Anti-tigit antibodies and methods of use

Abstract

The invention provides anti-TIGIT (T-cell immunoreceptor with Ig and ITIM domains) antibodies and methods of using the same.

What is claimed is: 
     
         1 . An antibody that specifically binds to human TIGIT, wherein the antibody binds to an epitope on human TIGIT comprising one or more of amino acid residues Ser78, Ser80, and Lys82 of human TIGIT. 
     
     
         2 . The antibody of  claim 1 , wherein the epitope comprises amino acid residues Ser80 and Lys82 of human TIGIT. 
     
     
         3 . The antibody of  claim 1  or  2 , wherein the epitope comprises amino acid residues Ser78, Ser80, and Lys82 of human TIGIT. 
     
     
         4 . The antibody of any one of  claims 1 - 3 , wherein the epitope further comprises amino acid residue Ala67 of human TIGIT. 
     
     
         5 . The antibody of any one of  claims 1 - 4 , wherein the epitope further comprises one or more additional amino acid residues selected from the group consisting of Glu60, Leu65, and Ile68 of human TIGIT. 
     
     
         6 . The antibody of any one of  claims 1 - 5 , wherein the epitope further comprises one or more additional amino acid residues selected from the group consisting of Gln56, Asn70, Leu73, and His111 of human TIGIT. 
     
     
         7 . The antibody of any one of  claims 1 - 6 , wherein the epitope further comprises one or more additional amino acid residues selected from the group consisting of Thr55, Asn58, Asp63, Gln64, His76, Ile77, and Pro79 of human TIGIT. 
     
     
         8 . The antibody of any one of  claims 1 - 7 , wherein the epitope consists of amino acid residues Thr55, Gln56, Asn58, Glu60, Asp63, Gln64, Leu65, Ala67, Ile68, Asn70, Leu73, His76, Ile77, Ser78, Pro79, Ser80, Lys82, and His111 of human TIGIT. 
     
     
         9 . An antibody that specifically binds to human TIGIT, wherein the antibody binds to an epitope on human TIGIT comprising one or more of amino acid residues Thr55, Ser80, and Lys82 of human TIGIT. 
     
     
         10 . The antibody of  claim 9 , wherein the epitope comprises amino acid residue Lys82 of human TIGIT. 
     
     
         11 . The antibody of  claim 9  or  10 , wherein the epitope comprises amino acid residues Thr55, Ser80, and Lys82 of human TIGIT. 
     
     
         12 . The antibody of any one of  claims 9 - 11 , wherein the epitope further comprises amino acid residue Gln56 of human TIGIT. 
     
     
         13 . The antibody of any one of  claims 9 - 12 , wherein the epitope further comprises amino acid residue Ile77 or Pro79 of human TIGIT. 
     
     
         14 . The antibody of  claim 13 , wherein the epitope further comprises amino acid residues Ile77 and Pro79 of human TIGIT. 
     
     
         15 . The antibody of any one of  claims 9 - 14 , wherein the epitope further comprises amino acid residue Asn58 or Glu60 of human TIGIT. 
     
     
         16 . The antibody of  claim 15 , wherein the epitope further comprises amino acid residues Asn58 and Glu60 of human TIGIT. 
     
     
         17 . The antibody of any one of  claims 9 - 16 , wherein the epitope further comprises one or more additional amino acid residues selected from the group consisting of Leu65, Ile68, Leu73, His76, Ser78, and His111 of human TIGIT. 
     
     
         18 . The antibody of  claim 17 , wherein the epitope further comprises amino acid residues Leu65, Ile68, Leu73, His76, Ser78, and His111 of human TIGIT. 
     
     
         19 . The antibody of any one of  claims 9 - 18 , wherein the epitope consists of Thr55, Gln56, Asn58, Glu60, Leu65, Ile68, Leu73, His76, Ile77, Ser78, Pro79, Ser80, Lys82, and His111 of human TIGIT. 
     
     
         20 . An antibody that specifically binds to human TIGIT, wherein the antibody comprises a paratope comprising one or more amino acid residues selected from the group consisting of heavy chain variable region amino acid residues Asn32, Tyr52, Arg52b, Phe53, Lys54, Tyr56, Asp58, Tyr99, Asp100, Leu100a, Leu100b, and Ala100c and light chain variable region amino acid residues Tyr27d, Tyr92, Ser93, Thr94, and Phe96. 
     
