Methods of treating her2-positive cancers using pd-1 axis binding antagonists and anti-her2 antibodies

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.

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 H HER2) and a light chain variable region (V L HER2), and the second antigen binding domain comprises a heavy chain variable region (V H CD3) and a light chain variable region (V L CD3). 
     
     
         28 . The method of  claim 27 , wherein the first antigen binding domain comprises a heavy chain variable region (V H HER2) 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 L HER2) 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 H HER2) comprises the amino acid sequence of SEQ ID NO:34 and/or a light chain variable region (V L HER2) 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 H HER2-V L HER2-V H CD3-V L CD3, (2) V H CD3-V L CD3-V H HER2-V L HER2, (3) V H CD3-V L CD3-V L HER2-V H HER2, (4) V H HER2-V L HER2-V L CD3-V H CD3, (5) V L HER2-V H HER2-V H CD3-V L CD3, or (6) V L CD3-V H CD3-V H HER2-V L HER2. 
     
     
         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 (CH1 1 ) domain, a first CH2 (CH2 1 ) domain, a first CH3 (CH3 1 ) 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 (CH1 2 ) domain, second CH2 (CH2 2 ) domain, and a second CH3 (CH3 2 ) 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 CH3 1  and CH3 2  domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH3 1  domain is positionable in the cavity or protuberance, respectively, in the CH3 2  domain. 
     
     
         38 . The method of  claim 37 , wherein the CH3 1  and CH3 2  domains meet at an interface between said protuberance and cavity. 
     
     
         39 . The method of  claim 35 , wherein the CH2 1  and CH2 2  domains each comprise a protuberance or cavity, and wherein the protuberance or cavity in the CH2 1  domain is positionable in the cavity or protuberance, respectively, in the CH2 2  domain. 
     
     
         40 . The method of  claim 39 , wherein the CH2 1  and CH2 2  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. 
     
     
         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. 
     
     
         65 - 69 . (canceled) 
     
     
         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. 
     
     
         72 - 74 . (canceled) 
     
     
         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. 
     
     
         77 . (canceled) 
     
     
         78 . (canceled) 
     
     
         79 . The method of  claim 63 , wherein the PD-1 axis binding antagonist is a PD-L2 binding antagonist. 
     
     
         80 . (canceled) 
     
     
         81 . (canceled) 
     
     
         82 . The method of  claim 57 , wherein the anti-HER2 antibody is trastuzumab or pertuzumab. 
     
     
         83 . (canceled) 
     
     
         84 . (canceled) 
     
     
         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. 
     
     
         87 - 90 . (canceled) 
     
     
         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. 
     
     
         92 - 101 . (canceled) 
     
     
         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). 
     
     
         105 - 108 . (canceled) 
     
     
         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. 
     
     
         110 . (canceled) 
     
     
         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. 
     
     
         115 . (canceled) 
     
     
         116 . The method of  claim 1 , further comprising administering a chemotherapeutic agent for treating or delaying progression of cancer. 
     
     
         117 - 120 . (canceled) 
     
     
         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.