Methods of treating or delaying progression of cancer or immune related disease using the combination of Anti- PD-l1 antagonist antibodies and Anti-tigit antagonist antibodies

Abstract

The present disclosure describes combination treatment comprising an anti-PD-L1 antagonist antibody and an anti-TIGIT antagonist antibody and methods for use thereof, including methods of (1) delaying progression of cancer or reducing or inhibiting cancer relapse or cancer progression or (2) treating or delaying progression of an immune related disease or reducing or inhibiting progression of an immune related disease.

Description

METHODS OF TREATING OR DELAYING PROGRESSION OF CANCER OR AN IMMUNE RELATED DISEASE USING THE COMBINATION OF ANTI-PD-L1 ANTAGONIST ANTIBODIES AND ANTI-TIGIT ANTAGONIST ANTIBODIES CROSS REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the priority benefit of U.S. Provisional Application No. 61 / 846,941, filed July 16, 2013, U.S. Provisional Application No. 61 / 865,582, filed August 13, 2013, U.S. Provisional Application No. 61 / 950,754, filed March 10, 2014, U.S. Provisional Application No. 61 / 985,884, filed April 29, 2014, and U.S. Provisional Application No. 61 / 992,109, filed May, 12, 2014. SEQUENCE LISTING

[0002] This description contains a sequence listing in electronic form in ASCII text format. A copy of the sequence listing is available from the Canadian Intellectual Property Office. BACKGROUND OF THE INVENTION

[0003] The provision of two distinct signals to T-cells is a widely accepted model for lymphocyte activation of resting T lymphocytes by antigen-presenting cells (APCs). Lafferty et al, Aust. J. Exp. Biol. Med. ScL 53: 27-42 (1975). This model further provides for the discrimination of self from non-self and immune tolerance. Bretscher et al, Science 169: 1042-1049 (1970); Bretscher, P.A., P.N.A.S. USA 96: 185-190 (1999); Jenkins et al, J. Exp. Med. 165: 302-319 (1987). The primary signal, or antigen specific signal, is transduced through the T- cell receptor (TCR) following recognition of foreign antigen peptide presented in the context of the major histocompatibility-complex (MHC). The second or co-stimulatory signal is delivered to T-cells by co-stimulatory molecules expressed on antigen-presenting cells (APCs), and induce T-cells to promote clonal expansion, cytokine secretion and effector function. Lenschow et al., Ann. Rev. Immunol. 14:233 (1996). In the absence of co-stimulation, T-cells can become refractory to antigen stimulation, which results in a tolerogenic response to either foreign or endogenous antigens.

[0004] In the two-signal model, T-cells receive both positive co-stimulatory and negative co- inhibitory signals. The regulation of such positive and negative signals is critical to maximize the host's protective immune responses, while maintaining immune tolerance and preventing autoimmunity. Negative signals seem necessary for induction of T-cell tolerance, while positive signals promote T-cell activation.

[0005] Both co-stimulatory and co-inhibitory signals are provided to antigen-exposed T cells, and the interplay between co-stimulatory and co-inhibitory signals is essential to controlling the magnitude of an immune response. Further, the signals provided to the T cells change as an infection or immune provocation is cleared, worsens, or persists, and these changes powerfully affect the responding T cells and re-shape the immune response.

[0006] The mechanism of co-stimulation is of therapeutic interest because the manipulation of co-stimulatory signals has shown to provide a means to either enhance or terminate cell-based immune response. Recently, it has been discovered that T cell dysfunction or anergy occurs concurrently with an induced and sustained expression of the inhibitory receptor, programmed death 1 polypeptide (PD-1). As a result, therapeutic targeting of PD-1 and other molecules which signal through interactions with PD-1, such as programmed death ligand 1 (PD-Ll) and programmed death ligand 2 (PD-L2) are an area of intense interest.

[0007] PD-L1 is overexpressed in many cancers and is often associated with poor prognosis (Okazaki T et al., Intern. Immun. 2007 19(7):813) (Thompson RH et al., Cancer Res 2006, 66(7):3381). Interestingly, the majority of tumor infiltrating T lymphocytes predominantly express PD-1, in contrast to T lymphocytes in normal tissues and peripheral blood T lymphocytes indicating that up-regulation of PD-1 on tumor-reactive T cells can contribute to impaired antitumor immune responses (Blood 2009 114(8):1537). This may be due to exploitation of PD-L1 signaling mediated by PD-L1 expressing tumor cells interacting with PD-1 expressing T cells to result in attenuation of T cell activation and evasion of immune surveillance (Sharpe et al., Nat Rev 2002) (Keir ME et al., 2008 Annu. Rev. Immunol. 26:677). Therefore, inhibition of the PD-L1 / PD- 1 interaction may enhance CD8+ T cell-mediated killing of tumors.

[0008] The inhibition of PD-1 axis signaling through its direct ligands (e.g., PD-Ll, PD-L2) has been proposed as a means to enhance T cell immunity for the treatment of cancer (e.g., tumor immunity). Moreover, similar enhancements to T cell immunity have been observed by inhibiting the binding of PD-L1 to the binding partner B7-1. Furthermore, combining inhibition of PD-1 signaling with other signaling pathways that are deregulated in tumor cells may further enhance treatment efficacy. There remains a need for such an optimal therapy for treating, stabilizing, preventing, and / or delaying development of various cancers.

[0009] <deleted> BRIEF SUMMARY OF THE INVENTION

[0010] The present invention describes a combination treatment comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity.

[0011] Provided herein are methods for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity.

[0012] Provided herein are also methods for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity.

[0013] Provided herein are also methods for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity.

[0014] Provided herein are also methods for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity.

[0015] In some embodiments, the immune related disease is associated with a T cell dysfunctional disorder. In some embodiments, the T cell dysfunctional disorder is characterized by decreased responsiveness to antigenic stimulation. In some embodiments, the T cell dysfunctional disorder is characterized by T cell anergy or decreased ability to secrete cytokines, proliferate or execute cytolytic activity. In some embodiments, the T cell dysfunctional disorder is characterized by T cell exhaustion. In some embodiments, the T cells are CD4+ and CD8+ T cells. In some embodiments, the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection and tumor immunity.

[0016] Provided herein are also methods of increasing, enhancing or stimulating an immune response or function in an individual by administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity.

[0017] Provided herein are also methods of treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity.

[0018] Provided herein are also methods for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity.

[0019] Provided herein are also methods for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity.

[0020] Provided herein are also methods for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and agent that modulates the CD226 expression and / or activity.

[0021] In some embodiments, the immune related disease is associated with a T cell dysfunctional disorder. In some embodiments, the T cell dysfunctional disorder is characterized by decreased responsiveness to antigenic stimulation. In some embodiments, the T cell dysfunctional disorder is characterized by T cell anergy, or decreased ability to secrete cytokines, proliferate or execute cytolytic activity. In some embodiments, the T cell dysfunctional disorder is characterized by T cell exhaustion. In some embodiments, the T cells are CD4+ and CD8+ T cells. In some embodiments, the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection and tumor immunity.

[0022] Provided herein are also methods of increasing, enhancing or stimulating an immune response or function in an individual by administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity.

[0023] In some embodiments, the agent that modulates the CD226 expression and / or activity is capable of increasing and / or stimulating CD226 expression and / or activity.

[0024] In some embodiments, the agent that modulates the CD226 expression and / or activity is selected from 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 intracellular signaling mediated by TIGIT binding to PVR.

[0025] In some embodiments, 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, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or antigen-binding fragment thereof.

[0026] In some embodiments, 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. In some embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or antigen-binding fragment thereof.

[0027] In some embodiments, the antagonist of PVR 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.

[0028] In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVR is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0029] In some embodiments, the agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVR is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0030] The present invention also describes a combination treatment comprising 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.

[0031] Provided herein are methods of increasing, enhancing or stimulating an immune response or function in an individual by administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity and an agent that decreases or inhibits one or more additional immune co-inhibitory receptors.

[0032] In some embodiments, the one or more additional immune co-inhibitory receptor is selected from the group consisting of PD-1, CTLA-4, LAG3, TIM3, BTLA and VISTA. In some embodiments, the one or more additional immune co-inhibitory receptor is selected from the group of PD-1, CTLA-4, LAG3 and TIM3.

[0033] The present invention also describes a combination treatment comprising 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 receptor.

[0034] Provided herein are methods of increasing, enhancing or stimulating an immune response or function in an individual by administering to the individual 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 receptor.

[0035] In some embodiments, the one or more additional immune co-stimulatory receptor is selected from the group consisting of CD226, OX-40, CD28, CD27, CD137, HVEM, and GITR. In some embodiments, the one or more additional immune co-stimulatory receptor is selected from the group of CD226, OX-40, CD27, CD137, HVEM and GITR. In some embodiments, the one or more additional immune co-stimulatory receptor is selected from the group consisting of OX-40 and CD27.

[0036] In some embodiments, any of the above methods further comprise administering at least one chemotherapeutic agent.

[0037] In some embodiments, the individual in any of the above methods has cancer. In some embodiments, the individual in any of the above methods is a human.

[0038] In some embodiments, the 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.

[0039] In some embodiments, the number of CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination. In some embodiments, the number of activated CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination. In some embodiments, the activated CD4 and / or CD8 T cells is characterized by γ-IFN+ producing CD4 and / or CD8 T cells and / or enhanced cytolytic activity relative to prior to the administration of the combination. In some embodiments, the CD4 and / or CD8 T cells exhibit increased release of cytokines selected from the group consisting of IFN-<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>, TNF-<semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>, and interleukins.

[0040] In some embodiments, the CD4 and / or CD8 T cell is an effector memory T cell. In some embodiments, the CD4 and / or CD8 effector memory T cell is characterized by γ-IFN+ producing CD4 and / or CD8 T cells and / or enhanced cytolytic activity. In some embodiments, the CD4 and / or CD8 effector memory T cell is characterized by having the expression of CD44high CD62Llow.

[0041] In some embodiments, the cancer in any of the above methods has elevated levels of T cell infiltration.

[0042] In some embodiments, 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, and an agent that inhibits the interaction and / or the intracellular signaling mediated by TIGIT binding to PVR.

[0043] In some embodiments, 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.

[0044] In some embodiments, 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.

[0045] In some embodiments, the agent that inhibits 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.

[0046] In some embodiments, the antagonist of TIGIT expression and / or activity is an anti- TIGIT antibody or antigen-binding fragment thereof.

[0047] In some embodiments, 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 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 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).

[0048] In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDG TKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNR FSGVPDRFSGSGSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14).

[0049] In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a heavy chain comprising the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGI VFYADAVRGRFTISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQG TLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGG TSYNQKFKGKATLTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQG TSVTVSS (SEQ ID NO:16).

[0050] In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises a light chain comprising the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDG TKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNR FSGVPDRFSGSGSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14) and the antibody heavy chain comprises the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGI VFYADAVRGRFTISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQG TLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGG TSYNQKFKGKATLTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQG TSVTVSS (SEQ ID NO:16).

[0051] In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof, wherein the antibody is selected from a humanized antibody, a chimeric antibody, a bispecific antibody, a heteroconjugate antibody, and an immunotoxin.

[0052] In some embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR is at least 90% identical to an HVR set forth in any 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), and RPLGHNTFDS (SEQ ID NO:6) or 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)...

[0053] In some embodiments, the anti-TIGIT antibody or fragment thereof comprises the light chain and / or heavy chain comprising amino acid sequences at least 90% identical to the amino acid sequences set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGDG TKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNR FSGVPDRFSGSGSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14), or EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGI VFYADAVRGRFTISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQG TLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGG TSYNQKFKGKATLTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQG TSVTVSS (SEQ ID NO:16), respectively.

[0054] In some embodiments, 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.

[0055] In some embodiments, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to its ligand binding partners. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In some embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. In some embodiments, the PD-1 binding antagonist is an antibody. In some embodiments, the PD-1 binding antagonist is MDX-1106 (nivolumab). In some embodiments, the PD-1 binding antagonist is Merck 3475 (lambrolizumab). In some embodiments, the PD-1 binding antagonist is CT-011 (pidilizumab). In some embodiments, the PD-1 binding antagonist is AMP-224.

[0056] In some embodiments, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In some embodiments, the PD-L1 binding antagonist inhibits the binding of PD- L1 to PD-1. In some embodiments, the PD-L1 binding antagonist inhibits the binding of PD- L1 to B7-1. In some embodiments, the PD-L1 binding antagonist inhibits the binding of PD- L1 to both PD-1 and B7-1. In some embodiments, the PD-L1 binding antagonist is an antibody.

[0057] In some embodiments, the PD-L1 binding antagonist is selected from the group consisting of: YW243.55.S70, MPDL3280A, MDX-1105 and MEDI 4736.

[0058] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22).

[0059] In some embodiments, the anti-PD-L1 antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSA (SEQ ID NO:23) and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24).

[0060] In some embodiments, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some embodiments, the PD-L2 binding antagonist is an antibody. In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

[0061] In some embodiments, the cancer being treated 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.

[0062] In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered continuously. In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered intermittently. In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered before the PD-1 axis binding antagonist. In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered simultaneous with the PD-1 axis binding antagonist. In some embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered after the PD-1 axis binding antagonist.

[0063] Also provided herein are kits comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity to treat or delay progression of cancer in an individual.

[0064] Also provided herein are kits comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the agent that decreases or inhibits TIGIT expression and / or activity to treat or delay progression of cancer in an individual.

[0065] Also provided herein are kits 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 a PD-1 axis binding antagonist to treat or delay progression of cancer in an individual.

[0066] Also provided herein are kits comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity to enhance immune function of an individual having cancer.

[0067] Also provided herein are kits comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the agent that decreases or inhibits TIGIT expression and / or activity to enhance immune function of an individual having cancer.

[0068] Also provided herein are kits 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 a PD-1 axis binding antagonist to enhance immune function of an individual having cancer.

[0069] Also provided herein are kits comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates the CD226 expression and / or activity to treat or delay progression of cancer in an individual.

[0070] Also provided herein are kits comprising a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the agent that modulates the CD226 expression and / or activity to treat or delay progression of cancer in an individual.

[0071] Also provided herein are kits comprising an agent that modulates the CD226 expression and / or activity and a package insert comprising instructions for using the agent modulates the CD226 expression and / or activity in combination with a PD-1 axis binding antagonist to treat or delay progression of cancer in an individual.

[0072] Also provided herein are kits comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates the CD226 expression and / or activity to enhance immune function of an individual having cancer.

[0073] Also provided herein are kits comprising a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the agent that modulates the CD226 expression and / or activity to enhance immune function of an individual having cancer.

[0074] Also provided herein are kits comprising an agent modulates the CD226 expression and / or activity and a package insert comprising instructions for using the agent that modulates the CD226 expression and / or activity in combination with a PD-1 axis binding antagonist to enhance immune function of an individual having cancer.

[0075] In some embodiments, the kits comprising the PD-1 axis binding antagonist is an anti-PD-L1 antibody. In some embodiments, the kits comprising the PD-1 axis binding antagonist is an anti-PD-1 antibody. In some embodiments, the kits comprising 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, and an agent that inhibits the interaction and / or the intracellular signaling mediated by TIGIT binding to PVR. In some embodiments, the kits comprising the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or antigen-binding fragment thereof.

[0076] In some embodiments, the kits comprises an agent that modulates the CD226 expression and / or activity which is capable of increasing and / or stimulating CD226 expression and / or activity. In some embodiments, the kits comprising the agent that modulates the CD226 expression and / or activity is selected from 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 intracellular signaling mediated by TIGIT binding to PVR. In some embodiments, the kits comprising the agent that inhibits and / or blocks the interaction of CD226 with TIGIT and / or the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or antigen-binding fragment thereof.

[0077] In certain aspects, the present disclosure provides a method for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for treating or delaying progression of cancer in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity in the manufacture of a medicament for treating or delaying progression of cancer in an individual, wherein the an agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in treating or delaying progression of cancer in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits TIGIT expression and / or activity for use in treating or delaying progression of cancer in combination with a PD-1 axis binding antagonist.

[0078] In other aspects, the present disclosure provides a method for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for reducing or inhibiting cancer relapse or cancer progression in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity in the manufacture of a medicament for reducing or inhibiting cancer relapse or cancer progression in an individual, wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD- 1 axis binding antagonist for use in reducing or inhibiting cancer relapse or cancer progression in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits TIGIT expression and / or activity for use in reducing or inhibiting cancer relapse or cancer progression in combination with a PD-1 axis binding antagonist.

[0079] In other aspects, the present disclosure provides a method for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for treating or delaying progression of an immune related disease in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity in the manufacture of a medicament for treating or delaying progression of an immune related disease in an individual, wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD- 1 axis binding antagonist for use in treating or delaying progression of an immune related disease in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits TIGIT expression and / or activity for use in treating or delaying progression of an immune related disease in combination with a PD-1 axis binding antagonist.

[0080] In other aspects, the present disclosure provides a combination comprising an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity.

[0081] In other aspects, the present disclosure provides a method for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for reducing or inhibiting progression of an immune related disease in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity in the manufacture of a medicament for reducing or inhibiting progression of an immune related disease in an individual, wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in reducing or inhibiting progression of an immune related disease in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits TIGIT expression and / or activity for use in reducing or inhibiting progression of an immune related disease in combination with a PD-1 axis binding antagonist.

[0082] In certain embodiments that may be combined with any of the preceding embodiments, the immune related disease is associated with a T cell dysfunctional disorder. In certain embodiments that may be combined with any of the preceding embodiments, the immune related disease is a viral infection. In certain embodiments that may be combined with any of the preceding embodiments, the viral infection is a chronic viral infection. In certain embodiments that may be combined with any of the preceding embodiments, the T cell dysfunctional disorder is characterized by decreased responsiveness to antigenic stimulation. In certain embodiments that may be combined with any of the preceding embodiments, the T cell dysfunctional disorder is characterized by T cell anergy or decreased ability to secrete cytokines, proliferate or execute cytolytic activity. In certain embodiments that may be combined with any of the preceding embodiments, the T cell dysfunctional disorder is characterized by T cell exhaustion. In certain embodiments that may be combined with any of the preceding embodiments, the T cells are CD4+ and CD8+ T cells. In certain embodiments that may be combined with any of the preceding embodiments, the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity.

[0083] In other aspects, the present disclosure provides a method of increasing, enhancing or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD- 1 axis binding antagonist for use in enhancing or stimulating an immune response or function in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits TIGIT expression and / or activity for use in enhancing or stimulating an immune response or function in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a combination comprising an effective amount of a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity.

[0084] In other aspects, the present disclosure provides a method of treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for treating or delaying progression of cancer in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that modulates CD226 expression and / or activity in the manufacture of a medicament for treating or delaying progression of cancer in an individual, wherein the agent that modulates CD226 expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in treating or delaying progression of cancer in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates CD226 expression and / or activity for use in treating or delaying progression of cancer in combination with a PD-1 axis binding antagonist.

[0085] In other aspects, the present disclosure provides a method for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for reducing or inhibiting cancer relapse or cancer progression in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that modulates CD226 expression and / or activity in the manufacture of a medicament for reducing or inhibiting cancer relapse or cancer progression in an individual, wherein the agent that modulates CD226 expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in reducing or inhibiting cancer relapse or cancer progression in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates CD226 expression and / or activity for use in reducing or inhibiting cancer relapse or cancer progression in combination with a PD-1 axis binding antagonist.

[0086] In other aspects, the present disclosure provides a method for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for treating or delaying progression of an immune related disease in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that modulates CD226 expression and / or activity in the manufacture of a medicament for treating or delaying progression of an immune related disease in an individual, wherein the agent that modulates CD226 expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in treating or delaying progression of an immune related disease in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates CD226 expression and / or activity for use in treating or delaying progression of an immune related disease in combination with a PD-1 axis binding antagonist.

[0087] In other aspects, the present disclosure provides a combination comprising an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity.

[0088] In other aspects, the present disclosure provides a method for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for reducing or inhibiting progression of an immune related disease in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that modulates CD226 expression and / or activity in the manufacture of a medicament for reducing or inhibiting progression of an immune related disease in an individual, wherein the agent that modulates CD226 expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in reducing or inhibiting progression of an immune related disease in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates CD226 expression and / or activity for use in reducing or inhibiting progression of an immune related disease in combination with a PD-1 axis binding antagonist.

[0089] In certain embodiments that may be combined with any of the preceding embodiments, the immune related disease is associated with a T cell dysfunctional disorder. In certain embodiments that may be combined with any of the preceding embodiments, the immune related disease is a viral infection. In certain embodiments that may be combined with any of the preceding embodiments, the viral infection is a chronic viral infection. In certain embodiments that may be combined with any of the preceding embodiments, the T cell dysfunctional disorder is characterized by decreased responsiveness to antigenic stimulation. In certain embodiments that may be combined with any of the preceding embodiments, the T cell dysfunctional disorder is characterized by T cell anergy, or decreased ability to secrete cytokines, proliferate or execute cytolytic activity. In certain embodiments that may be combined with any of the preceding embodiments, the T cell dysfunctional disorder is characterized by T cell exhaustion. In certain embodiments that may be combined with any of the preceding embodiments, the T cells are CD4+ and CD8+ T cells. In certain embodiments that may be combined with any of the preceding embodiments, the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection and tumor immunity.

[0090] In other aspects, the present disclosure provides a method of increasing, enhancing, or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the PD-1 axis binding agent is used in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides use of an effective amount of an agent that modulates CD226 expression and / or activity in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the an agent that modulates CD226 expression and / or activity is used in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a pharmaceutical composition comprising a PD-1 axis binding antagonist for use in enhancing or stimulating an immune response or function in combination with an agent that modulates CD226 expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that modulates CD226 expression and / or activity for use in enhancing or stimulating an immune response or function in combination with a PD-1 axis binding antagonist. In other aspects, the present disclosure provides a combination comprising an effective amount of a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity.

[0091] In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that increases and / or stimulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that increases and / or stimulates the interaction of CD226 with PVR. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that inhibits and / or blocks the interaction of CD226 with TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the antisense polynucleotide targets TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the interfering RNA targets TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the catalytic RNA targets TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the RNA-DNA chimera targets TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an antagonist of TIGIT expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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.

[0092] In other aspects, the present disclosure provides a method of increasing, enhancing, or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity and an agent that decreases or inhibits one or more additional immune co- inhibitory receptors. In other aspects, the present disclosure provides use of an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with an agent that decreases or inhibits one or more additional immune co-inhibitory receptors. In other aspects, the present disclosure provides use of an effective amount of an agent that decreases or inhibits one or more additional immune co- inhibitory receptors in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the agent that decreases or inhibits one or more additional immune co-inhibitory receptors is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits TIGIT expression and / or activity for use in enhancing or stimulating an immune response or function in combination with an agent that decreases or inhibits one or more additional immune co-inhibitory receptors. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits one or more additional immune co-inhibitory receptors for use in enhancing or stimulating an immune response or function in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a combination comprising 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the one or more additional immune co-inhibitory receptor is selected from the group consisting of PD-1, CTLA-4, LAG3 and TIM3.

[0093] In other aspects, the present disclosure provides a method of increasing, enhancing, or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity and an agent that increases or activates one or more additional immune co- stimulatory receptors. In other aspects, the present disclosure provides use of an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the agent that decreases or inhibits TIGIT expression and / or activity is used in combination with an agent that increases or activates one or more additional immune co-stimulatory receptors. In other aspects, the present disclosure provides use of an effective amount of an a agent that increases or activates one or more additional immune co- stimulatory receptors in the manufacture of a medicament for enhancing or stimulating an immune response or function in an individual, wherein the a agent that increases or activates one or more additional immune co-stimulatory receptors is used in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that decreases or inhibits TIGIT expression and / or activity for use in enhancing or stimulating an immune response or function in combination with an agent that increases or activates one or more additional immune co-stimulatory receptors. In other aspects, the present disclosure provides a pharmaceutical composition comprising an agent that increases or activates one or more additional immune co-stimulatory receptors for use in enhancing or stimulating an immune response or function in combination with an agent that decreases or inhibits TIGIT expression and / or activity. In other aspects, the present disclosure provides a combination comprising 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. In certain embodiments that may be combined with any of the preceding embodiments, the one or more additional immune co-stimulatory receptors is selected from the group consisting of CD226, OX-40, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS, NKG2D, and 2B4. In certain embodiments that may be combined with any of the preceding embodiments, the one or more additional immune co-stimulatory receptors is selected from the group consisting of CD226, OX-40, CD27, CD137, HVEM and GITR. In certain embodiments that may be combined with any of the preceding embodiments, the one or more additional immune co-stimulatory receptors is selected from the group consisting of OX-40 and CD27.

[0094] In certain embodiments that may be combined with any of the preceding embodiments, the method further comprises administering at least one chemotherapeutic agent. In certain embodiments that may be combined with any of the preceding embodiments, the individual has cancer. In certain embodiments that may be combined with any of the preceding embodiments, the individual is a human. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the number of CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination. In certain embodiments that may be combined with any of the preceding embodiments, the number of activated CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination. In certain embodiments that may be combined with any of the preceding embodiments, activated CD4 and / or CD8 T cells are characterized by γ-IFN+ producing CD4 and / or CD8 T cells and / or enhanced cytolytic activity relative to prior to the administration of the combination. In certain embodiments that may be combined with any of the preceding embodiments, the CD4 and / or CD8 T cells exhibit increased release of cytokines selected from the group consisting of IFN- <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>, TNF-<semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> and interleukins. In certain embodiments that may be combined with any of the preceding embodiments, the CD4 and / or CD8 T cells are effector memory T cells. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the CD4 and / or CD8 effector memory T cells are characterized by having the expression of CD44high CD62Llow. In certain embodiments that may be combined with any of the preceding embodiments, the cancer has elevated levels of T cell infiltration. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the antisense polynucleotide targets TIGIT.

[0095] In certain embodiments that may be combined with any of the preceding embodiments, the interfering RNA targets TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the catalytic RNA targets TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the RNA-DNA chimera targets TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is an anti- TIGIT antibody or antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or antigen- binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from the amino acid sequences (1) KSSQSLYYSGVKENLLA (SEQ ID NO:1), ASIRFT (SEQ ID NO:2), QQGINNPLT (SEQ ID NO:3), GFTFSSFTMH (SEQ ID NO:4), FIRSGSGIVFYADAVRG (SEQ ID NO:5), and RPLGHNTFDS (SEQ ID NO:6); or (2) RSSQSLVNSYGNTFLS (SEQ ID NO:7), GISNRFS (SEQ ID NO:8), LQGTHQPPT (SEQ ID NO:9), GYSFTGHLMN (SEQ ID NO:10), LIIPYNGGTSYNQKFKG (SEQ ID NO:11), and GLRGFYAMDY (SEQ ID NO:12). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or antigen- binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGD GTKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISN RFSGVPDRFSGSGSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof, wherein the antibody heavy chain comprises the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSG IVFYADAVRGRFTISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQ GTLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNG GTSYNQKFKGKATLTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWG QGTSVTVSS (SEQ ID NO:16). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGD GTKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISN RFSGVPDRFSGSGSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14), and the antibody heavy chain comprises the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSG IVFYADAVRGRFTISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQ GTLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNG GTSYNQKFKGKATLTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWG QGTSVTVSS (SEQ ID NO: 16). In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR that is at least 90% identical to an HVR set forth in any one of (1) KSSQSLYYSGVKENLLA (SEQ ID NO:1), ASIRFT (SEQ ID NO:2), QQGINNPLT (SEQ ID NO:3), GFTFSSFTMH (SEQ ID NO:4), FIRSGSGIVFYADAVRG (SEQ ID NO:5), and RPLGHNTFDS (SEQ ID NO:6); or (2) RSSQSLVNSYGNTFLS (SEQ ID NO:7), GISNRFS (SEQ ID NO:8), LQGTHQPPT (SEQ ID NO:9), GYSFTGHLMN (SEQ ID NO:10), LIIPYNGGTSYNQKFKG (SEQ ID NO:11), and GLRGFYAMDY (SEQ ID NO:12). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or fragment thereof comprises the light chain comprising amino acid sequences at least 90% identical to the amino acid sequences set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGD GTKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISN RFSGVPDRFSGSGSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14); and / or the heavy chain comprising amino acid sequences at least 90% identical to the amino acid sequences set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSG IVFYADAVRGRFTISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQ GTLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNG GTSYNQKFKGKATLTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWG QGTSVTVSS (SEQ ID NO:16). In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to its ligand binding partners. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L2. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist inhibits the binding of PD-1 to both PD-L1 and PD-L2. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is an antibody. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is MDX- 1106. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is MK-3475. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is CT-011. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 binding antagonist is AMP-224. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is a PD-L1 binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1. In certain embodiments that may be combined with any of the preceding embodiments, the PD- L1 binding antagonist inhibits the binding of PD-L1 to B7-1. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist inhibits the binding of PD-L1 to both PD-1 and B7-1. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist is an anti- PD-L1 antibody. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L1 binding antagonist is selected from the group consisting of YW243.55.S70, MPDL3280A, MDX-1105, and MEDI4736. In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1antibody comprises a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22). In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSA (SEQ ID NO:23), EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSSASTK (SEQ ID NO:40), or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSS (SEQ ID NO:41), and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24). In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L2 binding antagonist is an antibody. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L2 binding antagonist is an immunoadhesin. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered continuously. In certain embodiments that may be combined with any of the preceding embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered intermittently. In certain embodiments that may be combined with any of the preceding embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered before the PD-1 axis binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered simultaneous with the PD-1 axis binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is administered after the PD-1 axis binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is administered before the agent that modulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is administered simultaneous with the agent that modulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is administered after the agent that modulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, 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.

