Anti-TIGIT antibody and its use

Abstract

This specification describes the treatment and prevention of cancer using antibodies that bind to TIGIT, and the use of anti-TIGIT antibodies in the manufacture of a medicament for the treatment or prevention of cancer. Also described herein is a method of blocking the binding of TIGIT to CD155 without changing certain immune parameters by administering an antibody that binds to TIGIT. In particular, the present disclosure describes treating cancer by administering an anti-TIGIT antibody (e.g., domvanalimab) to a human subject in need of cancer treatment, wherein the anti-TIGIT antibody has reduced binding to one or more FcγRs (e.g., activating FcγRs) compared to wild-type (WT) IgG1.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 337,471, filed May 2, 2022, U.S. Provisional Patent Application No. 63 / 427,688, filed November 23, 2022, and U.S. Provisional Patent Application No. 63 / 433,390, filed December 16, 2022, each of which is incorporated by reference in its entirety.

[0002] The present specification describes the treatment and prevention of cancer using an antibody that binds to TIGIT, and the use of an anti-TIGIT antibody (e.g., domvanalimab) in the manufacture of a medicament for the treatment or prevention of cancer. Also described herein is a method for blocking the binding of TIGIT to CD155 without changing specific immune parameters by administering an antibody that binds to TIGIT (e.g., domvanalimab). [Background technology]

[0003] The following discussion is provided to aid the reader in understanding the present disclosure and is not admitted to describe or constitute prior art against it.

[0004] Antigen-specific immune responses are complex and often unpredictable biological processes controlled by multiple layers of positive and negative regulators. T cells are initially stimulated via the T cell receptor (TCR) upon recognition of their cognate peptide antigens presented by major histocompatibility complex (MHC) molecules on antigen-presenting cells. Optimal T cell activation requires a "second signal" provided by costimulatory molecules such as CD28. Immune responses are further positively regulated by costimulatory molecules such as OX40, GITR, and 4-lBB, which belong to the TNF receptor superfamily, and negatively regulated by checkpoint molecules such as PD-1 and CTLA-4. The function of checkpoint molecules is to prevent unwanted overreactions of the body's immune system. However, they also limit the immune system's ability to effectively fight cancer and infectious diseases. Blockade of PD-1 or CTLA-4 function with antagonistic monoclonal IgG antibodies has been reported to be effective in cancer immunotherapy in humans (for reviews, see Pardoll, Nat. Rev. Cancer, 12:252-264, 2012; Mahoney et al., Nat. Rev. Drug Discov. 14:561-584, 2015; Shin et al., Curr. Opin. Immunol. 33:23-35, 2015; Marquez-Rodas et al. Ann. Transl. Med. 3:267, 2015).

[0005] Other checkpoint molecules, such as TIM-3, LAG-3, TIGIT, BTLA, and VISTA, have been reported (Mercier et al., Front. Immunol. 6:418, 2015). TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a member of the immunoglobulin superfamily that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic tail and is expressed on activated T cells and a subset of natural killer (NK) cells (Yu et al., Nat. Immunol. 10:48-57, 2009). TIGIT is known to interact with CD155 (also known as PVR and necl-5), CD112 (also known as PVRL2 and nectin-2), and possibly CD113 (also known as PVRL3 and nectin-3) (Mercier et al., supra; Martinet et al., Nat. Rev. Immunol. 15:243-254, 2015). Binding of TIGIT to the high-affinity ligand CD155 expressed on antigen-presenting cells has been reported to suppress the function of T cells and NK cells (Mercier et al., supra; Jailer et al., J. Immunol. 186:1338-1342, 2011; Stanietsky et al., Eur. J. Immunol. 43:2138-2150, 2013; Li et al., J. Biol. Chem. 289:17647-17657, 2014; Zhang et al. Cancer Immunol. Immunother. Epub on Feb. 3, 2016). TIGIT has also been reported to indirectly inhibit T cells by regulating cytokine production by dendritic cells (Yu et al., supra).

[0006] Tumors constitute a highly suppressive microenvironment, in which infiltrating T cells can be exhausted and NK cells are silenced by checkpoint molecules such as PD-1 and TIGIT to evade immune responses (Johnston et al., Cancer Cell. 26:926-937, 2014; Chauvin et al., J. Clin. Invest. 125:2046-2058, 2015; Inozume et al., J. Invest. Dermatol. Epub on Oct. 12, 2015). High levels of TIGIT expression on CD8+ T cells have been reported to correlate with poor clinical outcomes in AML subjects (Kong et al., Clin. Cancer Res. Epub on Jan. 13, 2016). The functional defects of exhausted TIGIT+ CD8+ T cells from AML subjects have been reported to be reversed by siRNA-mediated knockdown of TIGIT expression (Kong et al., supra). It has also been reported that effector CD8+ T cells during HIV infection in the blood and SIV infection in lymphoid tissues exhibit higher levels of TIGIT (Chew et al., PLOS Pathogens, 12:e1005349, 2016). In addition, ex vivo antibody blockade of TIGIT has been reported to restore virus-specific CD8+ T cell effector responses.

[0007] Outside the tumor microenvironment, immune cells circulating in the periphery and other tissues also express certain immune checkpoints, particularly TIGIT. Most of these cells are not involved in anti-tumor immune control. Therefore, while destroying TIGIT-expressing immune cells within tumors may be beneficial, destroying TIGIT-expressing immune cells outside tumors (e.g., in the circulation and other tissues / organs) is not expected to contribute to anti-tumor control and may actually lead to undesirable side effects, such as the emergence of systemic autoimmunity (which may result from the depletion of circulating TIGIT+ regulatory T cells (Tregs)) or a decline in systemic antiviral defense (which may result from the depletion of circulating TIGIT+ effector T cells (Teffs)). There remains a need for effective treatment regimens for anti-TIGIT antibodies with improved safety. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Pardoll,Nat.Rev.Cancer,12:252-264,2012;Mahoney et al.,Nat.Rev.Drug Discov.14:561-584,2015 [Non-patent document 2] Shin et al.,Curr.Opin.Immunol.33:23-35,2015;Marquez-Rodas et al.Ann.Transl.Med.3:267,2015 [Non-patent document 3] Mercier et al.,Front.Immunol.6:418,2015 [Non-patent document 4] Yu et al., Nat. Immunol. 10:48-57, 2009 [Non-patent document 5] Martinet et al.,Nat.Rev.Immunol.15:243-254,2015 [Non-patent document 6] Jailer et al.,J.Immunol.186:1338-1342,2011 [Non-Patent Document 7] Stanietsky et al.,Eur.J.Immunol.43:2138-2150,2013 [Non-patent document 8] Li et al.,J.Biol.Chem.289:17647-17657,2014 [Non-Patent Document 9] Zhang et al.Cancer Immunol.Immunother.Epub on Feb.3,2016 [Non-Patent Document 10] Johnston et al.,Cancer Cell.26:926-937,2014 [Non-Patent Document 11] Chauvin et al.,J.Clin.Invest.125:2046-2058,2015 [Non-Patent Document 12] Inozume et al.,J.Invest.Dermatol.Epub on Oct.12,2015 [Non-Patent Document 13] Kong et al.,Clin.Cancer Res.Epub on Jan.13,2016 [Non-Patent Document 14] Chew et al.,PLOS Pathogens,12:e1005349,2016 Summary of the Invention

[0009] Antibodies that bind to TIGIT and methods of using the same are described herein. In particular, the present disclosure describes treating cancer by administering an anti-TIGIT antibody (e.g., domvanalimab) to a human subject in need of cancer treatment, where the anti-TIGIT antibody has reduced binding to one or more FcγRs (e.g., activating FcγRs) compared to wild-type (WT) IgG1. In some embodiments, the anti-TIGIT antibody may be unable to bind to one or more FcγRs (e.g., activating FcγRs). As a result of this reduced or absent binding, the anti-TIGIT antibody has reduced or absent Fc effector function, and treatment with such an anti-TIGIT antibody may result in reduced or negligible depletion of peripheral lymphocyte populations in regulatory and CD4+ T cells, and / or a reduced number and / or severity of one or more immune-related adverse events, compared to an Fc-matched anti-TIGIT antibody. Improvement in immune-mediated adverse events has numerous benefits for patients, which may include, for example, fewer treatment interruptions, fewer dose reductions, fewer discontinuations, or any combination thereof.

[0010] In one aspect, the present disclosure provides a method of treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, wherein the treatment results in a reduction in one or more adverse events compared to a similar treatment comprising an Fc-matched anti-TIGIT antibody.

[0011] In another aspect, the present disclosure provides a method of treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, wherein the subject is less likely to experience one or more adverse events compared to treatment with an Fc-matched anti-TIGIT antibody.

[0012] In another aspect, the present disclosure provides an anti-TIGIT antibody having reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1 for use in treating cancer in a human subject in need thereof. In some embodiments, the treatment results in a reduction in one or more adverse events compared to a similar treatment comprising an Fc-targeted anti-TIGIT antibody. In some embodiments, the subject is less likely to experience one or more adverse events compared to treatment with an Fc-targeted anti-TIGIT antibody.

[0013] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, for use in treating cancer in a human subject in need thereof. In some embodiments, the treatment results in a reduction in one or more adverse events compared to a similar treatment comprising an Fc-targeted anti-TIGIT antibody. In some embodiments, the subject is less likely to experience one or more adverse events compared to treatment with an Fc-targeted anti-TIGIT antibody.

[0014] In another aspect, the present disclosure provides the use of an anti-TIGIT antibody having reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1 for the manufacture of a medicament for treating cancer in a human subject in need thereof. In some embodiments, the treatment results in a reduction in one or more adverse events compared to a similar treatment comprising an Fc-targeted anti-TIGIT antibody. In some embodiments, the subject is less likely to experience one or more adverse events compared to treatment with an Fc-targeted anti-TIGIT antibody.

[0015] In some embodiments of the foregoing aspects, the Fc-enabled anti-TIGIT antibody is selected from AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipeliimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, JS006, larzapastzug, and an Fc-enabled version of domvanalimab comprising a wild-type IgG1 Fc region.

[0016] In another aspect, the disclosure provides a method of treating cancer in a human subject in need thereof without significantly increasing the likelihood of adverse events compared to standard of care, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, in combination with one or more additional therapies. In some embodiments, the one or more additional therapies are standard of care.

[0017] In another aspect, the disclosure provides an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs relative to wild-type (WT) human IgG1, and one or more additional therapies, for use in treating cancer in a human subject in need thereof, without significantly increasing the likelihood of adverse events relative to the standard of care. In some embodiments, the one or more additional therapies are the standard of care.

[0018] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, wherein the anti-TIGIT antibody is used in combination with one or more additional therapies to treat cancer in a human subject in need thereof without significantly increasing the likelihood of adverse events compared to standard of care. In some embodiments, the one or more additional therapies are standard of care.

[0019] In another aspect, the present disclosure provides a method for reducing one or more adverse events experienced by a human subject being treated for cancer with an anti-TIGIT antibody, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1.

[0020] In another aspect, the present disclosure provides an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1 for use in reducing one or more adverse events experienced by a human subject being treated for cancer with the anti-TIGIT antibody.

[0021] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, for use in reducing one or more adverse events experienced by a human subject being treated for cancer with the anti-TIGIT antibody.

[0022] In another aspect, the disclosure provides a method of reducing one or more adverse events experienced by a human subject being treated for cancer with an anti-TIGIT antibody and an additional immunotherapeutic agent, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, and the additional immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab.

[0023] In another aspect, the disclosure provides an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, and an additional immunotherapeutic agent, for use in reducing one or more adverse events experienced by a human subject being treated for cancer with the anti-TIGIT antibody and an additional immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab.

[0024] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1 for use in reducing one or more adverse events experienced by a human subject being treated for cancer with the anti-TIGIT antibody and an additional immunotherapeutic agent, wherein the anti-TIGIT antibody is used in combination with the additional immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab.

[0025] In some embodiments of the foregoing aspects, the adverse event is a treatment-related adverse event, an immune-related adverse event, or a treatment-related immune-related adverse event, hi some embodiments, the adverse event is an infusion-related reaction, rash, maculopapular rash, fever, myocarditis, pneumonitis, immune-mediated lung disease, interstitial lung disease, immune-mediated hepatitis, and / or immune-mediated enterocolitis. In some embodiments, the immune-related adverse event is selected from: (i) skin or subcutaneous tissue disorder, gastrointestinal disorder, hepatic biliary disorder, endocrine disorder, or respiratory, thoracic, or mediastinal disorder; (ii) skin or subcutaneous tissue disorder; (iii) rash, oral mucositis, dry mouth, colitis, diarrhea, hepatitis, pneumonitis, endocrine disorder, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, or a combination thereof; (iv) arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reaction, maculopapular rash, pneumonitis, pruritus, psoriasis, rash, facial swelling, or a combination thereof; or (v) infusion-related reaction, maculopapular rash, pruritus, psoriasis, rash, or a combination thereof.

[0026] In some embodiments of the foregoing aspects, the adverse event is an immune-related adverse event or an infusion-related adverse event.

[0027] In another aspect, the present disclosure provides a method for reducing one or more dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with an anti-TIGIT antibody, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1.

[0028] In another aspect, the present disclosure provides anti-TIGIT antibodies that have reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, for use in reducing one or more dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with the anti-TIGIT antibody.

[0029] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, for use in reducing one or more dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with the anti-TIGIT antibody.

[0030] In another aspect, the disclosure provides a method of reducing one or more dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with an anti-TIGIT antibody and an additional immunotherapeutic agent, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1. In some embodiments, the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab.

[0031] In another aspect, the disclosure provides an anti-TIGIT antibody and an additional immunotherapeutic agent that have reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, for use in reducing one or more dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with the anti-TIGIT antibody and an additional immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab.

[0032] In another aspect, the present disclosure provides a pharmaceutical composition comprising an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, for use in reducing one or more dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with an anti-TIGIT antibody and an additional immunotherapeutic agent, wherein the anti-TIGIT antibody is used in combination with an additional immunotherapeutic agent. In some embodiments, the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab.

[0033] In some embodiments of the foregoing aspects, the method may further comprise a reduction in one or more immune-related adverse events compared to a similar treatment comprising an Fc-targeted anti-TIGIT antibody. In some embodiments, the immune-related adverse event is selected from (i) skin or subcutaneous tissue disorders, gastrointestinal disorders, hepatobiliary disorders, endocrine disorders, or respiratory, thoracic, or mediastinal disorders, (ii) skin or subcutaneous tissue disorders, (iii) rash, oral mucositis, dry mouth, colitis, diarrhea, hepatitis, pneumonia, endocrine disorders, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, or a combination thereof, (iv) arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reactions, maculopapular rash, pneumonia, pruritus, psoriasis, rash, facial swelling, or a combination thereof, or (v) infusion-related reactions, maculopapular rash, pruritus, psoriasis, rash, or a combination thereof.

[0034] In some of the foregoing aspects and embodiments, the administration comprises one or more administration cycles, hi some embodiments, an administration cycle comprises administering the anti-TIGIT antibody to the subject once every two weeks, once every three weeks, or once every four weeks.

[0035] In some embodiments of the aforementioned aspects and embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg. In some embodiments of the aforementioned aspects, the anti-TIGIT antibody is administered to the subject at a dose of about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 800 mg to about 1200 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg. In some embodiments, an administration cycle comprises administering the anti-TIGIT antibody to the subject at a dose of about 800 mg once every three weeks, about 1200 mg once every three weeks, or about 1600 mg once every four weeks.

[0036] In some embodiments of the foregoing aspects and embodiments, the method may further comprise administering one or more additional therapeutic agents, optionally an immunotherapeutic agent, a chemotherapeutic agent, a chemotherapy regimen, or a combination thereof. In some embodiments, the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimbelemab; or, optionally, Avelumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimbelemab. 2a R antagonist, A 2b R antagonist, A 2a R and A 2b The ATP-adenosine axis targeting agent is selected from R antagonists, CD73 inhibitors, and CD39 inhibitors. In some embodiments, the chemotherapy regimen is a fluoropyrimidine-containing chemotherapy (e.g., fluorouracil, capecitabine, floxuridine) or a platinum-containing chemotherapy (e.g., carboplatin, cisplatin, or oxaliplatin). In some embodiments, the chemotherapy regimen is FOLFOX, CAPOX, cisplatin and pemetrexed, carboplatin and pemetrexed, carboplatin and paclitaxel, or carboplatin and nab-paclitaxel.

[0037] In some of the foregoing aspects and embodiments, the method may further include administering one or more additional therapeutic agents, wherein the one or more additional therapeutic agents is dimvelemab. In some embodiments, the therapeutically effective amount of dimvelemab is about 360 mg administered intravenously every three weeks, or about 480 mg administered intravenously every four weeks. In some embodiments, the therapeutically effective amount of dimvelemab is about 720 mg administered intravenously every six weeks, about 760 mg administered intravenously every six weeks, about 960 mg administered intravenously every six weeks, or about 720 mg to about 960 mg administered intravenously every six weeks.

[0038] In some of the above aspects and embodiments, the method can further include administering one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are etramadenant. In some embodiments, the therapeutically effective amount of etramadenant is about 50 mg to about 250 mg orally administered per day, about 50 mg to about 225 mg orally administered per day, about 50 mg to about 150 mg orally administered per day, or about 100 mg to about 250 mg orally administered per day. In some embodiments, the therapeutically effective amount of etramadenant is about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg orally administered per day.

[0039] In some embodiments of the foregoing aspects and embodiments, the method may further include administering one or more additional therapeutic agents, wherein at least one additional therapeutic agent is dimvelemab and at least one additional therapeutic agent is etramadenant. In some embodiments, the therapeutically effective amount of dimvelemab is about 360 mg administered intravenously every three weeks or about 480 mg administered intravenously every four weeks, and the therapeutically effective amount of etramadenant is about 50 mg to about 250 mg administered orally per day, or about 50 mg to about 150 mg administered orally per day. In some embodiments, the therapeutically effective amount of dimvelemab is about 720 mg administered intravenously every 6 weeks, about 760 mg administered intravenously every 6 weeks, about 960 mg administered intravenously every 6 weeks, or about 720 mg to about 960 mg administered intravenously every 6 weeks, and the therapeutically effective amount of etramadenant is about 50 mg to about 250 mg administered orally per day, or about 50 mg to about 150 mg administered orally per day.

[0040] In some of the foregoing aspects and embodiments, the method may further include administering one or more additional therapeutic agents, wherein the one or more additional therapeutic agents is quemlicustat. In some embodiments, the therapeutically effective amount of quemlicustat is about 100 mg to about 200 mg administered intravenously every two weeks, or about 300 mg administered intravenously every three weeks.

[0041] In some embodiments of the foregoing aspects and embodiments, the method may further comprise administering one or more additional therapeutic agents, wherein at least one additional therapeutic agent is dimvelemab and at least one additional therapeutic agent is quemlicustat. In some embodiments, the therapeutically effective amount of dimvelemab is about 360 mg administered intravenously every 3 weeks or about 480 mg administered intravenously every 4 weeks, and the therapeutically effective amount of quemlicustat is about 300 mg administered intravenously every 3 weeks. In some embodiments, the therapeutically effective amount of dimvelemab is about 720 mg administered intravenously every 6 weeks, about 760 mg administered intravenously every 6 weeks, about 960 mg administered intravenously every 6 weeks, or about 760 mg to about 960 mg administered intravenously every 6 weeks, and the therapeutically effective amount of quemlicustat is about 300 mg administered intravenously every 3 weeks.

[0042] In some of the foregoing aspects and embodiments, the anti-TIGIT antibody with reduced binding to one or more activating human FcγR is an IgG4 or IgG1 with reduced ability to bind to one or more activating human FcγR.

[0043] In some of the foregoing aspects and embodiments, the anti-TIGIT antibody that has reduced binding to one or more activating human FcγR does not bind to one or more activating human FcγR.

[0044] In some embodiments of the aforementioned aspects and embodiments, the anti-TIGIT antibody comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 3, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 7.

[0045] In some of the foregoing aspects and embodiments, the anti-TIGIT antibody comprises a heavy chain variable region having at least 90% sequence identity to SEQ ID NO: 8 or 10 and a light chain variable region having at least 90% sequence identity to SEQ ID NO: 9 or 11.

[0046] In some of the foregoing aspects and embodiments, the anti-TIGIT antibody comprises a heavy chain having at least 90% sequence identity to SEQ ID NO:12 and a light chain having at least 90% sequence identity to SEQ ID NO:13.

[0047] In some of the foregoing aspects and embodiments, the anti-TIGIT antibody binds to the same epitope of TIGIT as domvanalimab, or the anti-TIGIT antibody competitively inhibits the binding of domvanalimab to human TIGIT by at least 50%.

[0048] In some of the foregoing aspects and embodiments, the cancer is a solid tumor, and optionally the tumor is a locally advanced and / or unresectable tumor, a metastatic tumor, a recurrent tumor, a tumor that no longer responds to treatment, and optionally the treatment is standard of care, a checkpoint inhibitor, a PD-1 antagonist, or a PD-L1 antagonist, or any combination thereof. In some embodiments, the cancer is lung cancer, a genitourinary cancer, or a gastrointestinal cancer. In some embodiments, the cancer is lung cancer, such as non-small cell lung cancer (NSCLC), and optionally the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and (ii) no longer responds to treatment, and optionally the treatment is standard of care, a checkpoint inhibitor, a PD-1 antagonist, or a PD-L1 antagonist, or (iii) a combination of (i) and (ii). In some embodiments, the lung cancer is squamous or non-squamous, unresectable, locally advanced, or metastatic. In some embodiments, the cancer is gastrointestinal cancer, such as esophageal, gastric, or colorectal cancer, pancreatic, or liver cancer, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care, checkpoint inhibitors, PD-1 antagonists, or PD-L1 antagonists. In some embodiments, the gastrointestinal cancer is esophageal or gastric cancer, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care. In some embodiments, the gastrointestinal cancer is esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastroesophageal junction adenocarcinoma, or gastric adenocarcinoma, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard therapy. In some embodiments, the cancer is NSCLC, head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma (RCC), breast cancer, colorectal cancer (CRC), melanoma, bladder cancer, ovarian cancer, endometrial cancer, Merkel cell, or gastroesophageal cancer. In some embodiments, the subject is checkpoint inhibitor (CPI) naive.Alternatively, in some embodiments, the subject is experiencing CPI.

[0049] In some of the foregoing aspects and embodiments, the cancer may be PD-L1 positive as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test. The cutoff for PD-L1 positivity varies depending on the test and the tumor.

