# US 2019/0169304 A1 · Combination therapy comprising ox40 binding agonists and tigit inhibitors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2019/0169304 A1 - Document ID: US20190169304A1 - Status: Published application - Kind: A1 - Application number: 16/271,520 - Filed: 2019-02-08 - Published: 2019-06-06 - Earliest claimed: 2014-11-06 - Assignees: Genentech, Inc. - Applicants: Genentech, Inc. - Inventors: Jeong M. Kim; Jane L. Grogan - Web page: https://patentgrep.com/patent/US20190169304A1 ## CPC - C07K 16/2878: {against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95} - A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - A61P 37/02: Immunomodulators - A61P 37/04: Immunostimulants - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07K 16/28: against receptors, cell surface antigens or cell surface determinants - C07K 16/2803: {against the immunoglobulin superfamily} - C07K 16/30: from tumour cells - A61K 2039/505: {comprising antibodies} - A61K 2039/507: {Comprising a combination of two or more separate antibodies} - C07K 2317/732: Antibody-dependent cellular cytotoxicity [ADCC] - C07K 2317/75: Agonist effect on antigen - C07K 2317/76: Antagonist effect on antigen, e.g. neutralization or inhibition of binding - C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value - 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 - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## Abstract The present invention describes combination therapy comprising an OX40 binding agonist and an agent that decreases or inhibits TIGIT expression and/or TIGIT 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 ### Claim 1 A method for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of an OX40 binding agonist and an agent that decreases or inhibits TIGIT expression and/or activity. ### Claim 2 A method for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effective amount of an OX40 binding agonist and an agent that decreases or inhibits TIGIT expression and/or activity. ### Claim 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 an OX40 binding agonist and an agent that decreases or inhibits TIGIT expression and/or activity. ### Claim 4 A method for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effective amount of an OX40 binding agonist and an agent that decreases or inhibits TIGIT expression and/or activity. ### Claim 5 (depends on 3, 4) The method of claim 3 or 4, wherein the immune related disease is associated with a T cell dysfunctional disorder. ### Claim 6 (depends on 5) The method of claim 5, wherein the T cell dysfunctional disorder is characterized by decreased responsiveness to antigenic stimulation. ### Claim 7 (depends on 5) The method of claim 5, wherein the T cell dysfunctional disorder is characterized by T cell anergy or decreased ability to secrete cytokines, proliferate, or execute cytolytic activity. ### Claim 8 (depends on 5) The method of claim 5, wherein the T cell dysfunctional disorder is characterized by T cell exhaustion. ### Claim 9 (depends on 3, 4, 5, 6, 7, 8) The method of any one of claims 3-8, wherein the T cells are CD4+ and CD8+ T cells. ### Claim 10 (depends on 3, 4, 5, 6, 7, 8, 9) The method of any one of claims 3-9, wherein the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. ### Claim 11 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 OX40 binding agonist and an agent that decreases or inhibits TIGIT expression and/or activity. ### Claim 12 A method of treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of an OX40 binding agonist and an agent that modulates CD226 expression and/or activity. ### Claim 13 A method for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effective amount of an OX40 binding agonist and an agent that modulates CD226 expression and/or activity. ### Claim 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 an OX40 binding agonist and an agent that modulates CD226 expression and/or activity. ### Claim 15 A method for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effective amount of an OX40 binding agonist and an agent that modulates CD226 expression and/or activity. ### Claim 16 (depends on 14, 15) The method of claim 14 or 15, wherein the immune related disease is associated with a T cell dysfunctional disorder. ### Claim 17 (depends on 16) The method of claim 16, wherein the T cell dysfunctional disorder is characterized by decreased responsiveness to antigenic stimulation. ### Claim 18 (depends on 16) The method of claim 16, wherein the T cell dysfunctional disorder is characterized by T cell anergy or decreased ability to secrete cytokines, proliferate, or execute cytolytic activity. ### Claim 19 (depends on 16) The method of claim 16, wherein the T cell dysfunctional disorder is characterized by T cell exhaustion. ### Claim 20 (depends on 16, 17, 18, 19) The method of any one of claims 16-19, wherein the T cell is a CD4+ T cell and/or a CD8+ T cell. ### Claim 21 (depends on 14, 15, 16, 17, 18, 19, 20) The method of any one of claims 14-20, wherein the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. ### Claim 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 an OX40 binding agonist and an agent that modulates CD226 expression and/or activity. ### Claim 23 (depends on 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22) The method of any one of claims 12-22, wherein the agent that modulates CD226 expression and/or activity is an agent that increases and/or stimulates CD226 expression and/or activity. ### Claim 24 (depends on 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23) The method of any one of claims 12-23, wherein the agent that