     
         21 . The antibody of  claim 20 , wherein the paratope consists of heavy chain variable region amino acid residues Asn32, Tyr52, Arg52b, Phe53, Lys54, Tyr56, Asp58, Tyr99, Asp100, Leu100a, Leu100b, and Ala100c and light chain variable region amino acid residues Tyr27d, Tyr92, Ser93, Thr94, and Phe96. 
     
     
         22 . An antibody that specifically binds to human TIGIT, wherein the antibody binds to an epitope on human TIGIT comprising one or more amino acid residues selected from the group consisting of Gln53, His111, and Tyr113 of human TIGIT. 
     
     
         23 . The antibody of  claim 22 , wherein the epitope further comprises Gln56 of human TIGIT. 
     
     
         24 . The antibody of  claim 22  or  23 , wherein the epitope further comprises Glu60, Leu65, Ile68, Asn70, Leu73, and His76 of human TIGIT. 
     
     
         25 . An antibody that specifically binds to human TIGIT, wherein the antibody comprises the following six hypervariable regions (HVRs):
 an HVR-H1 comprising the amino acid sequence of SNSAAWN (SEQ ID NO: 1);   an HVR-H2 comprising the amino acid sequence of KTYYRFKWYSDYAVSVKG (SEQ ID NO: 2);   an HVR-H3 comprising the amino acid sequence of ESTTYDLLAGPFDY (SEQ ID NO: 3);   an HVR-L1 comprising the amino acid sequence of KSSQTVLYSSNNKKYLA (SEQ ID NO: 4);   an HVR-L2 comprising the amino acid sequence of WASTRES (SEQ ID NO: 5); and   an HVR-L3 comprising the amino acid sequence of QQYYSTPFT (SEQ ID NO: 6).   
     
     
         26 . The antibody of  claim 25 , wherein the antibody further comprises the following light chain variable region framework regions (FRs):
 an FR-L1 comprising the amino acid sequence of DIVMTQSPDSLAVSLGERATINC (SEQ ID NO: 7);   an FR-L2 comprising the amino acid sequence of WYQQKPGQPPNLLIY (SEQ ID NO: 8);   an FR-L3 comprising the amino acid sequence of GVPDRFSGSGSGTDFTLTISSLQAEDVAVYYC (SEQ ID NO: 9); and   an FR-L4 comprising the amino acid sequence of FGPGTKVEIK (SEQ ID NO: 10).   
     
     
         27 . The antibody of  claim 25  or  26 , wherein the antibody further comprises the following heavy chain variable region FRs:
 an FR-H1 comprising the amino acid sequence of X 1 VQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 11), wherein X 1  is Q or E; 
 an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12); 
 an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and 
 an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14). 
 
     
     
         28 . The antibody of  claim 27 , wherein the antibody further comprises the following heavy chain variable region FRs:
 an FR-H1 comprising the amino acid sequence of EVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 15);   an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);   an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and   an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).   
     
     
         29 . The antibody of  claim 27 , wherein the antibody further comprises the following heavy chain variable region FRs:
 an FR-H1 comprising the amino acid sequence of QVQLQQSGPGLVKPSQTLSLTCAISGDSVS (SEQ ID NO: 16);   an FR-H2 comprising the amino acid sequence of WIRQSPSRGLEWLG (SEQ ID NO: 12);   an FR-H3 comprising the amino acid sequence of RITINPDTSKNQFSLQLNSVTPEDTAVFYCTR (SEQ ID NO: 13); and   an FR-H4 comprising the amino acid sequence of WGQGTLVTVSS (SEQ ID NO: 14).   
     
     
         30 . An antibody that specifically binds to human TIGIT, wherein the antibody comprises the following six HVRs:
 an HVR-H1 comprising the amino acid sequence of SYPMN (SEQ ID NO: 17);   an HVR-H2 comprising the amino acid sequence of WINTNTGNPTYVQGFTG (SEQ ID NO: 18);   an HVR-H3 comprising the amino acid sequence of TGGHTYDSYAFDV (SEQ ID NO: 19);   an HVR-L1 comprising the amino acid sequence of RASQVISSSLA (SEQ ID NO: 20);   an HVR-L2 comprising the amino acid sequence of AASTLQS (SEQ ID NO: 21); and   an HVR-L3 comprising the amino acid sequence of QHLHGYPX 1 N (SEQ ID NO: 22), wherein X 1  is C or S.   
     