[0050] In some of the foregoing aspects and embodiments, the cancer has PD-L1 expression at a Tumor Proportion Score (TPS) of 50% or greater, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test. In some of the foregoing aspects and embodiments, the cancer has PD-L1 expression at a %TC of 50% or greater, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

[0051] In some of the foregoing aspects and embodiments, PD-L1 expression in the cancer corresponds to a TPS of less than 50%, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test. In some embodiments, PD-L1 expression in the cancer is about 1-10%, about 10%-20%, about 20-30%, about 30-40%, about 40-49%, about 1-49%, about 1-25%, or about 25-49%, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test. In some embodiments, PD-L1 expression in the cancer is less than 1%, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

[0052] In some of the foregoing aspects and embodiments, the cancer has PD-L1 expression of CPS 1 or greater, CPS 5 or greater, or CPS 10 or greater, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

[0053] In some of the foregoing aspects and embodiments, the cancer has PD-L1 expression of 1% or more TAP, 5% or more TAP, or 10% or more TAP, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

[0054] In some embodiments of the foregoing aspects and embodiments, the cancer is tumor mutational burden-high (TMB-H; 10 mutations / megabase (mut / Mb) or greater, as measured by an FDA-approved test.

[0055] In some of the foregoing aspects and embodiments, the cancer is not TMB-H.

[0056] In some of the foregoing aspects and embodiments, the cancer does not have an actionable mutation in an oncogene, e.g., a mutation for which a targeted therapy has been approved by a local health agency and is available for use. In some of the foregoing aspects and embodiments, the cancer does not have an actionable oncogenic mutation in ALK, EGFR, ROS, BRAF, or NTRK, and / or has wild-type ALK, EGFR, ROS, BRAF, and / or NTRK.

[0057] In some of the foregoing aspects and embodiments, the cancer expresses or overexpresses one or more biomarkers selected from CD73, DNAM-1, PVR, TIGIT, and CD8-Ki67.

[0058] In some embodiments of the foregoing aspects and embodiments, the treatment results in a decrease in tumor size, a decrease in tumor number, a decrease in metastases, stable disease, a partial response, a complete response, or a combination thereof.

[0059] In some of the foregoing aspects and embodiments, the treatment results in improved overall survival, progression-free survival, disease control rate, overall response rate, or a combination thereof, compared to placebo or standard of care.

[0060] In some embodiments of the foregoing aspects and embodiments, the treatment results in an increased time to progression, increased disease-free survival, increased duration of response, increased duration of clinical benefit, increased time to treatment failure, decreased time to initial response, or any combination thereof, compared to placebo or standard of care.

[0061] In some embodiments of the foregoing aspects and embodiments, an anti-TIGIT antibody that exhibits reduced binding to one or more activating human FcγRs relative to wild-type (WT) human IgG1 is formulated for dilution in an aqueous solution comprising about 10 mg / mL to about 100 mg / mL of antibody or about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 to about 30 mM histidine (His) / histidine-Cl (His-Cl), about 4% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, dextrose, trehalose, sorbitol, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.05 mg / mL to about 0.6 mg / mL of polysorbate 80.

[0062] In some embodiments of the foregoing aspects and embodiments, an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1 is formulated for dilution as an aqueous solution comprising about 10 mg / mL to about 100 mg / mL of antibody or about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 to about 25 mM His / His-Cl, about 5% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, dextrose, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.1 mg / mL to about 0.3 mg / mL of polysorbate 80.

[0063] The foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the present disclosure as claimed. Other objects, advantages, and features will become apparent to those skilled in the art from the following brief description of the drawings and detailed description of the present disclosure. [Brief explanation of the drawings]

[0064] [Figure 1A]

[0039] Figure 1 shows the results of an ELISA assay demonstrating that domvanalimab does not bind to human Fcγ receptors (FcγR), particularly FcγR 1 (Figure 1A), FcγR 2A (Figure 1B), FcγR 2B (Figure 1C), FcγR 3A (Figure 1D), and FcγR 3B (Figure 1E). In each figure, circles = human IgG1, squares = domvanalimab, and triangles = buffer only. [Figure 1B]

[0039] Figure 1 shows the results of an ELISA assay demonstrating that domvanalimab does not bind to human Fcγ receptors (FcγR), particularly FcγR 1 (Figure 1A), FcγR 2A (Figure 1B), FcγR 2B (Figure 1C), FcγR 3A (Figure 1D), and FcγR 3B (Figure 1E). In each figure, circles = human IgG1, squares = domvanalimab, and triangles = buffer only. [Figure 1C]

[0039] Figure 1 shows the results of an ELISA assay demonstrating that domvanalimab does not bind to human Fcγ receptors (FcγR), particularly FcγR 1 (Figure 1A), FcγR 2A (Figure 1B), FcγR 2B (Figure 1C), FcγR 3A (Figure 1D), and FcγR 3B (Figure 1E). In each figure, circles = human IgG1, squares = domvanalimab, and triangles = buffer only. [Figure 1D]

[0039] Figure 1 shows the results of an ELISA assay demonstrating that domvanalimab does not bind to human Fcγ receptors (FcγR), particularly FcγR 1 (Figure 1A), FcγR 2A (Figure 1B), FcγR 2B (Figure 1C), FcγR 3A (Figure 1D), and FcγR 3B (Figure 1E). In each figure, circles = human IgG1, squares = domvanalimab, and triangles = buffer only. [Figure 1E]

[0039] Figure 1 shows the results of an ELISA assay demonstrating that domvanalimab does not bind to human Fcγ receptors (FcγR), particularly FcγR 1 (Figure 1A), FcγR 2A (Figure 1B), FcγR 2B (Figure 1C), FcγR 3A (Figure 1D), and FcγR 3B (Figure 1E). In each figure, circles = human IgG1, squares = domvanalimab, and triangles = buffer only.

[0065] [Figure 2] NK-mediated ADCC against Treg or CD8+ target cells isolated from peripheral blood mononuclear cell suspensions is shown, with representative histograms showing TIGIT expression. Paired symbols indicate treatment with human IgG isotype (squares) or anti-TIGIT antibody (circles) tiragolumab ("Tira") or donvanaramib ("Dom") for each NK-T cell donor pair. **** indicates P<0.0001.

[0066] [Figure 3A] FIG. 1 shows the principle of the receptor occupancy (RO) assay.

[0067] [Figure 3B] 1 shows exemplary flow cytometry data illustrating the principles of the RO assay.

[0068] [Figure 4A-1] Figure 4A shows the evaluation of TIGIT, CD226, and CD155 expression in the tumor microenvironment. Figure 4A shows CD155 and PD-L1 ligand expression on CD14+ monocytes (CD45+CD3-CD16-CD56-CD14+) and cancer / stromal cells (CD45-), as well as co-expression of PD-1, TIGIT, and CD226 on a broad range of T cell populations. Figure 4B shows a contour plot of PD-1 expression on CD8+ T cells (NSCLC subjects) encompassing various states of activation and differentiation. Each population was further characterized into tissue-resident (CD103+) and circulating (CD103-) CD8+ populations, yielding six subsets. Figure 4C shows the co-expression of TIGIT and CD226 on the six CD8+ T populations from (B) and the co-expression of PD-1, TIGIT, and CD226 on putative tumor-specific CD39+CD103+CD8+ T cells. Lines connect populations from the same subject. Each symbol represents a unique subject, and bars and errors indicate median ± range. [Figure 4A-2]Figure 4A shows the evaluation of TIGIT, CD226, and CD155 expression in the tumor microenvironment. Figure 4A shows CD155 and PD-L1 ligand expression on CD14+ monocytes (CD45+CD3-CD16-CD56-CD14+) and cancer / stromal cells (CD45-), as well as co-expression of PD-1, TIGIT, and CD226 on a broad range of T cell populations. Figure 4B shows a contour plot of PD-1 expression on CD8+ T cells (NSCLC subjects) encompassing various states of activation and differentiation. Each population was further characterized into tissue-resident (CD103+) and circulating (CD103-) CD8+ populations, yielding six subsets. Figure 4C shows the co-expression of TIGIT and CD226 on the six CD8+ T populations from (B) and the co-expression of PD-1, TIGIT, and CD226 on putative tumor-specific CD39+CD103+CD8+ T cells. Lines connect populations from the same subject. Each symbol represents a unique subject, and bars and errors indicate median ± range. [Figure 4B] Figure 4A shows the evaluation of TIGIT, CD226, and CD155 expression in the tumor microenvironment. Figure 4A shows CD155 and PD-L1 ligand expression on CD14+ monocytes (CD45+CD3-CD16-CD56-CD14+) and cancer / stromal cells (CD45-), as well as co-expression of PD-1, TIGIT, and CD226 on a broad range of T cell populations. Figure 4B shows a contour plot of PD-1 expression on CD8+ T cells (NSCLC subjects) encompassing various states of activation and differentiation. Each population was further characterized into tissue-resident (CD103+) and circulating (CD103-) CD8+ populations, yielding six subsets. Figure 4C shows the co-expression of TIGIT and CD226 on the six CD8+ T populations from (B) and the co-expression of PD-1, TIGIT, and CD226 on putative tumor-specific CD39+CD103+CD8+ T cells. Lines connect populations from the same subject. Each symbol represents a unique subject, and bars and errors indicate median ± range. [Figure 4C]Figure 4A shows the evaluation of TIGIT, CD226, and CD155 expression in the tumor microenvironment. Figure 4A shows CD155 and PD-L1 ligand expression on CD14+ monocytes (CD45+CD3-CD16-CD56-CD14+) and cancer / stromal cells (CD45-), as well as co-expression of PD-1, TIGIT, and CD226 on a broad range of T cell populations. Figure 4B shows a contour plot of PD-1 expression on CD8+ T cells (NSCLC subjects) encompassing various states of activation and differentiation. Each population was further characterized into tissue-resident (CD103+) and circulating (CD103-) CD8+ populations, yielding six subsets. Figure 4C shows the co-expression of TIGIT and CD226 on the six CD8+ T populations from (B) and the co-expression of PD-1, TIGIT, and CD226 on putative tumor-specific CD39+CD103+CD8+ T cells. Lines connect populations from the same subject. Each symbol represents a unique subject, and bars and errors indicate median ± range.

[0069] [Figure 5A] 1 shows the percent change from baseline in measurable target lesions by RECIST 1.1 over time for two participants in a study of the safety and tolerability of domvanalimab in combination with dimvelemab (Example 5).

[0070] [Figure 5B] 5B is an image of a scan showing a reduction in target lesion size in two partial responders from FIG. 5A. The scan shows one of two target lesions, and each participant has a lesion not recorded in the scan shown here. [Figure 5C] 5B is an image of a scan showing a reduction in target lesion size in two partial responders from FIG. 5A. The scan shows one of two target lesions, and each participant has a lesion not recorded in the scan shown here.

[0071] [Figure 6-1]Absolute T-cell counts by individual (top row), cohort (middle row), or study (bottom row) are shown for 11 patients who received domvanalimab in combination with zimbelemab. Time is on the x-axis (D1 = day 1, etc.). Treatment began on day 1. "D1 pre" is the sample obtained day 1 before the start of treatment, and "D1 post" is the sample obtained day 1 after administration of the combination treatment. The percent change from baseline in cell counts per μl of whole blood (WB) is on the y-axis. Patient dosing is indicated by a triangle on the x-axis. Whole blood samples were obtained at the indicated times, and absolute cell counts were measured as described in the Examples. Gray shading of the rectangles identifies the range measured in six healthy donors. AB154 = domvanalimab; AB122 = zimbelemab. [Figure 6-2] Absolute T-cell counts by individual (top row), cohort (middle row), or study (bottom row) are shown for 11 patients who received domvanalimab in combination with zimbelemab. Time is on the x-axis (D1 = day 1, etc.). Treatment began on day 1. "D1 pre" is the sample obtained day 1 before the start of treatment, and "D1 post" is the sample obtained day 1 after administration of the combination treatment. The percent change from baseline in cell counts per μl of whole blood (WB) is on the y-axis. Patient dosing is indicated by a triangle on the x-axis. Whole blood samples were obtained at the indicated times, and absolute cell counts were measured as described in the Examples. Gray shading of the rectangles identifies the range measured in six healthy donors. AB154 = domvanalimab; AB122 = zimbelemab. [Figure 6-3]Absolute T-cell counts by individual (top row), cohort (middle row), or study (bottom row) are shown for 11 patients who received domvanalimab in combination with zimbelemab. Time is on the x-axis (D1 = day 1, etc.). Treatment began on day 1. "D1 pre" is the sample obtained day 1 before the start of treatment, and "D1 post" is the sample obtained day 1 after administration of the combination treatment. The percent change from baseline in cell counts per μl of whole blood (WB) is on the y-axis. Patient dosing is indicated by a triangle on the x-axis. Whole blood samples were obtained at the indicated times, and absolute cell counts were measured as described in the Examples. Gray shading of the rectangles identifies the range measured in six healthy donors. AB154 = domvanalimab; AB122 = zimbelemab. [Figure 6-4] Absolute T-cell counts by individual (top row), cohort (middle row), or study (bottom row) are shown for 11 patients who received domvanalimab in combination with zimbelemab. Time is on the x-axis (D1 = day 1, etc.). Treatment began on day 1. "D1 pre" is the sample obtained day 1 before the start of treatment, and "D1 post" is the sample obtained day 1 after administration of the combination treatment. The percent change from baseline in cell counts per μl of whole blood (WB) is on the y-axis. Patient dosing is indicated by a triangle on the x-axis. Whole blood samples were obtained at the indicated times, and absolute cell counts were measured as described in the Examples. Gray shading of the rectangles identifies the range measured in six healthy donors. AB154 = domvanalimab; AB122 = zimbelemab.

[0072] [Figure 7A] FIG. 1 shows a representative gating strategy.

[0073] [Figure 7B-1]Figure 1 shows the frequencies of T cells and NK cells measured in whole blood samples from two partial responders in the study of Example 5. One patient had esophageal cancer and one patient had gastroesophageal junction (GEJ) cancer. Both patients were treated Q3W with domvanalimab (10 mg / kg) and dimvelemab (360 mg). Time is on the x-axis (C1D1 = Day 1 of Cycle 1, etc.). Treatment began on Day 1. "D1 pre" is the sample obtained on Day 1 before the start of treatment, and "C1D1 4hr" is the sample obtained approximately 4 hours on Day 1 after administration of the combination treatment. Fold change from baseline is on the y-axis. Whole blood samples were obtained at the indicated times, and cell counts were measured as described in the Examples. [Figure 7B-2] Figure 1 shows the frequencies of T cells and NK cells measured in whole blood samples from two partial responders in the study of Example 5. One patient had esophageal cancer and one patient had gastroesophageal junction (GEJ) cancer. Both patients were treated Q3W with domvanalimab (10 mg / kg) and dimvelemab (360 mg). Time is on the x-axis (C1D1 = Day 1 of Cycle 1, etc.). Treatment began on Day 1. "D1 pre" is the sample obtained on Day 1 before the start of treatment, and "C1D1 4hr" is the sample obtained approximately 4 hours on Day 1 after administration of the combination treatment. Fold change from baseline is on the y-axis. Whole blood samples were obtained at the indicated times, and cell counts were measured as described in the Examples.

[0074] [Figure 8] 1 shows that T cell expansion was observed in peripheral blood samples obtained from patients treated with domvanalimab alone or in combination with zimvelemab or zimvelemab and etramadenant.

[0075] [Figure 9A]Figure 9 shows lymphoid cell expansion in patients treated with zimvelemab, zimvelemab and domvanalimab, or zimvelemab, domvanalimab and etramadenant enrolled in the clinical trial described in Example 7. Lymphoid cells are CD8+Ki67+ T cells (Figure 9A), CD56+Ki67+ NK cells (Figure 9B), and memory CD39+CD103+CD8+ T cells (Figure 9C). Time is on the x-axis and is measured in days (e.g., D1 = day 1). Treatment cycles are also identified on the x-axis (e.g., C1D1 = cycle 1, day 1). Treatment began on day 1. "C1D1 pre" refers to a sample obtained on day 1 before the start of treatment, and "C1D1 4hr" refers to a sample obtained approximately 4 hours after administration of treatment on day 1. Whole blood samples were obtained at the indicated times, and cell counts were measured as described in the Examples. Each line represents an individual patient. [Figure 9B] Figure 9 shows lymphoid cell expansion in patients treated with zimvelemab, zimvelemab and domvanalimab, or zimvelemab, domvanalimab and etramadenant enrolled in the clinical trial described in Example 7. Lymphoid cells are CD8+Ki67+ T cells (Figure 9A), CD56+Ki67+ NK cells (Figure 9B), and memory CD39+CD103+CD8+ T cells (Figure 9C). Time is on the x-axis and is measured in days (e.g., D1 = day 1). Treatment cycles are also identified on the x-axis (e.g., C1D1 = cycle 1, day 1). Treatment began on day 1. "C1D1 pre" refers to a sample obtained on day 1 before the start of treatment, and "C1D1 4hr" refers to a sample obtained approximately 4 hours after administration of treatment on day 1. Whole blood samples were obtained at the indicated times, and cell counts were measured as described in the Examples. Each line represents an individual patient. [Figure 9C]Figure 9 shows lymphoid cell expansion in patients treated with zimvelemab, zimvelemab and domvanalimab, or zimvelemab, domvanalimab and etramadenant enrolled in the clinical trial described in Example 7. Lymphoid cells are CD8+Ki67+ T cells (Figure 9A), CD56+Ki67+ NK cells (Figure 9B), and memory CD39+CD103+CD8+ T cells (Figure 9C). Time is on the x-axis and is measured in days (e.g., D1 = day 1). Treatment cycles are also identified on the x-axis (e.g., C1D1 = cycle 1, day 1). Treatment began on day 1. "C1D1 pre" refers to a sample obtained on day 1 before the start of treatment, and "C1D1 4hr" refers to a sample obtained approximately 4 hours after administration of treatment on day 1. Whole blood samples were obtained at the indicated times, and cell counts were measured as described in the Examples. Each line represents an individual patient.

[0076] [Figure 10] A swimmer's plot is shown for all intent-to-treat (ITT) patients, including 13 patients: patients treated in group 1, zimbelemab ("Z"); patients treated in group 2, domvanalimab and zimbelemab ("DZ"); and patients treated in group 3, etramadenant, domvanalimab, and zimbelemab ("EDZ"). Thirty-one patients with partial responses (PRs) remain on treatment, and another 14 patients with stable disease (SDs) remain on active treatment. Across all treatment groups, the time to initial response, scored with an orange triangle for PR and a purple square for SDs, ranged from 1.2 to 14.6 months. There was an additional delayed response in the domvanalimab-containing group, observed as late as 14 months after initiating therapy. The median duration of response had not yet been reached in either group.

[0077] [Figure 11]Kaplan-Meier curves estimating progression-free survival (PFS) across the three groups of ITT-13 patients are shown. There was early separation of the curves at the first scan, as indicated by 6-month progression-free survival rates of 43% in group 1, 65% in group 2, and 63% in group 3. Median PFS was 5.4 months in group 1, 12 months in group 2, and 10.9 months in group 3. Compared with dimvelemab monotherapy, there was a 45% and 35% reduction in the probability of progression or death for groups 2 and 3, respectively.

[0078] [Figure 12] Spider plots of 12 patients from Group 1 who crossed over to treatment with EDZ (Group 3) are shown. At the time of the ITT-13 data cut, 5 patients were continuing on crossover treatment. DETAILED DESCRIPTION OF THE INVENTION

[0079] Described herein are antibodies that bind to TIGIT (e.g., domvanalimab) and methods of using such antibodies for treating a disease, such as cancer, in a subject. Provided herein is the use of an anti-TIGIT antibody of the present disclosure for the manufacture of a medicament for treating a disease, such as cancer. Also provided herein is a cancer treatment comprising administering an anti-TIGIT antibody (e.g., domvanalimab) to a human subject in need of cancer treatment. For purposes of this disclosure, an anti-TIGIT antibody lacks or has reduced Fc effector function, e.g., due to the absence or reduction of binding to one or more human Fc gamma receptors (FcγRs) compared to wild-type (WT) human IgG1. Generally, the one or more human FcγRs are activating human FcγRs (e.g., FcγRI, FcγRIIA, FcγRIIIA). Fc effector functions associated with binding to activating FcγRs include antibody-dependent cell-mediated cytotoxicity (ADCC), complement-mediated cytotoxicity (CDC), antibody-mediated cellular phagocytosis (ADCP), cytokine / chemokine induction, and endocytosis of opsonized targets.

[0080] Treatment with such an anti-TIGIT antibody (e.g., domvanalimab) may not significantly reduce one or more peripheral lymphocyte populations, including, for example, regulatory T cells and / or CD8+ T cells. For example, any reduction may be within the normal range seen in healthy subjects or may not be significantly different therefrom. Alternatively, or in addition, any reduction may be less than that produced using an Fc-matched anti-TIGIT antibody. Treatment with such an anti-TIGIT antibody (e.g., domvanalimab) may also result in reduced adverse events, e.g., immune-related adverse events, compared to an Fc-matched anti-TIGIT antibody, while still achieving efficacy. Non-limiting examples of Fc-enabled anti-TIGIT antibodies include AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, larzapastzug, and JS006. Some individuals may be completely immune-related adverse events. Non-limiting examples of immune-related adverse events include rash, pruritus, maculopapular rash, infusion-related reactions, arthritis, psoriasis, facial swelling, oral mucositis, dry mouth, colitis, diarrhea, immune-mediated hepatitis, pneumonia, endocrine disorders, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, and any combination thereof. Alternatively, or in addition, treatment with such anti-TIGIT antibodies may result in fewer treatment interruptions (including fewer dose reductions) and / or fewer treatment discontinuations for a patient or group of patients compared to Fc-matched anti-TIGIT antibodies.

[0081] As described in more detail below, this treatment and the positive results it provides in terms of both efficacy and safety are unexpected and represent a departure from the understanding in the art that human FcγR engagement and Fc effector function were required for anti-TIGIT antibodies to have clinical utility in humans. In contrast to that expectation, the present disclosure highlights that anti-TIGIT antibodies with reduced or eliminated ability to bind to one or more human FcγRs (e.g., activating human FcγRs) are not only effective, but may also be significantly safer than Fc-matched anti-TIGIT antibodies. In addition to providing efficacy and safety benefits to patients, this therapeutic profile, described in more detail below, may facilitate additional clinical benefits, including, but not limited to, clinical settings, patient populations, combination therapies, and dosing regimens.

[0082] I. Definition It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0083] Unless otherwise defined, all technical and scientific terms used herein have the meanings commonly understood by those skilled in the art. Unless otherwise specified, materials and / or methodologies known to those skilled in the art may be utilized in carrying out the methods described herein based on the guidance provided herein. When ranges are provided, they include the boundaries and individual values within the range. For example, a range of 1 to 5 includes the boundaries 1 and 5, as well as the values 2, 3, and 4.

[0084] As used herein, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise. Reference to an object in the singular does not mean "one and only one," but rather "one or more," unless expressly stated.

[0085] As used herein, "about" when used in conjunction with a numerical value means the stated numerical value, as well as ±10% of the numerical value. For example, "about 10" should be understood as both "10" and "9 to 11."

[0086] Also, as used herein, "and / or" refers to and includes any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted as alternatives ("or").

[0087] As used herein, a phrase of the form "A / B" or of the form "A and / or B" means (A), (B), or (A and B). A phrase of the form "at least one of A, B, and C" means (A), (B), (C), (A and B), (A and C), (B and C), or (A, B, and C).

