METHODS OF TREATING CANCER USING PD-1 AXIS BINDING ANTAGONISTS AND TIGIT INHIBITORS

• US 20150216970A1
• Filed: 07/16/2014
• Published: 08/06/2015
• Est. Priority Date: 07/16/2013
• Status: Active Grant

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: GROGAN, Jane, JOHNSTON, Robert J., IRVING, Bryan, HACKNEY, Jason, YU, Xin, EATON, Dan, BOWLES, Kristin, COMPS-AGRAR, Laetitia
• Granted Patent: US 9,873,740 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0331 Animal model for proliferative diseases
• CPC Class Codes: A01K 2267/0387 Animal model for diseases of the immune system
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• 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: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: C07K 14/70596 Molecules with a "CD"-designation not provided for elsewhere
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• 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 16/3015 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 16/3046 : Stomach, Intestines
• CPC Class Codes: C07K 16/3053 : Skin, nerves, brain
• CPC Class Codes: C07K 16/3061 : Blood cells
• CPC Class Codes: C07K 16/3069 : Reproductive system, e.g. ovaria, uterus, testes, prostate
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention describes combination treatment comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and/or activity and methods for use thereof, including methods of treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer or chronic infection.

Claims

1. A method for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and/or activity.

2. (canceled)

3. A method for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and/or activity.

5. The method of claim 3, wherein the immune related disease is associated with a T cell dysfunctional disorder.

8. The method of claim 5, wherein the T cell dysfunctional disorder is characterized by T cell exhaustion.

10. The method of claim 3, wherein the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity.

4. (canceled)

6-7. -7. (canceled)

9. (canceled)

11. (canceled)

12. A method of treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and/or activity.

26. The method of any one of claims 12, 14, and 22, wherein the agent that modulates CD226 expression and/or activity is selected from the group consisting of an agent that inhibits and/or blocks the interaction of CD226 with TIGIT, an antagonist of TIGIT expression and/or activity, an antagonist of PVR expression and/or activity, an agent that inhibits and/or blocks the interaction of TIGIT with PVR, an agent that inhibits and/or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and/or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVR, an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL2, an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL3, and combinations thereof.

28. The method of claim 26, wherein the agent that inhibits and/or blocks the interaction of CD226 with TIGIT is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, or an inhibitory polypeptide.

29. The method of claim 28, wherein the inhibitory antibody or antigen-binding fragment thereof is an anti-TIGIT antibody or antigen-binding fragment thereof.

31. The method of claim 26, wherein the agent that modulates CD226 expression and/or activity is an antagonist of TIGIT expression and/or activity.

32. The method of claim 31, wherein the antagonist of TIGIT expression and/or activity is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, or an inhibitory polypeptide.

33. The method of claim 32, wherein the inhibitory antibody or antigen-binding fragment thereof is an anti-TIGIT antibody or antigen-binding fragment thereof.

49. The method of any one of claims 12, 14, 22, and 42, further comprising administering at least one chemotherapeutic agent.

59. The method of claim 12, wherein the cancer has elevated levels of T cell infiltration.

71. The method of claim 29, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from the amino acid sequences (1) KSSQSLYYSGVKENLLA (SEQ ID NO:

1), ASIRFT (SEQ ID NO;

2), QQGINNPLT (SEQ ID NO;

3), GFTFSSFTMH (SEQ ID NO;

4), FIRSGSGIVFYADAVRG (SEQ ID NO;

5), and RPLGHNTFDS (SEQ ID NO;

6);

or

(2) RSSQSLVNSYGNTFLS (SEQ ID NO;

7), GISNRFS (SEQ ID NO;

8), LQGTHQPPT (SEQ ID NO;

9), GYSFTGHLMN (SEQ ID NO;

10), LIIPYNGGTSYNQKFKG (SEQ ID NO;

11), and GLRGFYAMDY (SEQ ID NO;

12).

72. The method of claim 71, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO:

13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLNNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGS GTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO;

14).

73. The method of claim 71, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHVVRQSPGKGLEWVVAFIRSGSGIVFYADAVRGRFTIS RDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO:

15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLT VDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO;

16).

74. The method of claim 71, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO:

13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGS GTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO;

14), and a heavy chain comprising the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTIS RDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO;

15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLT VDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO;

     16).

75. The method of claim 29, wherein the anti-TIGIT antibody or antigen-binding fragment thereof is selected from the group consisting of a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugate antibody, and an immunotoxin.

76. The method of claim 29, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR that is at least 90% identical to an HVR set forth in any one of (1) KSSQSLYYSGVKENLLA (SEQ ID NO:

1), ASIRFT (SEQ ID NO;

2), QQGINNPLT (SEQ ID NO;

3), GFTFSSFTMH (SEQ ID NO;

4), FIRSGSGIVFYADAVRG (SEQ ID NO;

5), and RPLGHNTFDS (SEQ ID NO;

6);

or (2) RSSQSLVNSYGNTFLS (SEQ ID NO;

7), GISNRFS (SEQ ID NO;

8), LQGTHQPPT (SEQ ID NO;

9), GYSFTGHLMN (SEQ ID NO;

10), LIIPYNGGTSYNQKFKG (SEQ ID NO;

11), and GLRGFYAMDY (SEQ ID NO;

12).

78. The method of any one of claims 12, 14, and 22, 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.

89. The method of claim 78, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

90. The method of claim 89, wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1.

93. The method of claim 89, wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody.

94. The method of claim 93, wherein the anti-PD-L1 antibody is selected from the group consisting of YW243.55.S70, MPDL3280A, MDX-1105, and MEDI4736.

95. The method of claim 93, wherein the anti-PD-L1 antibody comprises a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:

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

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

19); and

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

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

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

22).