modulates CD226 expression and/or activity is an agent that increases and/or stimulates the interaction of CD226 with PVR. ### Claim 25 (depends on 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24) The method of any one of claims 12-24, wherein the agent that modulates CD226 expression and/or activity is an agent that increases and/or stimulates the intracellular signaling mediated by CD226 binding to PVR. ### Claim 26 (depends on 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25) The method of any one of claims 12-25, 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. ### Claim 27 (depends on 26) The method of claim 26, wherein the agent that modulates CD226 expression and/or activity is an agent that inhibits and/or blocks the interaction of CD226 with TIGIT. ### Claim 28 (depends on 26, 27) The method of claim 26 or 27, 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. ### Claim 29 (depends on 26, 27) The method of claim 26 or 27, wherein the agent that inhibits and/or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or antigen-binding fragment thereof. ### Claim 30 (depends on 26, 27) The method of claim 26 or 27, wherein the agent that inhibits and/or blocks the interaction of CD226 with TIGIT is an inhibitory nucleic acid selected from the group consisting of an antisense polynucleotide, an interfering RNA, a catalytic RNA, and an RNA-DNA chimera. ### Claim 31 (depends on 26) The method of claim 26, wherein the agent that modulates CD226 expression and/or activity is an antagonist of TIGIT expression and/or activity. ### Claim 32 (depends on 26, 31) The method of claim 26 or 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, and an inhibitory polypeptide. ### Claim 33 (depends on 26, 31) The method of claim 26 or 31, wherein the antagonist of TIGIT expression and/or activity is an anti-TIGIT antibody or antigen-binding fragment thereof. ### Claim 34 (depends on 26, 31) The method of claim 26 or 31, wherein the antagonist of TIGIT expression and/or activity is an inhibitory nucleic acid selected from the group consisting of an antisense polynucleotide, an interfering RNA, a catalytic RNA, and an RNA-DNA chimera. ### Claim 35 (depends on 26) The method of claim 26, wherein the antagonist of PVR expression and/or activity is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 36 (depends on 26) The method of claim 26, wherein the agent that inhibits and/or blocks the interaction of TIGIT with PVR is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 37 (depends on 26) The method of claim 26, wherein the agent that inhibits and/or blocks the interaction of TIGIT with PVRL2 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 38 (depends on 26) The method of claim 26, wherein the agent that inhibits and/or blocks the interaction of TIGIT with PVRL3 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 39 (depends on 26) The method of claim 26, wherein the agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVR is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 40 (depends on 26) The method of claim 26, wherein the agent that inhibits and/or blocks the interaction of TIGIT with PVRL2 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 41 (depends on 26) The method of claim 26, wherein the agent that inhibits and/or blocks the interaction of TIGIT with PVRL3 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 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 OX40 binding agonist, 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. ### Claim 43 (depends on 42) The method of claim 42, wherein the one or more additional immune co-inhibitory receptor is selected from the group consisting of PD-L1, PD-1, CTLA-4, LAG3, TIM3, BTLA, VISTA, B7H4, and CD96. ### Claim 44 (depends on 42) The method of claim 42, wherein the one or more additional immune co-inhibitory receptor is selected from the group consisting of PD-L1, PD-1, CTLA-4, LAG3, and TIM3. ### Claim 45 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 OX40 binding agonist, an effective amount of an agent that decreases or inhibits TIGIT expression and/or activity, and an agent that increases or activates one or more additional immune co-stimulatory receptors or their ligands. ### Claim 46 (depends on 45) The method of claim 45, wherein the one or more additional immune co-stimulatory receptors or their ligands is selected from the group consisting of CD226, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS, NKG2D, and 2B4. ### Claim 47 (depends on 45) The method of claim 45, wherein the one or more additional immune co-stimulatory receptors or their ligands is selected from the group consisting of CD226, CD27, CD137, HVEM, and GITR. ### Claim 48 (depends on 45) The method of claim 45, wherein the one or more additional immune co-stimulatory receptors or their ligands is CD27. ### Claim 49 The method of any one of the preceding claims, further comprising administering at least one chemotherapeutic agent. ### Claim 50 The method of any one of the preceding claims, wherein the individual has cancer. ### Claim 51 The method of any one of the preceding claims, wherein CD4 and/or CD8 T cells in the individual have increased or enhanced priming, activation, proliferation, cytokine release, and/or cytolytic activity relative to prior to the administration of the combination. ### Claim 52 The method of any one of the preceding claims, wherein the number of CD4 and/or CD8 T cells is elevated relative to prior to administration of the combination. ### Claim 53 The method of any one of the preceding claims, wherein the number of activated CD4 and/or CD8 T cells is elevated