[0096] In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity to treat or delay progression of cancer in an individual.

[0097] In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the agent that decreases or inhibits TIGIT expression and / or activity to treat or delay progression of cancer in an individual.

[0098] In other aspects, the present disclosure provides 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 a PD-1 axis binding antagonist to treat or delay progression of cancer in an individual.

[0099] In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity to enhance immune function of an individual having cancer.

[0100] In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and an agent that decreases or inhibits TIGIT expression and / or activity, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the agent that decreases or inhibits TIGIT expression and / or activity to enhance immune function of an individual having cancer.

[0101] In other aspects, the present disclosure provides 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 a PD-1 axis binding antagonist to enhance immune function of an individual having cancer.

[0102] In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates CD226 expression and / or activity to treat or delay progression of cancer in an individual.

[0103] In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the agent that modulates CD226 expression and / or activity to treat or delay progression of cancer in an individual.

[0104] In other aspects, the present disclosure provides 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 a PD-1 axis binding antagonist to treat or delay progression of cancer in an individual.

[0105] In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an agent that modulates CD226 expression and / or activity to enhance immune function of an individual having cancer.

[0106] In other aspects, the present disclosure provides a kit comprising a PD-1 axis binding antagonist and an agent that modulates CD226 expression and / or activity, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the agent that modulates CD226 expression and / or activity to enhance immune function of an individual having cancer.

[0107] In other aspects, the present disclosure provides 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 a PD-1 axis binding antagonist to enhance immune function of an individual having cancer.

[0108] In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody. In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1 antibody is selected from the group consisting of YW243.55.S70, MPDL3280A, MDX-1105 and MEDI4736. In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1antibody comprises a heavy chain comprising HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22). In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-L1antibody comprises a heavy chain variable region comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSA (SEQ ID NO:23), EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSSASTK (SEQ ID NO:40), or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSS (SEQ ID NO:41), and a light chain variable region comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24). In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is an anti-PD-1 antibody. In certain embodiments that may be combined with any of the preceding embodiments, the anti-PD-1 antibody is MDX-1106, MK-3475, or CT-011. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is AMP- 224. In certain embodiments that may be combined with any of the preceding embodiments, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L2 binding antagonist is an antibody. In certain embodiments that may be combined with any of the preceding embodiments, the PD-L2 binding antagonist is an immunoadhesin.

[0109] In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits TIGIT expression and / or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity in combination with an agent that decreases or inhibits one or more additional immune co- inhibitory receptors to treat or delay progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising 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, and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity and the agent that decreases or inhibits one or more additional immune co-inhibitory receptors to treat or delay progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits one or more additional immune co-inhibitory receptors and a package insert comprising instructions for using the agent that decreases or inhibits one or more additional immune co-inhibitory receptors in combination with an agent that decreases or inhibits TIGIT expression and / or activity to treat or delay progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits TIGIT expression and / or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity in combination with an agent that decreases or inhibits one or more additional immune co-inhibitory receptors to enhance immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising 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, and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity and the agent that decreases or inhibits one or more additional immune co-inhibitory receptors to enhance immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits one or more additional immune co-inhibitory receptors and a package insert comprising instructions for using the agent that decreases or inhibits one or more additional immune co-inhibitory receptors in combination with an agent that decreases or inhibits TIGIT expression and / or activity to enhance immune function of an individual having cancer. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the one or more additional immune co-inhibitory receptor is selected from the group consisting of PD-1, CTLA-4, LAG3 and TIM3.

[0110] In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits TIGIT expression and / or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity in combination with an agent that increases or activates one or more additional immune co- stimulatory receptors to treat or delay progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising 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, and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity and the agent that increases or activates one or more additional immune co-stimulatory receptors to treat or delay progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that increases or activates one or more additional immune co- stimulatory receptors and a package insert comprising instructions for using the agent that increases or activates one or more additional immune co-stimulatory receptors in combination with an agent that decreases or inhibits TIGIT expression and / or activity to treat or delay progression of cancer in an individual. In other aspects, the present disclosure provides a kit comprising an agent that decreases or inhibits TIGIT expression and / or activity and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity in combination with an agent that increases or activates one or more additional immune co-stimulatory receptors to enhance immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising 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, and a package insert comprising instructions for using the agent that decreases or inhibits TIGIT expression and / or activity and the agent that increases or activates one or more additional immune co- stimulatory receptors to enhance immune function of an individual having cancer. In other aspects, the present disclosure provides a kit comprising an agent that increases or activates one or more additional immune co-stimulatory receptors and a package insert comprising instructions for using the agent that increases or activates one or more additional immune co- stimulatory receptors in combination with an agent that decreases or inhibits TIGIT expression and / or activity to enhance immune function of an individual having cancer. In certain embodiments that may be combined with any of the preceding embodiments, the or more additional immune co-stimulatory receptor is selected from the group consisting of CD226, OX-40, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS, NKG2D, and 2B4. In certain embodiments that may be combined with any of the preceding embodiments, the one or more additional immune co-stimulatory receptor is selected from the group consisting of CD226, OX-40, CD27, CD137, HVEM and GITR. In certain embodiments that may be combined with any of the preceding embodiments, the one or more additional immune co- stimulatory receptor is selected from the group consisting of OX-40 and CD27.

[0111] In certain embodiments that may be combined with any of the preceding embodiments, the individual is a human. In certain embodiments that may be combined with any of the preceding embodiments, the agent that decreases or inhibits TIGIT expression and / or activity is selected from the group consisting of an antagonist of TIGIT expression and / or activity, an antagonist of PVR expression and / or activity, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVR, an agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVRL2, and an agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVRL3. In certain embodiments that may be combined with any of the preceding embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that increases and / or stimulates CD226 expression and / or activity. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that increases and / or stimulates the interaction of CD226 with PVR. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is selected from the group consisting of an agent that inhibits and / or blocks the interaction of CD226 with TIGIT, an antagonist of TIGIT expression and / or activity, an antagonist of PVR expression and / or activity, an agent that inhibits and / or blocks the interaction of TIGIT with PVR, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL2, an agent that inhibits and / or blocks the interaction of TIGIT with PVRL3, an agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVR, an agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVRL2, and an agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVRL3. In certain embodiments that may be combined with any of the preceding embodiments, the agent that modulates CD226 expression and / or activity is an agent that inhibits and / or blocks the interaction of CD226 with TIGIT. In certain embodiments that may be combined with any of the preceding embodiments, 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. In certain embodiments that may be combined with any of the preceding embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or antigen-binding fragment thereof. In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof comprises at least one HVR comprising an amino acid sequence selected from the amino acid sequences (1) KSSQSLYYSGVKENLLA (SEQ ID NO:1), ASIRFT (SEQ ID NO:2), QQGINNPLT (SEQ ID NO:3), GFTFSSFTMH (SEQ ID NO:4), FIRSGSGIVFYADAVRG (SEQ ID NO:5), and RPLGHNTFDS (SEQ ID NO:6); or (2) RSSQSLVNSYGNTFLS (SEQ ID NO:7), GISNRFS (SEQ ID NO:8), LQGTHQPPT (SEQ ID NO:9), GYSFTGHLMN (SEQ ID NO:10), LIIPYNGGTSYNQKFKG (SEQ ID NO:11), and GLRGFYAMDY (SEQ ID NO:12). In certain embodiments that may be combined with any of the preceding embodiments, the anti- TIGIT antibody or antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGD GTKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISN RFSGVPDRFSGSGSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof, wherein the antibody heavy chain comprises the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSG IVFYADAVRGRFTISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQ GTLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNG GTSYNQKFKGKATLTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWG QGTSVTVSS (SEQ ID NO:16). In certain embodiments that may be combined with any of the preceding embodiments, the anti-TIGIT antibody or antigen-binding fragment thereof, wherein the antibody light chain comprises the amino acid sequence set forth in DIVMTQSPSSLAVSPGEKVTMTCKSSQSLYYSGVKENLLAWYQQKPGQS PKLLIYYASIRFTGVPDRFTGSGSGTDYTLTITSVQAEDMGQYFCQQGINNPLTFGD GTKLEIKR (SEQ ID NO:13) or DVVLTQTPLSLSVSFGDQVSISCRSSQSLVNSYGNTFLSWYLHKPGQSPQLLIFGISNRFSG VPDRFSGSGSGTDFTLKISTIKPEDLGMYYCLQGTHQPPTFGPGTKLEVK (SEQ ID NO:14), and the antibody heavy chain comprises the amino acid sequence set forth in EVQLVESGGGLTQPGKSLKLSCEASGFTFSSFTMHWVRQSPGKGLEWVAFIRSGSGIVFY ADAVRGRFTISRDNAKNLLFLQMNDLKSEDTAMYYCARRPLGHNTFDSWGQGTLVTVSS (SEQ ID NO:15) or EVQLQQSGPELVKPGTSMKISCKASGYSFTGHLMNWVKQSHGKNLEWIGLIIPYNGGTSY NQKFKGKATLTVDKSSSTAYMELLSLTSDDSAVYFCSRGLRGFYAMDYWGQGTSVTVSS (SEQ ID NO: 16). [0111A] Various embodiments of the claimed invention relate to use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for (a) treating or delaying progression of cancer or (b) reducing or inhibiting cancer relapse or cancer progression in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111B] Various embodiments of the claimed invention also relate to use of an effective amount of an anti-TIGIT antagonist antibody in the manufacture of a medicament for (a) treating or delaying progression of cancer in an individual or (b) reducing or inhibiting cancer relapse or cancer progression in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111C] Various embodiments of the claimed invention also relate to use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111D] Various embodiments of the claimed invention also relate to use of an effective amount of an anti-TIGIT antagonist antibody in the manufacture of a medicament for (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111E] Various embodiments of the claimed invention also relate to use of an effective amount of a PD-1 axis binding antagonist in the manufacture of a medicament for stimulating an immune response or function in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. [0111F] Various embodiments of the claimed invention also relate to use of an effective amount of an anti-TIGIT antagonist antibody in the manufacture of a medicament for stimulating an immune response or function in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. [0111G] Various embodiments of the claimed invention also relate to use of a PD-1 axis binding antagonist for (a) treating or delaying progression of cancer or (b) reducing or inhibiting cancer relapse or cancer progression in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111H] Various embodiments of the claimed invention also relate to use of an anti-TIGIT antagonist antibody for (a) treating or delaying progression of cancer or (b) reducing or inhibiting cancer relapse or cancer progression in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111I] Various embodiments of the claimed invention also relate to use of a PD-1 axis binding antagonist for (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111J] Various embodiments of the claimed invention also relate to use of an anti-TIGIT antagonist antibody for (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111K] Various embodiments of the claimed invention also relate to use of a PD-1 axis binding antagonist for stimulating an immune response or function in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. [0111L] Various embodiments of the claimed invention also relate to use of an anti-TIGIT antagonist antibody for stimulating an immune response or function in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. [0111M] Various embodiments of the claimed invention also relate to a PD-1 axis binding antagonist for use in (a) treating or delaying progression of cancer or (b) reducing or inhibiting cancer relapse or cancer progression in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111N] Various embodiments of the claimed invention also relate to an anti-TIGIT antagonist antibody for use in (a) treating or delaying progression of cancer or (b) reducing or inhibiting cancer relapse or cancer progression in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody.

[01110] Various embodiments of the claimed invention also relate to a PD-1 axis binding antagonist for use in (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111P] Various embodiments of the claimed invention also relate to an anti-TIGIT antagonist antibody for use in (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. [0111Q] Various embodiments of the claimed invention also relate to a PD-1 axis binding antagonist for use in stimulating an immune response or function in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. [0111R] Various embodiments of the claimed invention also relate to an anti-TIGIT antagonist antibody for use in stimulating an immune response or function in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. [0111S] Various embodiments of the claimed invention also relate to a kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody to (a) treat or delay progression of cancer in an individual or (b) stimulate an immune function of an individual having cancer, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. [0111T] Various embodiments of the claimed invention also relate to a kit comprising a PD-1 axis binding antagonist, an anti-TIGIT antagonist antibody, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody to (a) treat or delay progression of cancer in an individual or (b) stimulate an immune function of an individual having cancer, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. [0111U] Various embodiments of the claimed invention also relate to a kit comprising an anti- TIGIT antagonist antibody and a package insert comprising instructions for using the anti-TIGIT antagonist antibody thereof in combination with a PD-1 axis binding antagonist to (a) treat or delay progression of cancer in an individual or (b) stimulate an immune function of an individual having cancer, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0112] FIG. 1 shows that TIGIT is highly expressed on exhausted CD8+ and CD4+ T cells. FIG. 1A depicts MACS-enriched C57BL6 / J splenic CD8+ T cells that were stimulated with plate-bound anti-CD3 and anti-CD28 for 24-48 hours in vitro. Flow cytometry histograms representative of TIGIT expression (red) relative to isotype staining (gray). Quantitation of TIGIT MFI is also shown. ***, <semantics>P<0.001<annotation encoding="application / x-tex">P < 0.001< / annotation>< / semantics>. Data are representative of 2 independent experiments; <semantics>n=3<annotation encoding="application / x-tex">n = 3< / annotation>< / semantics>. In FIG. 1B- 1C, C57BL6 / J mice were infected with Armstrong strain LCMV, and splenocytes were analyzed 7 days after infection. Data are representative of 2 independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. FIG. 1B shows flow cytometry histogram representative of TIGIT expression by naïve (CD44low CD62Lhigh) and effector memory (CD44high CD62Llow) CD4+ and CD8+ T cells. Quantitation of TIGIT MFI is also shown. ***, P < 0.001. FIG. 1C shows flow cytometry histogram representative of TIGIT expression by PD-1high and PD-1low effector memory CD8+ T cells. Quantitation of TIGIT MFI is also shown. ***, P < 0.001. FIG. 1D shows that C57BL6 / J mice were briefly depleted of CD4+ T cells and infected with Clone 13 strain LCMV. Splenocytes were analyzed 42 days after infection. Flow cytometry histogram representative of TIGIT expression by naïve (CD44low CD62Lhigh), central memory (CD44high CD62Lhigh), and effector memory (CD44high CD62Llow) CD8+ T cells. Quantitation of TIGIT MFI is also shown. ***, P < 0.001. Data are representative of 2 independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0113] FIG. 2 shows the design of TIGIT was flanked by loxP sites using standard techniques.

[0114] FIG. 3 shows that TIGIT-deficient CD8+ and CD4+ T cells respond normally to acute viral infection. TIGITfl / fl CD4cre (CKO) and TIGITfl / fl littermates (WT) were infected with Armstrong strain LCMV. Splenocytes were analyzed 7 days after infection. Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. FIG. 3A shows representative FACS plots gated on CD8+ T cells, with activated (CD44high) cells boxed. Quantitation of activated CD8+ T cells as a percentage of total CD8+ T cells. FIG. 3B shows representative FACS plots gated on CD8+ T cells after stimulation in vitro, with IFNγ-producing cells boxed. Quantitation of IFNg-producing cells as a percentage of total CD8+ T cells. FIG. 3C shows representative FACS plots gated on CD4+ T cells, with activated (CD44high) cells boxed. Quantitation of activated CD4+ T cells as a percentage of total CD4+ T cells. FIG. 3D shows representative FACS plots gated on CD4+ T cells after stimulation in vitro, with IFNg- producing cells boxed. Quantitation of IFNg-producing cells as a percentage of total CD4+ T cells. Error bars depict the standard error of the mean.

[0115] FIG. 4 shows that TIGIT and PD-1 synergistically regulate the effector function of exhausted T cells in vivo. In FIG. 4A-4E, TIGITfl / flCD4-cre- (WT) and TIGITfl / flCD4-cre+ (CKO) mice were briefly depleted of CD4+ T cells and infected with Clone 13 strain LCMV. Splenocytes and liver viral titers were analyzed 42 days after infection. Data are representative of 2 independent experiments, and <semantics>n=6−9<annotation encoding="application / x-tex">n = 6-9< / annotation>< / semantics> per group. FIG. 4A depicts representative FACS plots gated on CD8+ T cells, with activated cells (CD44high CD62Llow) boxed. Quantitation of activated cells as a percentage of total CD8+ T cells. FIG. 4B depicts representative FACS plots gated on CD8+ T cells after stimulation in vitro, with IFNy+ cells boxed. Quantitation of IFNγ-producing cells as a percentage of CD8+ T cells. FIG. 4C depicts representative FACS plots gated on CD4+ T cells, with activated cells (CD44high CD62Llow) boxed. Quantitation of activated cells as a percentage of total CD4+ T cells. FIG. 4D depicts representative FACS plots gated on CD4+ T cells after stimulation in vitro, with IFN<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>+ cells boxed. Quantitation of IFN<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-producing cells as a percentage of CD4+ T cells. FIG. 4E depicts quantitation of liver LCMV titers. ***, P < 0.0001. In FIG. 4F-4H, C57BL6 / J mice were briefly depleted of CD4+ T cells and infected with Clone 13 strain LCMV. Mice were treated with isotype-matched control, anti-PD-L1, anti-TIGIT, or anti-PD- L1 + anti-TIGIT antibodies starting 28 days after infection. Splenocytes and liver viral titers were analyzed 42 days after infection. Data are representative of 2 independent experiments; <semantics>n=10<annotation encoding="application / x-tex">n = 10< / annotation>< / semantics>. FIG. 4F depicts representative FACS plots gated on CD8+ T cells, with activated cells (CD44high CD62Llow) boxed. Quantitation of activated cells as a percentage of total CD8+ T cells. ***, P < 0.0001. FIG. 4G depicts representative FACS plots gated on activated CD8+ T cells after stimulation in vitro, with IFNy+ cells boxed. Quantitation of IFN<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-producing cells as a percentage of activated CD8+ T cells. *. P = 0.0352. **, P = 0.0047. FIG. 4H depicts quantitation of liver LCMV titers. *, <semantics>P=0.0106<annotation encoding="application / x-tex">P = 0.0106< / annotation>< / semantics>. **, <semantics>P=0.0047<annotation encoding="application / x-tex">P = 0.0047< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0116] FIG. 5 shows TIGIT / PD-L1 co-blockade enhances CD4+ T cell effector function during chronic viral infection. C57BL6 / J mice were depleted of CD4+ T cells and infected with Clone 13 strain LCMV. Mice were treated with isotype control, anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT antibodies from 28 days after infection. Splenocytes and liver viral titers were analyzed 42 days after infection. Data are representative of 2 independent experiments; <semantics>n=10<annotation encoding="application / x-tex">n = 10< / annotation>< / semantics>. FIG. 5A depicts representative FACS plots gated on CD4+ T cells, with activated cells (CD44high CD62Llow) boxed. Quantitation of activated CD4+ T cells as a percentage of total CD4+ T cells. FIG. 5B depicts representative FACS plots gated on CD4+ T cells after stimulation in vitro, with IFN<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-producing cells boxed. Quantitation of IFN<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>- producing cells as a percentage of total CD4+ T cells. *, <semantics>P=0.019<annotation encoding="application / x-tex">P = 0.019< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0117] FIG. 6 shows TIGIT expression is elevated in human breast cancer and correlated with expression of CD8 and inhibitory co-receptors. Breast cancer gene expression microarray data generated by the Cancer Gene Atlas Network was analyzed. Gene expression data is normalized and expressed as relative ratios (log2). FIG. 6A depicts TIGIT expression in normal and all breast tumor samples (left) and in breast tumor subtypes (right). ***, P = 6x10-12. Box and whisker plots are shown. FIG. 6B depicts correlation of TIGIT and CD3E expression. R2 = 0.61. FIG. 6C depicts the correlation of TIGIT and CD8<semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> (left, R2 = 0.80) or CD4 (right, <semantics>R2=0.42<annotation encoding="application / x-tex">R2 = 0.42< / annotation>< / semantics>). FIG. 6D depicts the correlation of TIGIT and PD-1 (left, <semantics>R2=<annotation encoding="application / x-tex">R^2 =< / annotation>< / semantics> 0.87), LAG3 (center, <semantics>R2=0.80<annotation encoding="application / x-tex">R^2 = 0.80< / annotation>< / semantics>), and CTLA4 (right, <semantics>R2=0.76<annotation encoding="application / x-tex">R^2 = 0.76< / annotation>< / semantics>).

[0118] FIG. 7 shows that TIGIT and PD-1 inhibit anti-tumor T cell responses. In FIG. 7A- 7B, BALB / C mice were inoculated with CT26 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TILs) were analyzed 14 days after inoculation, when tumors had reached approximately <semantics>200mm3<annotation encoding="application / x-tex">200 \text{mm}^3< / annotation>< / semantics> in size. Data are representative of one experiment; <semantics>n=6<annotation encoding="application / x-tex">n = 6< / annotation>< / semantics>. FIG. 7A depicts flow cytometry histogram representative of TIGIT expression by splenic and tumor-infiltrating CD8+ T cells. Quantitation of TIGIT MFI is also shown. **, P = 0.0023. FIG. 7B depicts flow cytometry histogram representative of TIGIT expression by splenic and tumor-infiltrating CD4+ T cells. Quantitation of TIGIT MFI is also shown. ***, <semantics>P=0.0002<annotation encoding="application / x-tex">P = 0.0002< / annotation>< / semantics>. In FIG. 7C-7E, BALB / C mice were inoculated with CT26 colorectal carcinoma cells. When tumors reached approximately 200mm3 in size, mice were treated with isotype control, anti- PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT antibodies for three weeks. Data are representative of two independent experiments; <semantics>n=10−20<annotation encoding="application / x-tex">n = 10-20< / annotation>< / semantics> (FIG. 7C-7D) or 7-10 (FIG. 7E). FIG. 7C depicts median CT26 tumor volumes over time. FIG. 7D depicts mouse survival. FIG. 7E shows that approximately 60 days after initial inoculation, mice in complete remission (CR) that had received anti-TIGIT + anti-PD-L1, as well as naïve BALB / c mice, were inoculated with CT26 cells in their left thoracic flanks and inoculated with EMT6 breast carcinoma cells in their mammary fat pads. Median (left) and individual (right) tumor volumes for CT26 (squares) and EMT6 (triangles) in CR mice (purple and green) and naïve mice (black and orange) tumors are shown. FIG. 7F shows that mice were inoculated with CT26 tumors and treated as in FIG. 7C. Tumor-infiltrating and tumor-draining lymph node resident T cells were analyzed by flow cytometry. Representative FACS plots of CD8+ TILs after stimulation in vitro, with IFNy-producing cells boxed. Quantitation of IFNy-producing CD8+ TILs as a percentage of total CD8+ TILs. ***, <semantics>P=0.0003<annotation encoding="application / x-tex">P = 0.0003< / annotation>< / semantics>. Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0119] FIG. 8 shows CT26 tumor-infiltrating lymphocyte TIGIT expression is correlated with Tim-3 expression. BALB / C mice were inoculated with CT26 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TILs) were analyzed approximately 14 days after inoculation, when tumors had reached approximately 200mm3 in size. Data are representative of one experiment; <semantics>n=6<annotation encoding="application / x-tex">n = 6< / annotation>< / semantics>. FIG. 8A depicts representative histogram of TIGIT expression by splenic and tumor-infiltrating CD8+ T cells. Quantitation of TIGIT MFI. **, P = 0.0026. FIG. 8B depicts representative histogram of TIGIT expression by splenic and tumor-infiltrating CD4+ T cells. Quantitation of TIGIT MFI. ***, P < 0.0001. Error bars depict the standard error of the mean.

[0120] FIG. 9 shows MC38 tumor-infiltrating lymphocyte TIGIT expression is correlated with PD-1 and Tim-3 expression. C57BL6 / J mice were inoculated with MC38 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TILs) were analyzed approximately 14 days after inoculation, when tumors had reached approximately 200mm3 in size. Data are representative of one experiment; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. FIG. 9A depicts representative histogram of TIGIT expression by splenic and tumor-infiltrating CD8+ T cells. Quantitation of TIGIT MFI. ***, P < 0.0001. FIG. 9B depicts representative histogram of TIGIT expression by splenic and tumor-infiltrating CD4+ T cells. Quantitation of TIGIT MFI. *, P = <semantics>0.0136.**,P=0.0029<annotation encoding="application / x-tex">0.0136. **, P = 0.0029< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0121] FIG. 10 shows CT26 tumor growth in mice treated with anti-PD-L1 and / or anti- TIGIT. Naïve BALB / c mice were inoculated with CT26 tumor cells and treated with anti-PD- L1 and / or anti-TIGIT or isotype-matched control antibodies, as described in FIG. 4D-4F. Tumor volumes over time for individual mice in each treatment group are shown. Data are representative of two independent experiments.

[0122] FIG. 11 shows flow cytometric analysis of CD4+ TILs and tumor-draining lymph node T cells. BALB / C mice were inoculated with CT26 colorectal carcinoma cells. When tumors reached approximately 200mm3 in size, mice were treated with isotype control, anti- PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT antibodies for 7 days. Tumors and tumor- draining lymph nodes were harvested. Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. Representative FACS plots gated on tumor-draining lymph node CD8+ T cells after stimulation in vitro, with IFN<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-producing cells boxed. Quantitation of IFN<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>+ cells as a percentage of total CD8+ T cells. ***, P < 0.001. Quantitation of CD8+ T cells as a percentage of total TILs. **, <semantics>P=0.0065<annotation encoding="application / x-tex">P = 0.0065< / annotation>< / semantics>. Quantitation of activated (CD44high CD62Llow) <semantics>CD8+<annotation encoding="application / x-tex">CD8^+< / annotation>< / semantics> T cells as a percentage of total <semantics>CD8+<annotation encoding="application / x-tex">CD8^+< / annotation>< / semantics> TILs. *, P = 0.012. Quantitation of <semantics>CD8+<annotation encoding="application / x-tex">CD8^+< / annotation>< / semantics> T cells as a percentage of total tumor-draining lymph node cells. Quantitation of activated CD8+ T cells as a percentage of total CD8+ T cells in the tumor-draining lymph node. *, <semantics>P<0.05<annotation encoding="application / x-tex">P < 0.05< / annotation>< / semantics>. FIG. 11C depicts quantitation of CD4+ T cells as a percentage of total TILs. *, <semantics>P=0.016<annotation encoding="application / x-tex">P = 0.016< / annotation>< / semantics>. FIG. 11D depicts quantitation of activated CD4+ T cells as a percentage of total CD4+ TILs. FIG. 11E depicts quantitation of CD4+ T cells as a percentage of total tumor-draining lymph node cells. FIG. 11F depicts quantitation of activated CD4+ T cells as a percentage of total <semantics>CD4+<annotation encoding="application / x-tex">CD4^{+}< / annotation>< / semantics> T cells in the tumor-draining lymph node. FIG. 11A depicts quantitation of IFN<semantics>γ+<annotation encoding="application / x-tex">\gamma^{+}< / annotation>< / semantics> cells as a percentage of CD4+ TILs after stimulation in vitro. FIG. 11B depicts quantitation of IFN<semantics>γ+<annotation encoding="application / x-tex">\gamma^+< / annotation>< / semantics> cells as a percentage of CD4+ T cells in the tumor-draining lymph node after stimulation in vitro. Error bars depict the standard error of the mean.