     
         31 . The antibody of  claim 30 , wherein antibody comprises the following six HVRs:
 an HVR-H1 comprising the amino acid sequence of SYPMN (SEQ ID NO: 17);   an HVR-H2 comprising the amino acid sequence of WINTNTGNPTYVQGFTG (SEQ ID NO: 18);   an HVR-H3 comprising the amino acid sequence of TGGHTYDSYAFDV (SEQ ID NO: 19);   an HVR-L1 comprising the amino acid sequence of RASQVISSSLA (SEQ ID NO: 20);   an HVR-L2 comprising the amino acid sequence of AASTLQS (SEQ ID NO: 21); and   an HVR-L3 comprising the amino acid sequence of QHLHGYPSN (SEQ ID NO: 23).   
     
     
         32 . The antibody of any one of  claim 30  or  31 , wherein the antibody further comprises the following heavy chain variable region FRs:
 an FR-H1 comprising the amino acid sequence of EVQLVQSGSDLKKPGASVRVSCKASGYTFT (SEQ ID NO: 24); 
 an FR-H2 comprising the amino acid sequence of WVRQAPGHGLEWMG (SEQ ID NO: 25); 
 an FR-H3 comprising the amino acid sequence of RFVFSLDTSVNTAYLQISSLKAEDTAVYFCAR (SEQ ID NO: 26); and 
 an FR-H4 comprising the amino acid sequence of WGQGTMVTVSS (SEQ ID NO: 27). 
 
     
     
         33 . The antibody of  claim 30 , wherein antibody comprises the following six HVRs:
 an HVR-H1 comprising the amino acid sequence of SYPMN (SEQ ID NO: 17);   an HVR-H2 comprising the amino acid sequence of WINTNTGNPTYVQGFTG (SEQ ID NO: 18);   an HVR-H3 comprising the amino acid sequence of TGGHTYDSYAFDV (SEQ ID NO: 19);   an HVR-L1 comprising the amino acid sequence of RASQVISSSLA (SEQ ID NO: 20);   an HVR-L2 comprising the amino acid sequence of AASTLQS (SEQ ID NO: 21); and   an HVR-L3 comprising the amino acid sequence of QHLHGYPCN (SEQ ID NO: 28).   
     
     
         34 . The antibody of  claim 33 , wherein the antibody further comprises the following heavy chain variable region FRs:
 an FR-H1 comprising the amino acid sequence of QVQLVQSGSDLKKPGASVRVSCKASGYTFT (SEQ ID NO: 29);   an FR-H2 comprising the amino acid sequence of WVRQAPGHGLEWMG (SEQ ID NO: 25);   an FR-H3 comprising the amino acid sequence of RFVFSLDTSVNTAYLQISSLKAEDTAVYFCAR (SEQ ID NO: 26); and   an FR-H4 comprising the amino acid sequence of WGQGTMVTVSS (SEQ ID NO: 27).   
     
     
         35 . The antibody of any one of  claims 30 - 34 , wherein the antibody further comprises the following light chain variable region FRs:
 an FR-L1 comprising the amino acid sequence of DIQLTQSPTFLSASVGDRVTITC (SEQ ID NO: 30);   an FR-L2 comprising the amino acid sequence of WYQQNPGKAPKLLIY (SEQ ID NO: 31);   an FR-L3 comprising the amino acid sequence of GVPSRFSGSGSGTEFTLTISSLQPEDFVTYYC (SEQ ID NO: 32); and   an FR-L4 comprising the amino acid sequence of FGQGTKVEIK (SEQ ID NO: 33).   
     
     
         36 . An antibody that specifically binds to human TIGIT, wherein the antibody comprises (a) a heavy chain variable region (VH) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 34 or 35; (b) a light chain variable region (VL) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 36; or (c) a heavy chain variable region as in (a) and a light chain variable region as in (b). 
     
     
         37 . The antibody of  claim 36 , wherein the antibody comprises (a) a heavy chain variable region (VH) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 34; (b) a light chain variable region (VL) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 36; or (c) a heavy chain variable region as in (a) and a light chain variable region as in (b). 
     
