V_HCD3-V_LCD3, or (6) V_LCD3-V_HCD3-V_HHER2-V_LHER2.

35. The method of claim 25, wherein (a) the first antigen binding domain comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH1 (CH1₁) domain, a first CH2 (CH2₁) domain, a first CH3 (CH3₁) domain;

and (b) the second antigen binding domain comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a second CH1 (CH1₂) domain, second CH2 (CH2₂) domain, and a second CH3 (CH3₂) domain.

36. The method of claim 35, wherein at least one of the one or more heavy chain constant domains of the first antigen binding domain is paired with another heavy chain constant domain of the second antigen binding domain.

37. The method of claim 36, wherein the CH3₁ and CH3₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3₁ domain is positionable in the cavity or protuberance, respectively, in the CH3₂ domain.

38. The method of claim 37, wherein the CH3₁ and CH3₂ domains meet at an interface between said protuberance and cavity.

39. The method of claim 35, wherein the CH2₁ and CH2₂ domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2₁ domain is positionable in the cavity or protuberance, respectively, in the CH2₂ domain.

40. The method of claim 39, wherein the CH2₁ and CH2₂ domains meet at an interface between said protuberance and cavity.

41. The method of claim 1, wherein the anti-HER2 antibody comprises an aglycosylation site mutation.

42. The method of claim 41, wherein the aglycosylation site mutation is a substitution mutation.

43. The method of claim 42, wherein the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).

44. The method of claim 43, wherein the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, and D265A.

45. The method of claim 43, wherein the substitution mutation is a D265A mutation and an N297G mutation.

46. The method of claim 41, wherein the aglycosylation site mutation reduces effector function of the anti-HER2 antibody.

47. The method of claim 1, wherein the cancer is a HER2-positive cancer.

48. The method of claim 47, wherein the cancer is breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, or prostate cancer.

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

50. The method of claim 49, wherein cancer cells in the individual express PD-L1.

51. The method of claim 49, wherein the individual has cancer that is resistant to a HER2 targeted therapy.

52. The method of claim 49, wherein the individual is refractory to a HER2 targeted therapy.

53. The method of claim 51, wherein the HER2 targeted therapy is a treatment with an anti-HER2 antibody or an inhibitor of the HER2 pathway.

54. The method of claim 53, wherein the HER2 targeted therapy is a treatment with trastuzumab, pertuzumab, ado-trastuzumab emtansine, or lapatinib.

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

56. The method of claim 1, wherein the anti-HER2 antibody 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.

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

57. 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 anti-HER2 antibody.

58. The method of claim 57, 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 anti-HER2 antibody.

59. The method of claim 57, wherein the number of CD8 T cells is elevated relative to prior to administration of the combination.

60. The method of claim 59, wherein the CD8 T cell is an antigen-specific CD8 T cell.

61. The method of claim 57, wherein Treg function is suppressed relative to prior to the administration of the combination.

62. The method of claim 57, wherein T cell exhaustion is decreased relative to prior to the administration of the combination.

63. The method of claim 57, wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.

64. The method of claim 63, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist.

70. The method of claim 64, wherein the PD-1 binding antagonist is selected from the group consisting of MDX-1106 (nivolumab), MK-3475 (lambrolizumab), CT-011 (pidilizumab), and AMP-224.

71. The method of claim 63, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

75. The method of claim 71, wherein the PD-L1 binding antagonist is an antibody.

76. The method of claim 71, wherein the PD-L1 binding antagonist is selected from the group consisting of:

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

79. The method of claim 63, wherein the PD-1 axis binding antagonist is a PD-L2 binding antagonist.

82. The method of claim 57, wherein the anti-HER2 antibody is trastuzumab or pertuzumab.

85. The method of claim 57, wherein the anti-HER2 antibody is a multispecific antibody.

86. The method of claim 57, wherein the anti-HER2 antibody is a bispecific antibody.

91. The method of claim 86, wherein the bispecific antibody comprises a first antigen binding domain that binds to HER2, and a second antigen binding domain that binds to CD3, and wherein the second antigen binding domain binds to a human CD3 polypeptide.

102. The method of claim 57, wherein the anti-HER2 antibody comprises an aglycosylation site mutation.

103. The method of claim 102, wherein the aglycosylation site mutation is a substitution mutation.

104. The method of claim 103, wherein the substitution mutation is at amino acid residue N297, L234, L235, and/or D265 (EU numbering).

109. The method of claim 57, wherein the cancer is breast cancer, lung cancer, ovarian cancer, gastric cancer, bladder cancer, pancreatic cancer, endometrial cancer, colon cancer, kidney cancer, esophageal cancer, or prostate cancer.

111. The method of claim 57, wherein the individual has cancer that is resistant to a HER2 targeted therapy.

112. The method of claim 57, wherein the individual is refractory to a HER2 targeted therapy.

113. The method of claim 111, wherein the HER2 targeted therapy is a treatment with an anti-HER2 antibody or an inhibitor of the HER2 pathway.

114. The method of claim 113, wherein the HER2 targeted therapy is a treatment with trastuzumab, pertuzumab, ado-trastuzumab emtansine, or lapatinib.

65-69. -69. (canceled)

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121. 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 anti-HER2 antibody and an optional pharmaceutically acceptable carrier for treating or delaying progression of cancer in an individual.

122. (canceled)

123. (canceled)

124. A kit comprising a medicament comprising an anti-HER2 antibody 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.