[0123] FIG. 12 shows further flow cytometric analysis of CD8+ TILs. BALB / C mice were inoculated with CT26 colorectal carcinoma cells and treated with isotype control, anti-PD- L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT antibodies as described in FIG. 4. Tumors were harvested after 7 days of treatment and analyzed by flow cytometry. Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. FIG. 12A depicts quantitation of TNF<semantics>α+<annotation encoding="application / x-tex">\alpha^+< / annotation>< / semantics> cells as a percentage of total CD8+ TILs. **, <semantics>P<0.01<annotation encoding="application / x-tex">P < 0.01< / annotation>< / semantics>. FIG. 12B depicts quantitation of CD8+ TILs as a percentage of total TILs. **, P < 0.01. FIG. 12C depicts quantitation of activated (CD44high CD62Llow) CD8+ TILs as a percentage of total CD8+ TILs. *, P < 0.05. Error bars depict the standard error of the mean.

[0124] FIG. 13 shows flow cytometric analysis of tumor-draining lymph node resident CD8+ T cells. BALB / C mice were inoculated with CT26 colorectal carcinoma cells and treated with isotype control, anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT antibodies as described in FIG. 4. Tumor-draining lymph nodes were harvested after 7 days of treatment and analyzed by flow cytometry. Data are representative of two independent experiments; <semantics>n=<annotation encoding="application / x-tex">n =< / annotation>< / semantics> 5. FIG. 13A depicts representative FACS plots gated on tumor-draining lymph node resident CD8+ T cells after stimulation in vitro, with IFNγ-producing cells boxed. Quantitation of IFN<semantics>γ+<annotation encoding="application / x-tex">\gamma^+< / annotation>< / semantics> cells as a percentage of total CD8+ T cells. ***, P < 0.001. FIG. 13B depicts quantitation of CD8+ T cells as a percentage of total cells in the tumor-draining lymph node. FIG. 13C depicts quantitation of activated (CD44high CD62Llow) CD8+ T cells as a percentage of total CD8+ T cells. *, P < 0.05. Error bars depict the standard error of the mean. FIG. 13D depicts quantitation of TNF<semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>-producing cells as a percentage of total tumor-draining lymph node CD8+ T cells.

[0125] FIG. 14 shows co-expression of CD226 and TIGIT by tumor-infiltrating CD8+ T cells. C57BL6 / J mice were inoculated with MC38 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TILs) were analyzed approximately 14 days after inoculation, when tumors had reached approximately 200mm3 in size. Representative histogram of CD226 expression by splenic B cells (gray), splenic CD8+ T cells (blue), and TIGIT+ tumor-infiltrating CD8+ T cells (red). Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>.

[0126] FIG. 15 shows CD226 and TIGIT Co-Immunoprecipate (co-IP) on transfected cells. COS7 cells were co-transfected with expression plasmids containing the cDNA for either TIGIT-HA (5ng) or CD226-Flag (10ng) tagged proteins, or a control plasmid (pRK). Following transfection, the cells were washed and centrifuged and cell pellets lysed. The resultant supernatant was pre-cleared and centrifuged and then equally split into two tubes and immuno-precipitated with either an anti-HA or an anti-flag using standard procedures. The immune-precipitated proteins were subjected to SDS-PAGE and western blotted. Western blots were probed with either anti-Flag-HRP or anti-HA-HRP.

[0127] FIG. 16 shows TIGIT and CD226 interact in primary CD8+ T cells. MACS- enriched splenic C57BL6 / J CD8+ T cells were stimulated with plate-bound anti-CD3 and anti-CD28 antibodies and recombinant IL-2 for 48 hours and lysed. Cell lysates were immunoprecipitated with anti-TIGIT and probed with anti-CD226. Lanes: molecular weight ladder (1), input (2), co-immunoprecipitation flow-through (3), and co-immunoprecipitate. Arrow denotes the expected molecular weight of CD226.

[0128] FIG. 17 shows that detection of TIGIT / CD226 interaction by TR-FRET. FIG. 17A depicts the dissociation of Flag-ST-CD226 homodimers by HA-TIGIT. FRET ratio between Flag-ST-CD226 measured on COS-7 cells expressing a constant amount of Flag-ST-CD226 and increasing concentrations of HA-TIGIT. FIG. 17B depicts FRET ratio between Flag-ST- CD226 recorded after a 15-min incubation of either PBS (white bar) or anti-TIGIT antibody (black bar). FIG. 17C depicts the association of Flag-ST-CD226 with HA-TIGIT. FRET intensity between Flag-ST-CD226 and HA-TIGIT over the Flag-ST-CD226 expression as measured by an anti-Flag ELISA on the same batch of transfected COS-7 cells. FIG. 17D depicts FRET variation between Flag-ST-CD226 and HA-TIGIT after a 15-min incubation of PBS (white bar) or anti-TIGIT antibody (black bar). Data in A and C are representative of 4 independent experiments, each performed in triplicate. Data in B and D are representative of 2 independent experiments, each performed in triplicate.

[0129] FIG. 18 shows cell surface expression of Flag-ST-CD226 and HA-TIGIT. Anti- Flag and anti-HA ELISA on intact COS-7 cells expressing the indicated tagged-constructs. Data are representative of 3 independent experiments, each performed in triplicate.

[0130] FIG. 19 shows that CD226 blockade reverses the enhanced anti-viral T cell response induced by TIGIT / PD-L1 co-blockade. In FIG. 19A-19D, C57BL6 / J mice were briefly depleted of CD4+ T cells and infected with Clone 13 strain LCMV. Mice were treated with isotype-matched control, anti-CD226, anti-PD-L1 + anti-TIGIT, or anti-PD-L1 + anti- TIGIT + anti-CD226 antibodies starting 28 days after infection. Splenocytes and liver viral titers were analyzed 42 days after infection. FIG. 19A depicts quantitation of CD8+ T cells as a percentage of splenocytes. FIG. 19B depicts quantitation of activated CD8+ T cells as a percentage of total CD8+ T cells. ***, P < 0.001. FIG. 19C depicts quantitation of IFNg- producing cells as a percentage of activated CD8+ T cells. ***, P < 0.001. FIG. 19D depicts quantitation of liver LCMV titers. ***, <semantics>P<0.001<annotation encoding="application / x-tex">P < 0.001< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0131] FIG. 20 shows that TIGIT expression is elevated in human cancer and strongly correlated with CD8 and PD-1. Gene expression analyses of human cancers were performed as described in Example 11. Scatter plots show per-gene count data, normalized by library size. Box and whisker plots show the variance stabilized expression ratio of TIGIT and CD3e. FIG. 20A depicts the correlation of TIGIT and CD3e RNA expression in LUSC (grey) and normal lung (black). <semantics>ρ=0.86<annotation encoding="application / x-tex">\rho = 0.86< / annotation>< / semantics>. Quantification of TIGIT / CD3e expression ratios is also shown. LUSC ratio increase = <semantics>372%<annotation encoding="application / x-tex">372\%< / annotation>< / semantics>. ***, P = <semantics>1.46×10−46<annotation encoding="application / x-tex">1.46 \times 10^{-46}< / annotation>< / semantics>. FIG. 20B depicts the correlation of TIGIT and CD3e RNA expression in COAD (grey) and normal colon (black). <semantics>ρ=0.83<annotation encoding="application / x-tex">\rho = 0.83< / annotation>< / semantics>. Quantification of TIGIT / CD3e expression ratios is also shown. COAD ratio increase = <semantics>116%<annotation encoding="application / x-tex">116\%< / annotation>< / semantics>. ***, P = <semantics>3.66×10−6<annotation encoding="application / x-tex">3.66 \times 10^{-6}< / annotation>< / semantics>. FIG. 20C depicts the correlation of TIGIT and CD3e RNA expression in UCEC (grey) and normal uterine endrometrium (black). <semantics>ρ=0.87<annotation encoding="application / x-tex">\rho = 0.87< / annotation>< / semantics>. Quantification of TIGIT / CD3e expression ratios is also shown. UCEC ratio increase = 419%. ***, <semantics>P=7.41×10−5<annotation encoding="application / x-tex">P = 7.41 \times 10^{-5}< / annotation>< / semantics>. FIG. 20D depicts the correlation of TIGIT and CD3e RNA expression in BRCA (grey) and normal breast (black). <semantics>ρ=0.82<annotation encoding="application / x-tex">\rho = 0.82< / annotation>< / semantics>. Quantification of TIGIT / CD3e expression ratios is also shown. BRCA ratio increase = <semantics>313%<annotation encoding="application / x-tex">313\%< / annotation>< / semantics>. ***, P = <semantics>4.6×10−44<annotation encoding="application / x-tex">4.6 \times 10^{-44}< / annotation>< / semantics>. FIG. 20E depicts the correlation of TIGIT and CD3e RNA expression in kidney renal clear cell carcinoma (grey) and normal kidney (black). <semantics>ρ=0.94<annotation encoding="application / x-tex">\rho = 0.94< / annotation>< / semantics>. Quantification of TIGIT / CD3e expression ratios is also shown. FIG. 20F depicts the correlation of TIGIT and CD8A (left) or TIGIT and CD4 (right) in lung squamous cell carcinoma (grey) and normal lung (black). p = 0.77 and 0.48 respectively. FIG. 20G depicts the correlation of TIGIT and PD-1 (Pdcd1) in lung squamous cell carcinoma (grey) and normal lung (black). <semantics>ρ=0.82<annotation encoding="application / x-tex">\rho = 0.82< / annotation>< / semantics>. FIG. 20H depicts the correlation of TIGIT and CD226 in lung squamous cell carcinoma (red) and normal lung (black). <semantics>ρ=0.64<annotation encoding="application / x-tex">\rho = 0.64< / annotation>< / semantics>.

[0132] FIG. 21 shows analysis of T cell-associated gene expression in Lung Squamous Cell Carcinoma (LUSC). Gene expression in LUSC and normal tissue samples was analyzed as described in Example 11 and a heat map of the genes best correlated with the gene signature in LUSC samples was generated. Genes and samples were both clustered using hierarchical clustering using Ward linkage on the Euclidean distance matrix for the centered and scaled expression data.

[0133] FIG. 22 shows that TIGIT and PD-1 are coordinately expressed by human and murine tumor-infiltrating lymphocytes. FIG. 22A-22C shows analysis of lymphocytes from a freshly resected human NSCLC tumor, tumor-matched peripheral blood, and normal donor peripheral blood. Data are representative of two independently analyzed tumors. FIG. 22A depicts representative FACS plots representative of TIGIT expression by peripheral and tumor-infiltrating CD8+ T cells, with TIGIT+ cells boxed. FIG. 22B depicts representative FACS plots representative of TIGIT expression by peripheral and tumor-infiltrating CD4+ T cells, with TIGIT+ cells boxed. FIG. 22C depicts flow cytometry histogram representative of TIGIT expression by PD-1high (red) and PD-1low (blue) NSCLC-infiltrating CD8+ (left) and CD4+ (right) T cells. In FIG. 22D-22G, BALB / C mice were inoculated with syngeneic CT26 colorectal carcinoma cells. Splenocytes and tumor-infiltrating lymphocytes (TILs) were analyzed 14 days after inoculation, when tumors had reached approximately 200 mm3 in size. Data are representative of two independent experiments; <semantics>n=5−6<annotation encoding="application / x-tex">n = 5-6< / annotation>< / semantics>. FIG. 22D depicts representative FACS plot of TIGIT expression by tumor-infiltrating CD8+ T cells, with TIGIT cells boxed. FIG. 22E depicts representative FACS plot of TIGIT expression by tumor-infiltrating CD4+ T cells, with TIGIT+ cells boxed. Quantitation of the frequency of TIGIT+ T cells as a percentage of all T cells. *, <semantics>P=0.0134<annotation encoding="application / x-tex">P = 0.0134< / annotation>< / semantics>. ***, <semantics>P<0.0001<annotation encoding="application / x-tex">P < 0.0001< / annotation>< / semantics>. FIG. 22F depicts flow cytometry histogram representative of TIGIT expression by PD-1high and PD- 1low tumor-infiltrating CD8+ T cells and by splenic CD8+ T cells. Quantitation of TIGIT MFI is also shown. **, <semantics>P=0.0023<annotation encoding="application / x-tex">P = 0.0023< / annotation>< / semantics>. FIG. 22G depicts flow cytometry histogram representative of TIGIT expression by PD-1high and PD-1low tumor-infiltrating CD4+ T cells and by splenic CD4+ T cells. Quantitation of TIGIT MFI is also shown. ***, P = 0.0002. Error bars depict the standard error of the mean.

[0134] FIG. 23 shows characterization of TIGIT expression by human tumor-infiltrating T cells. FIG. 23A-23B depict FACS plots showing TIGIT expression by NSCLC tumor- infiltrating CD8+ and CD4+ T cells (FIG. 23A) and by donor-matched PBMC CD8+ and CD4+ T cells (FIG. 23B), with TIGIT+ cells boxed. FIG. 23C-23D depict FACS plots showing TIGIT expression by CRC tumor-infiltrating CD8+ and CD4+ T cells (FIG. 23C) and by donor-matched PBMC CD8+ and CD4+ T cells (FIG. 23D), with TIGIT+ cells boxed.

[0135] FIG. 24 shows that the TIGIT:CD226 interaction is not driven by PVR TIGIT:CD226 and TIGIT Q56R:CD226 interactions were detected by TR-FRET and the FRET ratio between Flag-ST-CD226 and HA-TIGIT or HA-TIGIT Q56R shows that WT and Q56R TIGIT bind CD226 with the same efficacy. Data are representative of three independent experiments performed in triplicate.

[0136] FIG. 25 shows that efficacy of TIGIT / PD-L1 antibody co-blockade in mice bearing MC38 tumors. In FIG. 25A-25C, MC38 tumor-bearing mice were generated as above and treated with blocking antibodies against PD-L1 (red), TIGIT (blue), TIGIT and PD-L1 (purple) or isotype-matched control antibodies (black) for three weeks. <semantics>N=10<annotation encoding="application / x-tex">N = 10< / annotation>< / semantics> (control, anti- PD-L1 alone, anti-TIGIT alone) or 20 (anti-TIGIT + anti-PD-L1). FIG. 25A depicts median (left) and individual (right) MC38 tumor volumes over time. FIG. 25B depicts MC38 tumor volumes after 14 days of antibody treatment. ***, <semantics>P=0.0005<annotation encoding="application / x-tex">P = 0.0005< / annotation>< / semantics>. **, <semantics>P=0.0093<annotation encoding="application / x-tex">P = 0.0093< / annotation>< / semantics>. *, <semantics>P=0.0433<annotation encoding="application / x-tex">P = 0.0433< / annotation>< / semantics>. FIG. 25C depicts mouse survival over time. Error bars depict the standard error of the mean.

[0137] FIG. 26 shows that further characterization of TIGIT expression by murine tumor- infiltrating T cells. FIG. 26A depicts that splenic C57BL6 / J CD8+ T cells were enriched by MACS and cultured with plate-coated anti-CD3 and anti-CD28 agonist antibodies. Representative histograms of TIGIT (red) and isotype-matched control (solid gray) staining over time. Quantitation of TIGIT MFI. ***, P < 0.001. Stimulated cells inducibly expressed PD-1 and constitutively expressed CD226 (data not shown). Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. In FIG. 26B-26E, wildtype C57BL6 / J mice were subcutaneously inoculated with syngeneic MC38 colorectal carcinoma cells. Tumors were allowed to grow without intervention until they reached 150-200 mm3 in size. Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. FIG. 26B depicts representative FACS plot of tumor-infiltrating CD8+ T cells, with TIGIT+ cells boxed. Quantitation of the frequency of TIGIT+ cells as a percentage of all tumor-infiltrating or splenic CD8+ T cells. ***, P < 0.0001. FIG. 26C depicts representative FACS plot of tumor-infiltrating CD4+ T cells, with TIGIT+ cells boxed. Quantitation of the frequency of TIGIT+ cells as a percentage of all tumor-infiltrating or splenic CD4+ T cells. ***, P < 0.0001. FIG. 26D depicts representative histogram of TIGIT expression by PD-1high and PD-1low tumor-infiltrating CD8+ T cells (red and blue, respectively) and by splenic CD8+ T cells (gray). Quantitation of TIGIT MFI. ***, P < 0.0001. FIG. 26E depicts representative histogram of TIGIT expression by PD-1high and PD-1low tumor-infiltrating CD4+ T cells and by splenic CD4+ T cells. Quantitation of TIGIT MFI. *, <semantics>P=0.0136<annotation encoding="application / x-tex">P = 0.0136< / annotation>< / semantics>. **, <semantics>P=0.0029<annotation encoding="application / x-tex">P = 0.0029< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0138] FIG. 27 shows that tumor-infiltrating CD8+ and CD4+ T cells maintain a high level of CD226 expression. Wildtype BALB / c mice were inoculated with CT26 tumor cells as described herein. After tumors have grown to approximately 150-200 mm3 in size, tumors and spleens were analyzed by flow cytometry. FIG. 27A depicts quantitation of CD226+ CD8+ T cells, CD4+ T cells, and non-T cells, as a percentage of all CD8+ T cells, CD4+ T cells, and non-T cells respectively. FIG. 27B depicts representative histograms of CD226 expression in tumor and spleen. Data are representative of two independent experiments; n = 5. Error bars depict the standard error of the mean.

[0139] FIG. 28 shows that TIGIT suppression of CD8+ T cell responses is dependent on CD226. BALB / C mice were subcutaneously inoculated with CT26 colorectal carcinoma cells in their right thoracic flanks. When tumors reached approximately 200mm3 in size, mice were treated with isotype control (black), anti-CD226 (orange), anti-PD-L1 (red), anti- TIGIT + anti-PD-L1 (purple), or anti-TIGIT + anti-PD-L1 + anti-CD226 (green) antibodies for three weeks. Data are representative of one experiment; <semantics>n=10<annotation encoding="application / x-tex">n = 10< / annotation>< / semantics> (A-B) or 5 (C-F). FIG. 28A depicts median (left) and individual (right) CT26 tumor volumes over time. FIG. 28B depicts mouse survival over time. In FIG 28C-28F, after 7 days of treatment, tumor- infiltrating lymphocytes and tumor-draining lymph node-resident lymphocytes were assessed by flow cytometry. FIG 28C depicts quantitation of IFNγ-producing CD8+ TILs as a percentage of total CD8+ TILs after stimulation in vitro. **, P < 0.01. FIG 28D depicts quantitation of IFNy-producing cells as a percentage of total CD8+ T cells after stimulation in vitro. *, P < 0.05. FIG 28E depicts quantitation of CD8+ TILs as a percentage of total TILs. **, P < 0.01. FIG 28F depicts quantitation of CD8+ T cells as a percentage of all tumor- draining lymph node-resident lymphocytes. Error bars depict the standard error of the mean.

[0140] FIG. 29 shows that TIGIT impairs CD226 function by directly disrupting CD226 homodimerization. FIG. 29A depicts that CD8+ T cells were MACS-enriched from TIGITfl / fl CD4crc (CKO) and TIGITfl / fl CD4wt (WT) littermates and stimulated in the presence of anti- CD226 or isotype-matched control antibodies as indicated. H3-thymidine uptake is shown as a ratio of cells cultured with anti-CD3 + PVR-Fc to cells cultured with anti-CD3 alone. **, P = <semantics>0.0061<annotation encoding="application / x-tex">0.0061< / annotation>< / semantics>. ***, P < <semantics>0.0001<annotation encoding="application / x-tex">0.0001< / annotation>< / semantics>. Data are representative of two independent experiments; n = 5. FIG. 29B depicts that wildtype C57BL6 / J CD8+ T cells were MACS-enriched and stimulated in the presence of anti-TIGIT, anti-CD226, and / or isotype-matched control antibodies as indicated. H3-thymidine uptake is shown as a ratio of cells cultured with anti-CD3 + PVR-Fc to cells cultured with anti-CD3 alone. ***, P < 0.001 in paired t tests. FIG. 29C depicts that primary human CD8+ T cells were MACS-enriched from blood and stimulated with sub- optimal levels of plate-bound anti-CD3 in the presence or absence of human recombinant PVR-Fc. Anti-TIGIT antibodies or isotype-matched control antibodies were added as indicated. Quantitation of <semantics>3H<annotation encoding="application / x-tex">{}^{3}H< / annotation>< / semantics>-thymidine uptake. **, P = 0.0071 and 0.0014 respectively. FIG. 29D depicts that CHO cells were transiently transfected with increasing concentrations of acceptor and donor FLAG-ST-CD226, as indicated. Quantification of FRET intensity relative to donor emission. Data are representative of three independent experiments; <semantics>n=3<annotation encoding="application / x-tex">n = 3< / annotation>< / semantics>. In FIG. 29E-29F, CHO cells were transiently transfected with FLAG-ST-CD226 and with increasing concentrations of HA-TIGIT, as indicated. Data are representative of two or more independent experiments; <semantics>n=4<annotation encoding="application / x-tex">n = 4< / annotation>< / semantics>. Data are normalized to the maximal signal. FIG. 29E depicts quantification of the CD226:CD226 FRET ratio (FRET ratio 1). FIG. 29F depicts quantification of the TIGIT:CD226 FRET ratio (FRET ratio 2). FIG. 29G depicts anti-FLAG (left) and anti-HA (right) immunoblots performed on either anti-FLAG or anti-HA immunoprecipitates prepared from COS-7 cells transfected with either an empty pRK vector or a combination of Flag-CD226 and HA-TIGIT. Data are representative of two independent experiments. FIG. 29H depicts quantification of the TIGIT:CD226 FRET ratio after incubation with PBS (white) or anti-TIGIT antibodies (red). ***, P < 0.001. Data are representative of 4 independent experiments; <semantics>n=3<annotation encoding="application / x-tex">n = 3< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0141] FIG. 30 shows that primary human T cells were MACS-enriched from blood and stimulated with anti-CD3 and anti-CD28. TIGIT and TIGIT cells were sorted, rested, re- stimulated, and labeled for FRET with the antibodies indicated. Data are representative of two independent experiments. ***, <semantics>P<0.001<annotation encoding="application / x-tex">P < 0.001< / annotation>< / semantics>. Error bars depict the standard error of the mean.

[0142] FIG. 31 shows that TIGIT and PD-1 co-blockade does not restore the effector function of exhausted CD4+ T cells during chronic viral infection. FIG. 31A depicts quantitation of CD8+ T cells as a percentage of all splenocytes. FIG. 31B depicts quantitation of GP33 Pentamer+ cells as a percentage of all splenic CD8+ T cells. **, <semantics>P=0.0040<annotation encoding="application / x-tex">P = 0.0040< / annotation>< / semantics>. FIG. 31C depicts representative FACS plots gated on gp33 pentamer+ CD8+ T cells after stimulation in vitro, with IFN<semantics>γ+<annotation encoding="application / x-tex">\gamma^+< / annotation>< / semantics> cells boxed. Quantitation of IFN<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-producing cells as a percentage of all gp33 pentamer+ CD8+ T cells. *, P = 0.0319. **, P = 0.0030. Error bars depict the standard error of the mean.

[0143] FIG. 32 shows that TIGIT / PD-L1 co-blockade efficacy is dependent on CD8+ T cells. In FIG. 32A-32B, wildtype BALB / c mice were inoculated with CT26 tumors as described in FIG. 7. When tumors reached 100-150 mm3 in size, mice were temporarily depleted of CD8+ T cells and treated with anti-TIGIT + anti-PD-L1. Data are representative of one experiment; <semantics>n=10<annotation encoding="application / x-tex">n = 10< / annotation>< / semantics> / group. FIG. 32A depicts median (left) and individual (right) CT26 tumor volumes over time. FIG. 32B depicts quantitation of CT26 tumor volumes 17 days after the start of treatment. ***, <semantics>P=0.0004<annotation encoding="application / x-tex">P = 0.0004< / annotation>< / semantics>. In FIG. 32C, wildtype BALB / c mice were inoculated with CT26 tumors and treated with anti-TIGIT + anti-PD-L1 and subsequently re- challenged with CT26 tumors with temporary depletion of CD8+ T cells at the time of re- challenge. Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. FIG. 32C depicts median (left) and individual (right) CT26 tumor volumes over time. Error bars depict the standard error of the mean.

[0144] FIG. 33 shows that PVR expression on tumor cells is dispensable for TIGIT / PD-L1 co-blockade efficacy. Wildtype BALB / c mice were inoculated with wildtype or PVR- deficient (PVR.KO) tumors as described. When tumors reached 150-200 mm3 in size, mice were treated with anti-TIGIT + anti-PD-L1 or isotype-matched control antibodies. Data are representative of one experiment; <semantics>n=10<annotation encoding="application / x-tex">n = 10< / annotation>< / semantics> / group. FIG. 33 depicts median (left) and individual (right) CT26 tumor volumes over time.

[0145] FIG. 34 shows the efficacy of TIGIT / PD-L1 antibody co-blockade in mice bearing EMT6 tumors. EMT6 tumor-bearing mice were generated as above and treated with blocking antibodies against PD-L1 (red), TIGIT (blue), TIGIT and PD-L1 (purple) or isotype-matched control antibodies (black) for three weeks. <semantics>N=10<annotation encoding="application / x-tex">N = 10< / annotation>< / semantics> (control, anti-PD-L1 alone, anti-TIGIT alone) or 20 (anti-TIGIT + anti-PD-L1). FIG. 34 depicts median (left) and individual (right) EMT6 tumor volumes over time.

[0146] FIG. 35 shows that TIGIT regulates tumor-infiltrating CD8+ T cell effector function. BALB / C mice were subcutaneously inoculated with CT26 colorectal carcinoma cells in their right thoracic flanks and treated with anti-PD-L1, anti-TIGIT, or anti-PD-L1 + anti-TIGIT, as described in FIG. 7. Tumor-draining lymph node (dLN) resident and tumor- infiltrating T cells were analyzed by flow cytometry 7 days after the start of treatment. Data are representative of two independent experiments; <semantics>n=5<annotation encoding="application / x-tex">n = 5< / annotation>< / semantics>. FIG. 35A depicts quantitation of IFNy / TNFα dual-producing dLN resident CD8+ and CD4+ T cells as percentages of total dLN resident CD8+ and CD4+ T cells respectively. Dual cytokine production by unstimulated T cells is also shown. **, <semantics>P=0.002<annotation encoding="application / x-tex">P = 0.002< / annotation>< / semantics>, 0.003, and 0.001 respectively. FIG. 35B depicts quantitation of IFNγ / TNFα dual-producing tumor-infiltrating CD8+ and CD4+ T cells as percentages of total tumor-infiltrating CD8+ and CD4+ T cells respectively. Dual cytokine production by unstimulated T cells is also shown. ***, P < 0.0001. Error bars depict the standard error of the mean.

[0147] FIG. 36 shows analysis of lymphocytes from resected human NSCLC tumors, tumor-matched peripheral blood, and normal donor peripheral blood. Data are pooled from three independently acquired sets of samples. FIG. 36A depicts quantitation of TIGIT cells as a percentage of all CD8+ T cells. *, P < 0.05. FIG. 36B depicts quantitation of TIGIT+ cells as a percentage of all CD4+ T cells.

[0148] FIG. 37 shows characterization of TIGIT expression in human tumors. FIG. 37A depicts representative flow cytometry histograms of TIGIT expression by NSCLC tumor- resident lymphocytes (red, CD45+ FSClow), myeloid cells (blue, CD45+ FSChigh), and non- hematopoietic cells (green, CD45) relative to subset-matched isotype staining (gray). FIG. 37B depicts gating strategy for PD-1high and PD-1low NSCLC tumor-infiltrating CD8+ and CD4+ T cells. DETAILED DESCRIPTION OF THE INVENTION I. General techniques

[0149] The techniques and procedures described or referenced herein are generally well understood and commonly employed using conventional methodology by those skilled in the art, such as, for example, the widely utilized methodologies described in Sambrook et al., Molecular Cloning: A Laboratory Manual 3d edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.; Current Protocols in Molecular Biology (F.M. Ausubel, et al. eds., (2003)); the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames and G.R. Taylor eds. (1995)), Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press; Animal Cell Culture (R.I. Freshney), ed., 1987); Introduction to Cell and Tissue Culture (J.P. Mather and P.E. Roberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons; Handbook of Experimental Immunology (D.M. Weir and C.C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (J.M. Miller and M.P. Calos, eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds., 1994); Current Protocols in Immunology (J.E. Coligan et al., eds., 1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999); Immunobiology (C.A. Janeway and P. Travers, 1997); Antibodies (P. Finch, 1997); Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989); Monoclonal Antibodies: A Practical Approach (P. Shepherd and C. Dean, eds., Oxford University Press, 2000); Using Antibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold Spring Harbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D. Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principles and Practice of Oncology (V.T. DeVita et al., eds., J.B. Lippincott Company, 1993). II. Definitions

[0150] The term "PD-1 axis binding antagonist" is a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T-cell dysfunction resulting from signaling on the PD-1 signaling axis — with a result being to restore or enhance T-cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.