     
         38 . The antibody of  claim 36 , wherein the antibody comprises (a) a heavy chain variable region (VH) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 35; (b) a light chain variable region (VL) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 36; or (c) a heavy chain variable region as in (a) and a light chain variable region as in (b). 
     
     
         39 . An antibody that specifically binds to human TIGIT, wherein the antibody comprises (a) a heavy chain variable region (VH) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 37; (b) a light chain variable region (VL) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 38; or (c) a heavy chain variable region as in (a) and a light chain variable region as in (b). 
     
     
         40 . An antibody that specifically binds to human TIGIT, wherein the antibody comprises (a) a heavy chain variable region (VH) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 39; (b) a light chain variable region (VL) having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 40; or (c) a heavy chain variable region as in (a) and a light chain variable region as in (b). 
     
     
         41 . The antibody of any one of  claims 1 - 21 ,  25 - 29 , and  36 - 38 , wherein the antibody is capable of binding to rabbit TIGIT. 
     
     
         42 . The antibody of any one of  claims 1 - 41 , wherein the antibody is capable of binding to both human TIGIT and cynomolgus monkey (cyno) TIGIT, but not murine TIGIT. 
     
     
         43 . The antibody of  claim 42 , wherein the antibody binds human TIGIT with a Kd of about 10 nM or lower and cyno TIGIT with a Kd of about 10 nM or lower. 
     
     
         44 . The antibody of  claim 43 , wherein the antibody binds human TIGIT with a Kd of about 0.1 nM to about 1 nM and cyno TIGIT with a Kd of about 0.5 nM to about 1 nM. 
     
     
         45 . The antibody of  claim 44 , wherein the antibody binds human TIGIT with a Kd of about 0.1 nM or lower and cyno TIGIT with a Kd of about 0.5 nM or lower. 
     
     
         46 . The antibody of any one of  claims 1 - 45 , wherein the antibody is an antagonist antibody. 
     
     
         47 . The antibody of  claim 46 , wherein the antagonist antibody specifically binds TIGIT and inhibits or blocks TIGIT interaction with poliovirus receptor (PVR). 
     
     
         48 . The antibody of  claim 47 , wherein the antagonist antibody inhibits intracellular signaling mediated by TIGIT binding to PVR. 
     
     
         49 . The antibody of any one of  claims 46 - 48 , wherein the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an 1050 value of 10 nM or lower. 
     
     
         50 . The antibody of any one of  claims 46 - 49 , wherein the antagonist antibody inhibits or blocks binding of human TIGIT to human PVR with an 1050 value of 1 nM to about 10 nM. 
     
     
         51 . The antibody of any one of  claims 46 - 50 , wherein the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an 1050 value of 50 nM or lower. 
     
     
         52 . The antibody of  claim 51 , wherein the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an 1050 value of 1 nM to about 50 nM. 
     
     
         53 . The antibody of  claim 52 , wherein the antagonist antibody inhibits or blocks binding of cyno TIGIT to cyno PVR with an 1050 value of 1 nM to about 5 nM. 
     
     
         54 . The antibody of any one of  claims 1 - 45 , wherein the antibody is an agonist antibody. 
     
     
         55 . The antibody of  claim 54 , wherein the agonist antibody specifically binds TIGIT and stimulates the interaction of PVR with CD226 or CD96. 
     
     
         56 . The antibody of  claim 55 , wherein the agonist antibody specifically binds TIGIT and stimulates the interaction of PVR with CD226 and CD96. 
     
     
         57 . The antibody of  claim 56 , wherein the agonist antibody specifically binds TIGIT and stimulates the interaction of human PVR with human CD226 and human CD96. 
     
     
         58 . The antibody of  claim 56 , wherein the agonist antibody specifically binds TIGIT and stimulates the interaction of cyno PVR with cyno CD226 and cyno CD96. 
     
     
         59 . An isolated antibody that competes for binding to TIGIT with the antibody of any one of  claims 1 - 58 . 
     
     
         60 . An isolated antibody that binds to the same epitope as the antibody of any one of  claims 1 - 58 . 
     
     
         61 . The antibody of any one of  claims 1 - 60 , wherein the antibody is monoclonal. 
     