96. The method of claim 95, wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:

23), EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK (SEQ ID NO;

40), or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO;

41), and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKWYSASFLYSGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO;

24).

100. The method of claim 12, wherein the cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, renal cell cancer, colorectal cancer, ovarian cancer, breast cancer, pancreatic cancer, gastric carcinoma, bladder cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer, thyroid cancer, sarcoma, prostate cancer, glioblastoma, cervical cancer, thymic carcinoma, leukemia, lymphomas, myelomas, mycoses fungoids, merkel cell cancer, and other hematologic malignancies.

13. (canceled)

14. A method for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and/or activity.

16. The method of claim 14, wherein the immune related disease is associated with a T cell dysfunctional disorder.

19. The method of claim 16, wherein the T cell dysfunctional disorder is characterized by T cell exhaustion.

21. The method of claim 14, wherein the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection and tumor immunity.

15. (canceled)

17-18. -18. (canceled)

20. (canceled)

22. A method of increasing, enhancing, or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and/or activity.

50. The method of claim 22 or 42, wherein the individual has cancer.

23-25. -25. (canceled)

27. (canceled)

30. (canceled)

34-41. -41. (canceled)

42. A method of increasing, enhancing, or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and/or activity and an agent that decreases or inhibits one or more additional immune co-inhibitory receptors.

43. The method of claim 42, wherein the one or more additional immune co-inhibitory receptor is selected from the group consisting of PD-1, CTLA-4, LAG3, TIM3, BTLA, VISTA, B7H4, and CD96.

44-48. -48. (canceled)

51-58. -58. (canceled)

60-70. -70. (canceled)

77. (canceled)

79-88. -88. (canceled)

91-92. -92. (canceled)

97-99. -99. (canceled)

101-120. -120. (canceled)

121. A kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates CD226 expression and/or activity to treat or delay progression of cancer in an individual.

159. The kit of claim 121 or 124, wherein the agent that modulates CD226 expression and/or activity is selected from the group consisting of an agent that inhibits and/or blocks the interaction of CD226 with TIGIT, an antagonist of TIGIT expression and/or activity, an antagonist of PVR expression and/or activity, an agent that inhibits and/or blocks the interaction of TIGIT with PVR, an agent that inhibits and/or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and/or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVR, an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL2, and an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL3.

161. The kit of claim 159, wherein the agent that inhibits and/or blocks the interaction of CD226 with TIGIT is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, or an inhibitory polypeptide.

162. The kit of claim 161, wherein the inhibitory antibody or antigen-binding fragment thereof is an anti-TIGIT antibody or antigen-binding fragment thereof.

167. The kit of claim 162, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from the amino acid sequences (1) KSSQSLYYSGVKENLLA (SEQ ID NO:

1), ASIRFT (SEQ ID NO;

2), QQGINNPLT (SEQ ID NO;

3), GFTFSSFTMH (SEQ ID NO;

4), FIRSGSGIVFYADAVRG (SEQ ID NO;

5), and RPLGHNTFDS (SEQ ID NO;

6);

or (2) RSSQSLVNSYGNTFLS (SEQ ID NO;

7), GISNRFS (SEQ ID NO;

8), LQGTHQPPT (SEQ ID NO;

9), GYSFTGHLMN (SEQ ID NO;

10), LIIPYNGGTSYNQKFKG (SEQ ID NO;

11), and GLRGFYAMDY (SEQ ID NO;

12).

168. The kit of claim 167, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO:

13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGS GTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO;

14), and a heavy chain comprising the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTIS RDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO;

15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLT VDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO;

     16)

122-123. -123. (canceled)

124. A kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates CD226 expression and/or activity to enhance immune function of an individual having cancer.

125-136. -136. (canceled)

137. A kit comprising an agent that decreases or inhibits TIGIT expression and/or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and/or activity in combination with an agent that decreases or inhibits one or more additional immune co-inhibitory receptors to treat or delay progression of cancer in an individual.

154. The kit of claim 137 or 140, wherein the agent that decreases or inhibits TIGIT expression and/or activity is selected from the group consisting of an antagonist of TIGIT expression and/or activity, an antagonist of PVR expression and/or activity, an agent that inhibits and/or blocks the interaction of TIGIT with PVR, an agent that inhibits and/or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and/or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVR, an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL2, and an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL3.

155. The kit of claim 154, wherein the antagonist of TIGIT expression and/or activity is an anti-TIGIT antibody or antigen-binding fragment thereof.

163. The kit of claim 155, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from the amino acid sequences (1) KSSQSLYYSGVKENLLA (SEQ ID NO:

1), ASIRFT (SEQ ID NO;

2), QQGINNPLT (SEQ ID NO;

3), GFTFSSFTMH (SEQ ID NO;

4), FIRSGSGIVFYADAVRG (SEQ ID NO;

5), and RPLGHNTFDS (SEQ ID NO;

6);

or (2) RSSQSLVNSYGNTFLS (SEQ ID NO;

7), GISNRFS (SEQ ID NO;

8), LQGTHQPPT (SEQ ID NO;

9), GYSFTGHLMN (SEQ ID NO;

10), LIIPYNGGTSYNQKFKG (SEQ ID NO;

11), and GLRGFYAMDY (SEQ ID NO;

12).

166. The kit of claim 163, wherein the anti-TIGIT antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO:

13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGSGS GTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO;

14), and a heavy chain comprising the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFTIS RDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO;

15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKATLT VDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO;

     16).

138-139. -139. (canceled)

140. A kit comprising an agent that decreases or inhibits TIGIT expression and/or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and/or activity in combination with an agent that decreases or inhibits one or more additional immune co-inhibitory receptors to enhance immune function of an individual having cancer.

141-153. -153. (canceled)

156-158. -158. (canceled)

160. (canceled)

164-165. -165. (canceled)