[0151] The term "PD-1 binding antagonists" is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners, such as PD-L1, PD-L2. In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its binding partners. In a specific aspect, the PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, a PD-1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-1 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In a specific aspect, a PD-1 binding antagonist is MDX-1106 described herein. In another specific aspect, a PD-1 binding antagonist is Merck 3745 described herein. In another specific aspect, a PD-1 binding antagonist is CT-011 described herein. In another specific aspect, a PD-1 binding antagonist is AMP-224 described herein.

[0152] The term "PD-L1 binding antagonists" is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD- L1 with either one or more of its binding partners, such as PD-1, B7-1. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, the PD-L1 binding antagonist inhibits binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, the PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners, such as PD-1, B7-1. In one embodiment, a PD-L1 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L1 so as to render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L1 binding antagonist is an anti-PD-L1 antibody. In a specific aspect, an anti-PD-L1 antibody is YW243.55.S70 described herein. In another specific aspect, an anti- PD-L1 antibody is MDX-1105 described herein. In still another specific aspect, an anti-PD- L1 antibody is MPDL3280A described herein. In another specific aspect, an anti-PD-L1 antibody is MEDI 4736 described herein.

[0153] The term "PD-L2 binding antagonists" is a molecule that decreases, blocks, inhibits, abrogates or interferes with signal transduction resulting from the interaction of PD- L2 with either one or more of its binding partners, such as PD-1. In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners. In a specific aspect, the PD-L2 binding antagonist inhibits binding of PD-L2 to PD- 1. In some embodiments, the PD-L2 antagonists include anti-PD-L2 antibodies, antigen binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides and other molecules that decrease, block, inhibit, abrogate or interfere with signal transduction resulting from the interaction of PD-L2 with either one or more of its binding partners, such as PD-1. In one embodiment, a PD-L2 binding antagonist reduces the negative co-stimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes mediated signaling through PD-L2 so as render a dysfunctional T-cell less dysfunctional (e.g., enhancing effector responses to antigen recognition). In some embodiments, a PD-L2 binding antagonist is an immunoadhesin.

[0154] The term "aptamer" refers to a nucleic acid molecule that is capable of binding to a target molecule, such as a polypeptide. For example, an aptamer of the invention can specifically bind to a TIGIT polypeptide, or to a molecule in a signaling pathway that modulates the expression of TIGIT. The generation and therapeutic use of aptamers are well established in the art. See, e.g., U.S. Pat. No. 5,475,096, and the therapeutic efficacy of Macugen® (Eyetech, New York) for treating age-related macular degeneration.

[0155] The term "antagonist" is used in the broadest sense, and includes any molecule that partially or fully blocks, inhibits, or neutralizes a biological activity of a native polypeptide disclosed herein. In a similar manner, the term "agonist" is used in the broadest sense and includes any molecule that mimics a biological activity of a native polypeptide disclosed herein. Suitable agonist or antagonist molecules specifically include agonist or antagonist antibodies or antibody fragments, fragments or amino acid sequence variants of native polypeptides, peptides, antisense oligonucleotides, small organic molecules, etc. Methods for identifying agonists or antagonists of a polypeptide may comprise contacting a polypeptide with a candidate agonist or antagonist molecule and measuring a detectable change in one or more biological activities normally associated with the polypeptide.

[0156] The terms "TIGIT antagonist" and "antagonist of TIGIT activity or TIGIT expression" are used interchangeably and refer to a compound that interferes with the normal functioning of TIGIT, either by decreasing transcription or translation of TIGIT-encoding nucleic acid, or by inhibiting or blocking TIGIT polypeptide activity, or both. Examples of TIGIT antagonists include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, TIGIT-specific aptamers, anti-TIGIT antibodies, TIGIT-binding fragments of anti-TIGIT antibodies, TIGIT-binding small molecules, TIGIT-binding peptides, and other polypeptides that specifically bind TIGIT (including, but not limited to, TIGIT-binding fragments of one or more TIGIT ligands, optionally fused to one or more additional domains), such that the interaction between the TIGIT antagonist and TIGIT results in a reduction or cessation of TIGIT activity or expression. It will be understood by one of ordinary skill in the art that in some instances, a TIGIT antagonist may antagonize one TIGIT activity without affecting another TIGIT activity. For example, a desirable TIGIT antagonist for use in certain of the methods herein is a TIGIT antagonist that antagonizes TIGIT activity in response to one of PVR interaction, PVRL3 interaction, or PVRL2 interaction, e.g., without affecting or minimally affecting any of the other TIGIT interactions.

[0157] The terms "PVR antagonist" and "antagonist of PVR activity or PVR expression" are used interchangeably and refer to a compound that interferes with the normal functioning of PVR, either by decreasing transcription or translation of PVR-encoding nucleic acid, or by inhibiting or blocking PVR polypeptide activity, or both. Examples of PVR antagonists include, but are not limited to, antisense polynucleotides, interfering RNAs, catalytic RNAs, RNA-DNA chimeras, PVR-specific aptamers, anti-PVR antibodies, PVR-binding fragments of anti-PVR antibodies, PVR-binding small molecules, PVR-binding peptides, and other polypeptides that specifically bind PVR (including, but not limited to, PVR-binding fragments of one or more PVR ligands, optionally fused to one or more additional domains), such that the interaction between the PVR antagonist and PVR results in a reduction or cessation of PVR activity or expression. It will be understood by one of ordinary skill in the art that in some instances, a PVR antagonist may antagonize one PVR activity without affecting another PVR activity. For example, a desirable PVR antagonist for use in certain of the methods herein is a PVR antagonist that antagonizes PVR activity in response to TIGIT interaction without impacting the PVR-CD96 and / or PVR-CD226 interactions.

[0158] The term "dysfunction" in the context of immune dysfunction, refers to a state of reduced immune responsiveness to antigenic stimulation. The term includes the common elements of both exhaustion and / or anergy in which antigen recognition may occur, but the ensuing immune response is ineffective to control infection or tumor growth.

[0159] The term "dysfunctional", as used herein, also includes refractory or unresponsive to antigen recognition, specifically, impaired capacity to translate antigen recognition into down-stream T-cell effector functions, such as proliferation, cytokine production (e.g., IL-2) and / or target cell killing.

[0160] The term "anergy" refers to the state of unresponsiveness to antigen stimulation resulting from incomplete or insufficient signals delivered through the T-cell receptor (e.g. increase in intracellular Ca+2 in the absence of ras-activation). T cell anergy can also result upon stimulation with antigen in the absence of co-stimulation, resulting in the cell becoming refractory to subsequent activation by the antigen even in the context of costimulation. The unresponsive state can often be overridden by the presence of Interleukin-2. Anergic T-cells do not undergo clonal expansion and / or acquire effector functions.

[0161] The term "exhaustion" refers to T cell exhaustion as a state of T cell dysfunction that arises from sustained TCR signaling that occurs during many chronic infections and cancer. It is distinguished from anergy in that it arises not through incomplete or deficient signaling, but from sustained signaling. It is defined by poor effector function, sustained expression of inhibitory receptors and a transcriptional state distinct from that of functional effector or memory T cells. Exhaustion prevents optimal control of infection and tumors. Exhaustion can result from both extrinsic negative regulatory pathways (e.g., immunoregulatory cytokines) as well as cell intrinsic negative regulatory (costimulatory) pathways (PD-1, B7-H3, B7-H4, etc.).

[0162] "Enhancing T-cell function" means to induce, cause or stimulate a T-cell to have a sustained or amplified biological function, or renew or reactivate exhausted or inactive T- cells. Examples of enhancing T-cell function include: increased secretion of <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-interferon from CD8+ T-cells, increased proliferation, increased antigen responsiveness (e.g., viral, pathogen, or tumor clearance) relative to such levels before the intervention. In one embodiment, the level of enhancement is as least 50%, alternatively 60%, 70%, 80%, 90%, 100%, 120%, 150%, 200%. The manner of measuring this enhancement is known to one of ordinary skill in the art.

[0163] A "T cell dysfunctional disorder" is a disorder or condition of T-cells characterized by decreased responsiveness to antigenic stimulation. In a particular embodiment, a T-cell dysfunctional disorder is a disorder that is specifically associated with inappropriate increased signaling through PD-1. In another embodiment, a T-cell dysfunctional disorder is one in which T-cells are anergic or have decreased ability to secrete cytokines, proliferate, or execute cytolytic activity. In a specific aspect, the decreased responsiveness results in ineffective control of a pathogen or tumor expressing an immunogen. Examples of T cell dysfunctional disorders characterized by T-cell dysfunction include unresolved acute infection, chronic infection and tumor immunity.

[0164] "Tumor immunity" refers to the process in which tumors evade immune recognition and clearance. Thus, as a therapeutic concept, tumor immunity is "treated" when such evasion is attenuated, and the tumors are recognized and attacked by the immune system. Examples of tumor recognition include tumor binding, tumor shrinkage and tumor clearance.

[0165] "Immunogenecity" refers to the ability of a particular substance to provoke an immune response. Tumors are immunogenic and enhancing tumor immunogenicity aids in the clearance of the tumor cells by the immune response. Examples of enhancing tumor immunogenicity include but not limited to treatment with a PD-1 axis binding antagonist (e.g., anti-PD-L1 antibodies and a TIGIT inhibitor (e.g., anti-TIGIT antibodies).

[0166] "Sustained response" refers to the sustained effect on reducing tumor growth after cessation of a treatment. For example, the tumor size may remain to be the same or smaller as compared to the size at the beginning of the administration phase. In some embodiments, the sustained response has a duration at least the same as the treatment duration, at least 1.5X, 2.0X, 2.5X, or 3.0X length of the treatment duration.

[0167] The term "antibody" includes monoclonal antibodies (including full length antibodies which have an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single-chain molecules, as well as antibody fragments <semantics>(e.g.,Fab,F(ab′)2,andFv)<annotation encoding="application / x-tex">(e.g., Fab, F(ab')_2, and Fv)< / annotation>< / semantics>. The term "immunoglobulin" (Ig) is used interchangeably with "antibody" herein.

[0168] The basic 4-chain antibody unit is a heterotetrameric glycoprotein composed of two identical light (L) chains and two identical heavy (H) chains. An IgM antibody consists of 5 of the basic heterotetramer units along with an additional polypeptide called a J chain, and contains 10 antigen binding sites, while IgA antibodies comprise from 2-5 of the basic 4- chain units which can polymerize to form polyvalent assemblages in combination with the J chain. In the case of IgGs, the 4-chain unit is generally about 150,000 daltons. Each L chain is linked to an H chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has at the N- terminus, a variable domain <semantics>(VH)<annotation encoding="application / x-tex">(V_H)< / annotation>< / semantics> followed by three constant domains <semantics>(CH)<annotation encoding="application / x-tex">(C_H)< / annotation>< / semantics> for each of the <semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> and <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics> chains and four <semantics>CH<annotation encoding="application / x-tex">C_H< / annotation>< / semantics> domains for <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics> and <semantics>ε<annotation encoding="application / x-tex">\varepsilon< / annotation>< / semantics> isotypes. Each L chain has at the N-terminus, a variable domain <semantics>(VL)<annotation encoding="application / x-tex">(V_L)< / annotation>< / semantics> followed by a constant domain at its other end. The <semantics>VL<annotation encoding="application / x-tex">V_L< / annotation>< / semantics> is aligned with the <semantics>VH<annotation encoding="application / x-tex">V_H< / annotation>< / semantics> and the <semantics>CL<annotation encoding="application / x-tex">C_L< / annotation>< / semantics> is aligned with the first constant domain of the heavy chain <semantics>(CH1)<annotation encoding="application / x-tex">(C_H 1)< / annotation>< / semantics>. Particular amino acid residues are believed to form an interface between the light chain and heavy chain variable domains. The pairing of a VH and VL together forms a single antigen- binding site. For the structure and properties of the different classes of antibodies, see e.g., Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, page 71 and Chapter 6. The L chain from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains. Depending on the amino acid sequence of the constant domain of their heavy chains (CH), immunoglobulins can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG and IgM, having heavy chains designated <semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics>, <semantics>δ<annotation encoding="application / x-tex">\delta< / annotation>< / semantics>, <semantics>ϵ<annotation encoding="application / x-tex">\epsilon< / annotation>< / semantics>, <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics> and <semantics>μ<annotation encoding="application / x-tex">\mu< / annotation>< / semantics>, respectively. The <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics> and <semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> classes are further divided into subclasses on the basis of relatively minor differences in the CH sequence and function, <semantics>e.g.<annotation encoding="application / x-tex">e.g.< / annotation>< / semantics>, humans express the following subclasses: IgG1, IgG2A, IgG2B, IgG3, IgG4, IgA1 and IgA2.

[0169] The "variable region" or "variable domain" of an antibody refers to the amino- terminal domains of the heavy or light chain of the antibody. The variable domains of the heavy chain and light chain may be referred to as "VH" and "VL", respectively. These domains are generally the most variable parts of the antibody (relative to other antibodies of the same class) and contain the antigen binding sites.

[0170] The term "variable" refers to the fact that certain segments of the variable domains differ extensively in sequence among antibodies. The V domain mediates antigen binding and defines the specificity of a particular antibody for its particular antigen. However, the variability is not evenly distributed across the entire span of the variable domains. Instead, it is concentrated in three segments called hypervariable regions (HVRs) both in the light-chain and the heavy chain variable domains. The more highly conserved portions of variable domains are called the framework regions (FR). The variable domains of native heavy and light chains each comprise four FR regions, largely adopting a beta-sheet configuration, connected by three HVRs, which form loops connecting, and in some cases forming part of, the beta-sheet structure. The HVRs in each chain are held together in close proximity by the FR regions and, with the HVRs from the other chain, contribute to the formation of the antigen binding site of antibodies (see Kabat et al., Sequences of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, MD (1991)). The constant domains are not involved directly in the binding of antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.

[0171] The term "monoclonal antibody" as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translation modifications (e.g., isomerizations, amidations) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site. In contrast to polyclonal antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. In addition to their specificity, the monoclonal antibodies are advantageous in that they are synthesized by the hybridoma culture, uncontaminated by other immunoglobulins. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present invention may be made by a variety of techniques, including, for example, the hybridoma method (e.g., Kohler and Milstein., Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14 (3): 253-260 (1995), Harlow et al., Antibodies: A Laboratory Manual, (Cold Spring Harbor Laboratory Press, 2nd ed. 1988); Hammerling et al., in: Monoclonal Antibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981)), recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567), phage-display technologies (see, e.g., Clackson et al., Nature, 352: 624-628 (1991); Marks et al., J. Mol. Biol. 222: 581-597 (1992); Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol. Biol. 340(5): 1073-1093 (2004); Fellouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004); and Lee et al., J. Immunol. Methods 284(1-2): 119-132 (2004), and technologies for producing human or human-like antibodies in animals that have parts or all of the human immunoglobulin loci or genes encoding human immunoglobulin sequences (see, e.g., WO 1998 / 24893; WO 1996 / 34096; WO 1996 / 33735; WO 1991 / 10741; Jakobovits et al., Proc. Natl. Acad. Sci. USA 90: 2551 (1993); Jakobovits et al., Nature 362: 255-258 (1993); Bruggemann et al., Year in Immunol. 7:33 (1993); U.S. Patent Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126; 5,633,425; and 5,661,016; Marks et al., Bio / Technology 10: 779-783 (1992); Lonberg et al., Nature 368: 856-859 (1994); Morrison, Nature 368: 812-813 (1994); Fishwild et al., Nature Biotechnol. 14: 845-851 (1996); Neuberger, Nature Biotechnol. 14: 826 (1996); and Lonberg and Huszar, Intern. Rev. Immunol. 13: 65-93 (1995).

[0172] The term "naked antibody" refers to an antibody that is not conjugated to a cytotoxic moiety or radiolabel.

[0173] The terms "full-length antibody," "intact antibody" or "whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antibody fragment. Specifically whole antibodies include those with heavy and light chains including an Fc region. The constant domains may be native sequence constant domains (e.g., human native sequence constant domains) or amino acid sequence variants thereof. In some cases, the intact antibody may have one or more effector functions.

[0174] An "antibody fragment" comprises a portion of an intact antibody, preferably the antigen binding and / or the variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2 and Fv fragments; diabodies; linear antibodies (see U.S. Patent 5,641,870, Example 2; Zapata et al., Protein Eng. 8(10): 1057-1062

[1995] ); single- chain antibody molecules and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produced two identical antigen-binding fragments, called "Fab" fragments, and a residual "Fc" fragment, a designation reflecting the ability to crystallize readily. The Fab fragment consists of an entire L chain along with the variable region domain of the H chain <semantics>(VH)<annotation encoding="application / x-tex">(V_H)< / annotation>< / semantics>, and the first constant domain of one heavy chain <semantics>(CH1)<annotation encoding="application / x-tex">(C_H1)< / annotation>< / semantics>. Each Fab fragment is monovalent with respect to antigen binding, i.e., it has a single antigen- binding site. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CH1 domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.

[0175] The Fc fragment comprises the carboxy-terminal portions of both H chains held together by disulfides. The effector functions of antibodies are determined by sequences in the Fc region, the region which is also recognized by Fc receptors (FcR) found on certain types of cells.

[0176] "Fv" is the minimum antibody fragment which contains a complete antigen- recognition and -binding site. This fragment consists of a dimer of one heavy- and one light- chain variable region domain in tight, non-covalent association. From the folding of these two domains emanate six hypervariable loops (3 loops each from the H and L chain) that contribute the amino acid residues for antigen binding and confer antigen binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three HVRs specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.

[0177] "Single-chain Fv" also abbreviated as "sFv" or "scFv" are antibody fragments that comprise the <semantics>VH<annotation encoding="application / x-tex">V_H< / annotation>< / semantics> and <semantics>VL<annotation encoding="application / x-tex">V_L< / annotation>< / semantics> antibody domains connected into a single polypeptide chain. Preferably, the sFv polypeptide further comprises a polypeptide linker between the VH and VL domains which enables the sFv to form the desired structure for antigen binding. For a review of the sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994).

[0178] "Functional fragments" of the antibodies of the invention comprise a portion of an intact antibody, generally including the antigen binding or variable region of the intact antibody or the Fc region of an antibody which retains or has modified FcR binding capability. Examples of antibody fragments include linear antibody, single-chain antibody molecules and multispecific antibodies formed from antibody fragments.

[0179] The term "diabodies" refers to small antibody fragments prepared by constructing sFv fragments (see preceding paragraph) with short linkers (about 5-10) residues) between the VH and VL domains such that inter-chain but not intra-chain pairing of the V domains is achieved, thereby resulting in a bivalent fragment, i.e., a fragment having two antigen- binding sites. Bispecific diabodies are heterodimers of two "crossover" sFv fragments in which the VH and VL domains of the two antibodies are present on different polypeptide chains. Diabodies are described in greater detail in, for example, EP 404,097; WO 93 / 11161; Hollinger et al., Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993).

[0180] The monoclonal antibodies herein specifically include "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). Chimeric antibodies of interest herein include PRIMATIZED® antibodies wherein the antigen-binding region of the antibody is derived from an antibody produced by, e.g., immunizing macaque monkeys with an antigen of interest. As used herein, "humanized antibody" is used a subset of "chimeric antibodies."

[0181] "Humanized" forms of non-human (e.g., murine) antibodies are chimeric antibodies that contain minimal sequence derived from non-human immunoglobulin. In one embodiment, a humanized antibody is a human immunoglobulin (recipient antibody) in which residues from an HVR (hereinafter defined) of the recipient are replaced by residues from an HVR of a non-human species (donor antibody) such as mouse, rat, rabbit or non- human primate having the desired specificity, affinity, and / or capacity. In some instances, framework ("FR") residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, humanized antibodies may comprise residues that are not found in the recipient antibody or in the donor antibody. These modifications may be made to further refine antibody performance, such as binding affinity. In general, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the hypervariable loops correspond to those of a non- human immunoglobulin sequence, and all or substantially all of the FR regions are those of a human immunoglobulin sequence, although the FR regions may include one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, immunogenicity, etc. The number of these amino acid substitutions in the FR are typically no more than 6 in the H chain, and in the L chain, no more than 3. The humanized antibody optionally will also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see, e.g., Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Pat. Nos. 6,982,321 and 7,087,409.

[0182] A "human antibody" is an antibody that possesses an amino-acid sequence corresponding to that of an antibody produced by a human and / or has been made using any of the techniques for making human antibodies as disclosed herein. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues. Human antibodies can be produced using various techniques known in the art, including phage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available for the preparation of human monoclonal antibodies are methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See also van Dijk and van de Winkel, Curr. Opin. Pharmacol., 5: 368-74 (2001). Human antibodies can be prepared by administering the antigen to a transgenic animal that has been modified to produce such antibodies in response to antigenic challenge, but whose endogenous loci have been disabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 regarding XENOMOUSETM technology). See also, for example, Li et al., Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006) regarding human antibodies generated via a human B-cell hybridoma technology.

[0183] The term "hypervariable region," "HVR," or "HV," when used herein refers to the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops. Generally, antibodies comprise six HVRs; three in the VH (H1, H2, H3), and three in the VL (L1, L2, L3). In native antibodies, H3 and L3 display the most diversity of the six HVRs, and H3 in particular is believed to play a unique role in conferring fine specificity to antibodies. See, e.g., Xu et al., Immunity 13:37-45 (2000); Johnson and Wu, in Methods in Molecular Biology 248:1-25 (Lo, ed., Human Press, Totowa, NJ, 2003). Indeed, naturally occurring camelid antibodies consisting of a heavy chain only are functional and stable in the absence of light chain. See, e.g., Hamers-Casterman et al., Nature 363:446- 448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0184] A number of HVR delineations are in use and are encompassed herein. The Kabat Complementarity Determining Regions (CDRs) are based on sequence variability and are the most commonly used (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Chothia refers instead to the location of the structural loops (Chothia and Lesk, J. Mol. Biol. 196:901-917) (1987)). The AbM HVRs represent a compromise between the Kabat HVRs and Chothia structural loops, and are used by Oxford Molecular's AbM antibody modeling software. The "contact" HVRs are based on an analysis of the available complex crystal structures. The residues from each of these HVRs are noted below. [Image disponible dans le document PDF, Image available in the PDF document]

[0185] HVRs may comprise "extended HVRs" as follows: 24-36 or 24-34 (L1), 46-56 or 50-56 (L2) and 89-97 or 89-96 (L3) in the VL and 26-35 (H1), 50-65 or 49-65 (H2) and 93- 102, 94-102, or 95-102 (H3) in the VH. The variable domain residues are numbered according to Kabat et al., supra, for each of these definitions.

[0186] The expression "variable-domain residue-numbering as in Kabat" or "amino-acid- position numbering as in Kabat," and variations thereof, refers to the numbering system used for heavy-chain variable domains or light-chain variable domains of the compilation of antibodies in Kabat et al., supra. Using this numbering system, the actual linear amino acid sequence may contain fewer or additional amino acids corresponding to a shortening of, or insertion into, a FR or HVR of the variable domain. For example, a heavy-chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues (e.g. residues 82a, 82b, and 82c, etc. according to Kabat) after heavy-chain FR residue 82. The Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a "standard" Kabat numbered sequence.

[0187] "Framework" or "FR" residues are those variable-domain residues other than the HVR residues as herein defined.

[0188] A "human consensus framework" or "acceptor human framework" is a framework that represents the most commonly occurring amino acid residues in a selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991). Examples include for the VL, the subgroup may be subgroup kappa I, kappa II, kappa III or kappa IV as in Kabat et al., supra. Additionally, for the VH, the subgroup may be subgroup I, subgroup II, or subgroup III as in Kabat et al., supra. Alternatively, a human consensus framework can be derived from the above in which particular residues, such as when a human framework residue is selected based on its homology to the donor framework by aligning the donor framework sequence with a collection of various human framework sequences. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereof, or it may contain pre-existing amino acid sequence changes. In some embodiments, the number of pre-existing amino acid changes are 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less.

[0189] A "VH subgroup III consensus framework" comprises the consensus sequence obtained from the amino acid sequences in variable heavy subgroup III of Kabat et al., supra. In one embodiment, the VH subgroup III consensus framework amino acid sequence comprises at least a portion or all of each of the following sequences: EVQLVESGGGLVQPGGSLRLSCAAS (HC-FR1)(SEQ ID NO:25), WVRQAPGKGLEWV (HC-FR2), (SEQ ID NO:26), RFTISADTSKNTAYLQMNSLRAEDTAVYYCAR (HC-FR3, SEQ ID NO:27), WGQGTLVTVSA (HC-FR4), (SEQ ID NO:28).

[0190] A "VL kappa I consensus framework" comprises the consensus sequence obtained from the amino acid sequences in variable light kappa subgroup I of Kabat et al., supra. In one embodiment, the VH subgroup I consensus framework amino acid sequence comprises at least a portion or all of each of the following sequences: DIQMTQSPSSLSASVGDRVTITC (LC-FR1) (SEQ ID NO:29), WYQQKPGKAPKLLIY (LC-FR2) (SEQ ID NO:30), GVPSRFSGSGSGTDFTLTISSLQPEDFATYYC (LC-FR3)(SEQ ID NO:31), FGQGTKVEIKR (LC-FR4)(SEQ ID NO:32).

[0191] An "amino-acid modification" at a specified position, e.g. of the Fc region, refers to the substitution or deletion of the specified residue, or the insertion of at least one amino acid residue adjacent the specified residue. Insertion "adjacent" to a specified residue means insertion within one to two residues thereof. The insertion may be N-terminal or C-terminal to the specified residue. The preferred amino acid modification herein is a substitution.

[0192] An "affinity-matured" antibody is one with one or more alterations in one or more HVRs thereof that result in an improvement in the affinity of the antibody for antigen, compared to a parent antibody that does not possess those alteration(s). In one embodiment, an affinity-matured antibody has nanomolar or even picomolar affinities for the target antigen. Affinity-matured antibodies are produced by procedures known in the art. For example, Marks et al., Bio / Technology 10:779-783 (1992) describes affinity maturation by VH- and VL-domain shuffling. Random mutagenesis of HVR and / or framework residues is described by, for example: Barbas et al. Proc Nat. Acad. Sci. USA 91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton et al. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol. 154(7):3310-9 (1995); and Hawkins et al, J. Mol. Biol. 226:889- 896 (1992).

[0193] As use herein, the term "specifically binds to" or is "specific for" refers to measurable and reproducible interactions such as binding between a target and an antibody, which is determinative of the presence of the target in the presence of a heterogeneous population of molecules including biological molecules. For example, an antibody that specifically binds to a target (which can be an epitope) is an antibody that binds this target with greater affinity, avidity, more readily, and / or with greater duration than it binds to other targets. In one embodiment, the extent of binding of an antibody to an unrelated target is less than about 10% of the binding of the antibody to the target as measured, e.g., by a radioimmunoassay (RIA). In certain embodiments, an antibody that specifically binds to a target has a dissociation constant (Kd) of <semantics>≤1μM<annotation encoding="application / x-tex">\leq 1 \mu M< / annotation>< / semantics>, <semantics>≤100 nM<annotation encoding="application / x-tex">\leq 100 \text{ nM}< / annotation>< / semantics>, <semantics>≤10 nM<annotation encoding="application / x-tex">\leq 10 \text{ nM}< / annotation>< / semantics>, or <semantics>≤0.1 nM<annotation encoding="application / x-tex">\leq 0.1 \text{ nM}< / annotation>< / semantics>. In certain embodiments, an antibody specifically binds to an epitope on a protein that is conserved among the protein from different species. In another embodiment, specific binding can include, but does not require exclusive binding.