relative to prior to administration of the combination. ### Claim 54 The method of any one of the preceding claims, wherein activated CD4 and/or CD8 T cells are characterized by IFN-γ+ producing CD4 and/or CD8 T cells and/or enhanced cytolytic activity relative to prior to the administration of the combination. ### Claim 55 (depends on 51, 52, 53, 54) The method of any one of claims 51-54, wherein the CD4 and/or CD8 T cells exhibit increased release of cytokines selected from the group consisting of IFN-γ, TNF-α, and interleukins. ### Claim 56 (depends on 51, 52, 53, 54, 55) The method of any one of claims 51-55, wherein the CD4 and/or CD8 T cells are effector memory T cells. ### Claim 57 (depends on 56) The method of claim 56, wherein the CD4 and/or CD8 effector memory T cells are characterized by γ-IFN+ producing CD4 and/or CD8 T cells and/or enhanced cytolytic activity. ### Claim 58 (depends on 56) The method of claim 56, wherein the CD4 and/or CD8 effector memory T cells are characterized by having the expression of CD44high CD62Llow. ### Claim 59 (depends on 1, 2, 12, 13, 23, 24) The method of any one of claims 1, 2, 12, 13, 23-24, and 49-58, wherein the cancer has elevated levels of T cell infiltration. ### Claim 60 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59) The method of any one of claims 1-11 and 42-59, 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, an agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL3, and combinations thereof. ### Claim 61 (depends on 60) The method of claim 60, wherein the antagonist of TIGIT expression and/or activity is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 62 (depends on 60) The method of claim 60, wherein the antagonist of PVR expression and/or activity is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 63 (depends on 60) The method of claim 60, wherein the agent that inhibits and/or blocks the interaction of TIGIT with PVR is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 64 (depends on 60) The method of claim 60, wherein the agent that inhibits and/or blocks the interaction of TIGIT with PVRL2 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 65 (depends on 60) The method of claim 60, wherein the agent that inhibits and/or blocks the interaction of TIGIT with PVRL3 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 66 (depends on 60) The method of claim 60, wherein the agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVR is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 67 (depends on 60) The method of claim 60, wherein the agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL2 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 68 (depends on 60) The method of claim 60, wherein the agent that inhibits and/or blocks the intracellular signaling mediated by TIGIT binding to PVRL3 is selected from the group consisting of a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. ### Claim 69 (depends on 60, 61) The method of claim 60 or 61, wherein the antagonist of TIGIT expression and/or activity is an inhibitory nucleic acid selected from the group consisting of an antisense polynucleotide, an interfering RNA, a catalytic RNA, and an RNA-DNA chimera. ### Claim 70 (depends on 60, 61) The method of claim 60 or 61, wherein the antagonist of TIGIT expression and/or activity is an anti-TIGIT antibody, or antigen-binding fragment thereof. ### Claim 71 (depends on 29, 70) The method of claim 29 or 70, 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: (a) 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 (b) 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). ### Claim 72 (depends on 71) The method of claim 71, wherein the anti-TIGIT antibody, or antigen-binding fragment thereof, comprises one of the following sets of six HVR sequences: (a) 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 (b) 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). ### Claim 73 (depends on 29, 70, 71, 72) The method of any one of claims 29 and 70-72, wherein the anti-TIGIT antibody, or antigen-binding fragment thereof, comprises a light chain comprising the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQSPKLLIYYASIRFTGVPDRFTG SGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGS GSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14). ### Claim 74 (depends on 29, 70, 71, 72, 73) The method of any one of claims 29 and 70-73, wherein the anti-TIGIT antibody, or antigen-binding fragment thereof, comprises a heavy chain comprising the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFT ISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKAT LTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO:16). ### Claim 75 (depends on 29, 70, 71, 72, 73, 74) The method of any one of claims 29 and 70-74, wherein the anti-TIGIT antibody, or antigen-binding fragment thereof, comprises a light chain comprising the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQSPKLLIYYASIRFTGVPDRFTG SGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGS GSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14), and a heavy chain comprising the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFT ISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKAT LTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). ### Claim 76 (depends on 29, 70, 71, 72, 73, 74, 75) The method of any one of claims 29 and 70-75, wherein the anti-TIGIT antibody, or antigen-binding fragment thereof, wherein the antibody is selected from the group consisting of a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugate antibody, and an immunotoxin. ### Claim 77 (depends on 29, 70, 71, 72, 73, 74, 75, 