[0088] The term "antibody," as used herein, is used in the broadest sense and encompasses a variety of antibodies and antibody-like structures (e.g., monospecific antibodies, multispecific antibodies, polyepitopic antibodies, etc.) that specifically bind to a single antigen or multiple antigens, including, but not limited to, full-length antibodies, antigen-binding fragments, heavy-chain antibodies, single-chain antibodies, and higher-order variants of single-chain antibodies. Thus, any reference to an antibody should be understood to refer to an intact antibody or an antigen-binding fragment, unless the context requires otherwise. Preferably, although not necessarily, antibodies useful herein may be isolated or recombinantly produced.

[0089] The terms "full-length antibody," "complete antibody," and "whole antibody" are used interchangeably herein and refer to an antibody having a structure substantially similar to a native antibody structure or having a heavy chain containing an Fc region.

[0090] "Native antibodies" are naturally occurring immunoglobulin molecules with diverse structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons, composed of two identical light chains (approximately 25 kDa each) and two identical heavy chains (approximately 50-70 kDa each) that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can be assigned to one of two types, called kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain. Heavy chains are classified as gamma, mu, alpha, delta, or epsilon and define the antibody's isotype as IgG, IgM, IgA, IgD, and IgE, respectively. The amino-terminal portion of each light and heavy chain contains a variable region of about 100 to 110 or more amino acids primarily responsible for antigen recognition (VL and VH, respectively). The carboxy-terminal portion of each chain defines a constant region primarily responsible for effector function. Within light and heavy chains, the variable and constant regions are joined by a "J" region of about 12 or more amino acids, and the heavy chain also contains a "D" region of about 10 or more amino acids.

[0091] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of antibody heavy and light chains generally have similar structures, and each domain contains four conserved framework regions (FR) and three hypervariable regions (CDR). (See, for example, Kindt et al., Kuby Immunology, 6 th(See, e.g., W.H. Freeman and Co., page 91 (2007)). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0092] "Framework region" or "FR" refers to variable domain residues other than the hypervariable region residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, the CDR and FR sequences generally appear in the following sequence: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4. The FR domains of the heavy and light chains may differ, as is well known in the art.

[0093] As used herein, the terms "hypervariable region" or "HVR", also commonly referred to as "complementarity-determining region" or "CDR", are used interchangeably and refer to each region of a variable domain that is hypervariable in sequence and / or forms structurally defined loops ("hypervariable loops") and / or contains antigen-contacting residues ("antigen contacts"). Generally, antibodies contain six CDRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). As used herein, a "CDR derived from a variable region" refers to a CDR that has no more than two amino acid substitutions compared to the corresponding CDR from the original variable region. Exemplary CDRs herein include (a) the hypervariable loops located at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)); (b) the CDRs located at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5 th Ed. Public Health Service, National Institutes of Health, Bethesda, MD (1991)), (c) antigen contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745 (1996)), and (d) combinations of (a), (b), and / or (c), as defined below for various antibodies of the disclosure. Unless otherwise indicated, CDR residues and other residues (e.g., FR residues) in the variable domain are numbered Eu as per Kabat et al., supra.

[0094] The term "isolated antibody" refers to an antibody that has been separated from a component of its natural environment. In some embodiments, an isolated antibody is purified to greater than 95% or greater than 99% purity, for example, as determined by electrophoresis or chromatography (e.g., ion exchange or reverse-phase HPLC).

[0095] The term "chimeric antibody" refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, while the remainder of the heavy and / or light chain is derived from a different source or species.

[0096] A "human antibody" is one that possesses an amino acid sequence corresponding to that of an antibody produced by a human or human cell, or derived from a non-human source utilizing a human antibody repertoire or other human antibody coding sequence. This definition of human antibody specifically excludes humanized antibodies, which contain non-human antigen-binding residues. Human antibodies can be generated using various techniques well 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. Available methods for preparing human monoclonal antibodies are 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.

[0097] A "humanized" antibody refers to an antibody comprising amino acid residues derived from non-human CDRs and human FRs. In certain embodiments, a humanized antibody comprises a variable domain in which all or substantially all of the CDRs correspond to those of a non-human antibody and all or substantially all of the FRs correspond to those of a human antibody. In certain embodiments in which all or substantially all of the FRs of a humanized antibody correspond to those of a human antibody, any of the FRs of the humanized antibody may contain one or more amino acid residues derived from a non-human FR, e.g., at one or more vernier position residues of the FR and / or at one or more other selected residues. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization. A humanized antibody retains the same binding specificity and affinity as the starting non-human antibody.

[0098] The term "monoclonal antibody" refers to an antibody that is derived from a single copy or clone, including, for example, any eukaryotic, prokaryotic, or phage clone. The term "monoclonal antibody" is not limited to antibodies produced through hybridoma technology. Monoclonal antibodies can be produced using hybridoma technology, which is well known in the art, as well as recombinant, phage display, synthetic, or combinations of such techniques, and other techniques readily known in the art.

[0099] The term "epitope" refers to the specific site on an antigen to which an antibody binds. The specific site on an antigen to which an antibody binds can be determined, for example, by crystallography. Methods such as hydroxyl radical protein footprinting and alanine scanning mutagenesis can also be used, but may provide lower resolution.

[0100] The term "Fc region" is used herein to define the 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 can vary, the human IgG heavy chain Fc region is usually defined to stretch from the amino acid residue at position Cys226, or from the amino acid residue at position Pro230, to its carboxyl-terminus. The C-terminal lysine of the Fc region (residue 447 according to the EU numbering system) can be removed, for example, during antibody production or purification, or by recombinantly engineering the nucleic acid encoding the antibody heavy chain. Thus, a composition of intact antibodies can include antibody populations in which all Lys447 residues have been removed, antibody populations in which none of the Lys447 residues have been removed, and antibody populations having a mixture of antibodies with and without the Lys447 residue.

[0101] A "functional Fc region" possesses the "effector functions" of a native-sequence Fc region. Exemplary "effector functions" include C1q binding, complement-dependent cytotoxicity (CDC), Fc receptor binding, antibody-dependent cell-mediated cytotoxicity (ADCC), phagocytosis, down-regulation of cell surface receptors (e.g., B cell receptors; BCR), and the like. Such effector functions generally require an Fc region in combination with a binding domain (e.g., an antibody variable domain) and can be assessed using various assays disclosed herein or otherwise known in the art. A functional Fc region may have effector functions substantially similar to wild-type IgG, reduced effector functions compared to wild-type IgG, or enhanced effector functions compared to wild-type IgG. For antibodies comprising a human Fc region, the comparison is typically to wild-type human IgG1.

[0102] As used herein, the term "Fc-matched antibody" refers to an antibody that has similar or enhanced binding to human FcγRs compared to wild-type (WT) human IgG1 and elicits Fc effector functions, including, but not limited to, ADCC, CDC, and ADCP.

[0103] A "native sequence Fc region" comprises an amino acid sequence identical to that of an Fc region found in nature. Native sequence human Fc regions include native sequence human IgG1 Fc regions (non-A and A allotypes), native sequence human IgG2 Fc regions, native sequence human IgG3 Fc regions, and native sequence human IgG4 Fc regions, as well as naturally occurring variants thereof.

[0104] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by at least one amino acid modification (e.g., about 1 to about 10 amino acid modifications, in some embodiments, about 1 to about 5 amino acid modifications), preferably one or more amino acid substitutions. A variant Fc region herein preferably has at least about 80% homology to a native-sequence Fc region and / or the Fc region of a parent polypeptide, preferably at least about 90% homology thereto, or preferably at least about 95% homology thereto. In some embodiments, a variant Fc region may have reduced or enhanced effector function compared to wild-type IgG. For antibodies comprising a human Fc region, the comparison is typically to wild-type human IgG1.

[0105] As used herein, "Fc component" refers to the hinge region, CH2 domain, or CH3 domain of the Fc region.

[0106] The "hinge region" is generally defined as a stretch of about residues 216-230 of IgG (Eu numbering), about residues 226-243 of IgG (Kabat numbering), or about residues 1-15 of IgG (IMGT unique numbering).

[0107] The term "antibody fragment" refers to a molecule other than an intact antibody that contains a portion of the intact antibody that binds to the antigen to which the intact antibody binds. Examples of antigen-binding fragments include diabodies, Fab, Fab', F(ab'), F(ab) c , Fv fragments, disulfide-stabilized Fv fragments (dsFv), (dsFv)2, bispecific dsFv (dsFv-dsFv'), disulfide-stabilized diabodies (ds diabodies), triabodies, tetrabodies, single-chain antibody molecules, scFv, scFv dimers, single-domain antibodies, single-domain antibodies, and multivalent domain antibodies. Typically, binding fragments compete for specific binding with the intact antibody from which they were derived. Binding fragments can be produced by recombinant DNA techniques or by enzymatic or chemical separation of intact immunoglobulins.

[0108] The term "Fab" refers to the portion of an antibody that consists of a single light chain (both variable and constant regions) linked by disulfide bonds to the variable region and first constant region of a single heavy chain.

[0109] The term "Fab'" refers to a Fab fragment that includes part of the hinge region.

[0110] The term "F(ab')2" refers to a dimer of Fab'. 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.

[0111] The term "Fv" refers to the minimum fragment of an antibody that contains a complete antigen-binding site. The Fv fragment consists of the variable region of a single light chain bound to the variable region of a single heavy chain.

[0112] The term "single-chain antibody" refers to an antibody consisting of a heavy chain variable region and a light chain variable region connected by a linker. In most, but not all, cases, the linker can be a peptide. The length of the linker varies depending on the type of single-chain antibody. Two or more single-chain antibodies can be covalently or non-covalently linked together to form higher-order forms. Single-chain antibodies and their higher-order forms can include, but are not limited to, single-domain antibodies, multivalent domain antibodies, single-chain variant fragments (scFv), bivalent scFv (di-scFv), trivalent scFv (tri-scFv), tetravalent scFv (tetra-scFv), diabodies, and triabodies and tetrabodies.

[0113] The terms "single-chain Fv antibody" and "scFv" are used interchangeably herein to refer to a single-chain antibody consisting of a heavy chain variable region and a light chain variable region connected by a linker. In most, but not all, cases, the linker can be a peptide. The linker peptide is preferably about 5 to 30 amino acids in length, or about 10 to 25 amino acids in length. Typically, the linker stabilizes the variable domains without interfering with proper folding and creation of an active binding site. In a preferred embodiment, the linker peptide is rich in glycine and serine or threonine. Two or more scFvs can be covalently or noncovalently linked together to form higher-order forms such as di-scFv, tri-scFv, and tetra-scFv. The antigen-binding sites of each scFv in the higher-order form can target the same or different antigens or epitopes.

[0114] The term "single chain Fv-Fc antibody" or "scFv-Fc" refers to a full-length antibody consisting of an scFv linked to an Fc region.

[0115] A "diabody" is a higher-order variant of a single-chain antibody consisting of two single-chain antibodies. For each single-chain antibody, a linker that is too short to allow pairing between the two domains on the same chain is used, forcing the domain to pair with a complementary domain on another chain, thereby creating two antigen-binding sites. In most, but not all, cases, the linker can be a peptide. The antigen-binding sites can target the same or different antigens or epitopes. Triabodies (three single-chain antibodies assembled to form three antigen-binding sites), tetrabodies (four single-chain antibodies assembled to form four antigen-binding sites), and higher-order variants can also be produced. See, for example, Holliger P. et al., Proc Natl Acad Sci USA. July 15; 90(14):6444-8 (1993); EP 404097; WO 93 / 11161.

[0116] A "single domain antibody" refers to an antibody fragment containing only the variable region of a heavy chain or the variable region of a light chain. H The domains are covalently linked with peptide linkers to create multivalent domain antibodies. H The domains can target the same or different antigens or epitopes.

[0117] The term "heavy chain antibody" refers to an antibody consisting of two heavy chains. The heavy chain antibody may be an IgG-like antibody from camel, llama, alpaca, shark, etc., or an IgNAR from cartilaginous fish. See, for example, Riechmann L. and Muyldermans S., J Immunol Methods. December 10; 231(1-2):25-38(1999); Muyldermans S., J Biotechnol. June; 74(4):277-302(2001); WO 94 / 04678; WO 94 / 25591; or U.S. Patent No. 6,005,079. Heavy chain antibodies have been derived from Camelidae (camels, dromedaries, and llamas). Although lacking light chains, camelized antibodies have a standard antigen-binding repertoire (Hamers-Casterman C. et al., Nature. June 3; 363(6428):446-8(1993); Nguyen VK et al. "Heavy-chain antibodies in Camelidae; a case of evolutionary innovation," Immunogenetics. April; 54(1):39-47(2002); Nguyen VK et al. Immunology. May; 109(1):93-101(2003)). The variable domain of heavy-chain antibodies (VHH domain) represents the smallest known antigen-binding unit generated by the adaptive immune response (Koch-Nolte F. et al., FASEB J. November; 21(13):3490-8. Epub 2007 Jun. 15(2007)).

[0118] "Nanobody" refers to an antibody that consists of a VHH domain derived from a heavy chain antibody and two constant domains, CH2 and CH3.

[0119] "Percent (%) identity" with respect to a reference amino acid sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways that are within the skill of the art, for example, using publicly available computer software such as BLAST, BLAST-2, or CLUSTAL software. Those skilled in the art can determine appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment over the full length of the sequences being compared. Generally speaking, the percent sequence identity of a given amino acid sequence A to, with, or relative to a given amino acid sequence B is calculated as follows: fraction X / Y times 100, where X is the number of amino acid residues scored as identical matches by a sequence alignment program in that program's alignment of A and B, and Y is the total number of amino acid residues in B. It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % amino acid sequence identity of A to B will not equal the % amino acid sequence identity of B to A.

[0120] As used herein, the phrase "therapeutically effective amount" with respect to an anti-TIGIT antibody refers to a dosing regimen (i.e., amount and interval) of the antibody that provides the specific pharmacological effect for which the drug is administered in a subject in need of such treatment. For prophylactic use, a therapeutically effective amount may be effective to eliminate or reduce the risk, reduce the severity, or delay the onset of disease, including biochemical, histological, and / or behavioral signs or symptoms of the disease. For treatment, a therapeutically effective amount may be effective to reduce, ameliorate, or eliminate one or more signs or symptoms associated with the disease, delay disease progression, prolong survival, reduce the dose of other drugs required to treat the disease, or a combination thereof. With particular reference to cancer, a therapeutically effective amount may, for example, result in the death of cancer cells, reduce the number of cancer cells, reduce tumor burden, eliminate tumors or metastases, or reduce metastatic spread. It is emphasized that a therapeutically effective amount of an anti-TIGIT antibody may not always be effective to treat cancer in every individual subject, even if such a dose is considered therapeutically effective by those skilled in the art. A therapeutically effective amount can vary based on, for example, the subject's age and weight, and / or the subject's overall health, the stage of the subject's cancer, the route of administration, and previous or concurrent treatments.

[0121] The terms "treat," "treatment," or "treating," as used herein with respect to cancer, refer to a course of action that eliminates, reduces, inhibits, alleviates, improves, or prevents the worsening of, either temporarily or permanently, the disease, disorder, or condition to which the term applies, or at least one symptom associated therewith. Treatment includes alleviating symptoms, reducing the extent of disease, inhibiting active disease (e.g., arresting the onset or further development of the disease, disorder, or condition or clinical symptoms associated therewith), delaying or slowing the progression of disease, improving quality of life, and / or prolonging a subject's survival as compared to expected survival if not receiving treatment or as compared to the published standard of care for the particular disease.

[0122] As used herein, the term "in need of treatment" refers to a determination made by a physician or other caregiver that a subject needs or will benefit from treatment. For example, "treating cancer in a subject in need of treatment" can also be expressed as "treating cancer in a subject in need thereof" and refers to treating a subject that a physician or other caregiver has determined to need or will benefit from treatment. This determination is made based on various factors within the physician's or caregiver's expertise and may include a positive diagnosis of a disease, disorder, or condition. In some instances, a physician or other caregiver may determine that a subject needs or will benefit from treatment with an anti-TIGIT antibody. In these instances, additional determination is still required for effective treatment, i.e., which anti-TIGIT antibody or group of anti-TIGIT antibodies is appropriate.

[0123] The terms "prevent," "preventing," "prevention," "prevention," and the like generally refer to a course of action initiated in a manner that prevents, suppresses, inhibits, or reduces the risk of a subject developing a disease, disorder, condition, etc. (e.g., as determined by the absence of clinical symptoms) or delays its onset (e.g., prior to the onset of the disease, disorder, condition, or its symptoms), either temporarily or permanently, in situations where the subject is predisposed to having a particular disease, disorder, or condition. In certain instances, these terms also refer to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state. Prevention also refers to a course of action initiated in a subject after the subject has been treated for a disease, disorder, condition, or symptom thereof, in order to prevent the recurrence of the disease, disorder, condition, or symptom.

[0124] As used herein, the term "in need of prophylaxis" refers to a judgment made by a physician or other caregiver that a subject needs or would benefit from prophylactic measures. This judgment is made based on a variety of factors within the physician's or caregiver's expertise.

[0125] The terms "individual," "subject," and "patient" are used interchangeably herein and refer to any individual human being.

[0126] II. TIGIT and Tregs TIGIT (also called T cell immunoreceptor with Ig and ITIM domains) is an immunoreceptor present on some T cells and natural killer (NK) cells. TIGIT is considered an immune checkpoint. Human TIGIT has the sequence according to SEQ ID NO: 1: MMTGTIETTGNISAEKGGSIILQCHLSSTTAQVTQVNWEQQDQLLAICNADLGWHISPSFKDRVAPGPGLGLTLQSLTVNDTGEYFCIYHTYPDGTYTGRIFLEVLESSVAEHGARFQIPLLGAMAATLVVICTAVIVWALTRKKKALRIHSVEGDLRRKSAGQEEWSPSAPSPPGSCVQAEAAPAGLCGEQRGEDCAELHDYFNVLSYRSLGNCSFFTETG (SEQ ID NO: 1).

[0127] Regulatory T cells (Tregs) are a specialized subpopulation of T cells that act to suppress immune responses, thereby maintaining homeostasis and self-tolerance. Tregs are immunosuppressive and generally suppress or downregulate the induction and proliferation of effector T cells. Many subtypes of Tregs exist, the best understood being those that express CD4, CD25, and FOXP3 (CD4 + CD25 + FOXP3 + Treg).

[0128] III. Anti-TIGIT antibody It is well known that the target binding specificity conferred by the variable region of an antibody is necessary for the primary functional activity of a given antibody. Regarding anti-TIGIT antibodies, some recent studies have also suggested the importance of FcγR co-engagement by anti-TIGIT antibodies to promote immune activation and tumor control. In particular, the depletion of Treg cells by antibody-dependent cellular cytotoxicity (ADCC) via FcγR co-engagement by anti-TIGIT antibodies was considered necessary for significant efficacy (see, for example, Chen et al., Front. Immunol, 2019, 10:292; Ward et al., BMJ, 2020, 8 (Suppl. 3), A253; Johnston et al., Ann Rev. Cancer Biol., 2021, 5:203-19). Indeed, Chen et al. (Front. Immunol., 2019, 10:292) stated that "for targets such as CTLA-4, TIGIT, and VISTA, competent Fc is required for optimal antitumor immune responses in various mouse models." Ward et al. (BMJ, 2020, 8(Suppl. 3), A253) similarly reported that "FcγRIIIA blockade or depletion of CD14+ and CD56+ cells reduced the functional activity of Fc-enhanced anti-TIGIT antibodies, confirming the requirement for FcγR coengagement to maximize T cell responses." Finally, Johnson et al. (Ann Rev. Cancer Biol., 2021, 5:203-19) reported that "there is emerging consensus that Fc effector function also plays a role in TIGIT antibody activity."

[0129] As a result, most anti-TIGIT antibodies currently in development are Fc-enabled, meaning that they possess wild-type or Fc-enhanced IgG1 constant regions that bind human FcγRI, human FcγRIIA, and human FcγRIIIA with moderate to high affinity and elicit Fc effector functions such as ADCC, CDC, and ADCP. These antibodies include, but are not limited to, tiragolumab, vibostolimab, etiglimab, osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006. Evidence of Treg depletion following administration has been shown for at least two of these antibodies: EOS-448 (Van den Mooter et al., "Preliminary data from a Phase I first LGO-in-human study of EOS884448, a novel potent anti-TIGIT antibody, monotherapy shows a favorable tolerability profile and early signs of clinical activity in immune-resistant advanced cancers." Poster presented at: AACR Annual Meeting 2021, April 10-15, 2021) and SEA-TGT (Smith A, et al., "SEA-TGT is an empowered anti-TIGIT antibody that displays superior combinatorial activity with several therapeutic agents." Poster presented at: AACR Annual Meeting 2021, April 10-15, 2021). 10-15, 2021). Despite the understanding in the art that Fc binding is required for anti-TIGIT antibodies to have clinical utility, the present disclosure relies on the use of anti-TIGIT antibodies with reduced or eliminated Fc function, particularly reduced or eliminated ADCC, CDC, and / or ADCP.

[0130] For purposes of the disclosed methods and pharmaceutical compositions, the therapeutic antibodies described herein are antibodies or fragments thereof that bind to human TIGIT and inhibit CD155 binding to TIGIT, but specific anti-TIGIT antibodies are not limited to the antigen-binding domain of any one antibody. While domvanalimab is a preferred anti-TIGIT antibody, antigen-binding domains from other anti-TIGIT antibodies (e.g., tiragolumab, vibostolimab, etiglimab, osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, JS006, AB308, etc.), or antigen-binding domains comprising at least six CDRs of these anti-TIGIT antibodies, can also be used. Therapeutic antibodies suitable for use in the disclosed methods and pharmaceutical uses may be human, humanized, or chimeric antibodies, and may be full-length antibodies or antibody fragments. In some embodiments, therapeutic antibodies suitable for use in the disclosed methods and pharmaceutical uses comprise an Fc region. These antibodies that include an Fc region may be IgA, IgG (i.e., IgG1, IgG2, IgG3, and IgG4), IgD, IgE, or IgM antibodies or variants thereof, but in all cases the Fc region has reduced binding to one or more FcγRs (e.g., activating FcγRs) compared to WT IgG1 or is unable to bind to one or more FcγRs (e.g., activating FcγRs).

[0131] The anti-TIGIT antibodies of the present disclosure have a 10 mAb binding affinity to human TIGIT as measured by surface plasmon resonance (SPR). -8 For example, the anti-TIGIT antibodies of the present disclosure have an equilibrium dissociation constant (KD) of 10 M or less as measured by SPR. -8 M or less, 10 -9 M or less, 10 -10 M or less, 10 -11 M or less, 10 -12 M or less, or 10 -13 In various embodiments, the anti-TIGIT antibodies of the present disclosure may have a KD for TIGIT of about 1 x 10 -9 M ~ approx. 1×10 -13 M, or approximately 1 x 10 -9 M ~ approx. 1×10 -12M, or approximately 1 x 10 -10 M ~ approx. 1×10 -13 M, or approximately 1 x 10 -10 M ~ approx. 1×10 -12 M, or approximately 1 x 10 -11 M ~ approx. 1×10 -13 M, or approximately 1 x 10 -10 M ~ approx. 1×10 -11 M, or approximately 1 x 10 -11 M ~ approx. 1×10 -12 It has a KD for TIGIT within the range of M.