[0194] As used herein, the term "immunoadhesin" designates antibody-like molecules which combine the binding specificity of a heterologous protein (an "adhesin") with the effector functions of immunoglobulin constant domains. Structurally, the immunoadhesins comprise a fusion of an amino acid sequence with the desired binding specificity which is other than the antigen recognition and binding site of an antibody (i.e., is "heterologous"), and an immunoglobulin constant domain sequence. The adhesin part of an immunoadhesin molecule typically is a contiguous amino acid sequence comprising at least the binding site of a receptor or a ligand. The immunoglobulin constant domain sequence in the immunoadhesin may be obtained from any immunoglobulin, such as IgG-1, IgG-2 (including IgG2A and IgG2B), IgG-3, or IgG-4 subtypes, IgA (including IgA-1 and IgA-2), IgE, IgD or IgM. The Ig fusions preferably include the substitution of a domain of a polypeptide or antibody described herein in the place of at least one variable region within an Ig molecule. In a particularly preferred embodiment, the immunoglobulin fusion includes the hinge, CH2 and CH3, or the hinge, CH1, CH2 and CH3 regions of an IgG1 molecule. For the production of immunoglobulin fusions see also US Patent No. 5,428,130 issued June 27, 1995. For example, useful immunoadhesins as second medicaments useful for combination therapy herein include polypeptides that comprise the extracellular or PD-1 binding portions of PD- L1 or PD-L2 or the extracellular or PD-L1 or PD-L2 binding portions of PD-1, fused to a constant domain of an immunoglobulin sequence, such as a PD-L1 ECD – Fc, a PD-L2 ECD - Fc, and a PD-1 ECD - Fc, respectively. Immunoadhesin combinations of Ig Fc and ECD of cell surface receptors are sometimes termed soluble receptors.

[0195] A "fusion protein" and a "fusion polypeptide" refer to a polypeptide having two portions covalently linked together, where each of the portions is a polypeptide having a different property. The property may be a biological property, such as activity in vitro or in vivo. The property may also be simple chemical or physical property, such as binding to a target molecule, catalysis of a reaction, etc. The two portions may be linked directly by a single peptide bond or through a peptide linker but are in reading frame with each other.

[0196] A "PD-1 oligopeptide," "PD-L1 oligopeptide," or "PD-L2 oligopeptide" is an oligopeptide that binds, preferably specifically, to a PD-1, PD-L1 or PD-L2 negative costimulatory polypeptide, respectively, including a receptor, ligand or signaling component, respectively, as described herein. Such oligopeptides may be chemically synthesized using known oligopeptide synthesis methodology or may be prepared and purified using recombinant technology. Such oligopeptides are usually at least about 5 amino acids in length, alternatively at least about 6, 7, 8, 9, 10, 11, 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, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 amino acids in length or more. Such oligopeptides may be identified using well known techniques. In this regard, it is noted that techniques for screening oligopeptide libraries for oligopeptides that are capable of specifically binding to a polypeptide target are well known in the art (see, e.g., U.S. Patent Nos. 5,556,762, 5,750,373, 4,708,871, 4,833,092, 5,223,409, 5,403,484, 5,571,689, 5,663,143; PCT Publication Nos. WO 84 / 03506 and WO84 / 03564; Geysen et al., Proc. Natl. Acad. Sci. U.S.A., 81:3998-4002 (1984); Geysen et al., Proc. Natl. Acad. Sci. U.S.A., 82:178-182 (1985); Geysen et al., in Synthetic Peptides as Antigens, 130-149 (1986); Geysen et al., J. Immunol. Meth., 102:259-274 (1987); Schoofs et al., J. Immunol., 140:611-616 (1988), Cwirla, S. E. et al. Proc. Natl. Acad. Sci. USA, 87:6378 (1990); Lowman, H.B. et al. Biochemistry, 30:10832 (1991); Clackson, T. et al. Nature, 352: 624 (1991); Marks, J. D. et al., J. Mol. Biol., 222:581 (1991); Kang, A.S. et al. Proc. Natl. Acad. Sci. USA, 88:8363 (1991), and Smith, G. P., Current Opin. Biotechnol., 2:668 (1991).

[0197] A "blocking" antibody or an "antagonist" antibody is one that inhibits or reduces a biological activity of the antigen it binds. In some embodiments, blocking antibodies or antagonist antibodies substantially or completely inhibit the biological activity of the antigen. The anti-PD-L1 antibodies of the invention block the signaling through PD-1 so as to restore a functional response by T-cells (e.g., proliferation, cytokine production, target cell killing) from a dysfunctional state to antigen stimulation.

[0198] An "agonist" or activating antibody is one that enhances or initiates signaling by the antigen to which it binds. In some embodiments, agonist antibodies cause or activate signaling without the presence of the natural ligand.

[0199] The term "Fc region" herein is used to define a C-terminal region of an immunoglobulin heavy chain, including native-sequence Fc regions and variant Fc regions. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy-chain Fc region is usually defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl-terminus thereof. The C-terminal lysine (residue 447 according to the EU numbering system) of the Fc region may be removed, for example, during production or purification of the antibody, or by recombinantly engineering the nucleic acid encoding a heavy chain of the antibody. Accordingly, a composition of intact antibodies may comprise antibody populations with all K447 residues removed, antibody populations with no K447 residues removed, and antibody populations having a mixture of antibodies with and without the K447 residue. Suitable native-sequence Fc regions for use in the antibodies of the invention include human IgG1, IgG2 (IgG2A, IgG2B), IgG3 and IgG4.

[0200] "Fc receptor" or "FcR" describes a receptor that binds to the Fc region of an antibody. The preferred FcR is a native sequence human FcR. Moreover, a preferred FcR is one which binds an IgG antibody (a gamma receptor) and includes receptors of the FcyRI, FcyRII, and FcyRIII subclasses, including allelic variants and alternatively spliced forms of these receptors, FcyRII receptors include FcyRIIA (an "activating receptor") and FcyRIIB (an "inhibiting receptor"), which have similar amino acid sequences that differ primarily in the cytoplasmic domains thereof. Activating receptor Fc\(\gamma\)RIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain. Inhibiting receptor FcyRIIB contains an immunoreceptor tyrosine-based inhibition motif (ITIM) in its cytoplasmic domain. (see M. Daëron, Annu. Rev. Immunol. 15:203-234 (1997). FcRs are reviewed in Ravetch and Kinet, Annu. Rev. Immunol. 9: 457-92 (1991); Capel et al., Immunomethods 4: 25-34 (1994); and de Haas et al., J. Lab. Clin. Med. 126: 330-41 (1995). Other FcRs, including those to be identified in the future, are encompassed by the term "FcR" herein.

[0201] The term "Fc receptor" or "FcR" also includes the neonatal receptor, FcRn, which is responsible for the transfer of maternal IgGs to the fetus. Guyer et al., J. Immunol. 117: 587 (1976) and Kim et al., J. Immunol. 24: 249 (1994). Methods of measuring binding to FcRn are known (see, e.g., Ghetie and Ward, Immunol. Today 18: (12): 592-8 (1997); Ghetie et al., Nature Biotechnology 15 (7): 637-40 (1997); Hinton et al., J. Biol. Chem. 279 (8): 6213-6 (2004); WO 2004 / 92219 (Hinton et al.). Binding to FcRn in vivo and serum half-life of human FcRn high-affinity binding polypeptides can be assayed, e.g., in transgenic mice or transfected human cell lines expressing human FcRn, or in primates to which the polypeptides having a variant Fc region are administered. WO 2004 / 42072 (Presta) describes antibody variants which improved or diminished binding to FcRs. See also, e.g., Shields et al., J. Biol. Chem. 9(2): 6591-6604 (2001).

[0202] The phrase "substantially reduced," or "substantially different," as used herein, denotes a sufficiently high degree of difference between two numeric values (generally one associated with a molecule and the other associated with a reference / comparator molecule) such that one of skill in the art would consider the difference between the two values to be of statistical significance within the context of the biological characteristic measured by said values (e.g., Kd values). The difference between said two values is, for example, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, and / or greater than about 50% as a function of the value for the reference / comparator molecule.

[0203] The term "substantially similar" or "substantially the same," as used herein, denotes a sufficiently high degree of similarity between two numeric values (for example, one associated with an antibody of the invention and the other associated with a reference / comparator antibody), such that one of skill in the art would consider the difference between the two values to be of little or no biological and / or statistical significance within the context of the biological characteristic measured by said values (e.g., Kd values). The difference between said two values is, for example, less than about 50%, less than about 40%, less than about 30%, less than about 20%, and / or less than about 10% as a function of the reference / comparator value.

[0204] "Carriers" as used herein include pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to the cell or mammal being exposed thereto at the dosages and concentrations employed. Often the physiologically acceptable carrier is an aqueous pH buffered solution. Examples of physiologically acceptable carriers include buffers such as phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEENTM, polyethylene glycol (PEG), and PLURONICSTM.

[0205] A "package insert" refers to instructions customarily included in commercial packages of medicaments that contain information about the indications customarily included in commercial packages of medicaments that contain information about the indications, usage, dosage, administration, contraindications, other medicaments to be combined with the packaged product, and / or warnings concerning the use of such medicaments, etc.

[0206] As used herein, the term "treatment" refers to clinical intervention designed to alter the natural course of the individual or cell being treated during the course of clinical pathology. Desirable effects of treatment include decreasing the rate of disease progression, ameliorating or palliating the disease state, and remission or improved prognosis. For example, an individual is successfully "treated" if one or more symptoms associated with cancer are mitigated or eliminated, including, but are not limited to, reducing the proliferation of (or destroying) cancerous cells, decreasing symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, delaying the progression of the disease, and / or prolonging survival of individuals.

[0207] As used herein, "delaying progression of a disease" means to defer, hinder, slow, retard, stabilize, and / or postpone development of the disease (such as cancer). This delay can be of varying lengths of time, depending on the history of the disease and / or individual being treated. As is evident to one skilled in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, a late stage cancer, such as development of metastasis, may be delayed.

[0208] As used herein, "reducing or inhibiting cancer relapse" means to reduce or inhibit tumor or cancer relapse or tumor or cancer progression.

[0209] As used herein, "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Included in this definition are benign and malignant cancers as well as dormant tumors or micrometastatses. Examples of cancer include but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia. More particular examples of such cancers include squamous cell cancer, lung cancer (including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, and squamous carcinoma of the lung), cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancer, as well as B-cell lymphoma (including low grade / follicular non-Hodgkin's lymphoma (NHL); small lymphocytic (SL) NHL; intermediate grade / follicular NHL; intermediate grade diffuse NHL; high grade immunoblastic NHL; high grade lymphoblastic NHL; high grade small non-cleaved cell NHL; bulky disease NHL; mantle cell lymphoma; AIDS-related lymphoma; and Waldenstrom's Macroglobulinemia); chronic lymphocytic leukemia (CLL); acute lymphoblastic leukemia (ALL); Hairy cell leukemia; chronic myeloblastic leukemia; and post-transplant lymphoproliferative disorder (PTLD), as well as abnormal vascular proliferation associated with phakomatoses, edema (such as that associated with brain tumors), and Meigs' syndrome.

[0210] As used herein, "metastasis" is meant the spread of cancer from its primary site to other places in the body. Cancer cells can break away from a primary tumor, penetrate into lymphatic and blood vessels, circulate through the bloodstream, and grow in a distant focus (metastasize) in normal tissues elsewhere in the body. Metastasis can be local or distant. Metastasis is a sequential process, contingent on tumor cells breaking off from the primary tumor, traveling through the bloodstream, and stopping at a distant site. At the new site, the cells establish a blood supply and can grow to form a life-threatening mass. Both stimulatory and inhibitory molecular pathways within the tumor cell regulate this behavior, and interactions between the tumor cell and host cells in the distant site are also significant.

[0211] An "effective amount" is at least the minimum concentration required to effect a measurable improvement or prevention of a particular disorder. An effective amount herein may vary according to factors such as the disease state, age, sex, and weight of the patient, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or detrimental effects of the treatment are outweighed by the therapeutically beneficial effects. For prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk, lessening the severity, or delaying the onset of the disease, including biochemical, histological and / or behavioral symptoms of the disease, its complications and intermediate pathological phenotypes presenting during development of the disease. For therapeutic use, beneficial or desired results include clinical results such as decreasing one or more symptoms resulting from the disease, increasing the quality of life of those suffering from the disease, decreasing the dose of other medications required to treat the disease, enhancing effect of another medication such as via targeting, delaying the progression of the disease, and / or prolonging survival. In the case of cancer or tumor, an effective amount of the drug may have the effect in reducing the number of cancer cells; reducing the tumor size; inhibiting (i.e., slow to some extent or desirably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., slow to some extent and desirably stop) tumor metastasis; inhibiting to some extent tumor growth; and / or relieving to some extent one or more of the symptoms associated with the disorder. An effective amount can be administered in one or more administrations. For purposes of this invention, an effective amount of drug, compound, or pharmaceutical composition is an amount sufficient to accomplish prophylactic or therapeutic treatment either directly or indirectly. As is understood in the clinical context, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" may be considered in the context of administering one or more therapeutic agents, and a single agent may be considered to be given in an effective amount if, in conjunction with one or more other agents, a desirable result may be or is achieved.

[0212] As used herein, "in conjunction with" refers to administration of one treatment modality in addition to another treatment modality. As such, "in conjunction with" refers to administration of one treatment modality before, during, or after administration of the other treatment modality to the individual.

[0213] As used herein, "subject" is meant a mammal, including, but not limited to, a human or non-human mammal, such as a bovine, equine, canine, ovine, or feline. Preferably, the subject is a human. Patients are also subjects herein.

[0214] As used herein, "complete response" or "CR" refers to disappearance of all target lesions; "partial response" or "PR" refers to at least a 30% decrease in the sum of the longest diameters (SLD) of target lesions, taking as reference the baseline SLD; and "stable disease" or "SD" refers to neither sufficient shrinkage of target lesions to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest SLD since the treatment started.

[0215] As used herein, "progressive disease" or "PD" refers to at least a 20% increase in the SLD of target lesions, taking as reference the smallest SLD recorded since the treatment started or the presence of one or more new lesions.

[0216] As used herein, "progression free survival" (PFS) refers to the length of time during and after treatment during which the disease being treated (e.g., cancer) does not get worse. Progression-free survival may include the amount of time patients have experienced a complete response or a partial response, as well as the amount of time patients have experienced stable disease.

[0217] As used herein, "overall response rate" (ORR) refers to the sum of complete response (CR) rate and partial response (PR) rate.

[0218] As used herein, "overall survival" refers to the percentage of individuals in a group who are likely to be alive after a particular duration of time.

[0219] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethiylenethiophosphoramide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicines; betulinic acid; a camptothecin (including the synthetic analogue topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryostatin; pemetrexed; callystatin; CC-1065 (including its adozelesin, carzelesin and bizelesin synthetic analogues); podophyllotoxin; podophyllinic acid; teniposide; cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; TLK-286; CDP323, an oral alpha-4 integrin inhibitor; a sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as the enediyne antibiotics (e. g., calicheamicin, especially calicheamicin gamma1I and calicheamicin omegaI1 (see, e.g., Nicolaou et al., Angew. Chem Intl. Ed. Engl., 33: 183-186 (1994)); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L- norleucine, doxorubicin (including ADRIAMYCIN®, morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HCl liposome injection (DOXIL®) and deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), an epothilone, and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, and imatinib (a 2- phenylaminopyrimidine derivative), as well as other c-Kit inhibitors; anti-adrenals such as aminoglutethimide, mitotane, trilostane; folic acid replenisher such as frolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; etoglucid; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"- trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A and anguidine); urethan; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa; taxoids, e.g., paclitaxel (TAXOL®), albumin-engineered nanoparticle formulation of paclitaxel (ABRAXANETM), and doxetaxel (TAXOTERE®); chloranbucil; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine (VELBAN®); platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine (ONCOVIN®); oxaliplatin; leucovovin; vinorelbine (NAVELBINE®); novantrone; edatrexate; daunomycin; aminopterin; ibandronate; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; pharmaceutically acceptable salts, acids or derivatives of any of the above; as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone, and FOLFOX, an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovovin.

[0220] Also included in this definition are anti-hormonal agents that act to regulate, reduce, block, or inhibit the effects of hormones that can promote the growth of cancer, and are often in the form of systemic, or whole-body treatment. They may be hormones themselves. Examples include anti-estrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene (EVISTA®), droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON®); anti-progesterones; estrogen receptor down- regulators (ERDs); estrogen receptor antagonists such as fulvestrant (FASLODEX®); agents that function to suppress or shut down the ovaries, for example, leutinizing hormone- releasing hormone (LHRH) agonists such as leuprolide acetate (LUPRON® and ELIGARD®), goserelin acetate, buserelin acetate and tripterelin; anti-androgens such as flutamide, nilutamide and bicalutamide; and aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutethimide, megestrol acetate (MEGASE®), exemestane (AROMASIN®), formestanie, fadrozole, vorozole (RIVISOR®), letrozole (FEMARA®), and anastrozole (ARIMIDEX®). In addition, such definition of chemotherapeutic agents includes bisphosphonates such as clodronate (for example, BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKELID®), or risedronate (ACTONEL®); as well as troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); anti-sense oligonucleotides, particularly those that inhibit expression of genes in signaling pathways implicated in abherant cell proliferation, such as, for example, PKC- alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R); vaccines such as THERATOPE® vaccine and gene therapy vaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitor (e.g., LURTOTECAN®); an anti-estrogen such as fulvestrant; a Kit inhibitor such as imatinib or EXEL-0862 (a tyrosine kinase inhibitor); EGFR inhibitor such as erlotinib or cetuximab; an anti-VEGF inhibitor such as bevacizumab; arinotecan; rmRH (e.g., ABARELIX®); lapatinib and lapatinib ditosylate (an ErbB-2 and EGFR dual tyrosine kinase small-molecule inhibitor also known as GW572016); 17AAG (geldanamycin derivative that is a heat shock protein (Hsp) 90 poison), and pharmaceutically acceptable salts, acids or derivatives of any of the above.

[0221] As used herein, the term "cytokine" refers generically to proteins released by one cell population that act on another cell as intercellular mediators or have an autocrine effect on the cells producing the proteins. Examples of such cytokines include lymphokines, monokines; interleukins ("ILs") such as IL-1, IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL10, IL-11, IL-12, IL-13, IL-15, IL-17A-F, IL-18 to IL-29 (such as IL-23), IL-31, including PROLEUKIN® rIL-2; a tumor-necrosis factor such as TNF-α or TNF-β, TGF-β1-3; and other polypeptide factors including leukemia inhibitory factor ("LIF"), ciliary neurotrophic factor ("CNTF"), CNTF-like cytokine ("CLC"), cardiotrophin ("CT"), and kit ligand ("KL").

[0222] As used herein, the term "chemokine" refers to soluble factors (e.g., cytokines) that have the ability to selectively induce chemotaxis and activation of leukocytes. They also trigger processes of angiogenesis, inflammation, wound healing, and tumorigenesis. Example chemokines include IL-8, a human homolog of murine keratinocyte chemoattractant (KC).

[0223] As used herein and in the appended claims, the singular forms "a," "or," and "the" include plural referents unless the context clearly dictates otherwise.

[0224] Reference to "about" a value or parameter herein includes (and describes) variations that are directed to that value or parameter per se. For example, description referring to "about X" includes description of "X".

[0225] The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate", ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis -(2-hydroxy-3-naphthoate)) salts, alkali metal (e.g., sodium and potassium) salts, alkaline earth metal (e.g., magnesium) salts, and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.

[0226] If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0227] If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0228] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and / or toxicologically, with the other ingredients comprising a formulation, and / or the mammal being treated therewith.

[0229] It is understood that aspects and variations of the invention described herein include "consisting" and / or "consisting essentially of" aspects and variations. III. Methods

[0230] In one aspect, provided herein is a method for treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity.

[0231] In another aspect, provided herein is a method for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effect amount of a PD-1 axis binding antagonist in combination with an agent that that decreases or inhibits TIGIT expression and / or activity. As disclosed herein, cancer relapse and / or cancer progression include, without limitation, cancer metastasis.

[0232] In another aspect, provided herein is a method for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effect amount of a PD-1 axis binding antagonist in combination with an agent that that decreases or inhibits TIGIT expression and / or activity.

[0233] In another aspect, provided herein is a method for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effect amount of a PD-1 axis binding antagonist in combination with an agent that that decreases or inhibits TIGIT expression and / or activity.

[0234] In some embodiments, the immune related disease is associated with T cell dysfunctional disorder. In some embodiments, the immune related disease is a viral infection. In certain embodiments, the viral infection is a chronic viral infection. In some embodiments, T cell dysfunctional disorder is characterized by decreased responsiveness to antigenic stimulation. In some embodiments, the T cell dysfunctional disorder is characterized by T cell anergy or decreased ability to secrete cytokines, proliferate or execute cytolytic activity. In some embodiments, the T cell dysfunctional disorder is characterized by T cell exhaustion. In some embodiments, the T cells are CD4+ and CD8+ T cells. In some embodiments, the T cell dysfunctional disorder includes unresolved acute infection, chronic infection and tumor immunity.

[0235] In another aspect, provided herein is a method for increasing, enhancing or stimulating an immune response or function in an individual comprising administering to the individual an effect amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity.

[0236] In another aspect, provided herein is a method of treating or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity.

[0237] In another aspect, provided herein is a method for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity.

[0238] In another aspect, provided herein is a method for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity.

[0239] In another aspect, provided herein is a method for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist and agent that modulates the CD226 expression and / or activity.

[0240] In some embodiments, the immune related disease is associated with T cell dysfunctional disorder. In some embodiments, the immune related disease is a viral infection. In certain embodiments, the viral infection is a chronic viral infection. In some embodiments, the T cell dysfunctional disorder is characterized by decreased responsiveness to antigenic stimulation. In some embodiments, the T cell dysfunctional disorder is characterized by T cell anergy, or decreased ability to secrete cytokines, proliferate or execute cytolytic activity. In some embodiments, the T cell dysfunctional disorder is characterized by T cell exhaustion. In some embodiments, the T cells are CD4+ and CD8+ T cells. In some embodiments, the immune related disease is selected from the group consisting of unresolved acute infection, chronic infection and tumor immunity.

[0241] In another aspect, provided herein is a method of increasing, enhancing or stimulating an immune response or function in an individual by administering to the individual an effective amount of a PD-1 axis binding antagonist and an agent that modulates the CD226 expression and / or activity.

[0242] In some embodiments, the agent that modulates the CD226 expression and / or activity is capable of increasing and / or stimulating CD226 expression and / or activity; increasing and / or stimulating the interaction of CD226 with PVR, PVRL2, and / or PVRL3; and increasing and / or stimulating the intracellular signaling mediated by CD226 binding to PVR, PVRL2, and / or PVRL3. As used herein, an agent that is capable of increasing and / or stimulating CD226 expression and / or activity includes, without limitation, agents that increase and / or stimulate CD226 expression and / or activity. As used herein, an agent that is capable of increasing and / or stimulating the interaction of CD226 with PVR, PVRL2, and / or PVRL3 includes, without limitation, agents that increase and / or stimulate the interaction of CD226 with PVR, PVRL2, and / or PVRL3. As used herein, an agent that is capable of increasing and / or stimulating the intracellular signaling mediated by CD226 binding to PVR, PVRL2, and / or PVRL3 includes, without limitation, agents that increase and / or stimulate the intracellular signaling mediated by CD226 binding to PVR, PVRL2, and / or PVRL3.

[0243] In some embodiments, the agent that modulates the CD226 expression and / or activity is selected from 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.

[0244] In some embodiments, 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, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an anti-TIGIT antibody or antigen-binding fragment thereof. In some embodiments, the agent that inhibits and / or blocks the interaction of CD226 with TIGIT is an inhibitory nucleic acid selected from an antisense polynucleotide, an interfering RNA, a catalytic RNA, and an RNA-DNA chimera.

[0245] In some embodiments, 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. In some embodiments, the antagonist of TIGIT expression and / or activity is an anti-TIGIT antibody or antigen-binding fragment thereof. In some embodiments, the antagonist of TIGIT expression and / or activity is an inhibitory nucleic acid selected from an antisense polynucleotide, an interfering RNA, a catalytic RNA, and an RNA-DNA chimera.

[0246] In some embodiments, the antagonist of PVR 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. In some embodiments, the antagonist of PVR expression and / or activity is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0247] In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVR is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVR is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0248] In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL2 is selected from a small molecule inhibitor, an inhibitory antibody or antigen- binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0249] In some embodiments, the agent that inhibits and / or blocks the interaction of TIGIT with PVRL3 is selected from a small molecule inhibitor, an inhibitory antibody or antigen- binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0250] In some embodiments, the agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVR is a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide. In some embodiments, the agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVR is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0251] In some embodiments, the agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVRL2 is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0252] In some embodiments, the agent that inhibits and / or blocks the intracellular signaling mediated by TIGIT binding to PVRL3 is selected from a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0253] In another aspect, provided herein is a method of increasing, enhancing or stimulating an immune response or function in an individual by administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity and an agent that decreases or inhibits the expression and / or activity of one or more additional immune co-inhibitory receptors. In some embodiments, the one of more additional immune co-inhibitory receptor is selected from PD-1, CTLA-4, LAG3, TIM3, BTLA VISTA, B7H4, and CD96. In some embodiments, one of more additional immune co-inhibitory receptor is selected from PD-1, CTLA-4, LAG3 and TIM3.

[0254] In another aspect, provided herein is a method of increasing, enhancing or stimulating an immune response or function in an individual by administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity and an agent that increases or activates the expression and / or activity of one or more additional immune co-stimulatory receptors. In some embodiments, the one of more additional immune co-stimulatory receptor is selected from CD226, OX-40, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS, NKG2D, and 2B4. In some embodiments, the one or more additional immune co-stimulatory receptor is selected from CD226, OX-40, CD28, CD27, CD137, HVEM, and GITR. In some embodiments, the one of more additional immune co-stimulatory receptor is selected from OX-40 and CD27.

[0255] The methods of this invention may find use in treating conditions where enhanced immunogenicity is desired such as increasing tumor immunogenicity for the treatment of cancer or T cell dysfunctional disorders.

[0256] A variety of cancers may be treated, or their progression may be delayed.

[0257] In some embodiments, the individual has non-small cell lung cancer. The non-small cell lung cancer may be at early stage or at late stage. In some embodiments, the individual has small cell lung cancer. The small cell lung cancer may be at early stage or at late stage. In some embodiments, the individual has renal cell cancer. The renal cell cancer may be at early stage or at late stage. In some embodiments, the individual has colorectal cancer. The colorectal cancer may be at early stage or late stage. In some embodiments, the individual has ovarian cancer. The ovarian cancer may be at early stage or at late stage. In some embodiments, the individual has breast cancer. The breast cancer may be at early stage or at late stage. In some embodiments, the individual has pancreatic cancer. The pancreatic cancer may be at early stage or at late stage. In some embodiments, the individual has gastric carcinoma. The gastric carcinoma may be at early stage or at late stage. In some embodiments, the individual has bladder cancer. The bladder cancer may be at early stage or at late stage. In some embodiments, the individual has esophageal cancer. The esophageal cancer may be at early stage or at late stage. In some embodiments, the individual has mesothelioma. The mesothelioma may be at early stage or at late stage. In some embodiments, the individual has melanoma. The melanoma may be at early stage or at late stage. In some embodiments, the individual has head and neck cancer. The head and neck cancer may be at early stage or at late stage. In some embodiments, the individual has thyroid cancer. The thyroid cancer may be at early stage or at late stage. In some embodiments, the individual has sarcoma. The sarcoma may be at early stage or late stage. In some embodiments, the individual has prostate cancer. The prostate cancer may be at early stage or at late stage. In some embodiments, the individual has glioblastoma. The glioblastoma may be at early stage or at late stage. In some embodiments, the individual has cervical cancer. The cervical cancer may be at early stage or at late stage. In some embodiments, the individual has thymic carcinoma. The thymic carcinoma may be at early stage or at late stage. In some embodiments, the individual has leukemia. The leukemia may be at early stage or at late stage. In some embodiments, the individual has lymphomas. The lymphoma may be at early stage or at late stage. In some embodiments, the individual has myelomas. The myelomas may be at early stage or at late stage. In some embodiments, the individual has mycoses fungoids. The mycoses fungoids may be at early stage or at late stage. In some embodiments, the individual has merkel cell cancer. The merkel cell cancer may be at early stage or at late stage. In some embodiments, the individual has hematologic malignancies. The hematological malignancies may be early stage or late stage. In some embodiments, the individual is a human.

[0258] In some embodiments of the methods of this invention, the 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.

[0259] In some embodiments of the methods of this invention, the number of CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination. In some embodiments of the methods of this invention, the number of activated CD4 and / or CD8 T cells is elevated relative to prior to administration of the combination.

[0260] In some embodiments of the methods of this invention, the activated CD4 and / or CD8 T cells is characterized by <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-IFN+ producing CD4 and / or CD8 T cells and / or enhanced cytolytic activity relative to prior to the administration of the combination.

[0261] In some embodiments of the methods of this invention, the CD4 and / or CD8 T cells exhibit increased release of cytokines selected from the group consisting of IFN-<semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>, TNF-<semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> and interleukins.