76) The method of any one of claims 29 and 70-76, 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 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); RPLGHNTFDS (SEQ ID NO: 6); 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). ### Claim 78 (depends on 29, 70, 71, 72) The method of any one of claims 29, 70-72, and 77, wherein the anti-TIGIT antibody, or antigen-binding fragment thereof, comprises a light chain comprising amino acid sequences at least 90% identical to the amino acid sequences set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQSPKLLIYYASIRFTGVPDRFTG SGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDGTKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSGVPDRFSGS GSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14); and/or comprises a heavy chain comprising amino acid sequences at least 90% identical to the amino acid sequences set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFYADAVRGRFT ISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSYNQKFKGKAT LTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO:16). ### Claim 79 (depends on 29, 70, 71, 72, 73, 74, 75, 76, 77) The method of any one of claims 29 and 70-77, wherein the anti-TIGIT antibody, or antigen-binding fragment thereof, binds to the same epitope as an antibody comprising one of the following sets of six HVR sequences: (a) 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 (b) 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). ### Claim 80 The method of any one of the preceding claims, 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. ### Claim 81 (depends on 80) The method of claim 80, wherein the OX40 agonist antibody depletes cells that express human OX40. ### Claim 82 (depends on 81) The method of claim 81, wherein the cells that express human OX40 are CD4+ effector T cells. ### Claim 83 (depends on 81) The method of claim 81, wherein the cells that express human OX40 are regulatory T (Treg) cells. ### Claim 84 The method of any one of the preceding claims, wherein the depleting is by ADCC and/or phagocytosis. ### Claim 85 (depends on 84) The method of claim 84, wherein the depleting is by ADCC. ### Claim 86 The method of any one of the preceding claims, wherein the OX40 agonist antibody binds human OX40 with an affinity of less than or equal to about 0.45 nM. ### Claim 87 (depends on 86) The method of claim 86, wherein the OX40 agonist antibody binds human OX40 with an affinity of less than or equal to about 0.4 nM. ### Claim 88 (depends on 86, 87) The method of claim 86 or 87, wherein the binding affinity of the OX40 agonist antibody is determined using radioimmunoassay. ### Claim 89 The method of any one of the preceding claims, wherein the OX40 agonist antibody binds human OX40 and cynomolgus OX40. ### Claim 90 (depends on 89) The method of claim 89, wherein binding is determined using a FACS assay. ### Claim 91 (depends on 89, 90) The method of claim 89 or 90, wherein binding to human OX40 has an EC50 of less than or equal to 0.3 μg/ml. ### Claim 92 (depends on 89, 90) The method of claim 89 or 90, wherein binding to human OX40 has an EC50 of less than or equal to 0.2 μg/ml. ### Claim 93 (depends on 89, 90, 91, 92) The method of any one of claims 89-92, wherein binding to cynomolgus OX40 has an EC50 of less than or equal to 1.5 μg/ml. ### Claim 94 (depends on 93) The method of claim 93, wherein binding to cynomolgus OX40 has an EC50 of less than or equal to 1.4 μg/ml. ### Claim 95 The method of any one of the preceding claims, 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. ### Claim 96 (depends on 95) The method of claim 95, wherein the cytokine is IFN-γ. ### Claim 97 The method of any one of the preceding claims, wherein the OX40 agonist antibody increases memory T cell proliferation and/or increasing cytokine production by the memory cell. ### Claim 98 (depends on 97) The method of claim 97, wherein the cytokine is IFN-γ. ### Claim 99 The method of any one of the preceding claims, wherein the OX40 agonist antibody inhibits Treg function. ### Claim 100 (depends on 99) The method of claim 99, wherein the OX40 agonist antibody inhibits Treg suppression of effector T cell function. ### Claim 101 (depends on 100) The method of claim 100, wherein effector T cell function is effector T cell proliferation and/or cytokine production. ### Claim 102 (depends on 100, 101) The method of claim 100 or 101, wherein the effector T cell is a CD4+ effector T cell. ### Claim 103 The method of any one of the preceding claims, wherein the OX40 agonist antibody increases OX40 signal transduction in a target cell that expresses OX40. ### Claim 104 (depends on 103) The method of claim 103, wherein OX40 signal transduction is detected by monitoring NFkB downstream signaling. ### Claim 105 The method of any one of the preceding claims, wherein the OX40 agonist antibody is stable after treatment at 40° C. for two weeks. ### Claim 106 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprising a variant IgG1 Fc polypeptide comprising a mutation that eliminates binding to human effector cells has diminished activity relative to the OX40 agonist antibody comprising a native sequence IgG1 Fc portion. ### Claim 107 (depends on 106) The method of claim 106, wherein the OX40 agonist antibody comprises a variant Fc portion comprising a DANA mutation. ### Claim 108 The method of any one of the preceding claims, wherein antibody cross-linking is required for anti-human OX40 agonist antibody function. ### Claim 109 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprises (a) a VH domain comprising (i) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22, 