[0132] In one embodiment, an anti-TIGIT antibody of the present disclosure comprises a heavy chain variable domain comprising CDRH1, CDRH2, and CDRH3 of domvanalimab, and a light chain variable domain comprising CDRL1, CDRL2, and CDRL3 of domvanalimab. Domvanalimab comprises a CDRH1 comprising the amino acid sequence of NFGMH (SEQ ID NO: 2), a CDRH2 comprising the amino acid sequence of FISSGSSSIYYADTVKG (SEQ ID NO: 3), a CDRH3 comprising the amino acid sequence of MRLDYYAMDY (SEQ ID NO: 4), a CDRL1 comprising the amino acid sequence of RASKSISKYLA (SEQ ID NO: 5), a CDRL2 comprising the amino acid sequence of SGSTLQS (SEQ ID NO: 6), and a CDRL3 of QQHNEYPWT (SEQ ID NO: 7).

[0133] In another embodiment, an anti-TIGIT antibody of the present disclosure comprises a heavy chain variable domain comprising the heavy chain variable domain of domvanalimab and a light chain variable domain comprising the light chain variable domain of domvanalimab, which comprises a variable heavy chain (VH) domain comprising the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGMHWVRQAPGKGLEWVAFISSGSSSIYYADTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARMRLDYYAMDYWGQGTMVTVSS (SEQ ID NO: 10) and a variable light chain (VL) domain comprising the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASKSISKYLAWYQQKPGKAPKLLIYSGSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIK (SEQ ID NO: 11). These VH and VL domains are humanized variants of EVQLQQSGPELVKPGASVKISCKTSGYTFTEYTMHWVKQSHGKNLEWIGGINPNNGGTSYNQKFKGRATLTVDKSSSTAYMELRSLTSDDSAVYYCARPGWYNYAMDYWGQGTSVTVSS (SEQ ID NO: 8) and DVQITQSPSYLAASPGETITINCRASKSISKYLAWYQEKPGKTNKLLIYSGSTLQSGIPSRFSGSGSGTDFTLTISSLEPEDFAMYYCQQHNEYPWTFGGGTKLEIK (SEQ ID NO: 9), respectively.

[0134] In another embodiment, the anti-TIGIT antibody of the present disclosure is domvanalimab. The mature gamma heavy chain amino acid sequence of domvanalimab is EVQLVESGGGLVQPGGSLRLSCAASGFTFSNFGMHWVRQAPGKGLEWVAFISSGSSSIYYADTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARMRLDYYAMDYWGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCWVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRWSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQ PREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 12), and the mature kappa light chain amino acid sequence of domvanalimab is DIQMTQSPSSLSASVGDRVTITCRASKSISKYLAWYQQKPGKAPKLLIYSGSTLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHNEYPWTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 13).

[0135] In some embodiments, the anti-TIGIT antibodies of the present disclosure are variants of domvanalimab. For purposes of this disclosure, a "variant antibody" or "variant" of domvanalimab refers to (i) an antibody having a heavy chain that comprises at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the heavy chain sequence of domvanalimab; (ii) an antibody having a light chain that comprises at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the light chain sequence of domvanalimab; (ii) antibodies having variable regions that contain at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the variable region sequences of domvanalimab, (iv) antibodies having CDRs that contain at least 55%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity to the CDR sequences of domvanalimab, and (v) any combination thereof. For example, suitable variants include immunoglobulins or immunoglobulin-like molecules that contain heavy and light chain amino acid sequences that are the same as or substantially similar to those of domvanalimab. Other suitable therapeutic antibodies may bind to the same isoform of TIGIT (e.g., TIGITv3) as domvanalimab, optionally to the same epitope of TIGIT, may block or neutralize TIGIT, or any combination thereof. Additional exemplary therapeutic antibodies are described, for example, in U.S. Patent No. 10,537,633.

[0136] In another embodiment, the anti-TIGIT antibodies of the present disclosure are those disclosed in WO 2017053748, WO 2016028656, WO 2016106302, WO 2016191643, WO 2018102536, WO 2019129261, WO 2019023504, WO 2020144178, WO 2018033798, WO 2018160704, WO 2020041541, WO 2020020281, WO 2019154415 , 2018234793, 2021008523, 2019168382, 2020098734, 2017059095, 2020251187, 2019129221, 2021043206, 2018128939, 2020242919, 2021216468, or 2017152088. In some embodiments, the anti-TIGIT antibody of the present disclosure comprises the light chain variable domain and the heavy chain variable domain of the anti-TIGIT antibody disclosed in WO 2017152088.

[0137] In another embodiment, the anti-TIGIT antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain, wherein the amino acid sequences of the light chain variable domain and the heavy chain variable domain have about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity, respectively, to the light chain variable domain and heavy chain variable domain amino acid sequences of an anti-TIGIT antibody selected from the group consisting of tiragolumab, vibostolimab, etiglimab, osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, JS006, COM902, IBI939, BGB-A1217, ASP8374, and M6223.

[0138] In another embodiment, the anti-TIGIT antibody of the present disclosure comprises a light chain variable domain and a heavy chain variable domain of an anti-TIGIT antibody selected from the group consisting of tiragolumab, vibostolimab, etiglimab, and osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, JS006, COM902, IBI939, BGB-A1217, ASP8374, and M6223.

[0139] For purposes of the disclosed treatments, methods, and uses, the epitope specificity for binding to TIGIT can vary. For example, in some embodiments, an anti-TIGIT antibody can bind to a TIGIT polypeptide at one or more amino acid residues, including D51, where the TIGIT polypeptide has an amino acid sequence corresponding to SEQ ID NO: 1. In various embodiments of the present disclosure, the anti-TIGIT antibody can competitively inhibit the binding of a reference antibody to human TIGIT, where the reference antibody is selected from the group consisting of domvanalimab, tiragolumab, vibostolimab, etiglimab, osipeliimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006, or is selected from the group consisting of domvanalimab, tiragolumab, vibostolimab, etiglimab, and osipeliimab. An antibody is said to competitively inhibit the binding of a reference antibody to human TIGIT if it preferentially binds to its epitope to the extent that it blocks the binding of the reference antibody to TIGIT by at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. Competitive inhibition can be determined by any method known in the art, such as a competitive flow assay. Briefly, the reference antibody and isotype control can be directly conjugated to a fluorophore according to the manufacturer's instructions. Cells expressing human TIGIT can be seeded at an appropriate density in a multi-well plate, and a dose-response curve can be generated by serially diluting each antibody, incubating the cells with each antibody concentration, and then measuring the mean fluorescence intensity of the fluorophore for the viable single-cell population by flow cytometry. EC 50 and EC 95Values can be calculated using standard four-parameter nonlinear regression analysis. Competition can then be assessed by using an unlabeled test antibody with a labeled reference antibody and measuring any changes in mean fluorescence intensity.

[0140] As described above, the anti-TIGIT antibodies of the present disclosure have reduced binding to one or more FcγRs (e.g., activating FcγRs) or are unable to bind to one or more FcγRs (e.g., activating FcγRs) compared to WT IgG1. Binding to FcγRs can be measured directly by the methods detailed in Example 1. Alternatively, or in addition, reduced binding to activating FcγRs can be demonstrated by the antibody exhibiting reduced Fc effector functions such as CDC, ADCC, and / or ADCP compared to WT IgG1.

[0141] In some embodiments, the anti-TIGIT antibody used in the methods and treatments of the present disclosure is an IgG, such as an IgG1 (e.g., an Fc-modified IgG1) or an IgG4. The four subclasses of IgG—IgG1, IgG2, IgG3, and IgG4—are highly conserved. The amino acid sequences of the constant regions of these peptides are well known in the art; see, for example, Rutishauser, U. et al. (1968) “Amino acid sequence of the Fc region of a human gamma G-immunoglobulin,” PNAS 61(4):1414-1421; Shinoda et al. (1981) “Complete amino acid sequence of the Fc region of a human delta chain,” PNAS 78(2):785-789; and Robinson et al. (1980) “Complete amino acid sequence of a mouse immunoglobulin alpha chain (MOPC 511),” PNAS 77(8):4909-4913.

[0142] Domvanalimab is an example of an anti-TIGIT antibody with reduced or eliminated ability to bind to FcγRs, particularly activating FcγRs such as FcγRI, FcγRIIA, and FcγRIIIA. For example, domvanalimab has an engineered IgG1 Fc, resulting in reduced binding to one or more FcγRs (e.g., activating FcγRs) compared to WT IgG1. Domvanalimab was tested for binding to FcγR isotypes I, IIA, IIB, IIIA, and IIIB by enzyme-linked immunosorbent assay. Compared to the wild-type IgG1 antibody control, no significant binding was observed with domvanalimab to any of the FcγR isotypes tested at concentrations up to 1 μM. Domvanalimab was also tested in an FcγR-IIIA (V158 high-affinity variant) effector reporter bioassay and was found to be inactive at concentrations up to 1 μM. CDC assays were performed using a Jurkat cell line stably overexpressing human complement and human TIGIT in the presence of increasing concentrations of domvanalimab up to 33 nM, and no cytotoxicity was observed for domvanalimab at any of the concentrations tested.

[0143] Other antibodies that bind to TIGIT and have either reduced or abolished ability to bind to FcγRs (e.g., activating FcγRs) include, but are not limited to, IgG4 or IgG1 antibodies with modified Fc regions. For example, anti-TIGIT antibodies of the present disclosure can be engineered by introducing constant region mutations that result in reduced Fc effector functions, such as CDC and ADCC or ADCP, compared to the same antibody without the mutations. Preferably, each or a combination of these Fc effector functions is reduced by at least 50%, 75%, 90%, or 95% compared to the antibody without the mutations. Measurement of CDC can be achieved according to U.S. Patent No. 10,537,633. Other assays for measuring CDC are described by Shields et al, 2001 J. Biol. Chem., Vol. 276, p 6591-6604; Chappel et al, 1993 J. Biol. Chem., Vol 268, p 25124-25131; Lazar et al, 2006 PNAS, 103; 4005-4010.

[0144] For example, the Fc region of tiragolumab, vibostolimab, etiglimab, osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, or JS006 can be engineered to contain mutations that result in reduced Fc effector function. Substitutions at any or all of positions 234, 235, 236, and / or 237 reduce affinity for Fcγ receptors, particularly the FcγRI receptor (see, e.g., U.S. Patent No. 6,624,821). Alanine is a preferred residue for substitution, and L234A / L235A is a preferred double mutation for reducing Fc effector function. Other combinations of mutations with reduced Fc effector function include L234A / L235A / G237A, E233P / L234V / L235A / ΔG236, A327G / A330S / P331S, K322A, L234A and L235A, L234F / L235E / P331S. Optionally, positions 234, 236, and / or 237 in human IgG2 are substituted with alanine, and position 235 is substituted with glutamine. (See, e.g., U.S. Pat. No. 5,624,821.) Two amino acid substitutions in the complement Clq binding site at EU index positions 330 and 331 reduce complement binding (see Tao et al., J. Exp. Med. 178:661 (1993) and Canfield and Morrison, J. Exp. Med. 173:1483 (1991)). Substitution of IgG2 residues at positions 233-236 with human IgG1 and IgG4 residues at positions 327, 330, and 331 significantly reduces ADCC and CDC (see, e.g., Armour KL. et al., 1999 Eur J Immunol. 29(8):2613-24, and Shields R L. et al., 2001 J Biol Chem. 276(9):6591-604). The N297A, N297Q, or N297G (Eu numbering) mutations reduce glycosylation, thereby reducing Fc effector function.Other substitutions can also be made in the constant regions of the antibodies of the disclosure to reduce Fc effector function, such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., U.S. Pat. No. 5,624,821; Tso et al., U.S. Pat. No. 5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA, 103:4005, 2006).

[0145] Anti-TIGIT antibodies suitable for the disclosed methods may be antibodies in which one or several amino acids at the amino or carboxy termini of the light and / or heavy chains, such as the C-terminal lysine of the heavy chain, may be deleted or derivatized in part or all of the molecule. Substitutions can be made in the constant region of the antibodies of the present disclosure to extend half-life in humans (see, e.g., Hinton et al., J. Biol. Chem. 279:6213, 2004). Exemplary substitutions include Gln at position 250 and / or Leu at position 428 (Eu numbering) to increase the half-life of the antibody.

[0146] In some embodiments, the antibody is a monoclonal antibody. In some embodiments of any of the embodiments disclosed herein, the antibody is a chimeric antibody, a humanized antibody, or a veneered antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.

[0147] Domvanalimab and suitable therapeutic antibody variants may be monoclonal or polyclonal antibodies, preferably monoclonal antibodies. Such monoclonal antibodies with TIGIT binding and / or neutralizing activity can be obtained, for example, by the following procedure: anti-TIGIT monoclonal antibodies can be prepared by known methods using TIGIT or a fragment thereof derived from a mammal, such as a human, as an antigen. Antibodies with TIGIT binding and / or neutralizing activity are then selected from the anti-TIGIT monoclonal antibodies thus obtained. Specifically, a desired antigen or cells expressing the desired antigen are used as a sensitizing antigen, and immunization is performed according to a conventional immunization method. Anti-TIGIT monoclonal antibodies can be prepared by fusing the obtained immune cells with known parent cells using a conventional cell fusion method and screening them for monoclonal antibody-producing cells (hybridomas) using a conventional screening method. Examples of animals to be immunized include mammals such as mice, rats, rabbits, sheep, monkeys, goats, donkeys, cattle, horses, and pigs. Antigens can be prepared using known TIGIT gene sequences by known methods, such as baculovirus-based methods (e.g., WO 98 / 46777). Domvanalimab and suitable therapeutic antibody variants can also be prepared as intrabodies, peptibodies, nanobodies, single domain antibodies, multispecific antibodies (e.g., bispecific antibodies, diabodies, triabodies, tetrabodies, tandem di-scFvs, tandem tri-scFvs), DARPins, heavy chain monomers, heavy chain dimers, or single domain antibodies (i.e., V H H fragments or "camelid-like" antibodies), any of which may be derived from the sequence and / or binding domain of domvanalimab.

[0148] Hybridomas can be prepared, for example, according to the method of Milstein et al. (Kohler, G. and Milstein, C., Methods Enzymol. (1981) 73:3-46). When the antigen has low immunogenicity, it may be conjugated to an immunogenic macromolecule such as albumin prior to immunization. The antigen used to prepare a monoclonal antibody having binding and / or neutralizing activity against human TIGIT is not particularly limited, as long as it allows the preparation of an antibody having binding and / or neutralizing activity against human TIGIT. For example, many variants of human TIGIT are known to exist, and any variant can be used as an immunogen as long as it allows the preparation of an antibody having binding and / or neutralizing activity against human TIGIT. Alternatively, under the same conditions, a peptide fragment or protein of TIGIT in which artificial mutations have been introduced into the native TIGIT sequence may be used as an immunogen. Suitable immunogens that can be used in preparing antibodies having TIGIT-binding and / or neutralizing activity in the present disclosure are described in Example 2 of US Pat. No. 10,537,633.

[0149] The TIGIT-binding activity of a therapeutic antibody can be determined by methods known to those skilled in the art. Methods for measuring the antigen-binding activity of an antibody include, for example, ELISA (enzyme-linked immunosorbent assay), EIA (enzyme-linked immunosorbent assay), RIA (radioimmunoassay), and fluorescent antibody assay. For example, when using an enzyme immunoassay, an antibody-containing sample, such as a purified antibody or the culture supernatant of antibody-producing cells, is added to an antigen-coated plate. A secondary antibody labeled with an enzyme such as alkaline phosphatase is added, and the plate is incubated. After washing, an enzyme substrate such as p-nitrophenyl phosphate is added, and the absorbance is measured to evaluate the antigen-binding activity. The binding and / or neutralizing activity of a therapeutic antibody to TIGIT can be measured, for example, by observing the effect of suppressing the proliferation of TIGIT-mediated cell lines. Another method for determining TIGIT-binding activity is the receptor occupancy (RO) assay. For example, RO can be evaluated by flow cytometry using whole blood samples taken before and after administration. A commercially available anti-TIGIT antibody (i.e., a competitive antibody) that competes with the anti-TIGIT antibody of interest (e.g., domvanalimab) can be used to determine the TIGIT RO, as measured by the decrease in detectable anti-TIGIT antibody signal that occurs after administration of the antibody of interest (e.g., domvanalimab). The competitive antibody can be any antibody that competes for binding to the epitope targeted by the antibody of interest (e.g., domvanalimab).

[0150] IV. Combinations with the Disclosed Anti-TIGIT Antibodies The present disclosure contemplates the use of anti-TIGIT antibodies with reduced or abolished Fc effector function (e.g., domvanalimab and other anti-TIGIT antibodies in Section III) alone or in combination with one or more additional therapies. Each additional therapy can be a therapeutic agent or another treatment modality. In embodiments including one or more additional therapeutic agents, each agent can target a different but complementary mechanism of action. The additional therapeutic agent can be a small chemical molecule; a macromolecule, e.g., a protein, antibody, peptibody, peptide, DNA, RNA, or fragment of such a macromolecule; or cell therapy or gene therapy. Non-limiting examples of additional treatment modalities include surgical resection of a tumor, bone marrow transplant, radiation therapy, and photodynamic therapy. The use of anti-TIGIT antibodies with reduced or abolished Fc effector function (e.g., domvanalimab) in combination with one or more additional therapies can have a synergistic or additive therapeutic or prophylactic effect against the underlying disease, disorder, or condition. Additionally, or alternatively, combination therapy may allow for dosage reduction of one or more of the therapies, thereby ameliorating, reducing, or eliminating adverse effects associated with one or more of the therapies.

[0151] In embodiments including one or more additional therapeutic modalities, the anti-TIGIT antibody with reduced or abolished Fc effector function can be administered before, after, or during treatment with the additional therapeutic modality. In embodiments including one or more additional therapeutic agents, the therapeutic agents used in such combination therapy can be formulated as a single composition or as separate compositions. When administered separately, each therapeutic agent in the combination can be administered simultaneously or near simultaneously, or at different times. Furthermore, therapeutic agents are "administered in combination" even if they have different dosage forms (e.g., oral capsules and intravenous), are given at different dosing intervals, one therapeutic agent is given on a fixed dosing regimen while another is titrated, tapered, or discontinued, or each therapeutic agent in the combination is independently titrated, tapered, or dose-up or -down, or discontinued and / or resumed during the course of treatment of the patient. When the therapeutic agents in the combination are formulated as separate compositions, in some embodiments, the separate compositions are provided together in a kit.

[0152] In some embodiments, one or more of the additional therapeutic agents is a chemotherapeutic agent. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, metredopa, and uredopa; ethylenimines and methylameramines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; nitrogen mustards such as chlorambucil and chlornaphazine; Chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, nobembine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, e.g., aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, calicheamicin, carabicin, carminomycin (c aminomycin), carzinophilin, chromomycin, dactinomycin, daunorubicin, detrevicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin, mycophenolic acid, nogalamycin, olivomycin, pomalidomide, peplomycin, porfiromycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubeni mexamex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as denopterin, methotrexate, pemetrexed, 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, 5-FU;Androgens, e.g., calsterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; antiadrenergics, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., furoic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine; bestravcil; bisantrene; edatrexate; defofamine; demecolcine; diaziquone; erformitin, acetic acid Elliptinium nitrate; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidamine; Mitoguazone; Mitoxantrone; Mopidamol; Nitracrine; Pentostatin; Fenamet; Pirarubicin; Podophyllic acid, 2-ethylhydrazide; Procarbazine; Razoxane; Sizofiran; Spirogermanium; Tenuazonic acid; Triazicone; 2,2',2''-Trichlorotriethylamine; Urethane; Vindesine; Dacarbazine; Manno Mustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, such as paclitaxel, nab-paclitaxel, and docetaxel; chlorambucil; gemcitabine, 6-thioguanine; mercaptopurine; methotrexate; platinum and platinum coordination complexes, such as cisplatin, carboplatin, and oxaliplatin; vinblastine; etoposide (VP -16); ifosfamide; mitomycin C, mitoxantrone; vincristine, vinorelbine, navelbine, novantrone; teniposide; daunomycin, aminopterin, xeloda, ibandronate; CPT11; topoisomerase inhibitors, e.g., irinotecan, topotecan, etoposide, mitoxantrone, teniposide; difluoromethylornithine (DMFO); retinoic acid; esperamycin, capecitabine; anthracyclines;and pharmaceutically acceptable salts, acids, or derivatives of any of the above. In certain embodiments, the combination therapy comprises a chemotherapy regimen comprising one or more chemotherapeutic agents. In one embodiment, the combination therapy comprises a chemotherapy regimen comprising FOLFOX (folinic acid, fluorouracil, and oxaliplatin), FOLFIRI (folinic acid, fluorouracil, and irinotecan), a taxane (e.g., docetaxel, paclitaxel, nab-paclitaxel, etc.), CAPOX (capecitabine and oxaliplatin), XELOX (capecitabine and oxaliplatin), irinotecan, fluoropyrimidine-containing chemotherapy (e.g., fluorouracil, capecitabine, floxuridine), a platinum-based chemotherapy agent, or gemcitabine.

[0153] In some embodiments, one or more of the additional therapeutic agents is a radiopharmaceutical. A radiopharmaceutical is a form of internal radiation therapy in which a radiation source (i.e., one or more radionuclides) is placed inside the subject's body. The radiation source can be in solid or liquid form. Non-limiting examples of radiopharmaceuticals include sodium iodide I-131, radium-223 dichloride, lobenguane iodine-131, radioiodinated vesicles (e.g., saposin C-dioleoylphosphatidylserine (SapC-DOPS) nanovesicles), various forms of brachytherapy, and various forms of targeted radionuclides. Targeted radionuclides include radionuclides associated (e.g., by covalent or ionic interactions) with a molecule (a "targeting agent") that specifically binds to a target on a cell, typically a cancer cell or immune cell. The targeting agent may be a small molecule, a sugar (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a saccharide (including oligosaccharides and polysaccharides), lipid, protein, or peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neo-antigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). In some embodiments, the targeting agent is an antibody, and the target is a tumor-associated antigen (i.e., an antigen enriched but not specific to cancer cells), a tumor-specific antigen (i.e., an antigen minimal or no expression in normal tissues), or a neo-antigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations in the tumor cell genome). Non-limiting examples of targeted radionuclides include somatostatin or its peptide analogs (e.g., 177Lu-Dotatate, etc.); prostate-specific membrane antigen or its peptide analogs (e.g., 177Lu-PSMA-617, 225Ac-PSMA-617, 177Lu-PSMA-I&T, 177Lu-MIP-1095, etc.); cognate ligands of the receptors, peptides derived from the ligands, or variants thereof (e.g., 188-relabeled VEGF 125-136or variants thereof with higher affinity for the VEGF receptor; or antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.), including radionuclides bound to antibodies targeting tumor antigens (e.g., 131I-tositumomab, 90Y-ibritumomab tiuxetan, CAM-H2-I131 (Precirix NV), I131-omburtamab, etc.).