     
         62 . The antibody of any one of  claims 1 - 60 , wherein the antibody is human, humanized, or chimeric. 
     
     
         63 . The antibody of  claim 62 , wherein at least a portion of the framework sequence is a human consensus framework sequence. 
     
     
         64 . The antibody of any one of  claims 1 - 63 , wherein the antibody is a full-length antibody. 
     
     
         65 . The antibody of any one of  claims 1 - 64 , wherein the antibody has a clearance following intravenous injection of about 3 ml/kg/day to about 10 ml/kg/day. 
     
     
         66 . The antibody of any one of  claim 65 , wherein the antibody has a clearance following intravenous injection of about 3 ml/kg/day to about 8 ml/kg/day. 
     
     
         67 . The antibody of any one of  claims 1 - 63 , wherein the antibody is an antibody fragment that binds TIGIT. 
     
     
         68 . The antibody of  claim 67 , wherein the antibody fragment is selected from the group consisting of Fab, Fab′, Fab′-SH, Fv, single chain variable fragment (scFv), and (Fab′) 2  fragments. 
     
     
         69 . The antibody of any one of  claims 1 - 68 , wherein the antibody is an IgG class antibody. 
     
     
         70 . The antibody of  claim 69 , wherein the IgG class antibody is an IgG1 subclass antibody. 
     
     
         71 . A polynucleotide encoding the antibody of any one of  claims 1 - 70 . 
     
     
         72 . A vector comprising the polynucleotide of  claim 71 . 
     
     
         73 . A host cell comprising the vector of  claim 72 . 
     
     
         74 . The host cell of  claim 73 , wherein the host cell is prokaryotic. 
     
     
         75 . The host cell of  claim 74 , wherein the host cell is  Escherichia coli.    
     
     
         76 . The host cell of  claim 73 , wherein the host cell is eukaryotic. 
     
     
         77 . The host cell of  claim 76 , wherein the host cell is a 293 cell, a CHO cell, a yeast cell, or a plant cell. 
     
     
         78 . A method of producing the antibody of any one of  claims 1 - 70 , the method comprising culturing the host cell of  claim 73  in a culture medium. 
     
     
         79 . The method of  claim 78 , wherein the method further comprises recovering the antibody from the host cell or culture medium. 
     
     
         80 . An immunoconjugate comprising the antibody of any one of  claims 1 - 70  and a cytotoxic agent. 
     
     
         81 . A composition comprising the antibody of any one of  claims 1 - 70 . 
     
     
         82 . The composition of  claim 81 , further comprising a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
         83 . The composition of  claim 82 , wherein the composition is a pharmaceutical composition. 
     
     
         84 . The composition of any one of  claims 81 - 83 , wherein the composition further comprises a PD-1 axis binding antagonist or an additional therapeutic agent. 
     
     
         85 . The antibody of any one of  claims 1 - 70  for use as a medicament. 
     
     
         86 . The antibody of any one of  claims 1 - 70  for use in treating or delaying progression of a cancer in a subject in need thereof. 
     
     
         87 . The antibody of  claim 86 , 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, mycoses fungoides, a merkel cell cancer, and a hematologic malignancy. 
     
     
         88 . The antibody of  claim 87 , wherein the myeloma is multiple myeloma (MM). 
     
     
         89 . The antibody of any one of  claims 1 - 70  for use in treating or delaying progression of an immune-related disease in a subject in need thereof. 
     
     
         90 . The antibody of  claim 89 , wherein the immune-related disease is associated with a T cell dysfunctional disorder. 
     
     
         91 . The antibody of  claim 90 , wherein the T cell dysfunctional disorder is characterized by T cell exhaustion. 
     
     
         92 . The antibody of any one of  claims 89 - 91 , wherein the immune-related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. 
     
     
         93 . The antibody of any one of  claims 1 - 70  for use in increasing, enhancing, or stimulating an immune response or function in a subject in need thereof. 
     
     
         94 . Use of the antibody of any one of  claims 1 - 70  in the manufacture of a medicament for treating or delaying progression of a cancer in a subject in need thereof. 
     
     
         95 . The use of  claim 94 , 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, mycoses fungoides, a merkel cell cancer, and a hematologic malignancy. 
     
     
         96 . The use of  claim 95 , wherein the myeloma is MM. 
     
