Methods for treating cancer using activatable Anti-ctla4 antibody in combination with pembrolizumab

HK40138712APending Publication Date: 2026-10-09ADAGENE PTE LTD
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Patent Information

Application Number
HK62026127027
Authority / Receiving Office
HK · HK
Patent Type
Applications
Current Assignee / Owner
Priority Date
2023-10-31
Filing Date
2026-08-04
Publication Date
2026-10-09
Estimated Expiration
2044-04-11

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Abstract

The present application provides compositions and methods for treating cancers, including advanced-stage metastatic cancer, using an activatable anti-CTLA4 antibody in combination with pembrolizumab.
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Description

This application provides compositions and methods for treating cancer (including advanced metastatic cancer) using a combination of an activating anti-CTLA4 antibody and pembrolizumab. Abstract

Claims

Attorney Docket No.: 69540-20027.40 CLAIMS What is claimed is:

1. A method of treating a cancer in a subject, comprising administering to the subject: (a) an effective amount of an activatable antibody, wherein the activatable antibody comprises an HVR-H1 comprising an amino acid sequence according to a formula YSISSGYHWSWI (SEQ ID NO: 23), an HVR-H2 comprising an amino acid sequence according to a formula LARIDWDDDKYYSTSLKSRL (SEQ ID NO: 35), an HVR-H3 comprising an amino acid sequence according to a formula ARSYVYFDY (SEQ ID NO: 45), an HVR-L1 comprising an amino acid sequence according to the formula RASQSVRGRFLA (SEQ ID NO: 58), an HVR-L2 comprises an amino acid sequence according to a formula DASNRATGI (SEQ ID NO: 66), and an HVR-L3 comprising an amino acid sequence according to a formula YCQQSSSWPPT (SEQ ID NO: 75), and wherein the activatable antibody further comprises: a polypeptide covalently attached to the N-terminus of the light chain of the anti- CTLA4 antibody, said polypeptide comprising, from N-terminus to C-terminus, a masking moiety (MM) and a cleavable moiety (CM), wherein the MM comprises an amino acid sequence EVGSYPNPSSDCVPYYYACAY (SEQ ID NO:192), and the cleavable moiety comprises an amino acid sequence SGRSAGGGGTPLGLAGSGGS (SEQ ID NO:221); and (b) an effective amount of pembrolizumab, wherein the activatable antibody is administered at a dose of from about 6 mg / kg to about 30 mg / kg once every 3 to 6 weeks , and wherein the pembrolizumab is administered at a dose of from about 100 mg to about 300 mg once every three weeks or about 200 mg to about 600 mg every six weeks.

2. The method of claim 1, wherein the activatable antibody is administered at a dose of from about 6 mg / kg to about 10 mg / kg once every 3 to 6 weeks . 92 sf-5866843.2Attorney Docket No.: 69540-20027.40 3. The method of claim 1, wherein the activatable antibody is administered at a dose of from about 10 mg / kg to about 20 mg / kg once every 3 to 6 weeks.

4. The method of claim 1, wherein the activatable antibody is administered at a dose of from about 20 mg / kg to about 30 mg / kg once every 3 to 6 weeks.

5. The method of claim 1, wherein the activatable antibody is administered at a dose of 10 mg / kg once every 3 weeks.

6. The method of claim 1, wherein the activatable antibody is administered at a dose of 20 mg / kg once every 3 weeks.

7. The method of claim 1, wherein the activatable antibody is administered at a dose of 20 mg / kg once every 6 weeks.

8. The method of claim 1, wherein the activatable antibody is administered at a dose of 30 mg / kg once every 6 weeks.

9. The method of claim 1, wherein the activatable anti-CTLA4 antibody is administered at a dose of about 6 mg / kg once every 3 to 6 weeks.

10. The method of any one of claim 1-6, wherein the pembrolizumab is administered at a dose of about 200 mg once every 3 weeks.