[0154] In some embodiments, one or more of the additional therapeutic agents is a hormone therapy. Hormonal therapy acts to regulate or inhibit hormone action on tumors. Examples of hormone therapy include, but are not limited to, selective estrogen receptor degraders such as fulvestrant, GDC-9545, SAR439859, RG6171, AZD9833, lindestrant, ZN-c5, LSZ102, D-0502, LY3484356, SHR9549, selective estrogen receptor modulators such as tamoxifen, raloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, toremifene, aromatase inhibitors such as aromatase inhibitors. These include nastrozole, exemestane, letrozole, and other aromatase inhibiting 4(5)-imidazoles, gonadotropin-releasing hormone agonists such as nafarelin, triptorelin, and goserelin, gonadotropin-releasing hormone antagonists such as degarelix, antiandrogens such as abiraterone, enzalutamide, apalutamide, dalotamide, flutamide, nilutamide, bicalutamide, and leuprolide, and 5α-reductase inhibitors such as finasteride and dutasteride. In certain embodiments, the combination therapy includes the administration of a hormone or related hormone agent. In one embodiment, the combination therapy includes the administration of enzalutamide.

[0155] In some embodiments, one or more of the additional therapeutic agents is an epigenetic modulator. Epigenetic modulators alter the epigenetic mechanisms that control gene expression and can be, for example, inhibitors or activators of epigenetic enzymes. Non-limiting examples of epigenetic modulators include DNA methyltransferase (DNMT) inhibitors, hypomethylating agents, and histone deacetylase (HDAC) inhibitors. In one or more embodiments, an anti-TIGIT antibody with reduced or eliminated Fc effector function (e.g., domvanalimab) can be combined with a DNA methyltransferase (DNMT) inhibitor or hypomethylating agent. Exemplary DNMT inhibitors include decitabine, zebularine, and azacitadine. In one or more embodiments, a combination of an anti-TIGIT antibody with reduced or eliminated Fc effector function (e.g., domvanalimab) with a histone deacetylase (HDAC) inhibitor is also contemplated. Exemplary HDAC inhibitors include vorinostat, gibinostat, abexinostat, panobinostat, belinstat, and trichostatin A.

[0156] In some embodiments, one or more of the additional therapeutic agents is an ATP-adenosine axis targeting agent. ATP-adenosine axis targeting agents alter signal transduction mediated by adenine nucleosides and nucleotides (e.g., adenosine, AMP, ADP, ATP), for example, by regulating adenosine levels or targeting adenosine receptors. Adenosine and ATP, acting at different classes of receptors, often have opposing effects on inflammation, cell proliferation, and cell death. For example, ATP and other adenine nucleotides have antitumor effects through activation of the PS2Y1 receptor subtype, while the accumulation of adenosine in the tumor microenvironment has been shown to inhibit the antitumor function of various immune cells and enhance the immunosuppressive activity of myeloid and regulatory T cells by binding to cell surface adenosine receptors. In certain embodiments, the ATP-adenosine axis targeting agent is an inhibitor of ectonucleotidase, which is involved in the conversion of ATP to adenosine, or an adenosine receptor antagonist. Ectonucleotidases involved in the conversion of ATP to adenosine include ectonucleoside triphosphate diphosphohydrolase 1 (ENTPD1, also known as CD39 or cluster of differentiation 39) and ecto-5'-nucleotidase (NT5E or 5NT, also known as CD73 or cluster of differentiation 73). Exemplary small molecule CD73 inhibitors include CB-708, ORIC-533, LY3475070, and AB680. Exemplary anti-CD39 and anti-CD73 antibodies include ES002, TTX-030, IPH-5201, SRF-617, CPI-006, oleculab (MEDI9447), NZV930, IPH5301, uriledolimab (TJD5, TJ004309), and BMS-986179. In one embodiment, the present disclosure contemplates the combination of an anti-TIGIT antibody with reduced or ablated Fc effector function described herein (e.g., domvanalimab) with a CD73 inhibitor, such as those described in WO 2017 / 120508, WO 2018 / 067424, WO 2018 / 094148, and WO 2020 / 046813. In a further embodiment, the CD73 inhibitor is quemlicustat.Adenosine binds to four different G protein-coupled receptors: A1R, A2R, A3R, A4R, A5R, A6R, A7R, A8R, A9R, A10R, A11R, A12R, A13R, A14R, A15R, A16R, A17R, A18R, A19R, A20R, A21R, A22R, A23R, A24R 2a R.A. 2b A2R antagonists can bind to and activate A2R, A3R, and A3R. A2R antagonists include etramadenant, inuadenant, tammine adenant, caffeine citrate, NUV-1182, TT-702, DZD-2269, INCB-106385, EVOEXS-21546, AZD-4635, imaradenant, RVU-330, sifoadenant, PBF-509, PBF-999, PBF-1129, and CS-3005. In some embodiments, the present disclosure provides a method for the treatment of TIGIT-related diseases by combining an anti-TIGIT antibody with reduced or abolished Fc effector function (e.g., domvanalimab) described herein with an A3R antagonist. 2a R antagonist, A 2b R antagonist or A 2a R and A 2b In some embodiments, the present disclosure contemplates combinations of an anti-TIGIT antibody with reduced or ablated Fc effector function described herein (e.g., domvanalimab) with an adenosine receptor antagonist described in WO 2018 / 136700, WO 2018 / 204661, WO 2018 / 213377, or WO 2020 / 023846, WO 2020 / 102646. In one embodiment, the adenosine receptor antagonist is etramedant.

[0157] In some embodiments, one or more of the additional therapeutic agents is a targeted therapy. In one aspect, the targeted therapy may include a chemotherapeutic agent, a radionuclide, a hormone therapy, or another small molecule drug conjugated to the targeting agent. The targeting agent may be a small molecule, a sugar (including oligosaccharides and polysaccharides), an antibody, a lipid, a protein, a peptide, a non-natural polymer, or an aptamer. In some embodiments, the targeting agent is a sugar (including oligosaccharides and polysaccharides), a lipid, a protein, or a peptide, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations or gene fusions in the tumor cell genome). In some embodiments, the targeting agent is an antibody, and the target is a tumor-associated antigen (enriched but not specific to cancer cells), a tumor-specific antigen (minimal or no expression in normal tissues), or a neoantigen (an antigen specific to the genome of cancer cells generated by nonsynonymous mutations or gene fusions in the tumor cell genome). In other embodiments, targeted therapies may inhibit or interfere with specific proteins that aid in tumor survival, growth, and / or spread. Non-limiting examples of such targeted therapies include signal transduction inhibitors, RAS signaling inhibitors, inhibitors of oncogenic transcription factors, activators of oncogenic transcription factor repressors, angiogenesis inhibitors, immunotherapeutic agents, ATP-adenosine axis targeting agents, AXL inhibitors, PARP inhibitors, PAK4 inhibitors, PI3K inhibitors, HIF2α inhibitors, CD39 inhibitors, CD73 inhibitors, A2R antagonists, TIGIT antagonists, and PD-1 antagonists. ATP-adenosine axis targeting agents are described above, while other agents are described in more detail below.

[0158] In some embodiments, one or more of the additional therapeutic agents is a signal transduction inhibitor. A signal transduction inhibitor is an agent that selectively inhibits one or more steps in a signal transduction pathway. Signal transduction inhibitors (STIs) contemplated by the present disclosure include, but are not limited to, (i) BCR-ABL kinase inhibitors (e.g., imatinib), (ii) epidermal growth factor receptor tyrosine kinase inhibitors (EGFR), including small molecule inhibitors (e.g., gefitinib, erlotinib, afatinib, icotinib, and osimertinib), and anti-EGFR antibodies. TKIs), (iii) inhibitors of the human epidermal growth factor (HER) family of transmembrane tyrosine kinases, for example, HER-2 / neu receptor inhibitors (e.g., trastuzumab, and HER-3 receptor inhibitors), (iv) vascular endothelial growth factor receptor (VEGFR) inhibitors, for example, small molecule inhibitors (e.g., axitinib, sunitinib, and sorafenib), VEGF kinase inhibitors (e.g., lenvatinib, cabozantinib, pazopanib, tivozanib, XL092, etc.), anti-VEGF antibodies (e.g., bevacizumab), and anti-VEGFR antibodies (e.g., ramucirumab, etc.);(v) inhibitors of AKT family kinases or the AKT pathway (e.g., rapamycin), (vi) inhibitors of serine / threonine-protein kinase B-Raf (BRAF), such as vemurafenib, dabrafenib, and encorafenib, (vii) inhibitors of rearrangements during transfection (RET), including, for example, selpacatinib and pralsetonib, (viii) inhibitors of tyrosine-protein kinase Met (MET) (e.g., tepotinib, tivantinib, cabozantinib, and crizotinib), (ix) inhibitors of anaplastic lymphoma kinase (ADL) (e.g., anaplastic lymphoma kinase (ALK)), (x) inhibitors of anaplastic lymphoma kinase (ADL ... (x) inhibitors of the RAS signaling pathway described elsewhere herein (e.g., inhibitors of KRAS, HRAS, RAF, MEK, ERK); (xi) inhibitors of FLT-3 (e.g., gilteritinib); (xii) inhibitors of Trop-2; (xiii) inhibitors of the JAK / STAT pathway, e.g., JAK inhibitors including tofacitinib and ruxolitinib, or STAT inhibitors such as napabucasin; (xiv) inhibitors of NF-kB; (xv) inhibitors of cell cycle kinases (e.g., flavopiridol); (xvi) inhibitors of phosphatidylinositol kinase (PI3K); and (xix) inhibitors of protein kinase B (AKT) (e.g., capivasertib, milansertib). In one or more embodiments, the additional therapeutic agent comprises an inhibitor of EGFR, VEGFR, HER-2, HER-3, BRAF, RET, MET, ALK, RAS (e.g., KRAS, MEK, ERK), FLT-3, JAK, STAT, NF-kB, PI3K, AKT, or any combination thereof;

[0159] In some embodiments, one or more of the additional therapeutic agents is a RAS signaling inhibitor. Oncogenic mutations in RAS family genes, such as HRAS, KRAS, and NRAS, are associated with various cancers. For example, in KRAS family genes, mutations such as G12C, G12D, G12V, G12A, G13D, Q61H, G13C, and G12S, among others, have been observed in multiple tumor types. Direct and indirect inhibitory strategies have been investigated to inhibit mutant RAS signaling. Indirect inhibitors target effectors other than RAS in the RAS signaling pathway, including, but not limited to, inhibitors of RAF, MEK, ERK, PI3K, PTEN, SOS (e.g., SOS1), mTORC1, SHP2 (PTPN11), and AKT. Non-limiting examples of indirect inhibitors under development include RMC-4630, RMC-5845, RMC-6291, RMC-6236, JAB-3068, JAB-3312, TNO155, RLY-1971, and BI1701963. Direct inhibitors of RAS mutants are also being explored, generally targeting the KRAS-GTP complex or the KRAS-GDP complex. Exemplary direct RAS inhibitors under development include, but are not limited to, sotorasib (AMG510), MRTX849, mRNA-5671, and ARS1620. In some embodiments, the one or more RAS signaling inhibitors are selected from the group consisting of a RAF inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an SOS1 inhibitor, an mTORC1 inhibitor, a SHP2 inhibitor, and an AKT inhibitor. In other embodiments, the one or more RAS signaling inhibitors directly inhibit RAS mutants.

[0160] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of phosphatidylinositol 3-kinase (PI3K), particularly an inhibitor of the PI3Kγ isoform. PI3Kγ inhibitors can stimulate anti-cancer immune responses through modulation of myeloid cells, for example, by inhibiting suppressive myeloid cells and attenuating immunosuppressive tumor-infiltrating macrophages, or by stimulating macrophages and dendritic cells to produce cytokines that contribute to effective T-cell responses, resulting in reduced cancer development and spread. Exemplary PI3Kγ inhibitors include copanlisib, duvelisib, AT-104, ZX-101, tenalisib, eganelisib, SF-1126, AZD3458, and pictilisib. In some embodiments, an anti-TIGIT antibody with reduced or ablated Fc effector function (e.g., domvanalimab) can be combined with one or more PI3Kγ inhibitors described in WO2020 / 0247496.

[0161] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of arginase. Arginase has been shown to be either responsible for or involved in inflammation-induced immune dysfunction, tumor immune escape, immunosuppression, and the immunopathology of infectious diseases. Exemplary arginase compounds include CB-1158 and OAT-1746. In some embodiments, an anti-TIGIT antibody with reduced or eliminated Fc effector function (e.g., domvanalimab) can be combined with one or more arginase inhibitors described in WO 2019 / 173188 and WO 2020 / 102646.

[0162] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of an oncogenic transcription factor or an activator of an oncogenic transcription factor repressor. Suitable agents may act at the expression level (e.g., RNAi, siRNA, etc.), via physical degradation, at the protein / protein level, at the protein / DNA level, or by binding to an activation / inhibition pocket. Non-limiting examples include inhibitors of one or more subunits of the MLL complex (e.g., HDAC, DOT1L, BRD4, menin, LEDGF, WDR5, KDM4C (JMJD2C), and PRMT1), inhibitors of hypoxia-inducible factor (HIF) transcription factors, etc.

[0163] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of hypoxia-inducible factor (HIF) transcription factors, particularly HIF-2α. Exemplary HIF-2α inhibitors include velzutifan, ARO-HIF2, PT-2385, AB521, and those described in International Publication Nos. 2021113436 and 2021188769. In some embodiments, an anti-TIGIT antibody with reduced or eliminated Fc effector function (e.g., domvanalimab) can be combined with one or more HIF-2α inhibitors described in International Publication No. 2021188769.

[0164] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of Anexselect (AXL). The AXL signaling pathway is associated with tumor growth and metastasis and is thought to mediate resistance to various cancer therapies. There are various AXL inhibitors under development that also inhibit other kinases within the TAM family (i.e., TYRO3, MERTK), as well as other receptor tyrosine kinases, including MET, FLT3, RON, and AURORA, among others. Exemplary multikinase inhibitors include sitravatinib, rebastinib, glesatinib, gilteritinib, merestinib, cabozantinib, foretinib, BMS777607, LY2801653, S49076, GSK1363089, and RXDX-106. AXL-specific inhibitors have also been developed, including small molecule inhibitors such as DS-1205, SGI-7079, SLC-391, TP-0903 (i.e., duvelmatinib), BGB324 (i.e., bemcentinib), and DP3975; anti-AXL antibodies such as ADCT-601; and antibody-drug conjugates (ADCs) such as BA3011. Another strategy for inhibiting AXL signaling involves targeting GAS6, the ligand for AXL. For example, AVB-500 is being developed as an Fc fusion protein that binds to the GAS6 ligand and thereby inhibits AXL signaling.

[0165] In some embodiments, one or more of the additional therapeutic agents is an inhibitor of p21-activated kinase 4 (PAK4). PAK4 overexpression has been demonstrated across a variety of cancer types, including those that are particularly resistant to PD-1 therapy. While there are no approved PAK4 inhibitors, several are in development and exhibit dual PAK4 / NAMPT inhibitor activity, e.g., ATG-019 and KPT-9274. In some embodiments, a compound according to the present disclosure is combined with a PAK4-selective inhibitor. In some embodiments, a compound according to the present disclosure is combined with a PAK4 / NAMPT dual inhibitor, e.g., ATG-019 or KPT-9274.

[0166] In some embodiments, one or more of the additional therapeutic agents is (i) an agent that inhibits the enzyme poly(ADP-ribose) polymerase (e.g., olaparib, niraparib, and rucaparib); (ii) an inhibitor of the Bcl-2 family of proteins (e.g., venetoclax, navitoclax, etc.); (iii) an inhibitor of MCL-1; (iv) an inhibitor of the CD47-SIRPα pathway (e.g., an anti-CD47 antibody); or (v) an isocitrate dehydrogenase (IDH) inhibitor, e.g., an IDH-1 or IDH-2 inhibitor (e.g., ivosidenib, enazidenib, etc.).

[0167] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent. Immunotherapeutic agents useful in cancer treatment typically induce or amplify an immune response against cancer cells. Non-limiting examples of suitable immunotherapeutic agents include immunomodulators; cellular immunotherapies; vaccines; gene therapies; ATP-adenosine axis targeting agents; and immune checkpoint modulators. ATP-adenosine axis targeting agents are described above. Immunomodulators, cellular immunotherapies, vaccines, gene therapies, and immune checkpoint modulators are further described below.

[0168] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, a cytokine or chemokine, such as IL1, IL2, IL12, IL18, ELC / CCL19, SLC / CCL21, MCP-1, IL-4, IL-18, TNF, IL-15, MDC, IFNa / b, M-CSF, IL-3, GM-CSF, IL-13, and anti-IL-10; bacterial lipopolysaccharide (LPS); organic or inorganic adjuvants that activate antigen-presenting cells and promote presentation of antigen epitopes on major histocompatibility complex molecules, including, but not limited to, major histocompatibility receptor (TLR) agonists, antagonists of the mevalonate pathway, agonists of STING; indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors and immunostimulatory oligonucleotides, and other T cell adjuvants.

[0169] In some embodiments, one or more of the additional therapeutic agents are immunotherapeutic agents, more specifically cell therapy. Cell therapy is a form of treatment in which viable cells are administered to a subject. In certain embodiments, one or more of the additional therapeutic agents are cellular immunotherapies that activate or suppress the immune system. Cellular immunotherapies useful for treating cancer typically induce or amplify an immune response. The cells can be autologous or allogeneic immune cells (e.g., monocytes, macrophages, dendritic cells, NK cells, T cells, etc.) collected from one or more subjects. Alternatively, the cells can be "(re)programmed" allogeneic immune cells produced from immune progenitor cells (e.g., lymphoid progenitor cells, myeloid progenitor cells, common dendritic cell progenitor cells, stem cells, induced pluripotent stem cells, etc.). In some embodiments, such cells may be expanded subsets of cells with distinct effector functions and / or maturation markers (e.g., adaptive memory NK cells, tumor-infiltrating lymphocytes, immature dendritic cells, monocyte-derived dendritic cells, plasmacytoid dendritic cells, conventional dendritic cells (sometimes referred to as classical dendritic cells), M1 macrophages, M2 macrophages, etc.), may be genetically modified to target the cells to specific antigens and / or to enhance the anti-tumor effect of the cells (e.g., engineered T cell receptor (TCR) cell therapy, chimeric antigen receptor (CAR) cell therapy, lymph node homing of antigen-loaded dendritic cells, etc.), may be engineered to increase expression of tumor-associated antigens, or any combination thereof. Non-limiting types of cell therapy include CAR-T cell therapy, CAR-NK cell therapy, TCR therapy, and dendritic cell vaccines. Exemplary cellular immunotherapies include sipuleucel-T, tifagen-lecleucel, lysocabtagene-malaleucel, idecabtagene-villeucel, brexacabtagene-autoleucel, and axicabtagene-ciloleucel, as well as CTX110, JCAR015, JCAR017, MB-CART19.1, MB-CART20.1, MB-CART2019.1, UniCAR02-T-CD123, BMCA-CAR-T, JNJ-68284528, BNT211, and NK-92 / 5.28.z.

[0170] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, a gene therapy. Gene therapy includes recombinant nucleic acids administered ex vivo to a subject or a subject's cells to modify the expression of an endogenous gene or to effect heterologous expression of a protein (e.g., small interfering RNA (siRNA) agents, double-stranded RNA (dsRNA) agents, microRNA (miRNA) agents, viral or bacterial gene delivery, etc.), as well as gene editing therapies that may or may not include nucleic acid components (e.g., meganucleases, zinc finger nucleases, TAL nucleases, CRISPR / Cas nucleases, etc.), oncolytic viruses, etc. Non-limiting examples of gene therapies that may be useful in cancer treatment include Gendicine® (rAd-p53), Oncorine® (rAD5-H101), talimogene laherparepvec, Mx-dnG1, ARO-HIF2 (Arrowhead), CTX110 (CRISPR Therapeutics), CTX120 (CRISPR Therapeutics), and CTX130 (CRISPR Therapeutics).

[0171] In some embodiments, one or more of the additional therapeutic agents is an immunotherapeutic agent, more specifically, an agent that modulates an immune checkpoint. Immune checkpoints are a series of inhibitory and stimulatory pathways that directly affect the function of immune cells (e.g., B cells, T cells, NK cells, etc.). Immune checkpoints are engaged when proteins on the surface of immune cells recognize and bind to their cognate ligands. The present invention contemplates the use of anti-TIGIT antibodies with reduced or abolished Fc effector function (e.g., domvanalimab) described herein in combination with agonists of stimulatory or costimulatory pathways and / or antagonists of inhibitory pathways. Agonists of stimulatory or costimulatory pathways and antagonists of inhibitory pathways may have utility as agents to overcome distinct immunosuppressive pathways within the tumor microenvironment, inhibit regulatory T cells, reverse / prevent T cell anergy or exhaustion, induce innate immune activation and / or inflammation at the tumor site, or any combination thereof.

[0172] In some embodiments, one or more of the additional therapeutic agents is an immune checkpoint inhibitor. As used herein, the term "immune checkpoint inhibitor" refers to an antagonist of an inhibitory or co-inhibitory immune checkpoint. The terms "immune checkpoint inhibitor," "checkpoint inhibitor," and "CPI" may be used interchangeably herein. Immune checkpoint inhibitors may antagonize inhibitory or co-inhibitory immune checkpoints by interfering with receptor-ligand binding and / or altering receptor signaling. Examples of immune checkpoints (ligands and receptors), some of which are selectively upregulated and can be blocked in various types of cancer cells, include PD-1 (programmed cell death protein 1); PD-L1 (PD1 ligand); BTLA (B and T lymphocyte attenuating factor); CTLA-4 (cytotoxic T lymphocyte-associated antigen 4); TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3); LAG-3 (lymphocyte activation gene 3); TIGIT (T cell immunoglobulin and mucin domain-containing protein 3); immune receptors; CD276 (B7-H3), PD-L2, galectin-9, CEACAM-1, BTLA, CD69, galectin-1, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4, as well as killer inhibitory receptors, which can be divided into two classes based on their structural features: i) killer cell immunoglobulin-like receptors (KIRs) and ii) C-type lectin receptors (members of the type II transmembrane receptor family). Other less well-defined immune checkpoints are also contemplated and have been described in the literature, including both receptors (e.g., the 2B4 (also known as CD244) receptor) and ligands (e.g., certain B7 family inhibitory ligands, such as B7-H3 (also known as CD276) and B7-H4 (also known as B7-S1, B7x, and VCTN1)). [See Pardoll, (April 2012) Nature Rev. Cancer 12:252-64].

[0173] In some embodiments, the immune checkpoint inhibitor is a CTLA-4 antagonist. In further embodiments, the CTLA-4 antagonist can be an antagonist CTLA-4 antibody. Suitable antagonist CTLA-4 antibodies include, for example, monospecific antibodies such as ipilimumab, tremelimumab, or zalifrelimab, and bispecific antibodies such as MEDI5752 and KN046.