     
         97 . Use of the antibody of any one of  claims 1 - 70  in the manufacture of a medicament for treating or delaying progression of an immune-related disease in a subject in need thereof. 
     
     
         98 . The use of  claim 97 , wherein the immune-related disease is associated with a T cell dysfunctional disorder. 
     
     
         99 . The use of  claim 98 , wherein the T cell dysfunctional disorder is characterized by T cell exhaustion. 
     
     
         100 . The use of any one of  claims 97 - 99 , wherein the immune-related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. 
     
     
         101 . Use of the antibody of any one of  claims 1 - 70  in the manufacture of a medicament for increasing, enhancing, or stimulating an immune response or function in a subject in need thereof. 
     
     
         102 . A method for treating or delaying progression of a cancer in a subject, the method comprising administering to the subject an effective amount of the antibody of any one of  claims 1 - 70 , thereby treating or delaying the progression of the cancer in the subject. 
     
     
         103 . The method of  claim 102 , 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, mycoses fungoides, a merkel cell cancer, and a hematologic malignancy. 
     
     
         104 . The method of  claim 103 , wherein the myeloma is MM. 
     
     
         105 . A method for treating or delaying progression of an immune-related disease in a subject, the method comprising administering to the subject an effective amount of the antibody of any one of  claims 1 - 70 , thereby treating or delaying the progression of the immune-related disease in the subject. 
     
     
         106 . The method of  claim 105 , wherein the immune-related disease is associated with a T cell dysfunctional disorder. 
     
     
         107 . The method of  claim 106 , wherein the T cell dysfunctional disorder is characterized by T cell exhaustion. 
     
     
         108 . The method of any one of  claims 105 - 107 , wherein the immune-related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. 
     
     
         109 . A method of increasing, enhancing, or stimulating an immune response or function in a subject, the comprising administering to the subject an effective amount of the antibody of any one of  claims 1 - 70 , thereby increasing, enhancing, or stimulating an immune response or function in the subject. 
     
     
         110 . The method of any one of  102 - 109 , further comprising administering to the subject a PD-1 axis binding antagonist. 
     
     
         111 . The method of  claim 110 , wherein the PD-1 axis binding antagonist is administered prior to or subsequent to the administration of the antibody. 
     
     
         112 . The method of  claim 110 , wherein the PD-1 axis binding antagonist is administered concurrently with the antibody. 
     
     
         113 . The method of any one of  claims 110 - 112 , 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. 
     
     
         114 . The method of  claim 113 , wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist. 
     
     
         115 . The method of  claim 114 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to its ligand binding partners. 
     
     
         116 . The method of  claim 115 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. 
     
     
         117 . The method of  claim 115 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. 
     
     
         118 . The method of  claim 115 , wherein the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. 
     
     
         119 . The method of any one of  claims 115 - 118 , wherein the PD-1 binding antagonist is an anti-PD-1 antibody. 
     
     
         120 . The method of  claim 115 , wherein the PD-1 binding antagonist is selected from the group consisting of MDX 1106 (nivolumab), MK-3475 (pembrolizumab), CT-011 (pidilizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, and BGB-108. 
     
     
         121 . The method of  claim 113 , wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist. 
     
     
         122 . The method of  claim 121 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1. 
     
     
         123 . The method of  claim 121 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to B7-1. 
     
     
         124 . The method of  claim 121 , wherein the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. 
     
     
         125 . The method of  claim 121 - 124 , wherein the PD-L1 binding antagonist is an anti-PD-L1 antibody. 
     
     
         126 . The method of  claim 125 , wherein the anti-PD-L1 antibody is selected from the group consisting of: MPDL3280A (atezolizumab), YW243.55.S70, MDX-1105, MEDI4736 (durvalumab), and MSB0010718C (avelumab). 
     
     
         127 . The method of  claim 126 , wherein the antibody is MPDL3280A. 
     
     
         128 . The method of  claim 113 , wherein the PD-1 axis binding antagonist is a PD-L2 binding antagonist. 
     
     
         129 . The method of  claim 128 , wherein the PD-L2 binding antagonist is an anti-PD-L2 antibody. 
     
     
         130 . The method of  claim 128 , wherein the PD-L2 binding antagonist is an immunoadhesin. 
     
     
         131 . The method of any one of  claims 102 - 130 , further comprising administering to the subject an OX40 binding agonist. 
     