[0262] In some embodiments of the methods of this invention, the CD4 and / or CD8 T cell is an effector memory T cell. In some embodiments of the methods of this invention, the CD4 and / or CD8 effector memory T cell is characterized by γ-IFN+ producing CD4 and / or CD8 T cells and / or enhanced cytolytic activity. In some embodiments of the methods of this invention, the CD4 and / or CD8 effector memory T cell is characterized by having the expression of CD44high CD62Llow.

[0263] In some embodiments of the methods of this invention, the cancer has elevated levels of T cell infiltration.

[0264] In some embodiments, the methods of the invention may further comprise administering an additional therapy. The additional therapy may be radiation therapy, surgery, chemotherapy, gene therapy, DNA therapy, viral therapy, RNA therapy, immunotherapy, bone marrow transplantation, nanotherapy, monoclonal antibody therapy, or a combination of the foregoing. The additional therapy may be in the form of an adjuvant or neoadjuvant therapy. In some embodiments, the additional therapy is the administration of side-effect limiting agents (e.g., agents intended to lessen the occurrence and / or severity of side effects of treatment, such as anti-nausea agents, etc.). In some embodiments, the additional therapy is radiation therapy. In some embodiments, the additional therapy is surgery. In some embodiments, the additional therapy may be one or more of the chemotherapeutic agents described hereinabove.

[0265] Any of the PD-1 axis binding antagonists and agents that decreases or inhibits TIGIT expression and / or activity described below may be used in the methods of the invention.

[0266] In some embodiments, any of the targets described herein (e.g., PD-1, PD-L1, PD- L2, CTLA-4, LAG3, TIM3, BTLA, VISTA, B7H4, CD96, B7-1, TIGIT, CD226, OX-40, CD28, CD27, CD137, HVEM, GITR, MICA, ICOS, NKG2D, 2B4, etc.) is a human protein. PD-1 axis binding antagonists

[0267] Provided herein is a method for treatment or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effect amount of a PD-1 axis binding antagonist in combination with an agent that that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effect amount of a PD-1 axis binding antagonist in combination with an agent that that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effect amount of a PD-1 axis binding antagonist in combination with an agent that that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for increasing, enhancing or stimulating an immune response or function in an individual comprising administering to the individual an effect amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity.

[0268] For example, a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.

[0269] In some embodiments, the PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its ligand binding partners. In a specific aspect the PD-1 ligand binding partners are PD-L1 and / or PD-L2. In another embodiment, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific aspect, PD-L1 binding partners are PD-1 and / or B7-1. In another embodiment, the PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partners. In a specific aspect, a PD-L2 binding partner is PD-1. The antagonist may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.

[0270] In some embodiments, the PD-1 binding antagonist is selected from MDX-1106 (nivolumab), Merck 3745 (lambrolizumab), CT-011 (pidilizumab), and AMP-224. In some embodiments, the PD-L1 binding antagonist is selected from YW243.55.S70, MPDL3280A, MDX-1105, and MEDI 4736. In some embodiments, the PD-L2 binding antagonist is AMP-224. In some embodiments, the PD-1 binding antagonist is AMP-224. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO2007 / 005874. Antibody YW243.55.S70 (SEQ ID No. 20) is an anti-PD-L1 described in WO 2010 / 077634 A1 and US 8,217,149. MDX-1106, also known as MDX-1106-04, ONO-4538, BMS-936558, or nivolumab, is an anti-PD-1 antibody described in WO2006 / 121168. Merck 3745, also known as MK 3475, MK-3475, SCH-900475, or lambrolizumab, is an anti-PD-1 antibody described in WO2009 / 114335. CT-011, also known as hBAT, hBAT-1, or pidilizumab, is an anti-PD-1 antibody described in WO2009 / 101611. AMP-224, also known as B7-DCIg, is a PD-L2-Fc fusion soluble receptor described in WO2010 / 027827 and WO2011 / 066342.

[0271] Examples of anti-PD-L1 antibodies useful for the methods of this invention, and methods for making thereof are described in PCT patent application WO 2010 / 077634 A1 and US 8,217,149.

[0272] In some embodiments, the PD-1 axis binding antagonist is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is capable of inhibiting binding between PD- L1 and PD-1 and / or between PD-L1 and B7-1. In some embodiments, the anti-PD-L1 antibody is a monoclonal antibody. In some embodiments, the anti-PD-L1 antibody is an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some embodiments, the anti-PD-L1 antibody is a humanized antibody. In some embodiments, the anti-PD-L1 antibody is a human antibody.

[0273] The anti-PD-L1 antibodies useful in this invention, including compositions containing such antibodies, such as those described in WO 2010 / 077634 A1 and US 8,217,149, may be used in combination with an agent that decreases or inhibits TIGIT expression and / or activity with or without any additional therapy (e.g., chemotherapy) to treat cancer or an immune related disease (e.g., T cell dysfunctional disorder, viral infection, chronic viral infection, etc.).

[0274] In one embodiment, the anti-PD-L1 antibody contains a heavy chain variable region polypeptide comprising an HVR-H1, HVR-H2 and HVR-H3 sequence, wherein: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO: 33); [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:19); further wherein: <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is D or G; <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> is S or L; <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> is T or S.

[0275] In one specific aspect, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is D; <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> is S and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> is T. In another aspect, the polypeptide further comprises variable region heavy chain framework sequences juxtaposed between the HVRs according to the formula: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)- (HC-FR3)-(HVR-H3)-(HC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a further aspect, the framework sequences are VH subgroup III consensus framework. In a still further aspect, at least one of the framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:25) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:26) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:27) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:28).

[0276] In a still further aspect, the heavy chain polypeptide is further combined with a variable region light chain comprising an HVR-L1, HVR-L2 and HVR-L3, wherein: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:35); (b) the HVR-L2 sequence is SASX9LX10S, (SEQ ID NO:36); (c) the HVR-L3 sequence is <semantics>QQX11X12X13X14PX15T<annotation encoding="application / x-tex">QQX_{11}X_{12}X_{13}X_{14}PX_{15}T< / annotation>< / semantics> (SEQ ID NO:37); further wherein: <semantics>X4<annotation encoding="application / x-tex">X_4< / annotation>< / semantics> is D or V; <semantics>X5<annotation encoding="application / x-tex">X_5< / annotation>< / semantics> is V or I; <semantics>X6<annotation encoding="application / x-tex">X_6< / annotation>< / semantics> is S or N; <semantics>X7<annotation encoding="application / x-tex">X_7< / annotation>< / semantics> is A or F; <semantics>X8<annotation encoding="application / x-tex">X_8< / annotation>< / semantics> is V or L; <semantics>X9<annotation encoding="application / x-tex">X_9< / annotation>< / semantics> is F or T; <semantics>X10<annotation encoding="application / x-tex">X_{10}< / annotation>< / semantics> is Y or A; <semantics>X11<annotation encoding="application / x-tex">X_{11}< / annotation>< / semantics> is Y, G, F, or S; <semantics>X12<annotation encoding="application / x-tex">X_{12}< / annotation>< / semantics> is L, Y, F or W; <semantics>X13<annotation encoding="application / x-tex">X_{13}< / annotation>< / semantics> is Y, N, A, T, G, F or I; <semantics>X14<annotation encoding="application / x-tex">X_{14}< / annotation>< / semantics> is H, V, P, T or I; <semantics>X15<annotation encoding="application / x-tex">X_{15}< / annotation>< / semantics> is A, W, R, P or T.

[0277] In a still further aspect, X4 is D; X5 is V; X6 is S; X7 is A; X8 is V; X9 is F; X10 is Y; X11 is Y; X12 is L; X13 is Y; X14 is H; X15 is A. In a still further aspect, the light chain further comprises variable region light chain framework sequences juxtaposed between the HVRs according to the formula: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)- (HVR-L3)-(LC-FR4). In a still further aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the framework sequences are VL kappa I consensus framework. In a still further aspect, at least one of the framework sequence is the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:30) [Image disponible dans le document PDF, Image available in the PDF document] LC-FR4 is FGQGTKVEIKR (SEQ ID NO:32).

[0278] In another embodiment, provided is an isolated anti-PD-L1 antibody or antigen binding fragment comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain comprises and HVR-H1, HVR-H2 and HVR-H3, wherein further: (i) the HVR-H1 sequence is GFTFSX1SWIH; (SEQ ID NO:33) (ii) the HVR-H2 sequence is AWIX2PYGGSX3YYADSVKG (SEQ ID NO:34) (iii) the HVR-H3 sequence is RHWPGGFDY, and (SEQ ID NO:19) (b) the light chain comprises and HVR-L1, HVR-L2 and HVR-L3, wherein further: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:37) further wherein: <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is D or G; <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> is S or L; <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> is T or S; <semantics>X4<annotation encoding="application / x-tex">X_4< / annotation>< / semantics> is D or V; <semantics>X5<annotation encoding="application / x-tex">X_5< / annotation>< / semantics> is V or I; <semantics>X6<annotation encoding="application / x-tex">X_6< / annotation>< / semantics> is S or N; <semantics>X7<annotation encoding="application / x-tex">X_7< / annotation>< / semantics> is A or F; <semantics>X8<annotation encoding="application / x-tex">X_8< / annotation>< / semantics> is V or L; <semantics>X9<annotation encoding="application / x-tex">X_9< / annotation>< / semantics> is F or T; <semantics>X10<annotation encoding="application / x-tex">X_{10}< / annotation>< / semantics> is Y or A; <semantics>X11<annotation encoding="application / x-tex">X_{11}< / annotation>< / semantics> is Y, G, F, or S; <semantics>X12<annotation encoding="application / x-tex">X_{12}< / annotation>< / semantics> is L, Y, F or W; <semantics>X13<annotation encoding="application / x-tex">X_{13}< / annotation>< / semantics> is Y, N, A, T, G, F or I; <semantics>X14<annotation encoding="application / x-tex">X_{14}< / annotation>< / semantics> is H, V, P, T or I; <semantics>X15<annotation encoding="application / x-tex">X_{15}< / annotation>< / semantics> is A, W, R, P or T.

[0279] In a specific aspect, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is D; <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> is S and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> is T. In another aspect, <semantics>X4<annotation encoding="application / x-tex">X_4< / annotation>< / semantics> is D; <semantics>X5<annotation encoding="application / x-tex">X_5< / annotation>< / semantics> is V; <semantics>X6<annotation encoding="application / x-tex">X_6< / annotation>< / semantics> is <semantics>S<annotation encoding="application / x-tex">S< / annotation>< / semantics>; <semantics>X7<annotation encoding="application / x-tex">X_7< / annotation>< / semantics> is <semantics>A<annotation encoding="application / x-tex">A< / annotation>< / semantics>; <semantics>X8<annotation encoding="application / x-tex">X_8< / annotation>< / semantics> is <semantics>V<annotation encoding="application / x-tex">V< / annotation>< / semantics>; <semantics>X9<annotation encoding="application / x-tex">X_9< / annotation>< / semantics> is <semantics>F<annotation encoding="application / x-tex">F< / annotation>< / semantics>; <semantics>X10<annotation encoding="application / x-tex">X_{10}< / annotation>< / semantics> is <semantics>Y<annotation encoding="application / x-tex">Y< / annotation>< / semantics>; <semantics>X11<annotation encoding="application / x-tex">X_{11}< / annotation>< / semantics> is <semantics>Y<annotation encoding="application / x-tex">Y< / annotation>< / semantics>; <semantics>X12<annotation encoding="application / x-tex">X_{12}< / annotation>< / semantics> is <semantics>L<annotation encoding="application / x-tex">L< / annotation>< / semantics>; <semantics>X13<annotation encoding="application / x-tex">X_{13}< / annotation>< / semantics> is <semantics>Y<annotation encoding="application / x-tex">Y< / annotation>< / semantics>; <semantics>X14<annotation encoding="application / x-tex">X_{14}< / annotation>< / semantics> is <semantics>H<annotation encoding="application / x-tex">H< / annotation>< / semantics>; <semantics>X15<annotation encoding="application / x-tex">X_{15}< / annotation>< / semantics> is <semantics>A<annotation encoding="application / x-tex">A< / annotation>< / semantics>. In yet another aspect, <semantics>X1<annotation encoding="application / x-tex">X_1< / annotation>< / semantics> is D; <semantics>X2<annotation encoding="application / x-tex">X_2< / annotation>< / semantics> is S and <semantics>X3<annotation encoding="application / x-tex">X_3< / annotation>< / semantics> is T, <semantics>X4<annotation encoding="application / x-tex">X_4< / annotation>< / semantics> is D; <semantics>X5<annotation encoding="application / x-tex">X_5< / annotation>< / semantics> is V; <semantics>X6<annotation encoding="application / x-tex">X_6< / annotation>< / semantics> is S; <semantics>X7<annotation encoding="application / x-tex">X_7< / annotation>< / semantics> is A; <semantics>X8<annotation encoding="application / x-tex">X_8< / annotation>< / semantics> is V; <semantics>X9<annotation encoding="application / x-tex">X_9< / annotation>< / semantics> is F; <semantics>X10<annotation encoding="application / x-tex">X_{10}< / annotation>< / semantics> is Y; <semantics>X11<annotation encoding="application / x-tex">X_{11}< / annotation>< / semantics> is Y; <semantics>X12<annotation encoding="application / x-tex">X_{12}< / annotation>< / semantics> is L; <semantics>X13<annotation encoding="application / x-tex">X_{13}< / annotation>< / semantics> is Y; <semantics>X14<annotation encoding="application / x-tex">X_{14}< / annotation>< / semantics> is H and <semantics>X15<annotation encoding="application / x-tex">X_{15}< / annotation>< / semantics> is A.

[0280] In a further aspect, the heavy chain variable region comprises one or more framework sequences juxtaposed between the HVRs as: (HC-FR1)-(HVR-H1)-(HC-FR2)- (HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and the light chain variable regions comprises one or more framework sequences juxtaposed between the HVRs as: (LC-FR1)-(HVR-L1)- (LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In a still further aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the heavy chain framework sequences are derived from a Kabat subgroup I, II, or III sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document]

[0281] In a still further aspect, the light chain framework sequences are derived from a Kabat kappa I, II, II or IV subgroup sequence. In a still further aspect, the light chain framework sequences are VL kappa I consensus framework. In a still further aspect, one or more of the light chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:29) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:30) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:31) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:32).

[0282] In a still further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a still further specific aspect, the human constant region is IgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region if IgG2A. In a still further specific aspect, the antibody has reduced or minimal effector function. In a still further specific aspect the minimal effector function results from an "effector-less Fc mutation" or aglycosylation. In still a further embodiment, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region.

[0283] In yet another embodiment, provided is an anti-PD-L1 antibody comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain further comprises and HVR-H1, HVR-H2 and an HVR-H3 sequence having at least 85% sequence identity to GFTFSDSWIH (SEQ ID NO:17), AWISPYGGSTYYADSVKG (SEQ ID NO:18) and RHWPGGFDY (SEQ ID NO:19), respectively, or (b) the light chain further comprises an HVR-L1, HVR-L2 and an HVR-L3 sequence having at least 85% sequence identity to RASQDVSTAVA (SEQ ID NO:20), SASFLYS (SEQ ID NO:21) and QQYLYHPAT (SEQ ID NO:22), respectively. (c) In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In another aspect, the heavy chain variable region comprises one or more framework sequences juxtaposed between the HVRs as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR- H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and the light chain variable regions comprises one or more framework sequences juxtaposed between the HVRs as: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC- FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the heavy chain framework sequences are derived from a Kabat subgroup I, II, or III sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:25) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:26) [Image disponible dans le document PDF, Image available in the PDF document] HC-FR4 WGQGTLVTVSA (SEQ ID NO:28).

[0284] In a still further aspect, the light chain framework sequences are derived from a Kabat kappa I, II, II or IV subgroup sequence. In a still further aspect, the light chain framework sequences are VL kappa I consensus framework. In a still further aspect, one or more of the light chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:29) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:30) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:32).

[0285] In a still further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a still further specific aspect, the human constant region is IgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region if IgG2A. In a still further specific aspect, the antibody has reduced or minimal effector function. In a still further specific aspect the minimal effector function results from an "effector-less Fc mutation" or aglycosylation. In still a further embodiment, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region.

[0286] In a still further embodiment, provided is an isolated anti-PD-L1 antibody comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSA (SEQ ID NO:23), EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSSASTK (SEQ ID NO:40), or EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSS (SEQ ID NO:41), or (b) the light chain sequences has at least 85% sequence identity to the light chain sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24).

[0287] In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In another aspect, the heavy chain variable region comprises one or more framework sequences juxtaposed between the HVRs as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and the light chain variable regions comprises one or more framework sequences juxtaposed between the HVRs as: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a further aspect, the heavy chain framework sequences are derived from a Kabat subgroup I, II, or III sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:25) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:26) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:28).

[0288] In a still further aspect, the light chain framework sequences are derived from a Kabat kappa I, II, II or IV subgroup sequence. In a still further aspect, the light chain framework sequences are VL kappa I consensus framework. In a still further aspect, one or more of the light chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:29) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:30) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:32).

[0289] In a still further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a still further specific aspect, the human constant region is IgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region if IgG2A. In a still further specific aspect, the antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from production in prokaryotic cells. In a still further specific aspect the minimal effector function results from an "effector-less Fc mutation" or aglycosylation. In still a further embodiment, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region.

[0290] In a still further embodiment, the invention provides for compositions comprising any of the above described anti-PD-L1 antibodies in combination with at least one pharmaceutically-acceptable carrier.

[0291] In a still further embodiment, provided is an isolated nucleic acid encoding a light chain or a heavy chain variable region sequence of an anti-PD-L1 antibody, wherein: (a) the heavy chain further comprises and HVR-H1, HVR-H2 and an HVR-H3 sequence having at least 85% sequence identity to GFTFSDSWIH (SEQ ID NO:17), AWISPYGGSTYYADSVKG (SEQ ID NO:18) and RHWPGGFDY (SEQ ID NO:19), respectively, and (b) the light chain further comprises an HVR-L1, HVR-L2 and an HVR-L3 sequence having at least 85% sequence identity to RASQDVSTAVA (SEQ ID NO:20), SASFLYS (SEQ ID NO:21) and QQYLYHPAT (SEQ ID NO:22), respectively.

[0292] In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In aspect, the heavy chain variable region comprises one or more framework sequences juxtaposed between the HVRs as: (HC-FR1)- (HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and the light chain variable regions comprises one or more framework sequences juxtaposed between the HVRs as: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a further aspect, the heavy chain framework sequences are derived from a Kabat subgroup I, II, or III sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:25) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:26) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:28).

[0293] In a still further aspect, the light chain framework sequences are derived from a Kabat kappa I, II, II or IV subgroup sequence. In a still further aspect, the light chain framework sequences are VL kappa I consensus framework. In a still further aspect, one or more of the light chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:29) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:30) [Image disponible dans le document PDF, Image available in the PDF document] LC-FR4 FGQGTKVEIKR (SEQ ID NO:32).

[0294] In a still further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a still further specific aspect, the human constant region is IgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region if IgG2A. In a still further specific aspect, the antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from production in prokaryotic cells. In a still further specific aspect the minimal effector function results from an "effector-less Fc mutation" or aglycosylation. In still a further aspect, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region.

[0295] In another further embodiment, provided is an isolated anti-PDL1 antibody comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence:EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVA WISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGF DYWGQGTLVTVSS (SEQ ID NO:41), or (b) the light chain sequences has at least 85% sequence identity to the light chain sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24).

[0296] In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In another aspect, the heavy chain variable region comprises one or more framework sequences juxtaposed between the HVRs as: (HC-FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and the light chain variable regions comprises one or more framework sequences juxtaposed between the HVRs as: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a further aspect, the heavy chain framework sequences are derived from a Kabat subgroup I, II, or III sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:25) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:26) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:42).

[0297] In a still further aspect, the light chain framework sequences are derived from a Kabat kappa I, II, II or IV subgroup sequence. In a still further aspect, the light chain framework sequences are VL kappa I consensus framework. In a still further aspect, one or more of the light chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:29) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:30) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:32).

[0298] In a still further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a still further specific aspect, the human constant region is IgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region if IgG2A. In a still further specific aspect, the antibody has reduced or minimal effector function. In a still further specific aspect, the minimal effector function results from production in prokaryotic cells. In a still further specific aspect the minimal effector function results from an "effector-less Fc mutation" or aglycosylation. In still a further embodiment, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region.

[0299] In a further aspect, the heavy chain variable region comprises one or more framework sequences juxtaposed between the HVRs as: (HC-FR1)-(HVR-H1)-(HC-FR2)- (HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and the light chain variable regions comprises one or more framework sequences juxtaposed between the HVRs as: (LC-FR1)-(HVR-L1)- (LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In a still further aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the heavy chain framework sequences are derived from a Kabat subgroup I, II, or III sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:45).

[0300] In a still further aspect, the light chain framework sequences are derived from a Kabat kappa I, II, II or IV subgroup sequence. In a still further aspect, the light chain framework sequences are VL kappa I consensus framework. In a still further aspect, one or more of the light chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:29) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:30) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:46).

[0301] In a still further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a still further specific aspect, the human constant region is IgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region if IgG2A. In a still further specific aspect, the antibody has reduced or minimal effector function. In a still further specific aspect the minimal effector function results from an "effector-less Fc mutation" or aglycosylation. In still a further embodiment, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region.

[0302] In yet another embodiment, provided is an anti-PDL1 antibody comprising a heavy chain and a light chain variable region sequence, wherein: (d) the heavy chain further comprises and HVR-H1, HVR-H2 and an HVR-H3 sequence having at least 85% sequence identity to GFTFSDSWIH (SEQ ID NO:17), AWISPYGGSTYYADSVKG (SEQ ID NO:18) and RHWPGGFDY (SEQ ID NO:19), respectively, or (e) the light chain further comprises an HVR-L1, HVR-L2 and an HVR-L3 sequence having at least 85% sequence identity to RASQDVSTAVA (SEQ ID NO:20), SASFLYS (SEQ ID NO:21) and QQYLYHPAT (SEQ ID NO:22), respectively.

[0303] In a specific aspect, the sequence identity is 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%. In another aspect, the heavy chain variable region comprises one or more framework sequences juxtaposed between the HVRs as: (HC- FR1)-(HVR-H1)-(HC-FR2)-(HVR-H2)-(HC-FR3)-(HVR-H3)-(HC-FR4), and the light chain variable regions comprises one or more framework sequences juxtaposed between the HVRs as: (LC-FR1)-(HVR-L1)-(LC-FR2)-(HVR-L2)-(LC-FR3)-(HVR-L3)-(LC-FR4). In yet another aspect, the framework sequences are derived from human consensus framework sequences. In a still further aspect, the heavy chain framework sequences are derived from a Kabat subgroup I, II, or III sequence. In a still further aspect, the heavy chain framework sequence is a VH subgroup III consensus framework. In a still further aspect, one or more of the heavy chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:25) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:26) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:47).

[0304] In a still further aspect, the light chain framework sequences are derived from a Kabat kappa I, II, II or IV subgroup sequence. In a still further aspect, the light chain framework sequences are VL kappa I consensus framework. In a still further aspect, one or more of the light chain framework sequences is the following: [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:29) [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:30) [Image disponible dans le document PDF, Image available in the PDF document] [Image disponible dans le document PDF, Image available in the PDF document] (SEQ ID NO:32).

[0305] In a still further specific aspect, the antibody further comprises a human or murine constant region. In a still further aspect, the human constant region is selected from the group consisting of IgG1, IgG2, IgG2, IgG3, IgG4. In a still further specific aspect, the human constant region is IgG1. In a still further aspect, the murine constant region is selected from the group consisting of IgG1, IgG2A, IgG2B, IgG3. In a still further aspect, the murine constant region if IgG2A. In a still further specific aspect, the antibody has reduced or minimal effector function. In a still further specific aspect the minimal effector function results from an "effector-less Fc mutation" or aglycosylation. In still a further embodiment, the effector-less Fc mutation is an N297A or D265A / N297A substitution in the constant region.

[0306] In a still further embodiment, provided is an isolated anti-PDL1 antibody comprising a heavy chain and a light chain variable region sequence, wherein: (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSSASTK (SEQ ID NO:40), or (b) the light chain sequences has at least 85% sequence identity to the light chain sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR (SEQ ID NO:24).

[0307] In some embodiments, provided is an isolated anti-PDL1 antibody comprising a heavy chain and a light chain variable region sequence, wherein the light chain variable region sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:24. In some embodiments, provided is an isolated anti-PDL1 antibody comprising a heavy chain and a light chain variable region sequence, wherein the heavy chain variable region sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:40. In some embodiments, provided is an isolated anti-PDL1 antibody comprising a heavy chain and a light chain variable region sequence, wherein the light chain variable region sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:24 and the heavy chain variable region sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:40.

[0308] In a still further embodiment, provided is an isolated anti-PDL1 antibody comprising a heavy chain and a light chain sequence, wherein: (a) the heavy chain sequence has at least 85% sequence identity to the heavy chain sequence: EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGG STYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGV HTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTP PVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:48), or (b) the light chain sequences has at least 85% sequence identity to the light chain sequence: DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSG VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSV FIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDST YSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:49).

[0309] In some embodiments, provided is an isolated anti-PDL1 antibody comprising a heavy chain and a light chain sequence, wherein the light chain sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:49. In some embodiments, provided is an isolated anti-PDL1 antibody comprising a heavy chain and a light chain sequence, wherein the heavy chain sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:48. In some embodiments, provided is an isolated anti- PDL1 antibody comprising a heavy chain and a light chain sequence, wherein the light chain sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:49 and the heavy chain sequence has at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:48.

[0310] In a still further aspect, the nucleic acid further comprises a vector suitable for expression of the nucleic acid encoding any of the previously described anti-PD-L1 antibodies. In a still further specific aspect, the vector further comprises a host cell suitable for expression of the nucleic acid. In a still further specific aspect, the host cell is a eukaryotic cell or a prokaryotic cell. In a still further specific aspect, the eukaryotic cell is a mammalian cell, such as Chinese Hamster Ovary (CHO).

[0311] The anti-PD-L1 antibody or antigen binding fragment thereof, may be made using methods known in the art, for example, by a process comprising culturing a host cell containing nucleic acid encoding any of the previously described anti-PD-L1 antibodies or antigen-binding fragment in a form suitable for expression, under conditions suitable to produce such antibody or fragment, and recovering the antibody or fragment.

[0312] In a still further embodiment, the invention provides for a composition comprising an anti-PD-L1 antibody or antigen binding fragment thereof as provided herein and at least one pharmaceutically acceptable carrier. Agents that decreases or inhibits TIGIT expression and / or activity

[0313] Provided herein is a method for treatment or delaying progression of cancer in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for reducing or inhibiting cancer relapse or cancer progression in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for treating or delaying progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for reducing or inhibiting progression of an immune related disease in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for increasing, enhancing or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of a PD-1 axis binding antagonist in combination with an agent that decreases or inhibits TIGIT expression and / or activity. Provided herein is also a method for increasing, enhancing or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity and an agent that decreases or inhibits one or more additional immune co-inhibitory receptors. Provided herein is also a method for increasing, enhancing or stimulating an immune response or function in an individual comprising administering to the individual an effective amount of an agent that decreases or inhibits TIGIT expression and / or activity and an agent that increases or activates one or more additional immune co-stimulatory receptors. For example, agent that decreases or inhibits TIGIT expression and / or activity includes 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.

[0314] In some embodiments, the antagonist of TIGIT expression and / or activity includes a small molecule inhibitor, an inhibitory antibody or antigen-binding fragment thereof, an aptamer, an inhibitory nucleic acid, and an inhibitory polypeptide.

[0315] In some ...