28, or 29, (ii) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, 30, 31, 32, 33 or 34, and (iii) HVR-H3 comprising an amino acid sequence selected from SEQ ID NO: 24, 35, or 39; and (iv) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25, (v) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26, and (vi) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27, 42, 43, 44, 45, 46, 47, or 48. ### Claim 110 (depends on 109) The method of claim 109, wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 27. ### Claim 111 (depends on 109) The method of claim 109, wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 46. ### Claim 112 (depends on 109) The method of claim 109, wherein the OX40 agonist antibody comprises (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 22; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 25; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (f) HVR-L3 comprising an amino acid sequence selected from SEQ ID NO: 47. ### Claim 113 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprises a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 76, 78, 80, 82, 84, 86, 88, 90, 92, 94, 96, 98, 100, 102, 104, 106, 108, 110, 112, 114, 116, 118, 120, 128, 134, or 136. ### Claim 114 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprises a VL having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 77, 79, 81, 83, 85, 87, 89, 91, 93, 95, 97, 99, 101, 103, 105, 107, 109, 111, 113, 115, 117, 119, 121, 129, 135, or 137. ### Claim 115 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprises a VH sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 76. ### Claim 116 (depends on 115) The method of claim 115, wherein the OX40 agonist antibody retains the ability to bind to human OX40. ### Claim 117 (depends on 115, 116) The method of claim 115 or 116, wherein a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 76. ### Claim 118 (depends on 115, 116, 117) The method of any one of claims 115-117, 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: 22, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 23, and (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 24. ### Claim 119 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprises a VL having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of SEQ ID NO: 77. ### Claim 120 (depends on 119) The method of claim 119, wherein the OX40 agonist antibody retains the ability to bind to human OX40. ### Claim 121 (depends on 119, 120) The method of claim 119 or 120, wherein a total of 1 to 10 amino acids have been substituted, inserted, and/or deleted in SEQ ID NO: 77. ### Claim 122 (depends on 119, 120, 121) The method of any one of claims 119-121, 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: 25; (b) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 26; and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 27. ### Claim 123 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 76. ### Claim 124 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 77. ### Claim 125 The method of any one of the preceding claims, wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 76 and a VL sequence of SEQ ID NO: 77. ### Claim 126 (depends on 1, 122) The method of any one of claims 1-122, wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 114. ### Claim 127 (depends on 1, 122) The method of any one of claims 1-122, wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 115. ### Claim 128 (depends on 1, 122, 126) The method of any one of claims 1-122, 126, and 127, wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 114 and a VL sequence of SEQ ID NO: 115. ### Claim 129 (depends on 1, 122) The method of any one of claims 1-122, wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 116. ### Claim 130 (depends on 1, 122) The method of any one of claims 1-122, wherein the OX40 agonist antibody comprises a VL sequence of SEQ ID NO: 117. ### Claim 131 (depends on 1, 122, 129) The method of any one of claims 1-122, 129, and 130, wherein the OX40 agonist antibody comprises a VH sequence of SEQ ID NO: 116 and a VL sequence of SEQ ID NO: 117. ### Claim 132 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 200; (b) a light chain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 201; or (c) both a heavy chain as in (a) and a light chain as in (b). ### Claim 133 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 203; (b) a light chain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 204; or (c) both a heavy chain as in (a) and a light chain as in (b). ### Claim 134 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 205; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 206; or (c) both a VH as in (a) and a VL as in (b). ### Claim 135 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 207; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 208; or (c) both a VH as in (a) and a VL as in (b). ### Claim 136 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 209; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 210; or (c) both a VH as in (a) and a VL as in (b). ### Claim 137 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 211; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 212; or (c) both a VH as in (a) and a VL as in (b). ### Claim 138 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a heavy chain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 213; (b) a light chain comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 214; or (c) both a heavy chain as in (a) and a light chain as in (b). ### Claim 139 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 215; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 216; or (c) both a VH as in (a) and a VL as in (b). ### Claim 140 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 217; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 218; or (c) both a VH as in (a) and a VL as in (b). ### Claim 141 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 219; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 220; or (c) both a VH as in (a) and a VL as in (b). ### Claim 142 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 219; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 221; or (c) both a VH as in (a) and a VL as in (b). ### Claim 143 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 222; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 220; or (c) both a VH as in (a) and a VL as in (b). ### Claim 144 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 222; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 221; or (c) both a VH as in (a) and a VL as in (b). ### Claim 145 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 223; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 220; or (c) both a VH as in (a) and a VL as in (b). ### Claim 146 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 223; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 221; or (c) both a VH as in (a) and a VL as in (b). ### Claim 147 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 224; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 225; or (c) both a VH as in (a) and a VL as in (b). ### Claim 148 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 224; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 226; or (c) both a VH as in (a) and a VL as in (b). ### Claim 149 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 227; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 225; or (c) both a VH as in (a) and a VL as in (b). ### Claim 150 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 227; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 226; or (c) both a VH as in (a) and a VL as in (b). ### Claim 151 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 228; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 225; or (c) both a VH as in (a) and a VL as in (b). ### Claim 152 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody comprises (a) a VH comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 228; (b) a VL comprising an amino acid sequence having at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 226; or (c) both a VH as in (a) and a VL as in (b). ### Claim 153 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108) The method of any one of claims 80-108, wherein the OX40 agonist antibody is antibody L106, antibody ACT35, MEDI6469, or MEDI0562. ### Claim 154 (depends on 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153) The method of any one of claims 80-153, wherein the OX40 agonist antibody is a full-length IgG1 antibody. ### Claim 155 (depends on 80) The method of claim 80, wherein the OX40 immunoadhesin is a trimeric OX40-Fc protein. ### Claim 156 (depends on 1, 2, 12, 13, 23, 24) The method of any one of claims 1, 2, 12, 13, 23-24, and 49-155, 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. ### Claim 157 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 42, 156) The method of any one of claims 1-11 and 42-156, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered continuously. ### Claim 158 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 42, 156) The method of any one of claims 1-11 and 42-156, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered intermittently. ### Claim 159 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 42, 158) The method of any one of claims 1-11 and 42-158, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered before the OX40 binding agonist. ### Claim 160 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 42, 158) The method of any one of claims 1-11 and 42-158, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered simultaneous with the OX40 binding agonist. ### Claim 161 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 42, 158) The method of any one of claims 1-11 and 42-158, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered after the OX40 binding agonist. ### Claim 162 (depends on 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 49, 156) The method of any one of claims 12-41 and 49-156, wherein the OX40 binding agonist is administered before the agent that modulates CD226 expression and/or activity. ### Claim 163 (depends on 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 49, 156) The method of any one of claims 12-41 and 49-156, wherein the OX40 binding agonist is administered simultaneous with the agent that modulates CD226 expression and/or activity. ### Claim 164 (depends on 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 49, 156) The method of any one of claims 12-41 and 49-156, wherein the OX40 binding agonist is administered after the agent that modulates CD226 expression and/or activity. ### Claim 165 (depends on 42, 43, 44, 49, 156) The method of any one of claims 42-44 and 49-156, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered before the agent that decreases or inhibits one or more additional immune co-inhibitory receptors. ### Claim 166 (depends on 42, 43, 44, 49, 156) The method of any one of claims 42-44 and 49-156, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered simultaneous with the agent that decreases or inhibits one or more additional immune co-inhibitory receptors. ### Claim 167 (depends on 42, 43, 44, 49, 156) The method of any one of claims 42-44 and 49-156, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered after the