     
         132 . The method of  claim 131 , wherein the OX40 binding agonist is administered prior to or subsequent to the administration of the antibody and/or the PD-1 axis binding antagonist. 
     
     
         133 . The method of  claim 131 , wherein the OX40 binding agonist is administered concurrently with the antibody and/or the PD-1 axis binding antagonist. 
     
     
         134 . The method of any one of  claims 131 - 133 , wherein the OX40 binding agonist is selected from the group consisting of an OX40 agonist antibody, an OX40L agonist fragment, an OX40 oligomeric receptor, and an OX40 immunoadhesin. 
     
     
         135 . The method of  claim 134 , wherein the OX40 agonist antibody depletes cells that express human OX40. 
     
     
         136 . The method of  claim 135 , wherein the cells that express human OX40 are CD4+ effector T cells. 
     
     
         137 . The method of  claim 135 , wherein the cells that express human OX40 are regulatory T (Treg) cells. 
     
     
         138 . The method of any one of  claims 135 - 137 , wherein the depleting is by ADCC and/or phagocytosis. 
     
     
         139 . The method of any one of  claims 134 - 138 , wherein the OX40 agonist antibody binds human OX40 with an affinity of less than or equal to about 1 nM. 
     
     
         140 . The method of  claim 139 , wherein the OX40 agonist antibody binds human OX40 with an affinity of less than or equal to about 0.45 nM. 
     
     
         141 . The method of  claim 140 , wherein the OX40 agonist antibody binds human OX40 with an affinity of less than or equal to about 0.4 nM. 
     
     
         142 . The method of any one of  claims 134 - 141 , wherein the OX40 agonist antibody binds human OX40 with an EC50 of less than or equal to 0.3 μg/ml. 
     
     
         143 . The method of  claim 142 , wherein the OX40 agonist antibody binds human OX40 with an EC50 of less than or equal to 0.2 μg/ml. 
     
     
         144 . The method of any one of  claims 134 - 143 , wherein the OX40 agonist antibody increases CD4+ effector T cell proliferation and/or increases cytokine production by the CD4+ effector T cell as compared to proliferation and/or cytokine production prior to treatment with the OX40 agonist antibody. 
     
     
         145 . The method of any one of  claims 134 - 144 , wherein the OX40 agonist antibody increases memory T cell proliferation and/or cytokine production by a memory T cell. 
     
     
         146 . The method of  claim 144  or  145 , wherein the cytokine production is IFN-γ production. 
     
     
         147 . The method of any one of  claims 134 - 146 , wherein the OX40 agonist antibody inhibits Treg function. 
     
     
         148 . The method of  claim 147 , wherein the OX40 agonist antibody inhibits Treg suppression of effector T cell function. 
     
     
         149 . The method of  claim 148 , wherein effector T cell function is effector T cell proliferation and/or cytokine production. 
     
     
         150 . The method of  claim 148  or  149 , wherein the effector T cell is a CD4+ effector T cell. 
     
     
         151 . The method of any one of  claims 134 - 150 , wherein the OX40 agonist antibody increases OX40 signal transduction in a target cell that expresses OX40. 
     
     
         152 . The method of  claim 151 , wherein OX40 signal transduction is detected by monitoring NFkB downstream signaling. 
     
     
         153 . The method of any one of  claims 134 - 152 , wherein the OX40 agonist antibody comprises a variant IgG1 Fc polypeptide comprising a mutation that eliminates binding to human effector cells and has diminished activity relative to the OX40 agonist antibody comprising a native sequence IgG1 Fc portion. 
     
     
         154 . The method of  claim 153 , wherein the OX40 agonist antibody comprises a variant IgG1 Fc polypeptide comprising a DANA mutation. 
     
     
         155 . The method of any one of  claims 134 - 154 , wherein the OX40 agonist antibody comprises (a) a VH domain comprising (i) a HVR-H1 comprising the amino acid sequence of SEQ ID NO: 278, 279, or 280, (ii) a HVR-H2 comprising the amino acid sequence of SEQ ID NO: 281, 282, 283, 284, 285, or 286, and (iii) a HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 287, 288, or 289; and (b) a VL domain comprising (i) a HVR-L1 comprising the amino acid sequence of SEQ ID NO: 290, (ii) a HVR-L2 comprising the amino acid sequence of SEQ ID NO: 291, and (iii) a HVR-L3 comprising the amino acid sequence of SEQ ID NO: 292, 293, 294, 295, 296, 297, 298, or 299. 
     
