Methods of treating cancer using pd-1 axis binding antagonists and tigit inhibitors

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.

1 - 166 . (canceled) 
     
     
         167 . A method of treating or delaying progression of cancer in an individual, the method comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that inhibits and/or blocks the interaction of CD226 with TIGIT, wherein the agent is an inhibitory antibody or antigen-binding fragment thereof, wherein the inhibitory antibody or antigen-binding fragment thereof is an anti-CD226 antibody or antigen-binding fragment thereof. 
     
     
         168 . The method of  claim 167 , wherein the anti-CD226 antibody or antigen-binding fragment thereof inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization. 
     
     
         169 . The method of  claim 168 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates CD226 expression and/or activity. 
     
     
         170 . The method of  claim 168 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates the interaction of CD226 with PVR. 
     
     
         171 . The method of  claim 168 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates the intracellular signaling mediated by CD226 binding to PVR. 
     
     
         172 . The method of  claim 167 , further comprising administering to the individual at least one chemotherapeutic agent. 
     
     
         173 . The method of  claim 167 , wherein the cancer has elevated levels of T cell infiltration. 
     
     
         174 . The method of  claim 167 , 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. 
     
     
         175 . The method of  claim 174 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist. 
     
     
         176 . The method of  claim 175 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1. 
     
     
         177 . The method of  claim 175 , wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody. 
     
     
         178 . The method of  claim 177 , wherein the anti-PD-L1 antibody is selected from the group consisting of MPDL3280A, MDX-1105, and MED14736. 
     
     
         179 . The method of  claim 177 , 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). 
     
     
         180 . The method of  claim 179 , wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:23), EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK (SEQ ID NO:40), or EVWLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:41), and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24). 
     
     
         181 . The method of  claim 167 , wherein the cancer is selected from the group consisting of a non-small cell lung cancer, a small cell lung cancer, a renal cell cancer, a colorectal cancer, an ovarian cancer, a breast cancer, a pancreatic cancer, a gastric carcinoma, a bladder cancer, an esophageal cancer, a mesothelioma, a melanoma, a head and neck cancer, a thyroid cancer, a sarcoma, a prostate cancer, a glioblastoma, a cervical cancer, a thymic carcinoma, a leukemia, a lymphoma, a myeloma, a mycosis fungoides, a Merkel cell cancer, and a hematologic malignancy. 
     
     
         182 . A method of increasing, enhancing, or stimulating an immune response or function in an individual, the method comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that inhibits and/or blocks the interaction of CD226 with TIGIT, wherein the agent is an inhibitory antibody or antigen-binding fragment thereof, wherein the inhibitory antibody or antigen-binding fragment thereof is an anti-CD226 antibody or antigen-binding fragment thereof. 
     
     
         183 . The method of  claim 182 , wherein the anti-CD226 antibody or antigen-binding fragment thereof inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization. 
     
     
         184 . The method of  claim 183 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates CD226 expression and/or activity. 
     
     
         185 . The method of  claim 183 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates the interaction of CD226 with PVR. 
     
     
         186 . The method of  claim 183 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates the intracellular signaling mediated by CD226 binding to PVR. 
     
     
         187 . The method of  claim 182 , further comprising administering to the individual at least one chemotherapeutic agent. 
     
     
         188 . The method of  claim 182 , wherein the individual has a cancer. 
     
     
         189 . The method of  claim 188 , wherein the cancer is selected from the group consisting of a non-small cell lung cancer, a small cell lung cancer, a renal cell cancer, a colorectal cancer, an ovarian cancer, a breast cancer, a pancreatic cancer, a gastric carcinoma, a bladder cancer, an esophageal cancer, a mesothelioma, a melanoma, a head and neck cancer, a thyroid cancer, a sarcoma, a prostate cancer, a glioblastoma, a cervical cancer, a thymic carcinoma, a leukemia, a lymphoma, a myeloma, a mycosis fungoides, a Merkel cell cancer, and a hematologic malignancy. 
     
     
         190 . The method of  claim 182 , 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. 
     
     
         191 . The method of  claim 190 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist. 
     
     
         192 . The method of  claim 191 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1. 
     
     
         193 . The method of  claim 191 , wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody. 
     
     
         194 . The method of  claim 193 , wherein the anti-PD-L1 antibody is selected from the group consisting of MPDL3280A, MDX-1105, and MED14736. 
     
     
         195 . The method of  claim 193 , 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). 
     
     
         196 . The method of  claim 195 , wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA (SEQ ID NO:23), EVWLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTK (SEQ ID NO:40), or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI SADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSS (SEQ ID NO:41), and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24). 
     
     
         197 . A method for treating or delaying progression of a viral infection in an individual, the method comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that inhibits and/or blocks the interaction of CD226 with TIGIT, wherein the agent is an inhibitory antibody or antigen-binding fragment thereof, wherein the inhibitory antibody or antigen-binding fragment thereof is an anti-CD226 antibody or antigen-binding fragment thereof. 
     
     
         198 . The method of  claim 197 , wherein the anti-CD226 antibody or antigen-binding fragment thereof inhibits and/or blocks the ability of TIGIT to disrupt CD226 homodimerization. 
     
     
         199 . The method of  claim 198 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates CD226 expression and/or activity. 
     
     
         200 . The method of  claim 198 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates the interaction of CD226 with PVR. 
     
     
         201 . The method of  claim 198 , wherein inhibiting and/or blocking the ability of TIGIT to disrupt CD226 homodimerization increases and/or stimulates the intracellular signaling mediated by CD226 binding to PVR. 
     
     
         202 . The method of  claim 197 , further comprising administering to the individual at least one chemotherapeutic agent. 
     
     
         203 . The method of  claim 197 , 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. 
     
     
         204 . The method of  claim 203 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist. 
     
     
         205 . The method of  claim 204 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1, B7-1, or both PD-1 and B7-1. 
     
     
         206 . The method of  claim 204 , wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody. 
     
     
         207 . The method of  claim 206 , wherein the anti-PD-L1 antibody is selected from the group consisting of MPDL3280A, MDX-1105, and MED14736. 
     
     
         208 . The method of  claim 206 , 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). 
     
     
         209 . The method of  claim 208 , wherein the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTI 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 DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFT LTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24).