11. The method of claim 1, 7, or 8, wherein the pembrolizumab is administered at a dose of about 400 mg once every six weeks.

12. The method of any one of claims 1-11, wherein the cancer is resistant or refractory to a prior therapy, wherein the prior therapy is an inhibitor of CTLA4, PD-1, or a PD-1 ligand.

13. The method of claim 12, wherein the prior therapy is ipilimumab.

14. The method of any one of claims 1-13, wherein the cancer is colorectal cancer.

15. The method of claim 14, wherein the CRC is microsatellite stable (MSS) CRC. 93 sf-5866843.2Attorney Docket No.: 69540-20027.40 16. The method of claim 15, wherein the MSS CRC has not metastasized to the liver.

17. The method of claim 15, wherein the MSS CRC has not metastasized to the peritoneum.

18. The method of claim 15, wherein the MSS CRC has not metastasized to the liver or to the peritoneum.

19. The method of any one of claims 1-13, wherein the cancer is endometrium cancer.

20. The method of any one of claims 1-13, wherein the cancer is neuroendocrine cancer, cecum adenocarcinoma, pancreatic cancer, or ovarian cancer.

21. The method of any one of claims 1-15, 19, or 20 wherein the cancer is an advanced stage metastatic cancer.

22. The method of claim 21, wherein the cancer has metastasized to the lung or the liver.

23. The method of any one of claims 1-22, wherein the activatable anti-CTLA4 antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 87, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 100 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:

100.

24. The method of claim 23, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 87 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

100.

25. The method of claim 24, wherein the activatable anti-CTLA4 antibody comprises a full heavy chain region of SEQ ID NO:320 or SEQ ID NO:

321.

26. The method of claim 25, wherein the activatable anti-CTLA4 antibody comprises a full light chain region of SEQ ID NO:322 or SEQ ID NO:

323. 94 sf-5866843.2Attorney Docket No.: 69540-20027.40 27. The method of any one of claims 1-26, wherein the subject is human.

28. The method of any one of claims 1-27, wherein the activatable anti-CTLA4 antibody and the pembrolizumab are both administered on day 1 of the 3 to 6 week dosing schedule.

29. A method of treating a cancer in a subject, comprising administering to the subject an effective amount of an activatable antibody in combination with pembrolizumab, wherein the activatable antibody comprises an HVR-H1 comprising an amino acid sequence according to a formula YSISSGYHWSWI (SEQ ID NO: 23), an HVR-H2 comprising an amino acid sequence according to a formula LARIDWDDDKYYSTSLKSRL (SEQ ID NO: 35), an HVR-H3 comprising an amino acid sequence according to a formula ARSYVYFDY (SEQ ID NO: 45), an HVR-L1 comprising an amino acid sequence according to the formula RASQSVRGRFLA (SEQ ID NO: 58), an HVR-L2 comprises an amino acid sequence according to a formula DASNRATGI (SEQ ID NO: 66), and an HVR-L3 comprising an amino acid sequence according to a formula YCQQSSSWPPT (SEQ ID NO: 75), and wherein the activatable antibody further comprises: a polypeptide covalently attached to the N-terminus of the light chain of the anti- CTLA4 antibody, said polypeptide comprising, from N-terminus to C-terminus, a masking moiety (MM) and a cleavable moiety (CM), wherein the MM comprises an amino acid sequence EVGSYPNPSSDCVPYYYACAY (SEQ ID NO:192), and the cleavable moiety comprises an amino acid sequence SGRSAGGGGTPLGLAGSGGS (SEQ ID NO:221), wherein the activatable antibody is administered as one to three loading doses of from about 20 mg / kg to about 50 mg / kg followed by maintenance doses of from about 5 mg / kg to about 20 mg / kg once every three weeks or once every six weeks.