[0174] In some embodiments, the immune checkpoint inhibitor is a PD-1 antagonist. In further embodiments, the PD-1 antagonist can be an antagonist PD-1 antibody. Suitable antagonist PD-1 antibodies include monospecific antibodies such as budigalimab, camrelizumab, cosibelimab, dostarimab, cemiplimab, ezabenlimab (BI-754091), MEDI-0680 (AMP-514; WO 2012 / 145493), nivolumab, pembrolizumab, pidilizumab (CT-011), retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, and zimbelemab; and bispecific antibodies such as LY3434172. In yet a further embodiment, the PD-1 antagonist may be a recombinant protein (AMP-224) composed of the extracellular domain of PD-L2 (B7-DC) fused to the Fc portion of IgG1. In a specific embodiment, the immune checkpoint inhibitor is dimvelemab.

[0175] In some embodiments, the immune checkpoint inhibitor is a PD-L1 antagonist. In further embodiments, the PD-1 antagonist may be an antagonist PD-L1 antibody small molecule or peptide. Suitable antagonist PD-L1 antibodies include monospecific antibodies such as avelumab, atezolizumab, balstilimab, durvalumab, BMS-936559, and embafolimab, and bispecific antibodies such as LY3434172 and KN046.

[0176] In some embodiments, one or more of the additional therapeutic agents activates a stimulatory or costimulatory immune checkpoint. Examples of stimulatory or costimulatory immune checkpoints (ligands and receptors) include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3, and CD2.

[0177] In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD137 (4-1BB) agonist. In further embodiments, the CD137 agonist can be an agonist CD137 antibody. Suitable CD137 antibodies include, for example, urelumab and PF-05082566 (WO 12 / 32433). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a GITR agonist. In further embodiments, the GITR agonist can be an agonist GITR antibody. Suitable GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO 06 / 105021, WO 09 / 009116), and MK-4166 (WO 11 / 028683). In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is an OX40 agonist. In further embodiments, the OX40 agonist can be an agonist OX40 antibody. Suitable OX40 antibodies include, for example, MEDI-6383, MEDI-6469, MEDI-0562, PF-04518600, GSK3174998, BMS-986178, and MOXR0916. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD40 agonist. In further embodiments, the CD40 agonist can be an agonist CD40 antibody such as dacetuzumab, cericlerumab, APX005M, ADC-1013, or CDX-1140. In some embodiments, the agent that activates a stimulatory or costimulatory immune checkpoint is a CD27 agonist. In a further embodiment, the CD27 agonist may be an agonist CD27 antibody. Suitable CD27 antibodies include, for example, varlilumab.

[0178] In some embodiments, one or more of the additional therapies are immunotherapeutic agents, more specifically, signal transduction inhibitors. Intracellular signaling molecules that affect immune cell function may also be suitable targets for improving anti-tumor immunity. For example, one or more of the additional therapies may be an inhibitor of an intracellular signaling molecule, such as an inhibitor of hematopoietic progenitor kinase 1 (HPK1). HPK1 is a serine / threonine kinase that functions as a negative regulator of activation signals generated by the T cell antigen receptor. As another example, one or more of the additional therapies may be an inhibitor of Cbl-b (e.g., AP401), an E3 ubiquitin ligase involved in regulating TCR signaling. As another example, one or more of the additional therapies may be an inhibitor of diacylglycerol kinase (DGK). In some embodiments, the inhibitor is a small molecule. Non-limiting examples of small molecule HKP1 inhibitors in clinical development include CFI-402411 and BGB-15025. Non-limiting examples of Cbl-b inhibitors in clinical development include AP401.

[0179] In some embodiments, one or more of the additional therapeutic agents is an agent that inhibits or depletes immunosuppressive immune cells. For example, to inhibit or deplete immunosuppressive macrophages or monocytes, the agent can be a CSF-1R antagonist, such as a CSF-1R antagonist antibody, including RG7155 (WO 11 / 70024, WO 11 / 107553, WO 11 / 131407, WO 13 / 87699, WO 13 / 119716, WO 13 / 132044) or FPA-008 (WO 11 / 140249, WO 13169264), or a CSF-1R antagonist antibody, including an antibody disclosed in WO 14 / 036357.

[0180] In some embodiments, each additional therapeutic agent can independently be a chemotherapeutic agent, a radiopharmaceutical, a hormone therapy, an epigenetic modulator, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. For example, in one embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or ablated Fc effector function (e.g., domvanalimab) in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, a hormone therapy, a targeting agent, an immunotherapeutic agent, a cell therapy, or a gene therapy. In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or ablated Fc effector function (e.g., domvanalimab) of the present disclosure in combination with one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeting agent, an immunotherapeutic agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or eliminated Fc effector function of the present disclosure (e.g., domvanalimab) in combination with one or more chemotherapeutic agents and one or more tyrosine kinase inhibitors, and optionally one or more additional therapeutic agents, each of which is independently a targeted agent, immunotherapeutic agent, or cell therapy. In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or eliminated Fc effector function of the present disclosure (e.g., domvanalimab) in combination with one or more chemotherapeutic agents and one or more inhibitors independently selected from (i) a BCR-ABL kinase inhibitor, (ii) an EGFR inhibitor (e.g., an EGFR TKI or an anti-EGFR antibody), (iii) a HER-2 / neu receptor inhibitor, (iv) an anti-angiogenic agent (e.g., an anti-VEGF antibody, a VEGFR TKI, a VEGF kinase inhibitor, etc.); (v) an AKT inhibitor, (vi) a BRAF inhibitor, (vii) a RET inhibitor, (viii) a MET inhibitor, and (ix) an ALK inhibitor, and optionally one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a targeted agent, an immunotherapeutic agent, or a cell therapy.In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or abolished Fc effector function of the present disclosure (e.g., domvanalimab) in combination with one or more immunotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, hormone therapy, targeted agent, chemotherapeutic agent, cell therapy, or gene therapy. In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or abolished Fc effector function of the present disclosure (e.g., domvanalimab) in combination with one or more immunotherapeutic agents and one or more chemotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a radiopharmaceutical, hormone therapy, targeted agent, cell therapy, or gene therapy. In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or abolished Fc effector function of the present disclosure (e.g., domvanalimab) in combination with one or more immunotherapeutic agents and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or abolished Fc effector function of the present disclosure (e.g., domvanalimab) in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents, and, optionally, one or more additional therapeutic agents, wherein each additional therapeutic agent is independently a chemotherapeutic agent, a targeted agent, an immunotherapeutic agent, or a cell therapy. In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or eliminated Fc effector function of the present disclosure (e.g., domvanalimab) in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents, and / or one or more chemotherapeutic agents, and optionally one or more additional therapeutic agents, each of which is independently a targeted agent, immunotherapeutic agent, or cell therapy.In another embodiment, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or eliminated Fc effector function of the present disclosure (e.g., domvanalimab) in combination with one or more immune checkpoint inhibitors and / or one or more ATP-adenosine axis targeting agents, and one or more inhibitors independently selected from: (i) a BCR-ABL kinase inhibitor, (ii) an EGFR inhibitor (e.g., an EGFR TKI or an anti-EGFR antibody), (iii) a HER-2 / neu receptor inhibitor, (iv) an anti-angiogenic agent (e.g., an anti-VEGF antibody, a VEGFR TKI, a VEGF kinase inhibitor, etc.); (v) an AKT inhibitor, (vi) a BRAF inhibitor, (vii) a RET inhibitor, (viii) a MET inhibitor, and (ix) an ALK inhibitor. In further embodiments of (a) above, the targeting agent may be a PI3K inhibitor, an arginase inhibitor, a HIF2α inhibitor, an AXL inhibitor, a PAK4 inhibitor, or an anti-angiogenic agent; (b) the immunotherapeutic agent is an ATP-adenosine axis targeting agent, cytokine therapy, immune checkpoint inhibitor, or a combination thereof; and (c) the ATP-adenosine axis targeting agent is A. 2a R and / or A 2bR antagonist, CD73 inhibitor, or CD39 inhibitor; (d) the ATP-adenosine axis targeting agent is etramadenant or quemlicustat; (e) the immunotherapeutic agent is budigalimab, camrelizumab, cosibelimab, dostarimab, cemiplimab, ezabenlimab, nivolumab, pembrolizumab, pidilizumab, retifanlimab, sasanlimab, spartalizumab, sintilimab, tislelizumab, toripalimab, zimbelemab, LY343417 2, an anti-PD-1 antagonist antibody or an anti-PD-1 antagonist antibody optionally selected from the group consisting of avelumab, atezolizumab, balstilimab, durvalumab, embafolimab, LY3434172, and KN046, (f) the immunotherapeutic agent is zimbelemab, (g) the anti-angiogenic agent is pazopanib, sorafenib, sunitinib, bevacizumab, axitinib, lenvatinib, tivozanib, or cabozantinib, or (h) any combination thereof. In still further embodiments of the above, the present disclosure contemplates the use of an anti-TIGIT antibody with reduced or eliminated Fc effector function of the present disclosure (e.g., domvanalimab) in combination with etramadenant, quemliclustat, zimbelemab, or any combination thereof. In any further of the above foregoing embodiments, the anti-TIGIT antibody may be domvanalimab.

[0181] In certain embodiments, the present disclosure provides a 2a R antagonist, A 2b R antagonist, A 2a R and A 2b Use of domvanalimab in combination with an antagonist of R, a CD73 inhibitor, a CD39 inhibitor, a HIF2α inhibitor, an AXL inhibitor, an HPK1 inhibitor, a PI3K inhibitor, an immune checkpoint inhibitor, or a combination thereof is contemplated.

[0182] In certain embodiments, the present disclosure provides a 2a R antagonist, A 2b R antagonist, A 2a R and A 2bThe use of domvanalimab in combination with an antagonist of R, a CD73 inhibitor, a CD39 inhibitor, a HIF2α inhibitor, a PD-1 antagonist, a PD-L1 antagonist, or a combination thereof is contemplated.

[0183] In certain embodiments, the present disclosure provides a 2a R antagonist, A 2b R antagonist, A 2a R and A 2b The use of domvanalimab in combination with an antagonist of R, a CD73 inhibitor, a CD39 inhibitor, a HIF2α inhibitor, a PD-1 antagonist, a PD-L1 antagonist, or a combination thereof is contemplated.

[0184] In certain embodiments, the present disclosure contemplates the use of domvanalimab in combination with a PD-1 antagonist or a PD-L1 antagonist.

[0185] In certain embodiments, the present disclosure contemplates the use of domvanalimab in combination with a CTLA-4 antagonist.

[0186] The choice of additional therapeutic agents may be informed by the current standard of care for the particular cancer and / or the mutational status and / or disease stage of the target cancer. Detailed standard of care guidelines are published, for example, by the National Comprehensive Cancer Network (NCCN). See, for example, NCCN Colon Cancer v3.2021, NCCN Hepatobiliary Cancer v5.2021, NCCN Kidney Cancer v3.2022, NCCN NSCLC v7.2021, NCCN Pancreatic Adenocarcinoma v2.2021, NCCN Esophageal and Esophagogastric Junction Cancers v4.2021, NCCN Gastric Cancer v5.2021, Cervical Cancer v1.2022, and Ovarian Cancer / Fallopian Tube Cancer / Primary Peritoneal Cancer v3.2021.

[0187] V. Pharmaceutical Compositions Provided herein are pharmaceutical compositions for use in the treatment or prevention of cancer and other diseases. The pharmaceutical compositions comprise an anti-TIGIT antibody (e.g., domvanalimab or another antibody of Section III) that has reduced ability to bind to FcγRs or that is unable to bind to FcγRs, particularly activating FcγRs.

[0188] The phrase "comprising domvanalimab or a fragment or variant thereof as an active ingredient" means that at least one of the active ingredients is domvanalimab or a fragment or variant thereof, and does not limit the percentage of the antibody. Similarly, the phrase "comprising an anti-TIGIT antibody with reduced or eliminated Fc effector function" and similar descriptions of the disclosed antibodies means that at least one of the active ingredients is an anti-TIGIT antibody or a fragment or variant thereof, and does not limit the percentage of the antibody. In addition, the pharmaceutical compositions of the present disclosure may also include other ingredients that enhance the treatment or prevention of cancer in combination with the anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof, or its equivalent. Non-limiting examples include, but are not limited to, checkpoint inhibitors (CPIs), such as CTLA-4 antagonists, PD-1 antagonists, PD-L1 antagonists, or combinations thereof. Specific CPIs that may be combined with the disclosed anti-TIGIT antibodies (e.g., domvanalimab) include, but are not limited to, ipilimumab (YERVOY®), nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), atezolizumab (TECENTRIQ®), and zimbelemab (AB122).

[0189] Pharmaceutical compositions of the anti-TIGIT antibodies of the present disclosure (e.g., domvanalimab, or a fragment or variant thereof, or an equivalent thereof) can be prepared as formulations (see, e.g., Remington's Pharmaceutical Sciences, Mark Publishing Company, Easton, USA). Pharmaceutical compositions generally contain carriers and / or excipients in addition to the antibody. For example, in some embodiments, the pharmaceutical composition comprises one or more surfactants (e.g., PEG and Tween®), excipients, antioxidants (e.g., ascorbic acid), colorants, flavoring agents, preservatives, stabilizers, buffers (e.g., phosphoric acid, citric acid, and other organic acids), chelating agents (e.g., EDTA, pentetic acid), suspending agents, isotonicity agents, binders, disintegrants, lubricants, flow enhancers, flavoring agents, light anhydrous silicic acid, lactose, crystalline cellulose, mannitol, starch, carmellose calcium, carmellose sodium, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetal diethylaminoacetate, polyvinylpyrrolidone, gelatin, medium-chain triglycerides, polyoxyethylene hydrogenated castor oil 60, sucrose, carboxymethylcellulose, corn starch, and inorganic salts. In some embodiments, the pharmaceutical composition comprises one or more other low molecular weight polypeptides, proteins, such as serum albumin, gelatin, and immunoglobulins. In some embodiments, the pharmaceutical composition comprises one or more amino acids, such as glycine, glutamine, histidine, asparagine, arginine, and lysine.

[0190] The anti-TIGIT antibody (e.g., domvanalimab or a fragment or variant thereof) may be prepared as an aqueous solution for injection, or may be dissolved in an isotonic solution containing, for example, saline, dextrose, or other excipients or isotonicity agents (i.e., isotonicity agents). Examples of isotonicity agents include D-sorbitol, D-mannose, D-mannitol, trehalose, sodium chloride, or any combination thereof. In addition, appropriate buffers (e.g., Tris / Tris-HCl, histidine / histidine HCl, etc.), chelating agents (e.g., EDTA, pentetic acid, etc.), preservatives, solubilizers, such as alcohols (e.g., ethanol), polyalcohols (e.g., propylene glycol, PEG, etc.), and nonionic surfactants (e.g., polysorbate 80, HCO-50, etc.) may be used in combination. In one embodiment, the anti-TIGIT antibody may be formulated for dilution as an aqueous solution containing about 10 mg / mL to about 100 mg / mL of antibody, or about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 10 mM to about 30 mM, or about 15 to about 30 mM of histidine / histidine-HCl, about 1% to about 10%, or about 4% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, dextrose, trehalose, sorbitol, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.05 mg / mL to about 0.6 mg / mL of polysorbate 80. In one embodiment, the anti-TIGIT antibody can be formulated for injection as an aqueous solution containing about 10 mg / mL to about 100 mg / mL of antibody, a buffer containing about 10 to about 25 mM or about 15 to about 25 mM His / His-Cl, about 3% to about 10% (weight / volume) of a stabilizer (e.g., sucrose, dextrose, mannitol, etc.), about 0 mg / mL to about 10 mg / mL of an isotonicity agent (e.g., NaCl, etc.), and about 0.1 mg / mL to about 0.3 mg / mL of a non-ionic surfactant (e.g., polysorbate 80).In one embodiment, the anti-TIGIT antibody may be formulated for injection as an aqueous solution containing about 10 mg / mL to about 100 mg / mL of antibody, a buffer containing about 10 to about 25 mM or about 15 to about 25 mM His / His-Cl, about 5% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, dextrose, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.1 mg / mL to about 0.3 mg / mL of polysorbate 80. In one embodiment, the anti-TIGIT antibody may be formulated for injection as an aqueous solution containing about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 10 to about 25 mM or about 15 to about 25 mM His / His-Cl, about 5% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, dextrose, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.1 mg / mL to about 0.3 mg / mL of polysorbate 80. In one embodiment, an anti-TIGIT antibody can be formulated for injection as an aqueous solution comprising or consisting of about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 to about 20 mM or about 20 mM His / His-Cl, about 5% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, dextrose, and mannitol, and about 0.1 mg / mL to about 0.2 mg / mL of polysorbate 80. In one embodiment, an anti-TIGIT antibody can be formulated for injection as an aqueous solution comprising or consisting of about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 to about 20 mM or about 20 mM His / His-Cl, about 5% to about 10% (weight / volume) sucrose, and about 0.1 mg / mL to about 0.2 mg / mL of polysorbate 80. In one embodiment, the anti-TIGIT antibody may be formulated for injection as an aqueous solution comprising or consisting of about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 to about 20 mM or about 20 mM His / His-Cl, about 8% (weight / volume) sucrose, and about 0.2 mg / mL polysorbate 80.In one embodiment, the anti-TIGIT antibody may be formulated for injection as an aqueous solution comprising or consisting of 20 mg / mL to 60 mg / mL of antibody, a buffer containing about 15 to about 20 mM or 20 mM His / His-Cl, 8% (weight / volume) sucrose, and 0.2 mg / mL polysorbate 80. In the aforementioned embodiment, the pH of the aqueous solution is preferably about pH 5.0 to about pH 6.0, about pH 5.3 to about pH 6.0, about pH 5.5 to about pH 6.0, about pH 5.5 to about pH 5.8, or about pH 5.8. In some of the aforementioned embodiments, the anti-TIGIT antibody is domvanalimab, an antigen-binding fragment of domvanalimab, or a variant of domvanalimab.

[0191] The pharmaceutical compositions of the present disclosure can be administered either orally or parenterally, but are preferably administered parenterally. Specifically, the pharmaceutical compositions are administered to patients by injection or transdermal administration. Injections include, for example, intravenous injection, intravenous infusion, intramuscular injection, and subcutaneous injection for systemic or local administration. For purposes of this disclosure, an injectable pharmaceutical composition can include an undiluted formulation (e.g., a formulation used "as is") or a formulation that is diluted with a physiological solution such as saline (0.9% sodium chloride), aqueous dextrose (e.g., 5% dextrose), etc., before administration.

[0192] In some embodiments, the anti-TIGIT antibody is domvanalimab, or an antigen-binding fragment of domvanalimab or a variant of domvanalimab, formulated as an aqueous solution for dilution prior to intravenous administration, the aqueous solution comprising or consisting of about 10 mg / mL to about 100 mg / mL of antibody or about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 10 mM to about 30 mM histidine / histidine-HCl, about 1% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, trehalose, sorbitol, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.05 mg / mL to about 0.6 mg / mL of polysorbate 80 or about 0.1 mg / mL to about 0.3 mg / mL of polysorbate 80.

[0193] In some embodiments, the anti-TIGIT antibody is domvanalimab, or an antigen-binding fragment of domvanalimab or a variant of domvanalimab, formulated as an aqueous solution for dilution prior to intravenous administration, the aqueous solution comprising or consisting of about 10 mg / mL to about 100 mg / mL of antibody or about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 mM to about 30 mM histidine / histidine-HCl, about 1% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, trehalose, sorbitol, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.05 mg / mL to about 0.6 mg / mL of polysorbate 80 or about 0.1 mg / mL to about 0.3 mg / mL of polysorbate 80.

[0194] In some embodiments, the anti-TIGIT antibody is domvanalimab, or an antigen-binding fragment of domvanalimab or a variant of domvanalimab, formulated as an aqueous solution for dilution prior to intravenous administration, the aqueous solution comprising or consisting of about 10 mg / mL to about 100 mg / mL of antibody or about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 mM to about 20 mM histidine / histidine-HCl, about 1% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, trehalose, sorbitol, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.05 mg / mL to about 0.6 mg / mL of polysorbate 80 or about 0.1 mg / mL to about 0.3 mg / mL of polysorbate 80.

[0195] In some embodiments, the anti-TIGIT antibody is domvanalimab, or an antigen-binding fragment of domvanalimab or a variant of domvanalimab, formulated as an aqueous solution for dilution prior to intravenous administration, the aqueous solution comprising or consisting of about 20 mg / mL to about 60 mg / mL of the antibody, a buffer containing about 15 mM to about 20 mM histidine / histidine-HCl, about 8% (weight / volume) of an excipient selected from sucrose, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.05 mg / mL to about 0.6 mg / mL of polysorbate 80 or about 0.1 mg / mL to about 0.3 mg / mL of polysorbate 80.

[0196] In some embodiments, the anti-TIGIT antibody is domvanalimab, or an antigen-binding fragment of domvanalimab or a variant of domvanalimab, formulated as an aqueous solution for dilution prior to intravenous administration, the aqueous solution comprising or consisting of about 20 mg / mL to about 60 mg / mL of the antibody, a buffer containing about 20 mM histidine / histidine-HCl, about 8% (weight / volume) sucrose, and about 0.2 mg / mL polysorbate 80. In some embodiments, the pH of the solution is pH 5.5 to pH 6.0, or about pH 5.8.

[0197] The administration method can be appropriately selected depending on the age, body weight, and condition of the patient. The single-administration dose can be selected, for example, from within the range of 0.0001 to 100 mg of antibody (e.g., domvanalimab or another antibody described herein) per kg of body weight. For example, when the antibody is administered intravenously to a human patient, the antibody dose can be selected from the range of 0.01 to 100 mg / kg of body weight, preferably 0.05 to 100 mg / kg of body weight, and more preferably 0.1 to 100 mg / kg of body weight. In some embodiments, the antibody may be administered at a concentration of, for example, about 0.01 to about 50 mg / kg, about 0.05 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.1 mg / kg to 30 mg / kg, about 0.1 mg / kg to about 20 mg / kg, about 0.3 mg / kg to 50 mg / kg, about 0.3 mg / kg to about 40 mg / kg, about 0.3 mg / kg to 30 mg / kg, or about 0.3 mg / kg to The antibody (domvanalimab, or another antibody described herein) is administered at a dose of about 20 mg / kg, about 0.4 mg / kg to 50 mg / kg, about 0.4 mg / kg to about 40 mg / kg, about 0.4 mg / kg to 30 mg / kg, about 0.4 mg / kg to about 20 mg / kg, about 0.5 mg / kg to 50 mg / kg, about 0.5 mg / kg to about 40 mg / kg, about 0.5 mg / kg to 30 mg / kg, or about 0.5 mg / kg to about 20 mg / kg of body weight. In a preferred embodiment, the antibody may be administered at a dose ranging from 0.1 mg / kg to 30 mg / kg, 0.5 mg / kg to 20 mg / kg, 0.5 mg / kg to 10 mg / kg, 1.0 mg / kg to 10 mg / kg, 10 mg / kg to 20 mg / kg, 10 mg / kg to 15 mg / kg, or 15 mg / kg to 20 mg / kg. Thus, the administered dose may be 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20 mg / kg, or any dose between the aforementioned doses.In certain embodiments, an effective amount of domvanalimab or a fragment or variant thereof is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 1.5 mg / kg, about 2 mg / kg, about 2.5 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg. For purposes of the aforementioned doses, these amounts may be administered as needed, for example, once weekly, once every other week (Q2W), once every three weeks (Q3W), or once every four weeks (Q4W). In some embodiments, for example, the antibody may be administered at a dose of 10 mg / kg Q2W, Q3W, or Q4W. In some embodiments, the antibody may be administered at a dose of 15 mg / kg Q2W, Q3W, or Q4W. In some embodiments, the antibody may be administered at a dose of 20 mg / kg Q2W, Q3W, or Q4W.