     
         156 . The method of  claim 155 , wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 278; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 281; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 287; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 290; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 291; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 292. 
     
     
         157 . The method of  claim 155 , wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 278; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 281; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 287; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 290; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 291; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 297. 
     
     
         158 . The method of  claim 155 , wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 278; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 281; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 287; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 290; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 291; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 298. 
     
     
         159 . The method of any one of  claims 134 - 158 , wherein the OX40 agonist antibody comprises a VH sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 300-325. 
     
     
         160 . The method of  claim 159 , wherein the OX40 agonist antibody comprises a VH sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 300. 
     
     
         161 . The method of  claim 160 , wherein a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 300. 
     
     
         162 . The method of any one of  claims 159 - 161 , wherein the OX40 agonist antibody comprises a VH comprising one, two, or three HVRs selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 278, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 281, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 287. 
     
     
         163 . The method of any one of  claims 134 - 162 , wherein the OX40 agonist antibody comprises a VL sequence having at least 90% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 326-351. 
     
     
         164 . The method of  claim 163 , wherein the OX40 agonist antibody comprises a VL having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 326. 
     
     
         165 . The method of  claim 164 , wherein a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 326. 
     
     
         166 . The method of any one of  claims 162 - 165 , wherein the OX40 agonist antibody comprises a VL comprising one, two, or three HVRs selected from (a) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 290; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 291; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 292. 
     
     
         167 . The method of any one of  claims 134 - 166 , wherein the OX40 agonist antibody comprises (a) a VH sequence of SEQ ID NO: 300; (b) a VL sequence of SEQ ID NO: 326; or (c) a VH sequence as in (a) and a VL sequence as in (b). 
     
     
         168 . The method of any one of  claims 134 - 166 , wherein the OX40 agonist antibody comprises (a) a VH sequence of SEQ ID NO: 319; (b) a VL sequence of SEQ ID NO: 345; or (c) a VH sequence as in (a) and a VL sequence as in (b). 
     
     
         169 . The method of any one of  claims 134 - 166 , wherein the OX40 agonist antibody comprises (a) a VH sequence of SEQ ID NO: 320; (b) a VL sequence of SEQ ID NO: 346; or (c) a VH sequence as in (a) and a VL sequence as in (b). 
     
     
         170 . The method of any one of  claims 134 - 154 , wherein the OX40 agonist antibody is antibody L106, antibody ACT35, MEDI6469, or MEDI0562. 
     
     
         171 . The method of any one of  claims 134 - 170 , wherein the OX40 agonist antibody is a full-length IgG1 antibody. 
     
     
         172 . The method of  claim 134 , wherein the OX40 immunoadhesin is a trimeric OX40-Fc protein. 
     
     
         173 . The method of any one of  claims 102 - 172 , further comprising administering to the subject an agent that decreases or inhibits one or more additional immune co-inhibitory receptors. 
     
     
         174 . The method of  claim 173 , 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. 
     
     
         175 . The method of any one of  claims 102 - 174 , further comprising administering to the subject an additional therapeutic agent. 
     
     
         176 . The method of  claim 175 , wherein the additional therapeutic agent is a chemotherapeutic agent. 
     
     
         177 . The method of any one of  claims 102 - 176 , wherein the antibody is administered subcutaneously, intravenously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intraventricularly, or intranasally. 
     
     
         178 . The method of any one of  claims 102 - 177 , wherein the subject is a human. 
     
     
         179 . A kit comprising the antibody of any one of  claims 1 - 70  and a package insert comprising instructions for using the antibody for treating or delaying progression of a cancer in a subject. 
     
     
         180 . A kit comprising the antibody of any one of  claims 1 - 70  and a package insert comprising instructions for using the antibody for treating or delaying progression of an immune-related disease in a subject. 
     
     
         181 . A kit comprising the antibody of any one of  claims 1 - 70  and a package insert comprising instructions for increasing, enhancing, or stimulating an immune response or function in a subject. 
     
     
         182 . The kit of any one of  claims 179 - 181 , wherein the subject is a human.