30. The method of claim 29, wherein the activatable antibody is administered as one to three loading doses of from about 20 mg / kg to about 40 mg / kg followed by maintenance doses of from about 6 mg / kg to about 20 mg / kg once every three weeks or once every six weeks.

31. The method of claim 29, wherein the activatable antibody is administered as one to three loading doses of from about 20 mg / kg to about 40 mg / kg followed by maintenance doses of from about 6 mg / kg to about 10 mg / kg once every three weeks or once every six weeks. 95 sf-5866843.2Attorney Docket No.: 69540-20027.40 32. The method of claim 29, wherein the activatable antibody is administered as one to three loading doses of from about 20 mg / kg to about 40 mg / kg followed by maintenance doses of from about 10 mg / kg to about 20 mg / kg once every three weeks or once every six weeks.

33. The method of claim 29, wherein the activatable antibody is administered as one loading dose of from about 20 mg / kg to about 40 mg / kg followed by maintenance doses of from about 6 mg / kg to about 10 mg / kg once every three weeks or once every six weeks.

34. The method of any one of claim 29-33, wherein the loading doses are 20 mg / kg.

35. The method of any one of claim 29-33, wherein the loading doses are 30 mg / kg.

36. The method of any one of claim 29-33, wherein the loading doses are 40 mg / kg.

37. The method of any one of claims 29-36, wherein a single loading dose is administered to the subject prior to administration of the maintenance doses.

38. The method of any one of claims 29-37, wherein two loading doses are administered to the subject prior to administration of the maintenance doses.

39. The method of any one of claims 29-37, wherein three loading doses are administered to the subject prior to administration of the maintenance doses.

40. The method of any one of claims 29-39, wherein the maintenance doses are administered at 10 mg / kg.

41. The method of claim 40, wherein the maintenance doses are administered once every three weeks.

42. The method of claim 40, wherein the maintenance doses are administered once every six weeks.

43. The method of any one of claims 29-39, wherein the maintenance doses are administered at 20 mg / kg. 96 sf-5866843.2Attorney Docket No.: 69540-20027.40 44. The method of claim 43, wherein the maintenance doses are administered once every three weeks.

45. The method of claim 43, wherein the maintenance doses are administered once every six weeks.

46. The method of any one of claims 29-45, wherein the first maintenance dose is administered three weeks after administration of the last loading dose.

47. The method of any one of claims 29-46, wherein the pembrolizumab is administered at a dose from about 100 mg to about 300 mg once every three weeks or about 200 mg to about 600 mg once every six weeks.

48. The method of any one of claims 29-47, wherein the cancer is resistant or refractory to a prior therapy, wherein the prior therapy is an inhibitor of CTLA4, PD-1, or a PD-1 ligand.

49. The method of claim 48, wherein the prior therapy is ipilimumab.

50. The method of any one of claims 29-47, wherein the cancer is colorectal cancer (CRC).

51. The method of claim 50, wherein the CRC is microsatellite stable (MSS) CRC.

52. The method of any one of claims 29-47, wherein the cancer is squamous cell carcinoma.

53. The method of any one of claims 29-47, wherein the cancer is anal squamous cell carcinoma or penile squamous cell carcinoma.

54. The method of any one of claims 29-47, wherein the cancer is pancreatic cancer.

55. The method of claim 54, wherein the cancer is pancreatic ductal adenocarcinoma (PDAC).

56. The method of any one of claims 29-47, wherein the cancer is ovarian cancer.

57. The method of any one of claims 29-47, wherein the cancer is NSCLC.

58. The method of any one of claims 29-47, wherein the cancer is hepatocellular carcinoma. 97 sf-5866843.2Attorney Docket No.: 69540-20027.40 59. The method of any one of claims 29-58, wherein the cancer is an advanced stage metastatic cancer.

60. The method of claim 59, wherein the cancer has metastasized to the lung or the liver.

61. The method of any one of claims 29-60, wherein the activatable antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 87, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 100 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:

100.