[0198] In some embodiments, the dose of the antibody (e.g., domvanalimab, or another antibody described herein) may be selected regardless of the subject's body weight. For example, in some embodiments, the dose of the antibody may be selected from within a range of 500 mg to 2000 mg of the antibody (e.g., domvanalimab, or another antibody described herein) regardless of the subject's body weight. In some embodiments, the dose of the antibody may be selected from a range of 700 mg to 1800 mg. In some embodiments, the dose of the antibody may be selected from a range of 700 mg to 1500 mg, or 700 mg to 1400 mg. In some embodiments, the dose of the antibody may be selected from a range of 1000 mg to 1500 mg. In some embodiments, the dose of the antibody may be selected from a range of 1200 mg to 1500 mg. In some embodiments, the dose of an antibody (e.g., domvanalimab or another antibody described herein) is about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, about 2000 mg, about 2100 mg, about 2200 mg, about 2300 mg, about 2400 mg, about 2500 mg, about 2600 mg, about 2700 mg, about 2800 mg, about 2900 mg, about 3000 mg, about 3100 mg, about 3200 mg, about 3300 mg, about 3400 mg, about 3500 mg, about 3600 mg, about 3700 mg, about 3800 mg, about 3900 mg, about 4000 mg, about 4100 mg, about 4200 mg, about 4300 mg, about 4400 mg, about 4500 mg, about 4600 mg, about 4700 mg, about 4800 mg, about 4900 mg The amount can be 125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, or about 1800 mg.

[0199] For purposes of any of the foregoing methods of treatment, a dosing cycle can include, for example, administration twice weekly, once weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. A subject can be administered 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more dosing cycles. For example, a subject can be administered multiple dosing cycles until a suitable clinical endpoint is reached, such as disease progression, remission, or other suitable clinical endpoint based on the subject's cancer or intolerance.

[0200] In certain embodiments, when the anti-TIGIT antibody is domvanalimab or an antigen-binding fragment thereof, a dosing cycle can include about 10 mg / kg to about 20 mg / kg of the antibody administered Q2W, Q3W, or Q4W. In a specific example, a dosing cycle can include about 10 mg / kg of the antibody administered Q2W. In another specific example, a dosing cycle can include about 15 mg / kg of the antibody administered Q2W. In another specific example, a dosing cycle can include about 15 mg / kg of the antibody administered Q3W. In another specific example, a dosing cycle can include about 20 mg / kg of the antibody administered Q3W. In another specific example, a dosing cycle can include about 20 mg / kg of the antibody administered Q4W. In some embodiments, a dosing cycle can include about 500 mg to about 2000 mg of the antibody administered Q2W, Q3W, or Q4W. In some embodiments, a dosage cycle can include about 600 mg to about 1600 mg of antibody administered Q2W, Q3W, or Q4W. In some embodiments, a dosage cycle can include about 1000 mg to about 1500 mg of antibody administered Q2W, Q3W, or Q4W. In particular examples, a dosage cycle can include about 600 mg to about 800 mg of antibody administered Q2W, Q3W, or Q4W. In particular examples, a dosage cycle can include about 900 mg to about 1200 mg of antibody administered Q2W, Q3W, or Q4W. In particular examples, a dosage cycle can include about 1200 mg to about 1600 mg of antibody administered Q2W, Q3W, or Q4W. In particular examples, a dosage cycle can include about 600 mg to about 800 mg of antibody administered Q2W. In a specific example, a dosage cycle can include about 900 mg to about 1200 mg of antibody administered Q3W. In a specific example, a dosage cycle can include about 1200 mg to about 1600 mg of antibody administered Q4W. In a specific example, a dosage cycle can include about 1000 mg of antibody administered Q2W. In another specific example, a dosage cycle can include about 1200 mg of antibody administered Q2W. In another specific example, a dosage cycle can include about 1200 mg of antibody administered Q3W. In another specific example, a dosage cycle can include about 1500 mg of antibody administered Q3W.In another particular example, a dosing cycle can include about 1500 mg of antibody administered Q4W. In one or more of the foregoing embodiments, the antibody may be administered intravenously, for example, by IV infusion.

[0201] In some embodiments, the administration method may include administering an anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof together with at least one other antibody. For example, in some embodiments, an anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof may be co-administered with an antagonist antibody that binds to another checkpoint target, such as CTLA-4, PD-1, or PD-L1. In some embodiments, an anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof and at least one other antibody may be co-administered in the same dose. In some embodiments, an anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof and at least one other antibody may be co-administered in different doses. In some embodiments, an anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof and at least one other antibody may be administered in the same formulation or in separate formulations that are administered independently. In embodiments in which the anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof and at least one other antibody are in separate formulations that are administered independently, the antibodies may be administered simultaneously (i.e., in parallel), near simultaneously, or sequentially (e.g., the anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof is administered first and the other antibody is administered some time thereafter, or the other antibody is administered first and the anti-TIGIT antibody (e.g., domvanalimab) or a fragment or variant thereof is administered some time thereafter).

[0202] Any of the pharmaceutical compositions disclosed herein, including those comprising domvanalimab and fragments or variants thereof, can be used to treat and / or prevent cancer and achieve the disclosed therapeutic endpoints. Optimal dosages and routes of administration may vary.

[0203] VI. Cancer Treatment and Prevention The present disclosure provides for the treatment and prevention of cancer using anti-TIGIT antibodies (e.g., domvanalimab and other antibodies of Section III) with reduced or absent Fc effector function. The methods feature unexpected advantages described herein. In some embodiments, improved safety allows for patient selection, dosing, and combination regimens. The anti-TIGIT antibodies (e.g., domvanalimab and other antibodies of Section III) of the present disclosure with reduced or absent Fc effector function and compositions comprising same can be used alone or in combination with one or more additional therapies to treat or prevent cancer and achieve specific biological endpoints, as described in more detail herein.

[0204] In general, the disclosed therapeutic methods involve administering to a subject with cancer an anti-TIGIT antibody that has reduced binding to FcγR compared to WT IgG1. Administration of the anti-TIGIT antibody (e.g., domvanalimab or another antibody of Section III) can include one or more (e.g., one, two, or three or more) administration cycles. The anti-TIGIT antibody (e.g., domvanalimab) can also be used in combination with one or more additional therapies. For example, in some embodiments, the anti-TIGIT antibody can be administered with an additional therapeutic agent, such as, for example, an immunotherapeutic agent or a chemotherapeutic agent.

[0205] Treatment may be demonstrated by clinical or non-clinical efficacy. Non-limiting examples of clinical efficacy may include a decrease in tumor size, a decrease in tumor number, a decrease in metastases, achieving stable disease (SD), achieving partial response (PR), achieving complete response (CR), an increase in overall survival (OS), an increase in progression-free survival (PFS), an increase in time to progression, an increase in disease-free survival, an increase in duration of response, an increase in duration of clinical benefit, an increase in time to treatment failure, a decrease in time to initial response, or any combination thereof. Non-limiting examples of non-clinical efficacy may include an increase in immune cell (e.g., T cell and / or NK cell) activation and / or proliferation in the periphery and / or tumor microenvironment, an increase in memory and antigen-experienced T cells (e.g., CD39+CD103+CD8+ T cells) in the periphery, an increase in pro-inflammatory cytokines and / or chemokines in blood, plasma, or serum, ctDNA dynamics, molecular responses due to TCR receptor dynamics, changes in gene expression in cells from the tumor microenvironment, or any combination thereof. Measurement of increase or decrease can be relative to baseline (ie, pre-treatment), SOC, or other CPI, as appropriate.

[0206] Unexpectedly, these treatments comprising anti-TIGIT antibodies with reduced binding to FcγRs relative to WT IgG1 may be better tolerated compared to similar treatments with Fc-matched anti-TIGIT antibodies (i.e., antibodies that bind to activating FcγRs substantially similar to WT IgG1 or have enhanced binding to WT IgG1), as demonstrated by fewer and / or less severe adverse events, fewer dose reductions, fewer temporary treatment interruptions (e.g., drug holidays or delayed treatment cycles), fewer treatment discontinuations, or any combination thereof. In particular, the disclosed treatments may have fewer and / or less severe treatment-emergent adverse events compared to similar treatments comprising an Fc-targeted anti-TIGIT antibody, fewer and / or less severe treatment-emergent adverse events (TEAEs) compared to similar treatments comprising an Fc-targeted anti-TIGIT antibody, fewer and / or less severe immune-related adverse events compared to similar treatments comprising an Fc-targeted anti-TIGIT antibody, or fewer and / or less severe treatment-related immune-related adverse events compared to similar treatments comprising an Fc-targeted anti-TIGIT antibody.

[0207] In one aspect, the present disclosure provides a method of treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs relative to wild-type (WT) human IgG1, wherein the treatment results in a reduction in one or more adverse events relative to a similar treatment comprising an Fc-matched anti-TIGIT antibody. In some embodiments, the subject does not experience the adverse events.

[0208] In another aspect, the present disclosure provides a method of treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, wherein the subject is less likely to experience one or more adverse events compared to a similar treatment comprising an Fc-matched anti-TIGIT antibody.

[0209] In another aspect, the present disclosure provides a method of treating cancer in a human subject in need thereof without significantly increasing the likelihood of one or more immune-related adverse events, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1 and one or more additional therapies. An assessment of whether there is an increased likelihood of experiencing an adverse event following administration of a treatment comprising an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs can be performed compared to a treatment lacking the anti-TIGIT antibody.

[0210] In another aspect, the present disclosure provides a method for reducing one or more adverse events experienced by a human subject being treated for cancer with an anti-TIGIT antibody, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1.

[0211] In another aspect, the present disclosure provides a method for reducing one or more adverse events experienced by a human subject being treated for cancer with an anti-TIGIT antibody and an additional immunotherapeutic agent, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1 and the additional immunotherapeutic agent.

[0212] In another aspect, the present disclosure provides a method for reducing dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with an anti-TIGIT antibody, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1.

[0213] In some embodiments of the foregoing methods, the adverse event is a TEAE, optionally a treatment-related TEAE. In further embodiments of the foregoing methods, the adverse event is an immune-related AE (irAE), optionally a treatment-related irAE.

[0214] While treatment circumstances vary, for purposes of this disclosure, an assessment of whether a treatment comprising an anti-TIGIT antibody with reduced binding to one or more activating human FcγRs results in a reduction in one or more adverse events, dose reduction, temporary treatment interruption, or treatment cessation compared to a similar treatment comprising an Fc-matched anti-TIGIT antibody can be made by comparing the occurrence of events (e.g., adverse events, dose reduction, temporary treatment interruption, treatment cessation) between the two populations. Given the disclosure and examples provided herein, one of skill in the art can determine appropriate populations for comparison.

[0215] The present disclosure also provides a method of blocking or preventing binding of TIGIT to CD155 in a human subject without significantly reducing Tregs, CD8+ T cells, CD4+ T cells, or a combination thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR compared to WT IgG1, wherein any reduction in Tregs, CD8+ T cells, CD4+ T cells, or a combination thereof differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% from baseline measurements before administration of the anti-TIGIT antibody. In some embodiments, the subject has cancer. In some embodiments of this method, the subject may receive one, two, three, four, or more administration cycles, which may include administration once per week, once per two weeks, once per three weeks, once per four weeks, once per five weeks, once per six weeks, once per seven weeks, or once per eight weeks. In some embodiments, any potential reduction in Tregs, CD8+ T cells, CD4+ T cells, or a combination thereof is assessed 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the anti-TIGIT antibody. In some embodiments, administration of the anti-TIGIT antibody does not result in immune-related adverse events. In some embodiments, the method may further include administering to the subject an immunotherapeutic agent, e.g., a checkpoint inhibitor (e.g., ipilimumab (YERVOY®), nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), atezolizumab (TECENTRIQ®), or zimvelemab (AB122).

[0216] Adverse events As used herein, the term "adverse event" or "AE" refers to any untoward medical occurrence in a subject administered a medicinal product, regardless of causal attribution. Thus, an AE can be any of the following: (i) any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease temporarily associated with the use of a medicinal product, whether or not considered medicinal product-related; (ii) any new disease or exacerbation of an existing disease (worsening of the characteristics, frequency, or severity of a known condition); (iii) the recurrence of an intermittent medical condition (e.g., headache) not present at baseline; or (iv) any deterioration in laboratory values or other clinical findings (e.g., ECG, X-ray) that are symptom-related or lead to a change in study or concomitant treatment or discontinuation of study treatment. Events that are part of the natural history of the disease under study (i.e., disease progression, death due to disease progression) should not be considered AEs. Instead, signs and symptoms of clinical sequelae resulting from disease progression should be considered only if they meet the AE definition.

[0217] The absence or presence of adverse events and their severity can be assessed by physical examination and / or laboratory evaluation. Clinically significant abnormal laboratory findings are not related to the underlying disease unless the findings are judged by a clinician to be more severe than expected for the subject's condition. Information about adverse events can be collected and coded into standard terms appropriate to the disease being treated, for example, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) or the Medical Dictionary for Regulatory Activities (MedDRA). Recommendations for testing and diagnosis are well known in the art; see, for example, Schneider et al., "Management of Immune-Related Adverse Events in Patients Treated with Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update," Journal of Clinical Oncology, 2021, Vol. 39, No. 36.

[0218] The terms "serious adverse event" and "serious adverse event" are not synonymous. Severity and severity can be assessed independently for each AE. A serious adverse event is any adverse event that meets any of the following criteria: (i) is fatal (i.e., the adverse event actually causes or leads to death), (ii) is life-threatening (i.e., the adverse event places the subject at immediate risk of death in the clinician's view), (iii) requires or prolongs hospitalization, (iv) produces persistent or significant impairment / disability (i.e., the adverse event results in a substantial interruption of the subject's ability to perform normal life functions), (v) is a congenital anomaly / birth defect, or (vi) is a significant medical event in the clinician's judgment (e.g., may endanger the subject or require medical / surgical intervention to prevent one of the outcomes listed above). Deaths that occur during treatment and are attributed solely to the progression of the disease being treated by the clinician should not be recorded as serious adverse events.

[0219] Severity refers to the intensity of the adverse event. A severe adverse event may be of relatively low medical importance (such as a severe headache without further findings). The severity grade assessment may be performed by a clinician, for example, according to the NCI CTCAE (version 5.0). The following table may be used to assess the severity of AEs that are not specifically listed in the NCI CTCAE. Not all grades may be appropriate for all AEs. [Table 21]

[0220] A treatment-emergent adverse event (TEAE) is defined as any event not present before the start of treatment or any pre-existing event that worsens in either intensity or frequency after exposure to treatment. Clinicians and healthcare professionals can use their knowledge of the subject, the circumstances surrounding the event, and an assessment of potential alternative causes to determine whether an adverse event is considered treatment-related. A treatment-related adverse event means that the event is at least possibly related to treatment. For example, there may be a plausible temporal relationship between the onset of the adverse event and the administration of the study treatment; the adverse event cannot be readily explained by the participant's clinical condition, intercurrent illness, or concomitant therapy; and / or the adverse event follows a pattern of known response to the study treatment; and / or the adverse event abates or resolves upon discontinuation or dose reduction of the study treatment and, if applicable, reappears upon rechallenge. An unrelated adverse event means that the event is unlikely to be related to treatment. For example, there is evidence that the adverse event has an etiology other than treatment (e.g., a pre-existing medical condition, underlying disease, intercurrent illness, or concomitant medication) and / or the adverse event does not have a plausible temporal relationship to the administration of treatment (e.g., cancer diagnosed 2 days after the first dose of study treatment).

[0221] CPI therapy may be associated with a range of side effects (i.e., adverse events) that are related to its mechanism of action and may differ from other systemic therapies, such as cytotoxic chemotherapy or radiation therapy. Side effects may involve any organ or system of the body. Side effects associated with CPI therapy include, but are not limited to, immune-related adverse events. Immune-related adverse events may be defined as treatment-emergent adverse events associated with standardized medical questions (SMQs) for hypersensitivity, immune-mediated disorders, and autoimmune disorders. Common immune-related adverse events associated with CPI therapy include immune-mediated cutaneous and subcutaneous, gastrointestinal (GI), pulmonary, endocrine, musculoskeletal, renal, hematological, neurological, cardiovascular, and ocular adverse events, as well as infusion-related reactions. As described above, it was predicted that for anti-TIGIT antibodies to be effective, particularly clinically effective, the antibody would need to be Fc-compatible. The incidence of adverse events, including immune-related adverse events, in humans resulting from treatment with CPI-containing regimens is well known in the art. For reported Fc-targeted anti-TIGIT antibodies, see, e.g., Mettu et al. 2022 Clin Cancer Res DOI: 10.1158 / 1078-0432.CCR-21-2780 (Etigilimab); Van den Mooter et al. 2021 AACR (Poster CT118); Niu et al. 2022 Annals of Oncology DOI: 10.1016 / j.annonc.2021.11.002; Cho et al. 2021 Annals of Oncology 32(suppl_7):S1428-S1457, and R. Shapira-Frommer et al. 2022 AACR (Poster CT508).

[0222] In some embodiments of the disclosed methods, the immune-related adverse event is a skin or subcutaneous tissue disorder, a GI disorder, a respiratory, thoracic, or mediastinal disorder, an endocrine disorder, a musculoskeletal or connective tissue disorder, a renal or urinary disorder, a hepatic or biliary disorder, a vascular or lymphatic system disorder, a nervous system disorder, a cardiac disorder, an infection or invasion, an injury, a poisoning or treatment complication, or an eye disorder, as these terms are characterized in the NCI CTCAE v5. In some embodiments, the immune-related adverse event is (i) a skin or subcutaneous tissue disorder, a GI disorder, a hepatic or biliary disorder, an endocrine disorder, or a respiratory, thoracic, or mediastinal disorder. In some embodiments, the immune-related adverse event can be grade 1, grade 2, grade 3, or grade 4. In some embodiments, the immune-related adverse event can be grade 3 or higher. In certain of the above embodiments, the immune-related adverse event can be a severe adverse event.

[0223] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-mediated skin or subcutaneous tissue disorders. Non-limiting examples of immune-related skin or subcutaneous disorders reported on the CPI include, but are not limited to, bullous dermatitis, dry skin, eczema, erythema multiforme, erythroderma, papular dermatosis, maculopapular rash, cutaneous pain, palmar-plantar erythroderma, pruritus, rash, Stevens-Johnson syndrome, and vitiligo. In some embodiments, the one or more immune-related adverse events are immune-mediated skin or subcutaneous tissue disorder adverse events, optionally selected from rash, maculopapular rash, psoriasis, pruritus, and vitiligo. In some embodiments, the one or more immune-related adverse events are immune-mediated skin or subcutaneous tissue disorders selected from rash, maculopapular rash, psoriasis, and pruritus. Despite the possibility of lower-grade presentation, immune-mediated skin toxicity can cause an increased symptom burden, affect health-related quality of life (QoL) among patients treated with CPIs, and / or lead to reduction, interruption, or discontinuation of treatment dose.

[0224] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-related GI disorders. Non-limiting examples of immune-related GI disorders reported in the CPI include, but are not limited to, colitis, diarrhea, enteritis, gastritis, hepatitis, oral mucositis, dry mouth, and pancreatitis. In some embodiments, the one or more immune-related adverse events are immune-related GI disorders selected from colitis, diarrhea, enteritis, gastritis, hepatitis, oral mucositis, dry mouth, and pancreatitis. In some embodiments, the one or more immune-related adverse events are hepatitis.

[0225] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-related respiratory, thoracic, or mediastinal disorders. Immune-related respiratory, thoracic, or mediastinal disorders reported on the CPI include, but are not limited to, dyspnea and pneumonia. In some embodiments, the one or more immune-related adverse events are pneumonia.

[0226] In some embodiments of the disclosed method, the one or more immune-related adverse events are immune-related endocrine disorders. Immune-related endocrine disorders reported in CPI include, but are not limited to, hypothyroidism, hyperthyroidism, thyrotoxicosis, primary adrenal insufficiency, hypophysitis, and diabetes. In some embodiments, the one or more immune-related adverse events are immune-mediated endocrine adverse events selected from hypothyroidism, hyperthyroidism, adrenal insufficiency, and diabetes.

[0227] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-related musculoskeletal or connective tissue disorders. Immune-related musculoskeletal or connective tissue disorders reported on the CPI include, but are not limited to, arthralgia, arthritis, myalgia, myositis, and polymyalgia-like syndrome. In some embodiments, the one or more immune-related adverse events are immune-related musculoskeletal or connective tissue disorders selected from arthralgia, arthritis, myalgia, myositis, and polymyalgia-like syndrome.

[0228] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-related renal or urinary disorders. Non-limiting examples of immune-related renal or urinary disorders reported in the CPI include nephritis or acute kidney injury (AKI). In some embodiments, the one or more immune-related adverse events are immune-related renal or urinary disorders selected from nephritis and AKI.

[0229] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-related nervous system disorders. Immune-related nervous system disorders reported in CPIs include, but are not limited to, myasthenia gravis or myasthenic syndrome, myasthenia gravis with myositis overlap, aseptic meningitis, encephalitis, reversible occipital leukoencephalopathy, Guillain-Barré syndrome or Guillain-Barré-like syndrome, enteric neuropathy, transverse myelitis, and various other peripheral neuropathic phenotypes and demyelinating disorders (e.g., multiple sclerosis, acute disseminated encephalomyelitis, optic neuritis, neuromyelitis optica, etc.). In some embodiments, the one or more immune-related adverse events are neuro-immune-related, optionally selected from myasthenia gravis, myasthenic syndrome, aseptic meningitis, encephalitis, reversible occipital leukoencephalopathy, Guillain-Barré syndrome or Guillain-Barré-like syndrome, enteric neuropathy, and transverse myelitis.

[0230] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-related hematological or lymphatic disorders. Immune-related hematological or lymphatic disorders reported on the CPI include, but are not limited to, cryoglobulinemia, anemia, thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome, decreased lymphocyte count, immune thrombocytopenia (ITP), and hemophilia A. In some embodiments, the one or more immune-related adverse events are a related hematological or lymphatic disorder selected from cryoglobulinemia, hemolytic anemia, acquired TTP, hemolytic uremic syndrome, aplastic anemia, lymphopenia, ITP, and acquired hemophilia A.