agent that decreases or inhibits one or more additional immune co-inhibitory receptors. ### Claim 168 (depends on 45, 156) The method of any one of claims 45-156, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered before the agent that increases or activates one or more additional immune co-stimulatory receptors or their ligands. ### Claim 169 (depends on 45, 156) The method of any one of claims 45-156, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered simultaneous with the agent that increases or activates one or more additional immune co-stimulatory receptors or their ligands. ### Claim 170 (depends on 45, 156) The method of any one of claims 45-156, wherein the agent that decreases or inhibits TIGIT expression and/or activity is administered after the agent that increases or activates one or more additional immune co-stimulatory receptors or their ligands. ### Claim 171 (depends on 42, 43, 44, 49, 156) The method of any one of claims 42-44 and 49-156, wherein the OX40 binding agonist is administered before the agent that decreases or inhibits one or more additional immune co-inhibitory receptors. ### Claim 172 (depends on 42, 43, 44, 49, 156) The method of any one of claims 42-44 and 49-156, wherein the OX40 binding agonist is administered simultaneous with the agent that decreases or inhibits one or more additional immune co-inhibitory receptors. ### Claim 173 (depends on 42, 43, 44, 49, 156) The method of any one of claims 42-44 and 49-156, wherein the OX40 binding agonist is administered after the agent that decreases or inhibits one or more additional immune co-inhibitory receptors. ### Claim 174 (depends on 45, 156) The method of any one of claims 45-156, wherein the OX40 binding agonist is administered before the agent that increases or activates one or more additional immune co-stimulatory receptors or their ligands. ### Claim 175 (depends on 45, 156) The method of any one of claims 45-156, wherein the OX40 binding agonist is administered simultaneous with the agent that increases or activates one or more additional immune co-stimulatory receptors or their ligands. ### Claim 176 (depends on 45, 156) The method of any one of claims 45-156, wherein the OX40 binding agonist is administered after the agent that increases or activates one or more additional immune co-stimulatory receptors or their ligands. ### Claim 177 A kit comprising an OX40 binding agonist and a package insert comprising instructions for using the OX40 binding agonist in combination with an agent that decreases or inhibits TIGIT expression and/or activity to treat or delay progression of cancer in an individual. ### Claim 178 A kit comprising an OX40 binding agonist and an agent that decreases or inhibits TIGIT expression and/or activity, and a package insert comprising instructions for using the OX40 binding agonist and the agent that decreases or inhibits TIGIT expression and/or activity to treat or delay progression of cancer in an individual. ### Claim 179 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 OX40 binding agonist to treat or delay progression of cancer in an individual. ### Claim 180 A kit comprising an OX40 binding agonist and a package insert comprising instructions for using the OX40 binding agonist in combination with an agent that decreases or inhibits TIGIT expression and/or activity to enhance immune function of an individual having cancer. ### Claim 181 A kit comprising an OX40 binding agonist and an agent that decreases or inhibits TIGIT expression and/or activity, and a package insert comprising instructions for using the OX40 binding agonist and the agent that decreases or inhibits TIGIT expression and/or activity to enhance immune function of an individual having cancer. ### Claim 182 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 OX40 binding agonist to enhance immune function of an individual having cancer. ### Claim 183 A kit comprising an OX40 binding agonist and a package insert comprising instructions for using the OX40 binding agonist in combination with an agent that modulates CD226 expression and/or activity to treat or delay progression of cancer in an individual. ### Claim 184 A kit comprising an OX40 binding agonist and an agent that modulates CD226 expression and/or activity, and a package insert comprising instructions for using the OX40 binding agonist and the agent that modulates CD226 expression and/or activity to treat or delay progression of cancer in an individual. ### Claim 185 A kit comprising an agent that modulates CD226 expression and/or activity and a package insert comprising instructions for using the agent modulates CD226 expression and/or activity in combination with an OX40 binding agonist to treat or delay progression of cancer in an individual. ### Claim 186 A kit comprising an OX40 binding agonist and a package insert comprising instructions for using the OX40 binding agonist in combination with an agent that modulates CD226 expression and/or activity to enhance immune function of an individual having cancer. ### Claim 187 A kit comprising an OX40 binding agonist and an agent that modulates CD226 expression and/or activity, and a package insert comprising instructions for using the OX40 binding agonist and the agent that modulates CD226 expression and/or activity to enhance immune function of an individual having cancer. ### Claim 188 A kit comprising an agent modulates CD226 expression and/or activity and a package insert comprising instructions for using the agent that modulates CD226 expression and/or activity in combination with an OX40 binding agonist to enhance immune function of an individual having cancer.