62. The method of claim 61, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 87 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

100.

63. The method of claim 62, wherein the activatable antibody comprises a full heavy chain region of SEQ ID NO:320 or SEQ ID NO:

321.

64. The method of claim 62, wherein the activatable antibody comprises a full light chain region of SEQ ID NO:322 or SEQ ID NO:

323.

65. The method of any one of claims 29-64, wherein the subject is human.

66. A method of treating a cancer in a subject, comprising administering to the subject an effective amount of an activatable antibody in combination with pembrolizumab, wherein the activatable antibody comprises an HVR-H1 comprising an amino acid sequence according to a formula YSISSGYHWSWI (SEQ ID NO: 23), an HVR-H2 comprising an amino acid sequence according to a formula LARIDWDDDKYYSTSLKSRL (SEQ ID NO: 35), an HVR-H3 comprising an amino acid sequence according to a formula ARSYVYFDY (SEQ ID NO: 45), an HVR-L1 comprising an amino acid sequence according to the formula RASQSVRGRFLA (SEQ ID NO: 58), an HVR-L2 comprises an amino acid sequence according to a formula 98 sf-5866843.2Attorney Docket No.: 69540-20027.40 DASNRATGI (SEQ ID NO: 66), and an HVR-L3 comprising an amino acid sequence according to a formula YCQQSSSWPPT (SEQ ID NO: 75), and wherein the activatable antibody further comprises: a polypeptide covalently attached to the N-terminus of the light chain of the anti- CTLA4 antibody, said polypeptide comprising, from N-terminus to C-terminus, a masking moiety (MM) and a cleavable moiety (CM), wherein the MM comprises an amino acid sequence EVGSYPNPSSDCVPYYYACAY (SEQ ID NO:192), and the cleavable moiety comprises an amino acid sequence SGRSAGGGGTPLGLAGSGGS (SEQ ID NO:221), wherein the activatable antibody is administered at a dose that provides a steady-state plasma concentration of the cleaved antibody of above the EC50 of the cleaved antibody.

67. A method of treating a cancer in a subject, comprising administering to the subject an effective amount of an activatable antibody in combination with pembrolizumab, wherein the activatable antibody comprises an HVR-H1 comprising an amino acid sequence according to a formula YSISSGYHWSWI (SEQ ID NO: 23), an HVR-H2 comprising an amino acid sequence according to a formula LARIDWDDDKYYSTSLKSRL (SEQ ID NO: 35), an HVR-H3 comprising an amino acid sequence according to a formula ARSYVYFDY (SEQ ID NO: 45), an HVR-L1 comprising an amino acid sequence according to the formula RASQSVRGRFLA (SEQ ID NO: 58), an HVR-L2 comprises an amino acid sequence according to a formula DASNRATGI (SEQ ID NO: 66), and an HVR-L3 comprising an amino acid sequence according to a formula YCQQSSSWPPT (SEQ ID NO: 75), and wherein the activatable antibody further comprises: a polypeptide covalently attached to the N-terminus of the light chain of the anti- CTLA4 antibody, said polypeptide comprising, from N-terminus to C-terminus, a masking moiety (MM) and a cleavable moiety (CM), wherein the MM comprises an amino acid sequence EVGSYPNPSSDCVPYYYACAY (SEQ ID NO:192), and the cleavable moiety comprises an amino acid sequence SGRSAGGGGTPLGLAGSGGS (SEQ ID NO:221), wherein the activatable antibody is administered at a dose that provides a steady-state plasma concentration of the cleaved antibody of above the EC90 of the cleaved antibody.