Claims

<pat:ClaimStatement>CLAIMS< / pat:ClaimStatement> <pat:Claims com:id="claims"> <pat:Claim com:id="CLM-00001"> <pat:ClaimNumber>1< / pat:ClaimNumber> <pat:ClaimText>1. Use of a PD-1 axis binding antagonist in the manufacture of a medicament for (a) treating or delaying progression of cancer or (b) reducing or inhibiting cancer relapse or cancer progression in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00002"> <pat:ClaimNumber>2< / pat:ClaimNumber> <pat:ClaimText>2. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for (a) treating or delaying progression of cancer in an individual or (b) reducing or inhibiting cancer relapse or cancer progression in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00003"> <pat:ClaimNumber>3< / pat:ClaimNumber> <pat:ClaimText>3. Use of a PD-1 axis binding antagonist in the manufacture of a medicament for (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00004"> <pat:ClaimNumber>4< / pat:ClaimNumber> <pat:ClaimText>4. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00005"> <pat:ClaimNumber>5< / pat:ClaimNumber> <pat:ClaimText>5. The use of claim 3 or claim 4, wherein the T cell dysfunction is characterized by T cell anergy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00006"> <pat:ClaimNumber>6< / pat:ClaimNumber> <pat:ClaimText>6. The use of claim 3 or claim 4, wherein the T cell dysfunction is characterized by T cell exhaustion. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00007"> <pat:ClaimNumber>7< / pat:ClaimNumber> <pat:ClaimText>7. The use of any one of claims 4 to 6, wherein the T cell dysfunction comprises dysfunctional CD4+ and CD8+ T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00008"> <pat:ClaimNumber>8< / pat:ClaimNumber> <pat:ClaimText>8. The use of any one of claims 3 to 7, wherein the immune related disease is a T cell dysfunctional disorder selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00009"> <pat:ClaimNumber>9< / pat:ClaimNumber> <pat:ClaimText>9. Use of a PD-1 axis binding antagonist in the manufacture of a medicament for stimulating an immune response or function in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00010"> <pat:ClaimNumber>10< / pat:ClaimNumber> <pat:ClaimText>10. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for stimulating an immune response or function in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00011"> <pat:ClaimNumber>11< / pat:ClaimNumber> <pat:ClaimText>11. The use of any one of claims 1 to 10, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are formulated together. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00012"> <pat:ClaimNumber>12< / pat:ClaimNumber> <pat:ClaimText>12. The use of any one of claims 1 to 11, wherein the medicament is for use in combination with at least one chemotherapeutic agent. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00013"> <pat:ClaimNumber>13< / pat:ClaimNumber> <pat:ClaimText>13. The use of any one of claims 3 to 12, wherein the individual has cancer. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00014"> <pat:ClaimNumber>14< / pat:ClaimNumber> <pat:ClaimText>14. The use of claim 1, 2, or 13, wherein the cancer comprises infiltrating T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00015"> <pat:ClaimNumber>15< / pat:ClaimNumber> <pat:ClaimText>15. The use of claim 1, 2, 13 or 14, wherein the cancer is selected from the group consisting of a non-small cell lung cancer, a small cell lung cancer, a renal cell cancer, a colorectal cancer, an ovarian cancer, a breast cancer, a pancreatic cancer, a gastric carcinoma, a bladder cancer, an esophageal cancer, a mesothelioma, a melanoma, a head and neck cancer, a thyroid cancer, a sarcoma, a prostate cancer, a glioblastoma, a cervical cancer, a thymic carcinoma, a leukemia, a lymphoma, a myeloma, a mycosis fungoides, a Merkel cell cancer, and an hematologic malignancy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00016"> <pat:ClaimNumber>16< / pat:ClaimNumber> <pat:ClaimText>16. The use of any one of claims 1 to 15, wherein the combination of anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist elevates the number of CD4+ or CD8+ T cells relative to prior to administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00017"> <pat:ClaimNumber>17< / pat:ClaimNumber> <pat:ClaimText>17. The use of any one of claims 1 to 16, wherein the combination of anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist elevates the number of activated CD4+ or CD8+ T cells relative to prior to administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00018"> <pat:ClaimNumber>18< / pat:ClaimNumber> <pat:ClaimText>18. The use of claim 17, wherein the activated CD4+ or CD8+ T cells are characterized by enhanced γ-IFN+ production or enhanced cytolytic activity relative to prior to the administration of the combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00019"> <pat:ClaimNumber>19< / pat:ClaimNumber> <pat:ClaimText>19. The use of any one of claims 14 to 18, wherein the combination of anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist increases the release of cytokines selected from the group consisting of IFN- <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>, TNF-<semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> and interleukins from the CD4+ or CD8+ T cells relative to prior to the administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00020"> <pat:ClaimNumber>20< / pat:ClaimNumber> <pat:ClaimText>20. The use of any one of claims 14 to 19, wherein the CD4+ or CD8+ T cells are effector memory T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00021"> <pat:ClaimNumber>21< / pat:ClaimNumber> <pat:ClaimText>21. The use of claim 20, wherein the CD4+ or CD8+ effector memory T cells are characterized by <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-IFN+ production or enhanced cytolytic activity relative to prior to the administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00022"> <pat:ClaimNumber>22< / pat:ClaimNumber> <pat:ClaimText>22. The use of claim 20, wherein the CD4+ or CD8+ effector memory T cells are characterized by having CD44high CD62Llow expression. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00023"> <pat:ClaimNumber>23< / pat:ClaimNumber> <pat:ClaimText>23. The use of any one of claims 1 to 22, wherein the anti-TIGIT antagonist antibody inhibits TIGIT activity, inhibits the interaction of TIGIT with PVR, inhibits the interaction of TIGIT with PVRL2, inhibits the interaction of TIGIT with PVRL3, inhibits the intracellular signaling mediated by TIGIT binding to PVR, inhibits the intracellular signaling mediated by TIGIT binding to PVRL2, inhibits the intracellular signaling mediated by TIGIT binding to PVRL3, or a combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00024"> <pat:ClaimNumber>24< / pat:ClaimNumber> <pat:ClaimText>24. The use of claim 23, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, and a heteroconjugate antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00025"> <pat:ClaimNumber>25< / pat:ClaimNumber> <pat:ClaimText>25. The use of any one of claims 1 to 24, wherein the anti-TIGIT antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00026"> <pat:ClaimNumber>26< / pat:ClaimNumber> <pat:ClaimText>26. The use of any one of claims 1 to 24, wherein the anti-TIGIT antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00027"> <pat:ClaimNumber>27< / pat:ClaimNumber> <pat:ClaimText>27. The use of claim 26, wherein the anti-TIGIT antagonist antibody is an IgG-1, an IgG-2, an IgG2A, an IgG2B, an IgG-3 or an IgG-4 subtype. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00028"> <pat:ClaimNumber>28< / pat:ClaimNumber> <pat:ClaimText>28. The use of claim 27, wherein the anti-TIGIT antagonist antibody is an IgG-1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00029"> <pat:ClaimNumber>29< / pat:ClaimNumber> <pat:ClaimText>29. The use of claim 27, wherein the anti-TIGIT antagonist antibody is an IgG-4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00030"> <pat:ClaimNumber>30< / pat:ClaimNumber> <pat:ClaimText>30. The use of any one of claims 1 to 29, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00031"> <pat:ClaimNumber>31< / pat:ClaimNumber> <pat:ClaimText>31. The use of claim 30, wherein the anti-TIGIT antagonist antibody is a monoclonal human antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00032"> <pat:ClaimNumber>32< / pat:ClaimNumber> <pat:ClaimText>32. The use of claim 30, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00033"> <pat:ClaimNumber>33< / pat:ClaimNumber> <pat:ClaimText>33. The use of claim 31, wherein the anti-TIGIT antagonist antibody is a monoclonal human IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00034"> <pat:ClaimNumber>34< / pat:ClaimNumber> <pat:ClaimText>34. The use of claim 31, wherein the anti-TIGIT antagonist antibody is a monoclonal human IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00035"> <pat:ClaimNumber>35< / pat:ClaimNumber> <pat:ClaimText>35. The use of claim 32, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00036"> <pat:ClaimNumber>36< / pat:ClaimNumber> <pat:ClaimText>36. The use of claim 32, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00037"> <pat:ClaimNumber>37< / pat:ClaimNumber> <pat:ClaimText>37. The use of any one of claims 1 to 36, wherein the anti-TIGIT antagonist antibody has a modified effector function as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00038"> <pat:ClaimNumber>38< / pat:ClaimNumber> <pat:ClaimText>38. The use of claim 37, wherein the anti-TIGIT antagonist antibody has a reduced or minimal effector function as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00039"> <pat:ClaimNumber>39< / pat:ClaimNumber> <pat:ClaimText>39. The use of claim 38, wherein the anti-TIGIT antagonist antibody comprises an N297A or D265A / N297A substitution in the constant region, according to EU numbering. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00040"> <pat:ClaimNumber>40< / pat:ClaimNumber> <pat:ClaimText>40. The use of claim 37, wherein the modified effector function of the anti-TIGIT antagonist antibody results in improved internalization capability, increased complement- mediated cell killing, or increased antibody-dependent cellular cytotoxicity as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00041"> <pat:ClaimNumber>41< / pat:ClaimNumber> <pat:ClaimText>41. The use of any one of claims 1 to 40, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00042"> <pat:ClaimNumber>42< / pat:ClaimNumber> <pat:ClaimText>42. The use of any one of claims 1 to 41, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to PD-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00043"> <pat:ClaimNumber>43< / pat:ClaimNumber> <pat:ClaimText>43. The use of any one of claims 1 to 41, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to B7-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00044"> <pat:ClaimNumber>44< / pat:ClaimNumber> <pat:ClaimText>44. The use of any one of claims 1 to 41, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to both PD-1 and B7-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00045"> <pat:ClaimNumber>45< / pat:ClaimNumber> <pat:ClaimText>45. The use of any one of claims 1 to 44, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising a HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), a HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and a HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising a HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), a HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and a HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22). < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00046"> <pat:ClaimNumber>46< / pat:ClaimNumber> <pat:ClaimText>46. The use of any one of claims 1 to 45, wherein the anti-PD-L1 antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00047"> <pat:ClaimNumber>47< / pat:ClaimNumber> <pat:ClaimText>47. The use of any one of claims 1 to 45, wherein the anti-PD-L1 antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00048"> <pat:ClaimNumber>48< / pat:ClaimNumber> <pat:ClaimText>48. The use of claim 47, wherein the anti-PD-L1 antagonist antibody is an IgG-1, an IgG-2, an IgG2A, an IgG2B, an IgG-3 or an IgG-4 subtype. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00049"> <pat:ClaimNumber>49< / pat:ClaimNumber> <pat:ClaimText>49. The use of claim 48, wherein the anti-PD-L1 antagonist antibody is an IgG-1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00050"> <pat:ClaimNumber>50< / pat:ClaimNumber> <pat:ClaimText>50. The use of claim 48, wherein the anti-PD-L1 antagonist antibody is an IgG-4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00051"> <pat:ClaimNumber>51< / pat:ClaimNumber> <pat:ClaimText>51. The use of any one of claims 1 to 50, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00052"> <pat:ClaimNumber>52< / pat:ClaimNumber> <pat:ClaimText>52. The use of claim 51, wherein the anti-PD-L1 antagonist antibody is a monoclonal human antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00053"> <pat:ClaimNumber>53< / pat:ClaimNumber> <pat:ClaimText>53. The use of claim 51, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00054"> <pat:ClaimNumber>54< / pat:ClaimNumber> <pat:ClaimText>54. The use of claim 52, wherein the anti-PD-L1 antagonist antibody is a monoclonal human IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00055"> <pat:ClaimNumber>55< / pat:ClaimNumber> <pat:ClaimText>55. The use of claim 52, wherein the anti-PD-L1 antagonist antibody is a monoclonal human IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00056"> <pat:ClaimNumber>56< / pat:ClaimNumber> <pat:ClaimText>56. The use of claim 53, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00057"> <pat:ClaimNumber>57< / pat:ClaimNumber> <pat:ClaimText>57. The use of claim 53, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00058"> <pat:ClaimNumber>58< / pat:ClaimNumber> <pat:ClaimText>58. The use of any one of claims 1 to 57, wherein the anti-PD-L1 antagonist antibody has a modified effector function as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00059"> <pat:ClaimNumber>59< / pat:ClaimNumber> <pat:ClaimText>59. The use of claim 58, wherein the anti-PD-L1 antagonist antibody has a reduced or minimal effector function as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00060"> <pat:ClaimNumber>60< / pat:ClaimNumber> <pat:ClaimText>60. The use of claim 59, wherein the anti-PD-L1 antagonist antibody comprises an N297A or D265A / N297A substitution in the constant region, according to EU numbering. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00061"> <pat:ClaimNumber>61< / pat:ClaimNumber> <pat:ClaimText>61. The use of claim 58, wherein the modified effector function of the anti-PD-L1 antagonist antibody results in improved internalization capability, increased complement- mediated cell killing, or increased antibody-dependent cellular cytotoxicity as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00062"> <pat:ClaimNumber>62< / pat:ClaimNumber> <pat:ClaimText>62. The use of any one of claims 1 to 61, wherein the anti-TIGIT antagonist antibody is formulated for continuous administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00063"> <pat:ClaimNumber>63< / pat:ClaimNumber> <pat:ClaimText>63. The use of any one of claims 1 to 61, wherein the anti-TIGIT antagonist antibody is formulated for intermittent administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00064"> <pat:ClaimNumber>64< / pat:ClaimNumber> <pat:ClaimText>64. The use of any one of claims 1 to 10 and 12 to 63, wherein the anti-TIGIT antagonist antibody is for administration before the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00065"> <pat:ClaimNumber>65< / pat:ClaimNumber> <pat:ClaimText>65. The use of any one of claims 1 to 63, wherein the anti-TIGIT antagonist antibody is for administration simultaneously with the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00066"> <pat:ClaimNumber>66< / pat:ClaimNumber> <pat:ClaimText>66. The use of any one of claims 1 to 10 and 12 to 63, wherein the anti-TIGIT antagonist antibody is for administration after the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00067"> <pat:ClaimNumber>67< / pat:ClaimNumber> <pat:ClaimText>67. Use of a PD-1 axis binding antagonist for treating or delaying progression of cancer in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00068"> <pat:ClaimNumber>68< / pat:ClaimNumber> <pat:ClaimText>68. Use of an anti-TIGIT antagonist antibody for treating or delaying progression of cancer in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00069"> <pat:ClaimNumber>69< / pat:ClaimNumber> <pat:ClaimText>69. Use of a PD-1 axis binding antagonist for treating or delaying progression of an immune related disease characterized by T cell dysfunction in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti- PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00070"> <pat:ClaimNumber>70< / pat:ClaimNumber> <pat:ClaimText>70. Use of an anti-TIGIT antagonist antibody for treating or delaying progression of an immune related disease characterized by T cell dysfunction in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00071"> <pat:ClaimNumber>71< / pat:ClaimNumber> <pat:ClaimText>71. The use of claim 69 or 70, wherein the T cell dysfunction is characterized by T cell anergy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00072"> <pat:ClaimNumber>72< / pat:ClaimNumber> <pat:ClaimText>72. The use of claim 69 or 70, wherein the T cell dysfunction is characterized by T cell exhaustion. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00073"> <pat:ClaimNumber>73< / pat:ClaimNumber> <pat:ClaimText>73. The use of any one of claims 69 to 72, wherein the T cell dysfunction comprises dysfunctional CD4+ or CD8+ T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00074"> <pat:ClaimNumber>74< / pat:ClaimNumber> <pat:ClaimText>74. The use of any one of claims 69 to 73, wherein the immune related disease is a T cell dysfunctional disorder selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00075"> <pat:ClaimNumber>75< / pat:ClaimNumber> <pat:ClaimText>75. Use of a PD-1 axis binding antagonist for stimulating an immune response or function in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00076"> <pat:ClaimNumber>76< / pat:ClaimNumber> <pat:ClaimText>76. Use of an anti-TIGIT antagonist antibody for stimulating an immune response or function in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00077"> <pat:ClaimNumber>77< / pat:ClaimNumber> <pat:ClaimText>77. The use of any one of claims 67 to 76, wherein the anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist are for use in combination with at least one chemotherapeutic agent. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00078"> <pat:ClaimNumber>78< / pat:ClaimNumber> <pat:ClaimText>78. The use of any one of claims 69 to 77, wherein the individual has cancer. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00079"> <pat:ClaimNumber>79< / pat:ClaimNumber> <pat:ClaimText>79. The use of claim 67, 68 or 78, wherein the cancer comprises infiltrating T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00080"> <pat:ClaimNumber>80< / pat:ClaimNumber> <pat:ClaimText>80. The use of claim 67, 68, 78 or 79, wherein the cancer is selected from the group consisting of a non-small cell lung cancer, a small cell lung cancer, a renal cell cancer, a colorectal cancer, an ovarian cancer, a breast cancer, a pancreatic cancer, a gastric carcinoma, a bladder cancer, an esophageal cancer, a mesothelioma, a melanoma, a head and neck cancer, a thyroid cancer, a sarcoma, a prostate cancer, a glioblastoma, a cervical cancer, a thymic carcinoma, a leukemia, a lymphoma, a myeloma, a mycosis fungoides, a Merkel cell cancer, and an hematologic malignancy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00081"> <pat:ClaimNumber>81< / pat:ClaimNumber> <pat:ClaimText>81. The use of any one of claims 67 to 80, wherein the combination of anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist elevates the number of CD4+ or CD8+ T cells relative to prior to administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00082"> <pat:ClaimNumber>82< / pat:ClaimNumber> <pat:ClaimText>82. The use of claim 81, wherein the combination of anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist elevates the number of activated CD4+ or CD8+ T cells relative to prior to administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00083"> <pat:ClaimNumber>83< / pat:ClaimNumber> <pat:ClaimText>83. The use of claim 82, wherein the activated CD4+ or CD8+ T cells are characterized by enhanced γ-IFN+ production or enhanced cytolytic activity relative to prior to the administration of the combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00084"> <pat:ClaimNumber>84< / pat:ClaimNumber> <pat:ClaimText>84. The use of claim 81, 82 or 83, wherein the combination of anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist increases the release of cytokines selected from the group consisting of IFN- <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>, TNF-<semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> and interleukins from the CD4+ or CD8+ T cells relative to prior to the administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00085"> <pat:ClaimNumber>85< / pat:ClaimNumber> <pat:ClaimText>85. The use of any one of claims 81 to 84, wherein the CD4+ or CD8+ T cells are effector memory T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00086"> <pat:ClaimNumber>86< / pat:ClaimNumber> <pat:ClaimText>86. The use of claim 85, wherein the CD4+ or CD8+ effector memory T cells are characterized by <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-IFN+ production or enhanced cytolytic activity relative to prior to the administration of the combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00087"> <pat:ClaimNumber>87< / pat:ClaimNumber> <pat:ClaimText>87. The use of claim 85, wherein the CD4 or CD8 effector memory T cells are characterized by having CD44high CD62Llow expression. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00088"> <pat:ClaimNumber>88< / pat:ClaimNumber> <pat:ClaimText>88. The use of any one of claims 67 to 87, wherein the anti-TIGIT antagonist antibody thereof inhibits TIGIT activity, inhibits the interaction of TIGIT with PVR, inhibits the interaction of TIGIT with PVRL2, inhibits the interaction of TIGIT with PVRL3, inhibits the intracellular signaling mediated by TIGIT binding to PVR, inhibits the intracellular signaling mediated by TIGIT binding to PVRL2, inhibits the intracellular signaling mediated by TIGIT binding to PVRL3, or a combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00089"> <pat:ClaimNumber>89< / pat:ClaimNumber> <pat:ClaimText>89. The use of claim 85, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, and a heteroconjugate antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00090"> <pat:ClaimNumber>90< / pat:ClaimNumber> <pat:ClaimText>90. The use of any one of claims 67 to 89, wherein the anti-TIGIT antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00091"> <pat:ClaimNumber>91< / pat:ClaimNumber> <pat:ClaimText>91. The use of any one of claims 67 to 89, wherein the anti-TIGIT antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00092"> <pat:ClaimNumber>92< / pat:ClaimNumber> <pat:ClaimText>92. The use of claim 91, wherein the anti-TIGIT antagonist antibody is an IgG-1, an IgG-2, an IgG2A, an IgG2B, an IgG-3 or an IgG-4 subtype. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00093"> <pat:ClaimNumber>93< / pat:ClaimNumber> <pat:ClaimText>93. The use of claim 92, wherein the anti-TIGIT antagonist antibody is an IgG-1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00094"> <pat:ClaimNumber>94< / pat:ClaimNumber> <pat:ClaimText>94. The use of claim 92, wherein the anti-TIGIT antagonist antibody is an IgG-4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00095"> <pat:ClaimNumber>95< / pat:ClaimNumber> <pat:ClaimText>95. The use of any one of claims 67 to 92, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00096"> <pat:ClaimNumber>96< / pat:ClaimNumber> <pat:ClaimText>96. The use of claim 95, wherein the anti-TIGIT antagonist antibody is a monoclonal human antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00097"> <pat:ClaimNumber>97< / pat:ClaimNumber> <pat:ClaimText>97. The use of claim 95, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00098"> <pat:ClaimNumber>98< / pat:ClaimNumber> <pat:ClaimText>98. The use of claim 96, wherein the anti-TIGIT antagonist antibody is a monoclonal human IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00099"> <pat:ClaimNumber>99< / pat:ClaimNumber> <pat:ClaimText>99. The use of claim 96, wherein the anti-TIGIT antagonist antibody is a monoclonal human IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00100"> <pat:ClaimNumber>100< / pat:ClaimNumber> <pat:ClaimText>100. The use of claim 97, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00101"> <pat:ClaimNumber>101< / pat:ClaimNumber> <pat:ClaimText>101. The use of claim 97, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00102"> <pat:ClaimNumber>102< / pat:ClaimNumber> <pat:ClaimText>102. The use of any one of claims 67 to 101, wherein the anti-TIGIT antagonist antibody has a modified effector function as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00103"> <pat:ClaimNumber>103< / pat:ClaimNumber> <pat:ClaimText>103. The use of claim 102, wherein the anti-TIGIT antagonist antibody has a reduced or minimal effector function as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00104"> <pat:ClaimNumber>104< / pat:ClaimNumber> <pat:ClaimText>104. The use of claim 103, wherein the anti-TIGIT antagonist antibody comprises an N297A or D265A / N297A substitution in the constant region, according to EU numbering. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00105"> <pat:ClaimNumber>105< / pat:ClaimNumber> <pat:ClaimText>105. The use of claim 102, wherein the modified effector function of the anti-TIGIT antagonist antibody results in improved internalization capability, increased complement- mediated cell killing, or increased antibody-dependent cellular cytotoxicity as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00106"> <pat:ClaimNumber>106< / pat:ClaimNumber> <pat:ClaimText>106. The use of any one of claims 67 to 105, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00107"> <pat:ClaimNumber>107< / pat:ClaimNumber> <pat:ClaimText>107. The use of any one of claims 67 to 106, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to PD-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00108"> <pat:ClaimNumber>108< / pat:ClaimNumber> <pat:ClaimText>108. The use of any one of claims 67 to 106, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to B7-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00109"> <pat:ClaimNumber>109< / pat:ClaimNumber> <pat:ClaimText>109. The use of any one of claims 67 to 106, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to both PD-1 and B7-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00110"> <pat:ClaimNumber>110< / pat:ClaimNumber> <pat:ClaimText>110. The use of any one of claims 67 to 109, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising a HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), a HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and a HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising a HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), a HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and a HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22). < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00111"> <pat:ClaimNumber>111< / pat:ClaimNumber> <pat:ClaimText>111. The use of any one of claims 67 to 110, wherein the anti-PD-L1 antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00112"> <pat:ClaimNumber>112< / pat:ClaimNumber> <pat:ClaimText>112. The use of any one of claims 67 to 110, wherein the anti-PD-L1 antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00113"> <pat:ClaimNumber>113< / pat:ClaimNumber> <pat:ClaimText>113. The use of claim 112, wherein the anti-PD-L1 antagonist antibody is an IgG-1, an IgG- 2, an IgG2A, an IgG2B, an IgG-3 or an IgG-4 subtype. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00114"> <pat:ClaimNumber>114< / pat:ClaimNumber> <pat:ClaimText>114. The use of claim 113, wherein the anti-PD-L1 antagonist antibody is an IgG-1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00115"> <pat:ClaimNumber>115< / pat:ClaimNumber> <pat:ClaimText>115. The use of claim 114, wherein the anti-PD-L1 antagonist antibody is an IgG-4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00116"> <pat:ClaimNumber>116< / pat:ClaimNumber> <pat:ClaimText>116. The use of any one of claims 67 to 115, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00117"> <pat:ClaimNumber>117< / pat:ClaimNumber> <pat:ClaimText>117. The use of claim 116, wherein the anti-PD-L1 antagonist antibody is a monoclonal human antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00118"> <pat:ClaimNumber>118< / pat:ClaimNumber> <pat:ClaimText>118. The use of claim 116, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00119"> <pat:ClaimNumber>119< / pat:ClaimNumber> <pat:ClaimText>119. The use of claim 117, wherein the anti-PD-L1 antagonist antibody is a monoclonal human IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00120"> <pat:ClaimNumber>120< / pat:ClaimNumber> <pat:ClaimText>120. The use of claim 117, wherein the anti-PD-L1 antagonist antibody is a monoclonal human IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00121"> <pat:ClaimNumber>121< / pat:ClaimNumber> <pat:ClaimText>121. The use of claim 118, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00122"> <pat:ClaimNumber>122< / pat:ClaimNumber> <pat:ClaimText>122. The use of claim 118, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00123"> <pat:ClaimNumber>123< / pat:ClaimNumber> <pat:ClaimText>123. The use of any one of claims 67 to 122, wherein the anti-PD-L1 antagonist antibody has a modified effector function as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00124"> <pat:ClaimNumber>124< / pat:ClaimNumber> <pat:ClaimText>124. The use of claim 123, wherein the anti-PD-L1 antagonist antibody has a reduced or minimal effector function as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00125"> <pat:ClaimNumber>125< / pat:ClaimNumber> <pat:ClaimText>125. The use of claim 124, wherein the anti-PD-L1 antagonist antibody comprises an N297A or D265A / N297A substitution in the constant region, according to EU numbering. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00126"> <pat:ClaimNumber>126< / pat:ClaimNumber> <pat:ClaimText>126. The use of claim 123, wherein the modified effector function of the anti-PD-L1 antagonist antibody results in improved internalization capability, increased complement- mediated cell killing, or increased antibody-dependent cellular cytotoxicity as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00127"> <pat:ClaimNumber>127< / pat:ClaimNumber> <pat:ClaimText>127. The use of any one of claims 67 to 126, wherein the anti-TIGIT antagonist antibody is formulated for continuous administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00128"> <pat:ClaimNumber>128< / pat:ClaimNumber> <pat:ClaimText>128. The use of any one of claims 67 to 126, wherein the anti-TIGIT antagonist antibody is formulated for intermittent administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00129"> <pat:ClaimNumber>129< / pat:ClaimNumber> <pat:ClaimText>129. The use of any one of claims 67 to 128, wherein the anti-TIGIT antagonist antibody is for administration before the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00130"> <pat:ClaimNumber>130< / pat:ClaimNumber> <pat:ClaimText>130. The use of any one of claims 67 to 128, wherein the anti-TIGIT antagonist antibody is for administration simultaneously with the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00131"> <pat:ClaimNumber>131< / pat:ClaimNumber> <pat:ClaimText>131. The use of any one of claims 67 to 128, wherein the anti-TIGIT antagonist antibody is for administration after the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00132"> <pat:ClaimNumber>132< / pat:ClaimNumber> <pat:ClaimText>132. The use of any one of claims 1 to 131, wherein the individual is a human patient. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00133"> <pat:ClaimNumber>133< / pat:ClaimNumber> <pat:ClaimText>133. A PD-1 axis binding antagonist for use in treating or delaying progression of cancer in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00134"> <pat:ClaimNumber>134< / pat:ClaimNumber> <pat:ClaimText>134. An anti-TIGIT antagonist antibody for use in treating or delaying progression of cancer in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00135"> <pat:ClaimNumber>135< / pat:ClaimNumber> <pat:ClaimText>135. A PD-1 axis binding antagonist for use in treating or delaying progression of an immune related disease characterized by T cell dysfunction in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti- PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00136"> <pat:ClaimNumber>136< / pat:ClaimNumber> <pat:ClaimText>136. An anti-TIGIT antagonist antibody for use in treating or delaying progression of an immune related disease characterized by T cell dysfunction in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00137"> <pat:ClaimNumber>137< / pat:ClaimNumber> <pat:ClaimText>137. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 135 or 136, wherein the T cell dysfunction is characterized by T cell anergy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00138"> <pat:ClaimNumber>138< / pat:ClaimNumber> <pat:ClaimText>138. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 135 or 136, wherein the T cell dysfunction is characterized by T cell exhaustion. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00139"> <pat:ClaimNumber>139< / pat:ClaimNumber> <pat:ClaimText>139. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 135 to 138, wherein the T cell dysfunction comprises dysfunctional CD4+ and CD8+ T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00140"> <pat:ClaimNumber>140< / pat:ClaimNumber> <pat:ClaimText>140. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 135 to 139, wherein the immune related disease is a T cell dysfunctional disorder selected from the group consisting of unresolved acute infection, chronic infection, and tumor immunity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00141"> <pat:ClaimNumber>141< / pat:ClaimNumber> <pat:ClaimText>141. A PD-1 axis binding antagonist for use in stimulating an immune response or function in an individual in combination with an anti-TIGIT antagonist antibody, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00142"> <pat:ClaimNumber>142< / pat:ClaimNumber> <pat:ClaimText>142. An anti-TIGIT antagonist antibody for use in stimulating an immune response or function in an individual in combination with a PD-1 axis binding antagonist, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00143"> <pat:ClaimNumber>143< / pat:ClaimNumber> <pat:ClaimText>143. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 142, wherein the anti-TIGIT antagonist antibody and PD-1 axis binding antagonist are for use in combination with at least one chemotherapeutic agent. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00144"> <pat:ClaimNumber>144< / pat:ClaimNumber> <pat:ClaimText>144. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 135 to 143, wherein the individual has cancer. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00145"> <pat:ClaimNumber>145< / pat:ClaimNumber> <pat:ClaimText>145. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 133, 134, or 144, wherein the cancer comprises infiltrating T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00146"> <pat:ClaimNumber>146< / pat:ClaimNumber> <pat:ClaimText>146. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 133, 134, 144 or 145, wherein the cancer is selected from the group consisting of a non-small cell lung cancer, a small cell lung cancer, a renal cell cancer, a colorectal cancer, an ovarian cancer, a breast cancer, a pancreatic cancer, a gastric carcinoma, a bladder cancer, an esophageal cancer, a mesothelioma, a melanoma, a head and neck cancer, a thyroid cancer, a sarcoma, a prostate cancer, a glioblastoma, a cervical cancer, a thymic carcinoma, a leukemia, a lymphoma, a myeloma, a mycosis fungoides, a Merkel cell cancer, and an hematologic malignancy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00147"> <pat:ClaimNumber>147< / pat:ClaimNumber> <pat:ClaimText>147. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 146, wherein the combination of anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist elevates the number of CD4+ or CD8+ T cells relative to prior to administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00148"> <pat:ClaimNumber>148< / pat:ClaimNumber> <pat:ClaimText>148. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 147, wherein the combination of anti-TIGIT antagonist and the PD-1 axis binding antagonist elevates the number of activated CD4+ or CD8+ T cells relative to prior to administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00149"> <pat:ClaimNumber>149< / pat:ClaimNumber> <pat:ClaimText>149. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 146, wherein the activated CD4+ or CD8+ T cells are characterized by enhanced γ-IFN+ production or enhanced cytolytic activity relative to prior to the administration of the combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00150"> <pat:ClaimNumber>150< / pat:ClaimNumber> <pat:ClaimText>150. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 147, 148 or 149, wherein the combination of anti-TIGIT antagonist antibody and the PD-1 axis binding antagonist increases the release of cytokines selected from the group consisting of IFN- γ, TNF-α and interleukins from the CD4+ or CD8+ T cells relative to prior to the administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00151"> <pat:ClaimNumber>151< / pat:ClaimNumber> <pat:ClaimText>151. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 147 to 150, wherein the CD4+ or CD8+ T cells are effector memory T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00152"> <pat:ClaimNumber>152< / pat:ClaimNumber> <pat:ClaimText>152. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 151, wherein the CD4+ or CD8+ effector memory T cells are characterized by <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-IFN+ production or enhanced cytolytic activity relative to prior to the administration of the combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00153"> <pat:ClaimNumber>153< / pat:ClaimNumber> <pat:ClaimText>153. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 151, wherein the CD4 or CD8 effector memory T cells are characterized by having CD44high CD62Llow expression. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00154"> <pat:ClaimNumber>154< / pat:ClaimNumber> <pat:ClaimText>154. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 153, wherein the anti-TIGIT antagonist antibody inhibits TIGIT activity, inhibits the interaction of TIGIT with PVR, inhibits the interaction of TIGIT with PVRL2, inhibits the interaction of TIGIT with PVRL3, inhibits the intracellular signaling mediated by TIGIT binding to PVR, inhibits the intracellular signaling mediated by TIGIT binding to PVRL2, inhibits the intracellular signaling mediated by TIGIT binding to PVRL3, or a combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00155"> <pat:ClaimNumber>155< / pat:ClaimNumber> <pat:ClaimText>155. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 154, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, and a heteroconjugate antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00156"> <pat:ClaimNumber>156< / pat:ClaimNumber> <pat:ClaimText>156. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 155, wherein the anti-TIGIT antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00157"> <pat:ClaimNumber>157< / pat:ClaimNumber> <pat:ClaimText>157. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 155, wherein the anti-TIGIT antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00158"> <pat:ClaimNumber>158< / pat:ClaimNumber> <pat:ClaimText>158. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 157, wherein the anti-TIGIT antagonist antibody is an IgG-1, an IgG-2, an IgG2A, an IgG2B, an IgG-3 or an IgG-4 subtype. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00159"> <pat:ClaimNumber>159< / pat:ClaimNumber> <pat:ClaimText>159. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 158, wherein the anti-TIGIT antagonist antibody is an IgG-1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00160"> <pat:ClaimNumber>160< / pat:ClaimNumber> <pat:ClaimText>160. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 158, wherein the anti-TIGIT antagonist antibody is an IgG-4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00161"> <pat:ClaimNumber>161< / pat:ClaimNumber> <pat:ClaimText>161. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 160, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00162"> <pat:ClaimNumber>162< / pat:ClaimNumber> <pat:ClaimText>162. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 161, wherein the anti-TIGIT antagonist antibody is a monoclonal human antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00163"> <pat:ClaimNumber>163< / pat:ClaimNumber> <pat:ClaimText>163. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 161, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00164"> <pat:ClaimNumber>164< / pat:ClaimNumber> <pat:ClaimText>164. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 162, wherein the anti-TIGIT antagonist antibody is a monoclonal human IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00165"> <pat:ClaimNumber>165< / pat:ClaimNumber> <pat:ClaimText>165. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 161, wherein the anti-TIGIT antagonist antibody is a monoclonal human IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00166"> <pat:ClaimNumber>166< / pat:ClaimNumber> <pat:ClaimText>166. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 163, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00167"> <pat:ClaimNumber>167< / pat:ClaimNumber> <pat:ClaimText>167. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 163, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00168"> <pat:ClaimNumber>168< / pat:ClaimNumber> <pat:ClaimText>168. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 167, wherein the anti-TIGIT antagonist antibody has a modified effector function as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00169"> <pat:ClaimNumber>169< / pat:ClaimNumber> <pat:ClaimText>169. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 168, wherein the anti-TIGIT antagonist antibody has a reduced or minimal effector function as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00170"> <pat:ClaimNumber>170< / pat:ClaimNumber> <pat:ClaimText>170. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 169, wherein the anti-TIGIT antagonist antibody comprises an N297A or D265A / N297A substitution in the constant region, according to EU numbering. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00171"> <pat:ClaimNumber>171< / pat:ClaimNumber> <pat:ClaimText>171. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 168, wherein the modified effector function of the anti-TIGIT antagonist antibody results in improved internalization capability, increased complement-mediated cell killing, or increased antibody-dependent cellular cytotoxicity as compared to a corresponding anti-TIGIT antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00172"> <pat:ClaimNumber>172< / pat:ClaimNumber> <pat:ClaimText>172. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 171, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00173"> <pat:ClaimNumber>173< / pat:ClaimNumber> <pat:ClaimText>173. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 172, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD- L1 to PD-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00174"> <pat:ClaimNumber>174< / pat:ClaimNumber> <pat:ClaimText>174. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 172, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD- L1 to B7-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00175"> <pat:ClaimNumber>175< / pat:ClaimNumber> <pat:ClaimText>175. · The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 172, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD- L1 to both PD-1 and B7-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00176"> <pat:ClaimNumber>176< / pat:ClaimNumber> <pat:ClaimText>176. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 173, 174 or 175, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising a HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), a HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and a HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising a HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), a HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and a HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22). < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00177"> <pat:ClaimNumber>177< / pat:ClaimNumber> <pat:ClaimText>177. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 176, wherein the anti-PD-L1 antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00178"> <pat:ClaimNumber>178< / pat:ClaimNumber> <pat:ClaimText>178. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 176, wherein the anti-PD-L1 antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00179"> <pat:ClaimNumber>179< / pat:ClaimNumber> <pat:ClaimText>179. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 177, wherein the anti-PD-L1 antagonist antibody is an IgG-1, an IgG-2, an IgG2A, an IgG2B, an IgG-3 or an IgG-4 subtype. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00180"> <pat:ClaimNumber>180< / pat:ClaimNumber> <pat:ClaimText>180. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 179, wherein the anti-PD-L1 antagonist antibody is an IgG-1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00181"> <pat:ClaimNumber>181< / pat:ClaimNumber> <pat:ClaimText>181. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 179, wherein the anti-PD-L1 antagonist antibody is an IgG-4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00182"> <pat:ClaimNumber>182< / pat:ClaimNumber> <pat:ClaimText>182. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 181, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00183"> <pat:ClaimNumber>183< / pat:ClaimNumber> <pat:ClaimText>183. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 182, wherein the anti-PD-L1 antagonist antibody is a monoclonal human antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00184"> <pat:ClaimNumber>184< / pat:ClaimNumber> <pat:ClaimText>184. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 182, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00185"> <pat:ClaimNumber>185< / pat:ClaimNumber> <pat:ClaimText>185. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 183, wherein the anti-PD-L1 antagonist antibody is a monoclonal human IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00186"> <pat:ClaimNumber>186< / pat:ClaimNumber> <pat:ClaimText>186. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 183, wherein the anti-PD-L1 antagonist antibody is a monoclonal human IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00187"> <pat:ClaimNumber>187< / pat:ClaimNumber> <pat:ClaimText>187. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 184, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00188"> <pat:ClaimNumber>188< / pat:ClaimNumber> <pat:ClaimText>188. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 184, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00189"> <pat:ClaimNumber>189< / pat:ClaimNumber> <pat:ClaimText>189. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 188, wherein the anti-PD-L1 antagonist antibody has a modified effector function as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00190"> <pat:ClaimNumber>190< / pat:ClaimNumber> <pat:ClaimText>190. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 189, wherein the anti-PD-L1 antagonist antibody has a reduced or minimal effector function as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00191"> <pat:ClaimNumber>191< / pat:ClaimNumber> <pat:ClaimText>191. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 190, wherein the anti-PD-L1 antagonist antibody comprises an N297A or D265A / N297A substitution in the constant region, according to EU numbering. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00192"> <pat:ClaimNumber>192< / pat:ClaimNumber> <pat:ClaimText>192. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of claim 189, wherein the modified effector function of the anti-PD-L1 antagonist antibody results in improved internalization capability, increased complement-mediated cell killing, or increased antibody-dependent cellular cytotoxicity as compared to a corresponding anti-PD-L1 antagonist antibody with a native sequence constant region. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00193"> <pat:ClaimNumber>193< / pat:ClaimNumber> <pat:ClaimText>193. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 192, wherein the anti-TIGIT antagonist antibody is formulated for continuous administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00194"> <pat:ClaimNumber>194< / pat:ClaimNumber> <pat:ClaimText>194. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 192, wherein the anti-TIGIT antagonist antibody is formulated for intermittent administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00195"> <pat:ClaimNumber>195< / pat:ClaimNumber> <pat:ClaimText>195. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 194, wherein the anti-TIGIT antagonist antibody is for administration before the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00196"> <pat:ClaimNumber>196< / pat:ClaimNumber> <pat:ClaimText>196. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 194, wherein the anti-TIGIT antagonist antibody is for administration simultaneously with the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00197"> <pat:ClaimNumber>197< / pat:ClaimNumber> <pat:ClaimText>197. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 194, wherein the anti-TIGIT antagonist antibody is for administration after the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00198"> <pat:ClaimNumber>198< / pat:ClaimNumber> <pat:ClaimText>198. The PD-1 axis binding antagonist or anti-TIGIT antagonist antibody for use of any one of claims 133 to 197, wherein the individual is a human patient. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00199"> <pat:ClaimNumber>199< / pat:ClaimNumber> <pat:ClaimText>199. A kit comprising a PD-1 axis binding antagonist and a package insert comprising instructions for using the PD-1 axis binding antagonist in combination with an anti-TIGIT antagonist antibody to (a) treat or delay progression of cancer in an individual or (b) stimulate an immune function of an individual having cancer, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00200"> <pat:ClaimNumber>200< / pat:ClaimNumber> <pat:ClaimText>200. A kit comprising a PD-1 axis binding antagonist, an anti-TIGIT antagonist antibody, and a package insert comprising instructions for using the PD-1 axis binding antagonist and the anti-TIGIT antagonist antibody to (a) treat or delay progression of cancer in an individual or (b) stimulate an immune function of an individual having cancer, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00201"> <pat:ClaimNumber>201< / pat:ClaimNumber> <pat:ClaimText>201. A kit comprising an anti-TIGIT antagonist antibody and a package insert comprising instructions for using the anti-TIGIT antagonist antibody thereof in combination with a PD-1 axis binding antagonist to (a) treat or delay progression of cancer in an individual or (b) stimulate an immune function of an individual having cancer, wherein the PD-1 axis binding antagonist is an anti-PD-L1 antagonist antibody, wherein the immune function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00202"> <pat:ClaimNumber>202< / pat:ClaimNumber> <pat:ClaimText>202. The kit of claim 199, 200 or 201, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising a HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), a HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and a HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising a HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), a HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and a HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22). < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00203"> <pat:ClaimNumber>203< / pat:ClaimNumber> <pat:ClaimText>203. The kit of any one of claims 199 to 202, wherein the anti-PD-L1 antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00204"> <pat:ClaimNumber>204< / pat:ClaimNumber> <pat:ClaimText>204. The kit of any one of claims 199 to 202, wherein the anti-PD-L1 antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00205"> <pat:ClaimNumber>205< / pat:ClaimNumber> <pat:ClaimText>205. The kit of any one of claims 199 to 204, wherein the anti-TIGIT antagonist antibody inhibits TIGIT activity, inhibits the interaction of TIGIT with PVR, inhibits the interaction of TIGIT with PVRL2, inhibits the interaction of TIGIT with PVRL3, inhibits the intracellular signaling mediated by TIGIT binding to PVR, inhibits the intracellular signaling mediated by TIGIT binding to PVRL2, and inhibits the intracellular signaling mediated by TIGIT binding to PVRL3. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00206"> <pat:ClaimNumber>206< / pat:ClaimNumber> <pat:ClaimText>206. The kit of any one of claims 199 to 205, wherein the anti-TIGIT antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00207"> <pat:ClaimNumber>207< / pat:ClaimNumber> <pat:ClaimText>207. The kit of any one of claims 199 to 205, wherein the anti-TIGIT antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00208"> <pat:ClaimNumber>208< / pat:ClaimNumber> <pat:ClaimText>208. The kit of any one of claims 199 to 207, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00209"> <pat:ClaimNumber>209< / pat:ClaimNumber> <pat:ClaimText>209. Use of an anti-PD-L1 antagonist antibody in the manufacture of a medicament for (a) treating or delaying progression of cancer or (b) reducing or inhibiting cancer relapse or cancer progression in an individual in combination with an anti-TIGIT antagonist antibody, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT, and wherein the anti-TIGIT antagonist antibody inhibits the interaction of PVR with TIGIT. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00210"> <pat:ClaimNumber>210< / pat:ClaimNumber> <pat:ClaimText>210. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for (a) treating or delaying progression of cancer in an individual or (b) reducing or inhibiting cancer relapse or cancer progression in combination with an anti-PD-L1 antagonist antibody, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT, and wherein the anti-TIGIT antagonist antibody inhibits the interaction of PVR with TIGIT. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00211"> <pat:ClaimNumber>211< / pat:ClaimNumber> <pat:ClaimText>211. Use of an anti-PD-L1 antagonist antibody in the manufacture of a medicament for (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with an anti-TIGIT antagonist antibody, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT, and wherein the anti-TIGIT antagonist antibody inhibits the interaction of PVR with TIGIT. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00212"> <pat:ClaimNumber>212< / pat:ClaimNumber> <pat:ClaimText>212. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for (a) treating or delaying progression or (b) reducing or inhibiting progression of an immune related disease characterized by T cell dysfunction in an individual in combination with an anti-PD-L1 antagonist antibody, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT, and wherein the anti-TIGIT antagonist antibody inhibits the interaction of PVR with TIGIT. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00213"> <pat:ClaimNumber>213< / pat:ClaimNumber> <pat:ClaimText>213. The use of claim 211 or 212, wherein the T cell dysfunction is characterized by T cell anergy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00214"> <pat:ClaimNumber>214< / pat:ClaimNumber> <pat:ClaimText>214. The use of claim 211 or 212, wherein the T cell dysfunction is characterized by T cell exhaustion. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00215"> <pat:ClaimNumber>215< / pat:ClaimNumber> <pat:ClaimText>215. The use of claim 212, 213 or 214, wherein the T cell dysfunction comprises dysfunctional CD4+ and CD8+ T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00216"> <pat:ClaimNumber>216< / pat:ClaimNumber> <pat:ClaimText>216. Use of an anti-PD-L1 antagonist antibody in the manufacture of a medicament for stimulating an immune response or function in an individual in combination with an anti-TIGIT antagonist antibody, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT, wherein the anti-TIGIT antagonist antibody inhibits the interaction of PVR with TIGIT, and wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00217"> <pat:ClaimNumber>217< / pat:ClaimNumber> <pat:ClaimText>217. Use of an anti-TIGIT antagonist antibody in the manufacture of a medicament for stimulating an immune response or function in an individual in combination with an anti-PD- L1 antagonist antibody, wherein the anti-TIGIT antagonist antibody inhibits the interaction of CD226 with TIGIT, wherein the anti-TIGIT antagonist antibody inhibits the interaction of PVR with TIGIT, and wherein the immune response or function is CD4+ or CD8+ T cell priming, activation, proliferation, cytokine release, or cytolytic activity. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00218"> <pat:ClaimNumber>218< / pat:ClaimNumber> <pat:ClaimText>218. The use of any one of claims 209 to 217, wherein the anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody are formulated together. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00219"> <pat:ClaimNumber>219< / pat:ClaimNumber> <pat:ClaimText>219. The use of any one of claims 211 to 218, wherein the individual has cancer. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00220"> <pat:ClaimNumber>220< / pat:ClaimNumber> <pat:ClaimText>220. The use of claim 209, 210, or 219, wherein the cancer comprises infiltrating T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00221"> <pat:ClaimNumber>221< / pat:ClaimNumber> <pat:ClaimText>221. The use of claim 209, 210, 219 or 220, wherein the cancer is selected from the group consisting of a non-small cell lung cancer, a small cell lung cancer, a renal cell cancer, a colorectal cancer, an ovarian cancer, a breast cancer, a pancreatic cancer, a gastric carcinoma, a bladder cancer, an esophageal cancer, a mesothelioma, a melanoma, a head and neck cancer, a thyroid cancer, a sarcoma, a prostate cancer, a glioblastoma, a cervical cancer, a thymic carcinoma, a leukemia, a lymphoma, a myeloma, a mycosis fungoides, a Merkel cell cancer, and an hematologic malignancy. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00222"> <pat:ClaimNumber>222< / pat:ClaimNumber> <pat:ClaimText>222. The use of any one of claims 209 to 221, wherein the combination of anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody elevates the number of CD4+ or CD8+ T cells relative to prior to administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00223"> <pat:ClaimNumber>223< / pat:ClaimNumber> <pat:ClaimText>223. The use of any one of claims 209 to 222, wherein the combination of anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody elevates the number of activated CD4+ or CD8+ T cells relative to prior to administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00224"> <pat:ClaimNumber>224< / pat:ClaimNumber> <pat:ClaimText>224. The use of claim 223, wherein the activated CD4+ or CD8+ T cells are characterized by enhanced γ-IFN+ production or enhanced cytolytic activity relative to prior to the administration of the combination thereof. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00225"> <pat:ClaimNumber>225< / pat:ClaimNumber> <pat:ClaimText>225. The use of claim 222, 223 or 224, wherein the combination of anti-TIGIT antagonist antibody and the anti-PD-L1 antagonist antibody increases the release of cytokines selected from the group consisting of IFN- <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>, TNF-<semantics>α<annotation encoding="application / x-tex">\alpha< / annotation>< / semantics> and interleukins from the CD4+ or CD8+ T cells relative to prior to the administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00226"> <pat:ClaimNumber>226< / pat:ClaimNumber> <pat:ClaimText>226. The use of any one of claims 220 to 225, wherein the CD4+ or CD8+ T cells are effector memory T cells. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00227"> <pat:ClaimNumber>227< / pat:ClaimNumber> <pat:ClaimText>227. The use of claim 226, wherein the CD4+ or CD8+ effector memory T cells are characterized by <semantics>γ<annotation encoding="application / x-tex">\gamma< / annotation>< / semantics>-IFN+ production or enhanced cytolytic activity relative to prior to the administration of the combination. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00228"> <pat:ClaimNumber>228< / pat:ClaimNumber> <pat:ClaimText>228. The use of claim 226, wherein the CD4+ or CD8+ effector memory T cells are characterized by having CD44high CD62Llow expression. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00229"> <pat:ClaimNumber>229< / pat:ClaimNumber> <pat:ClaimText>229. The use of any one of claims 209 to 228, wherein the anti-TIGIT antagonist antibody is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a bispecific antibody, and a heteroconjugate antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00230"> <pat:ClaimNumber>230< / pat:ClaimNumber> <pat:ClaimText>230. The use of any one of claims 209 to 229, wherein the anti-TIGIT antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00231"> <pat:ClaimNumber>231< / pat:ClaimNumber> <pat:ClaimText>231. The use of any one of claims 209 to 229, wherein the anti-TIGIT antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00232"> <pat:ClaimNumber>232< / pat:ClaimNumber> <pat:ClaimText>232. The use of claim 231, wherein the anti-TIGIT antagonist antibody is an IgG-1, an IgG-2, an IgG2A, an IgG2B, an IgG-3 or an IgG-4 subtype. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00233"> <pat:ClaimNumber>233< / pat:ClaimNumber> <pat:ClaimText>233. The use of claim 232, wherein the anti-TIGIT antagonist antibody is an IgG-1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00234"> <pat:ClaimNumber>234< / pat:ClaimNumber> <pat:ClaimText>234. The use of claim 232, wherein the anti-TIGIT antagonist antibody is an IgG-4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00235"> <pat:ClaimNumber>235< / pat:ClaimNumber> <pat:ClaimText>235. The use of any one of claims 209 to 234, wherein the anti-TIGIT antagonist antibody is a monoclonal antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00236"> <pat:ClaimNumber>236< / pat:ClaimNumber> <pat:ClaimText>236. The use of claim 235, wherein the anti-TIGIT antagonist antibody is a monoclonal human antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00237"> <pat:ClaimNumber>237< / pat:ClaimNumber> <pat:ClaimText>237. The use of claim 235, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00238"> <pat:ClaimNumber>238< / pat:ClaimNumber> <pat:ClaimText>238. The use of claim 236, wherein the anti-TIGIT antagonist antibody is a monoclonal human IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00239"> <pat:ClaimNumber>239< / pat:ClaimNumber> <pat:ClaimText>239. The use of claim 236, wherein the anti-TIGIT antagonist antibody is a monoclonal human IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00240"> <pat:ClaimNumber>240< / pat:ClaimNumber> <pat:ClaimText>240. The use of claim 237, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00241"> <pat:ClaimNumber>241< / pat:ClaimNumber> <pat:ClaimText>241. The use of claim 237, wherein the anti-TIGIT antagonist antibody is a monoclonal humanized IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00242"> <pat:ClaimNumber>242< / pat:ClaimNumber> <pat:ClaimText>242. The use of any one of claims 209 to 241, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to PD-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00243"> <pat:ClaimNumber>243< / pat:ClaimNumber> <pat:ClaimText>243. The use of any one of claims 209 to 241, wherein the anti-PD-L1 antagonist antibody inhibits the binding of PD-L1 to both PD-1 and B7-1. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00244"> <pat:ClaimNumber>244< / pat:ClaimNumber> <pat:ClaimText>244. The use of any one of claims 209 to 243, wherein the anti-PD-L1 antagonist antibody comprises a heavy chain comprising a HVR-H1 sequence of GFTFSDSWIH (SEQ ID NO:17), a HVR-H2 sequence of AWISPYGGSTYYADSVKG (SEQ ID NO:18), and a HVR-H3 sequence of RHWPGGFDY (SEQ ID NO:19); and a light chain comprising a HVR-L1 sequence of RASQDVSTAVA (SEQ ID NO:20), a HVR-L2 sequence of SASFLYS (SEQ ID NO:21), and a HVR-L3 sequence of QQYLYHPAT (SEQ ID NO:22). < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00245"> <pat:ClaimNumber>245< / pat:ClaimNumber> <pat:ClaimText>245. The use of any one of claims 209 to 244, wherein the anti-PD-L1 antagonist antibody is an antigen-binding antibody fragment. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00246"> <pat:ClaimNumber>246< / pat:ClaimNumber> <pat:ClaimText>246. The use of any one of claims 209 to 244, wherein the anti-PD-L1 antagonist antibody is a full-length antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00247"> <pat:ClaimNumber>247< / pat:ClaimNumber> <pat:ClaimText>247. The use of claim 246, wherein the anti-PD-L1 antagonist antibody is an IgG-1, an IgG-2, an IgG2A, an IgG2B, an IgG-3 or an IgG-4 subtype. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00248"> <pat:ClaimNumber>248< / pat:ClaimNumber> <pat:ClaimText>248. The use of claim 247, wherein the anti-PD-L1 antagonist antibody is an IgG-1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00249"> <pat:ClaimNumber>249< / pat:ClaimNumber> <pat:ClaimText>249. The use of claim 247, wherein the anti-PD-L1 antagonist antibody is an IgG-4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00250"> <pat:ClaimNumber>250< / pat:ClaimNumber> <pat:ClaimText>250. The use of any one of claims 209 to 249, wherein the anti-PD-L1 antagonist antibody is a monoclonal antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00251"> <pat:ClaimNumber>251< / pat:ClaimNumber> <pat:ClaimText>251. The use of claim 250, wherein the anti-PD-L1 antagonist antibody is a monoclonal human antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00252"> <pat:ClaimNumber>252< / pat:ClaimNumber> <pat:ClaimText>252. The use of claim 250, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00253"> <pat:ClaimNumber>253< / pat:ClaimNumber> <pat:ClaimText>253. The use of claim 251, wherein the anti-PD-L1 antagonist antibody is a monoclonal human IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00254"> <pat:ClaimNumber>254< / pat:ClaimNumber> <pat:ClaimText>254. The use of claim 251, wherein the anti-PD-L1 antagonist antibody is a monoclonal human IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00255"> <pat:ClaimNumber>255< / pat:ClaimNumber> <pat:ClaimText>255. The use of claim 252, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized IgG1 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00256"> <pat:ClaimNumber>256< / pat:ClaimNumber> <pat:ClaimText>256. The use of claim 252, wherein the anti-PD-L1 antagonist antibody is a monoclonal humanized IgG4 antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00257"> <pat:ClaimNumber>257< / pat:ClaimNumber> <pat:ClaimText>257. The use of any one of claims 209 to 256, wherein the anti-TIGIT antagonist antibody is formulated for continuous administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00258"> <pat:ClaimNumber>258< / pat:ClaimNumber> <pat:ClaimText>258. The use of any one of claims 209 to 256, wherein the anti-TIGIT antagonist antibody is formulated for intermittent administration. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00259"> <pat:ClaimNumber>259< / pat:ClaimNumber> <pat:ClaimText>259. The use of any one of claims 209 to 217 and 219 to 258, wherein the anti-TIGIT antagonist antibody is for administration before the anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00260"> <pat:ClaimNumber>260< / pat:ClaimNumber> <pat:ClaimText>260. The use of any one of claims 209 to 258, wherein the anti-TIGIT antagonist antibody is for administration simultaneously with the anti-PD-L1 antagonist antibody. < / pat:ClaimText> < / pat:Claim> <pat:Claim com:id="CLM-00261"> <pat:ClaimNumber>261< / pat:ClaimNumber> <pat:ClaimText>261. The use of any one of claims 209 to 217 and 219 to 258, wherein the anti-TIGIT antagonist antibody is for administration after the PD-1 axis binding antagonist. < / pat:ClaimText> < / pat:Claim> < / pat:Claims>