68. A method of treating a cancer in a subject, comprising administering to the subject an effective amount of an activatable antibody in combination with pembrolizumab, wherein the 99 sf-5866843.2Attorney Docket No.: 69540-20027.40 activatable antibody comprises an HVR-H1 comprising an amino acid sequence according to a formula YSISSGYHWSWI (SEQ ID NO: 23), an HVR-H2 comprising an amino acid sequence according to a formula LARIDWDDDKYYSTSLKSRL (SEQ ID NO: 35), an HVR-H3 comprising an amino acid sequence according to a formula ARSYVYFDY (SEQ ID NO: 45), an HVR-L1 comprising an amino acid sequence according to the formula RASQSVRGRFLA (SEQ ID NO: 58), an HVR-L2 comprises an amino acid sequence according to a formula DASNRATGI (SEQ ID NO: 66), and an HVR-L3 comprising an amino acid sequence according to a formula YCQQSSSWPPT (SEQ ID NO: 75), and wherein the activatable antibody further comprises: a polypeptide covalently attached to the N-terminus of the light chain of the anti- CTLA4 antibody, said polypeptide comprising, from N-terminus to C-terminus, a masking moiety (MM) and a cleavable moiety (CM), wherein the MM comprises an amino acid sequence EVGSYPNPSSDCVPYYYACAY (SEQ ID NO:192), and the cleavable moiety comprises an amino acid sequence SGRSAGGGGTPLGLAGSGGS (SEQ ID NO:221), wherein the activatable antibody is administered at a dose that provides a steady-state plasma concentration of the cleaved antibody of from about 100 nM to about 200 nM.

69. The method of claim 68, wherein the activatable antibody is administered at a dose that provides a steady-state plasma concentration of the cleaved antibody of from about 100 nM to about 175 nM.

70. The method of claim 68, wherein the activatable antibody is administered at a dose that provides a steady-state plasma concentration of the cleaved antibody of from about 100 nM to about 150 nM.

71. The method of claim 68, wherein the activatable antibody is administered at a dose that provides a steady-state plasma concentration of the cleaved antibody of from about 150 nM to about 200 nM.

72. The method of any one of claims 66-71, wherein the steady-state plasma concentration of the cleaved antibody is measured at the trough level of the anti-CTLA4 antibody. 100 sf-5866843.2Attorney Docket No.: 69540-20027.40 73. The method of any one of claims 66-72, wherein the activatable antibody is administered as a single loading dose or two loading doses followed by maintenance doses, wherein the amount of the loading dose is higher than the amount of the maintenance doses.

74. The method of claim 73, wherein a single loading dose of the activatable antibody is administered to the subject prior to the administration of the maintenance doses.

75. The method of claim 74, wherein the loading dose is about 20 mg / kg.

76. The method of claim 74, wherein the loading dose is about 30 mg / kg.

77. The method of claim 74, wherein the loading dose is about 40 mg / kg.

78. The method of claim 74, wherein the loading dose is about 50 mg / kg.

79. The method of claim 73, wherein two loading dose of the activatable antibody are administered to the subject prior to the administration of the maintenance doses.

80. The method of claim 79, wherein the loading doses are about 20 mg / kg.

81. The method of claim 79, wherein the loading doses are about 30 mg / kg.

82. The method of claim 79, wherein the loading doses are about 40 mg / kg.

83. The method of claim 79, wherein the loading doses are about 50 mg / kg.

84. The method of any one of claims 73-83, wherein the maintenance doses are about 10 mg / kg.

85. The method of any one of claims 73-84, wherein the activatable antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 87 or a variant 101 sf-5866843.2Attorney Docket No.: 69540-20027.40 thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO: 87, and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 100 or a variant thereof having at least about 90% sequence identity to the amino acid sequence of SEQ ID NO:

100.

86. The method of claim 85, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 87 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

100.

87. The method of claim 85, wherein the activatable antibody comprises a full heavy chain region of SEQ ID NO:320 or SEQ ID NO:

321.

88. The method of claim 86 wherein the activatable antibody comprises a full light chain region of SEQ ID NO:322 or SEQ ID NO:

323.

89. The method of any one of claims 73-88, wherein the subject is human. 102 sf-5866843.2