[0231] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-related cardiac disorders. Immune-related cardiac disorders reported in the CPI include, but are not limited to, myocarditis, pericarditis, arrhythmia, ventricular dysfunction associated with heart failure, vasculitis, and venous thromboembolism. In some embodiments, the one or more immune-related adverse events are immune-related cardiac disorders selected from myocarditis, pericarditis, arrhythmia, ventricular dysfunction associated with heart failure, vasculitis, and venous thromboembolism.

[0232] In some embodiments of the disclosed method, the one or more immune-related adverse events are immune-related ocular disorders. Immune-related ocular disorders reported in CPI include, but are not limited to, conjunctivitis, orbital inflammation, uveitis, iritis, and posterior scleritis. In some embodiments, the one or more immune-related adverse events are immune-related ocular disorders selected from conjunctivitis, orbital inflammation, uveitis, iritis, and posterior scleritis.

[0233] In some embodiments of the disclosed methods, the one or more immune-related adverse events are immune-related general disorders, injuries, or treatment complications. Non-limiting examples reported on the CPI include chills, facial swelling (edema), fatigue, fever, and infusion-related reactions. In some embodiments, the one or more immune-related adverse events are selected from chills, facial swelling (edema), fatigue, fever, and infusion-related reactions.

[0234] In some embodiments of the disclosed methods, the one or more immune-related adverse events are selected from rash, oral mucositis, dry mouth, colitis / diarrhea, hepatitis, pneumonia, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, nephritis, pancreatitis, myositis, arthritis, Guillain-Barré syndrome, myasthenia gravis, reversible occipital leukoencephalopathy, aseptic meningitis, enteric neuropathy, transverse myelitis, autoimmune encephalitis, cardiac toxicity (e.g., myocarditis and conduction abnormalities), hematologic toxicity (e.g., red blood cell hypoplasia, neutropenia, thrombocytopenia, acquired hemophilia A, and cryoglobulinemia), and ocular inflammation (e.g., posterior scleritis, conjunctivitis, uveitis, or orbital inflammation). In some embodiments, the one or more immune-related adverse events are selected from rash, oral mucositis, dry mouth, colitis, diarrhea, hepatitis, pneumonia, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, and diabetes. In some embodiments, the one or more immune-related adverse events are selected from arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reactions, maculopapular rash, pneumonitis, pruritus, psoriasis, rash, and facial swelling. In some embodiments, the one or more immune-related adverse events are selected from infusion-related reactions, maculopapular rash, pruritus, psoriasis, and rash.

[0235] In one or more of the foregoing embodiments, the occurrence of immune-related adverse events may be reduced by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 100%, or more. In one or more of the foregoing embodiments, the incidence of immune-mediated adverse events may occur in about 50% or less of the treated population, about 45% or less of the treated population, about 40% or less of the treated population, about 35% or less of the treated population, about 30% or less of the treated population, about 25% or less of the treated population, about 20% or less of the treated population, about 15% or less of the treated population, about 10% or less of the treated population, about 5% or less of the treated population, or less than 5% of the treated population.

[0236] In certain examples, the incidence of pruritus in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of rash in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of maculopapular rash in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of infusion-related reactions in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of immune-mediated hepatitis in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of pneumonia in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of arthritis in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of hyperthyroidism in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of hypothyroidism in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less.In certain examples, the incidence of psoriasis in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of facial swelling in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of skin or subcutaneous tissue disorders in a treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less. In certain examples, the incidence of gastrointestinal disorders in the treated population may be 40% or less, 35% or less, 30% or less, 25% or less, 20% or less, 20% or less, 15% or less, 10% or less, 5% or less, 4% or less, 3% or less, 2% or less, or 1% or less.

[0237] Without being bound by theory, a reduction in the number, frequency, and / or severity of immune-related adverse events may be the result of sustained maintenance of one or more immunological parameters over a period of time following administration and / or across multiple administration cycles. For example, the present disclosure demonstrates that the numbers of T cells, particularly Tregs and CD8+ T cells, measured in samples obtained from subjects treated with an anti-TIGIT antibody that has reduced FcγR binding relative to WT IgG1 are higher than corresponding measurements in a population of subjects treated with an Fc-matched anti-TIGIT antibody. Furthermore, the present disclosure demonstrates that an anti-TIGIT antibody with reduced FcγR binding relative to WT IgG1 does not reduce the total number of CD8+ T cells or Treg cells after treatment, or, if there is a reduction, the difference is smaller than corresponding measurements in a population of subjects treated with an Fc-matched anti-TIGIT antibody and / or is within the range seen in healthy subjects. As used herein, the term "corresponding measurements in a population of subjects" refers to average measurements for a population of subjects, typically composed of patients with similar diseases (e.g., cancer type and stage), obtained on the same day after administration using the same assay on the same sample type (e.g., blood, tumor biopsy). This maintenance of CD8+ T cells and Treg cells can be maintained for several days (e.g., 1, 2, 3, 4, 5, 6, or 7 days) or even several weeks (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more) after administration of an anti-TIGIT antibody with reduced or absent Fc effector function, through multiple administration cycles (e.g., 2, 3, 4, or more administration cycles). Because absolute cell counts vary from subject to subject, it may be preferable to refer to percent change from baseline or fold change from baseline, which can be calculated using measurements from a first sample at baseline and measurements from a second sample obtained a certain time after administration of the anti-TIGIT antibody.

[0238] b.Effectiveness For the purposes of any of the aforementioned treatment methods, treatment may be demonstrated by clinical or non-clinical efficacy. Non-limiting examples of clinical efficacy include a reduction in tumor size, a reduction in tumor number, a reduction in metastases, achieving stable disease (SD), achieving a partial response (PR), achieving a complete response (CR), an increase in overall survival (OS), an increase in progression-free survival (PFS), a prolonged time to progression, a prolonged disease-free survival, a prolonged duration of response, a prolonged duration of clinical benefit, a prolonged time to treatment failure, or any combination thereof. Non-limiting examples of non-clinical efficacy may include an increase in immune cell (e.g., T cell and / or NK cell) activation and / or proliferation in the periphery and / or tumor microenvironment, an increase in memory and antigen-experienced T cells (e.g., CD39+CD103+CD8+ T cells) in the periphery, an increase in pro-inflammatory cytokines and / or chemokines in the blood, plasma, or serum, ctDNA dynamics, molecular responses due to TCR receptor dynamics, changes in gene expression in cells from the tumor microenvironment, or any combination thereof.

[0239] In some embodiments, treatment results in a decrease in tumor size, a decrease in tumor number, a decrease in metastases, or a combination thereof. In some embodiments, treatment results in stable disease (SD), a partial response (PR), a complete response (CR), or a combination thereof. Those skilled in the art can determine the appropriate criteria for determining SD, PR, and CR depending on the type of cancer. For example, SD, PR, and CR can be defined for solid tumors based on the percentage change from baseline in measurable target lesions by RECIST 1.1 over time. For example, in some embodiments, PR can refer to a 30% (inclusive) reduction to 100%; complete response can refer to when all lesions have disappeared (i.e., a 100% reduction); and stable disease can typically refer to a less than 20% increase to a 30% (inclusive) reduction.

[0240] In some embodiments, the treatment results in improved overall survival (OS), progression-free survival (PFS), disease control rate (DCR), overall response rate (ORR), or a combination thereof, compared to placebo or the current standard of care. In some embodiments, the treatment results in improved overall survival (OS), progression-free survival (PFS), disease control rate (DCR), overall response rate (ORR), or a combination thereof, compared to treatment with an Fc-enabled anti-TIGIT antibody, e.g., AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, larzapastzug, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006. In some embodiments, the treatment results in improved overall survival (OS), progression-free survival (PFS), disease control rate, overall response rate, or a combination thereof, compared to treatment with a CPI (e.g., ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab alone). In certain of the above embodiments, the improvement may be statistically significant.

[0241] In some embodiments, the treatment results in a non-inferior overall survival (OS), progression-free survival (PFS), disease control rate (DCR), overall response rate (ORR), or a combination thereof, compared to the current standard of care. In some embodiments, the treatment results in a non-inferior overall survival (OS), progression-free survival (PFS), disease control rate (DCR), overall response rate (ORR), or a combination thereof, compared to treatment with an Fc-enabled anti-TIGIT antibody, e.g., AB308, BMS-986207, larzapastzug, tiragolumab, vibostolimab, etiglimab, osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006. In some embodiments, the treatment results in a non-inferior overall survival (OS), progression-free survival (PFS), disease control rate (DCR), overall response rate (ORR), or a combination thereof, compared to treatment with a CPI (e.g., ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab alone).

[0242] The present disclosure also demonstrates that the percent change from baseline in the number of CD8+ T cells and / or Tregs measured in blood or tumor biopsy samples obtained 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more after administration of an anti-TIGIT antibody differs by a smaller margin than corresponding measurements in a population of subjects treated with an Fc-matched anti-TIGIT antibody and / or is within the range seen in healthy subjects. In some subjects, the percent change from baseline in the number of CD8+ T cells and / or Tregs may not be significantly different from the baseline number of CD8+ T cells or Tregs before administration. Similarly, the number of CD8+ T cells or Tregs measured in blood or tumor biopsy samples obtained 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more after administration of an anti-TIGIT antibody may differ by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, respectively, compared to the baseline number of CD8+ T cells or Tregs before administration. Additionally or alternatively, the number of CD8+ T cells or Tregs measured in blood or tumor biopsy samples obtained after one, two, three, or four administration cycles of an anti-TIGIT antibody may not be significantly different from the baseline number of CD8+ T cells or Tregs, respectively, before treatment began. Additionally or alternatively, the number of CD8+ T cells or Tregs measured in blood or tumor biopsy samples obtained after one, two, three, or four administration cycles of an anti-TIGIT antibody may differ by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, respectively, compared to the baseline number of CD8+ T cells or Tregs before treatment began.

[0243] As a result, the ratio of CD8+ T cells to Tregs may not change significantly over the course of treatment. In other words, analysis of CD8+ T cells and Treg cells measured in blood or tumor samples 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more after administration of an anti-TIGIT antibody shows that the ratio of CD8+ T cells to Tregs differs by a smaller margin than corresponding measurements in a population of subjects treated with an Fc-targeted anti-TIGIT antibody and / or is within the range seen in healthy subjects. In some examples, the ratio of CD8+ T cells to Tregs differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% compared to the baseline ratio of CD8+ T cells to Tregs before treatment began. Similarly, analysis of CD8+ T cells and Treg cells measured in blood or tumor biopsies 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more after administration of an anti-TIGIT antibody may show that the ratio of CD8+ T cells to TIGIT+ Tregs differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% compared to the baseline ratio of CD8+ T cells to Tregs before treatment began. Additionally or alternatively, analysis of CD8+ T cells and Treg cells measured in blood or tumor biopsies after one, two, three, or four administration cycles of an anti-TIGIT antibody may show that the ratio of CD8+ T cells to Tregs differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% compared to the baseline ratio of CD8+ T cells to Tregs before treatment began.Additionally or alternatively, analysis of CD8+ T cells and Treg cells measured in blood or tumor biopsies after one, two, three, or four administration cycles of an anti-TIGIT antibody may show that the ratio of CD8+ T cells to TIGIT+ Tregs differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% compared to the baseline ratio of CD8+ T cells to Tregs before treatment began.

[0244] Furthermore, after administration of an anti-TIGIT antibody with reduced FcγR binding compared to WT IgG1, there may be (i) an increase in the proliferation of the subject's CD8+ T cells and / or NK cells, (ii) an increase in the subject's CD8+ T cell function, (iii) a decrease in CD8+ T cell exhaustion, or (iv) a combination thereof, compared to the subject's baseline measurements. Indeed, the subject may experience myeloid cell proliferation, lymphoid cell proliferation, or a combination thereof. Indeed, administration of the disclosed anti-TIGIT antibodies may result in monocyte activation, lymphocyte activation, or both. In some embodiments, 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more after administration of the anti-TIGIT antibody, there may be (i) an increase in the expansion or proliferation of the subject's CD8+ T cells and / or NK cells, (ii) an increase in the subject's CD8+ T cell function, (iii) a decrease in CD8+ T cell exhaustion, or (iv) a combination thereof. In some embodiments, 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more after administration of an anti-TIGIT antibody, the subject may exhibit expansion, proliferation, or activation of the myeloid and / or lymphoid lineages. In some embodiments, after 1, 2, 3, or 4 cycles of administration of an anti-TIGIT antibody, there may be (i) an increase in the expansion or proliferation of the subject's CD8+ T cells and / or NK cells, (ii) an increase in the subject's CD8+ T cell function, (iii) a decrease in CD8+ T cell exhaustion, or (iv) a combination thereof. In some embodiments, after 1, 2, 3, or 4 cycles of administration of an anti-TIGIT antibody, the subject may exhibit expansion, proliferation, or activation of the myeloid and / or lymphoid lineages. Furthermore, concurrent with such expansion / proliferation / activation, the decrease in total Tregs or TIGIT+ Tregs may not be significantly different or may differ by only 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% compared to a baseline measurement taken prior to the start of administration or treatment.

[0245] The number of myeloid and lymphoid cells in tissues or blood can be quantified (absolute or relative counts) by immunophenotyping, a process that uses antibodies (or other antigen-specific reagents) to detect and quantify cell-associated antigens. Lymphoid cell markers can include, but are not limited to, CD3, CD4, CD8, CD16, CD25, CD39, CD45, CD56, CD103, CD127, and FOXP3. CD4 and CD8 are involved in the differentiation of T cells (e.g., CD4) with different effector functions. + T cells and CD8 + T cells). Co-expression of different cell markers can further distinguish subgroups. For example, co-expression of CD39 and CD103 identifies tumor-specific T cells (CD8 + CD39 + CD103 + T cells) can be distinguished from bystander T cells in the tumor microenvironment (TME), while co-expression of CD4, CD25, and FOXP3 distinguishes Treg cells (CD4 + CD25 + FOXP3 + For myeloid cells, suitable markers may include, but are not limited to, CD14, CD68, CD80, CD83, CD86, CD163, and CD206. Ki67 may be used to distinguish between populations of Ki67-positive cells (e.g., CD4 + T cells, CD8 + T cells, CD163 + , CD206 + Examples of suitable markers of cell proliferation include, but are not limited to, an increase in IFNγ, Ki-67, and GranB, such as an increase in macrophages (e.g., macrophages) indicating cell proliferation. + and / or GranB + CD8 + Increased T cells in patients with CD8 + CD8 +Non-limiting examples of suitable markers of T cell function. A key feature of exhausted T cells is the persistent co-expression of multiple inhibitory surface receptors, commonly referred to as immune checkpoints, including, but not limited to, CTLA4, PD-1, TIM3, TIGIT, and SLAMF6. Recent evidence suggests that CD8 + The exhausted phenotype in T cells is not uniform, but includes various subgroups such as "progenitor" and "terminally differentiated," suggesting that different capacities for effector function and proliferation are distributed among the subgroups. See, e.g., McLane et al., "CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer," Annual Review of Immunology, 2019, 37:457-495, the disclosure of which is incorporated herein by reference. For example, terminally exhausted CD8+ T cells express TIM3 + and high levels of PD-1 on their surface (PD-1 高 ) is characterized by

[0246] Furthermore, the disclosed methods and treatments with anti-TIGIT antibodies with reduced or abolished FcγR binding are believed to not cause (or cause minimal) disruption to T cell receptor (TCR) diversity among various T cell populations. For example, the disclosed methods and treatments with anti-TIGIT antibodies with reduced or abolished FcγR binding may result in a treatment-induced increase in T cell receptor diversity, e.g., as measured in blood samples. The newly activated T cell clones may also progress to tumor sites, resulting in an increase in TCR diversity in tumor samples. In some embodiments, after 1, 2, 3, 4, 5, 6, or 7 days, or after 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more of administration of an anti-TIGIT antibody, the subject may maintain or increase TCR diversity compared to the baseline established before administration. In some embodiments, after 1, 2, 3, or 4 administration cycles of an anti-TIGIT antibody, the subject may maintain or increase TCR diversity compared to the baseline established before initiation of treatment. TCR diversity can be measured by methods known in the art, including, for example, RNAseq. See, e.g., Chiffelle et al., "T-cell repertoire analysis and metrics of diversity and clonality," Current Opinion in Biotechnology, 2020, 65:284-295, the disclosure of which is incorporated herein by reference.

[0247] In summary, the present disclosure provides for the administration of or treatment with anti-TIGIT antibodies that have reduced or absent Fc effector function due to reduced or incapable ability to bind to FcγRs (e.g., FcγRI, FcγRIIA, FcγRIIIA), and subjects may not generally experience the immune system perturbation that comes with Fc-addressed anti-TIGIT antibodies, thus making the disclosed methods unexpectedly safe.

[0248] Thus, the present disclosure provides treatment with fewer or less severe side effects and immune-related adverse events as well as a method for treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR relative to WT IgG1, wherein the ratio of CD8+ T cells to Tregs measured in the subject's first sample at baseline differs from that measured in a second sample one or more days or one or more weeks after the first administration of the anti-TIGIT antibody by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%. In some embodiments, administration can include one or more (e.g., 1, 2, 3, or 4 or more) administration cycles in which an anti-TIGIT antibody is administered and then re-administered at a later time point (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 or more weeks after the previous administration). For example, one or more administration cycles can include administering the anti-TIGIT antibody to the subject once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. In some embodiments, one or more administration cycles can include administering the anti-TIGIT antibody to the subject at a dose of about 10 mg / kg to about 20 mg / kg. In some embodiments, one or more administration cycles may include administering an anti-TIGIT antibody to a subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg. In some embodiments, the first sample and the second sample are selected from a blood sample, a tumor sample, and a combination thereof. In some embodiments, the second sample is obtained 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, 5, or 6 weeks after the first administration of the anti-TIGIT antibody.In some embodiments, the ratio of CD8+ T cells to Tregs differs by a smaller margin than the corresponding ratio at a corresponding time in patients treated with Fc-addressed anti-TIGIT antibodies, such as AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, larzapastzug, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006.

[0249] Additionally or alternatively, the present disclosure provides a method for treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR compared to WT IgG1, wherein the ratio of the subject's CD8+ T cells to TIGIT+ Tregs measured in a first sample at baseline differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% from that measured in a second sample one or more days or one or more weeks after the first administration of the anti-TIGIT antibody. In some embodiments, administration can include one or more (e.g., 1, 2, 3, or 4 or more) administration cycles in which an anti-TIGIT antibody is administered and then re-administered at a later time point (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 or more weeks after the previous administration). For example, one or more administration cycles can include administering the anti-TIGIT antibody to the subject once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. In some embodiments, one or more administration cycles can include administering the anti-TIGIT antibody to the subject at a dose of about 10 mg / kg to about 20 mg / kg. In some embodiments, one or more administration cycles may include administering an anti-TIGIT antibody to a subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg. In some embodiments, the first sample and the second sample are selected from a blood sample, a tumor sample, and a combination thereof. In some embodiments, the second sample is obtained 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, 5, or 6 weeks after the first administration of the anti-TIGIT antibody.In some embodiments, the ratio of CD8+ T cells to TIGIT+ Tregs differs by a smaller margin than the corresponding ratio at a corresponding time in patients treated with Fc-addressed anti-TIGIT antibodies, such as AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, larzapastzug, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006.

[0250] Additionally or alternatively, the present disclosure provides a method for treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR compared to WT IgG1, wherein the subject's Tregs, TIGIT+ Tregs, or a combination thereof measured in a first sample at baseline differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% from that measured in a second sample one or more days or one or more weeks after the first administration of the anti-TIGIT antibody. In some embodiments, administration can include one or more (e.g., 1, 2, 3, or 4 or more) administration cycles in which an anti-TIGIT antibody is administered and then re-administered at a later time point (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 or more weeks after the previous administration). For example, one or more administration cycles can include administering the anti-TIGIT antibody to the subject once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. In some embodiments, one or more administration cycles can include administering the anti-TIGIT antibody to the subject at a dose of about 10 mg / kg to about 20 mg / kg. In some embodiments, one or more administration cycles may include administering an anti-TIGIT antibody to a subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg. In some embodiments, the first sample and the second sample are selected from a blood sample, a tumor sample, and a combination thereof. In some embodiments, the second sample is obtained 1, 2, 3, 4, 5, 6, or 7 days, or 1, 2, 3, 4, 5, or 6 weeks after the first administration of the anti-TIGIT antibody.In some embodiments, the amount of Tregs or TIGIT+ Tregs differs by a smaller margin than the corresponding ratio at a corresponding time in patients treated with an Fc-enabled anti-TIGIT antibody, such as AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, larzapastzug, and JS006.

[0251] Additionally or alternatively, the present disclosure provides a method for treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR compared to WT IgG1, wherein the subject's Tregs, TIGIT+Tregs, or a combination thereof differ by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% during treatment with the anti-TIGIT antibody. In some embodiments, administration can include one or more (e.g., 1, 2, 3, or 4 or more) administration cycles in which an anti-TIGIT antibody is administered and then re-administered at a later time point (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 or more weeks after the previous administration). For example, one or more administration cycles can include administering the anti-TIGIT antibody to the subject once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. In some embodiments, one or more administration cycles can include administering the anti-TIGIT antibody to the subject at a dose of about 10 mg / kg to about 20 mg / kg. In some embodiments, one or more administration cycles may involve administering an anti-TIGIT antibody to a subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg. In some embodiments, the lack of significant differences in Tregs, TIGIT+Tregs, or a combination thereof may be observed at least one day, at least one week, at least two weeks, at least three weeks, or at least four weeks after administration of the anti-TIGIT antibody. In some embodiments, the lack of significant differences in Tregs, TIGIT+Tregs, or a combination thereof may be observed after one, two, three, four, or more administration cycles.In some embodiments, the amount of Tregs or TIGIT+ Tregs differs by a smaller margin than the corresponding ratio at a corresponding time in patients treated with Fc-enabled anti-TIGIT antibodies, such as AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, larzapastzug, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006.

[0252] Additionally or alternatively, the present disclosure provides a method for treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR relative to WT IgG1, wherein after administration of the anti-TIGIT antibody, there is (i) an increase in the expansion or proliferation of CD8+ T cells in the subject, (ii) an increase in CD8+ T cell function in the subject, (iii) a decrease in CD8+ T cell exhaustion, or (iv) a combination thereof. In some embodiments, the decrease in Tregs or TIGIT+ Tregs is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% or less. In some embodiments, administration can include one or more (e.g., 1, 2, 3, or 4 or more) administration cycles in which an anti-TIGIT antibody is administered and then re-administered at a later time point (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 or more weeks after the prior administration). For example, one or more administration cycles can include administering the anti-TIGIT antibody to the subject once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. In some embodiments, one or more administration cycles can include administering the anti-TIGIT antibody to the subject at a dose of about 15 mg / kg. In some embodiments, one or more administration cycles may include administering an anti-TIGIT antibody to a subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg. In some embodiments, (i) an increase in the subject's CD8+ T cell expansion or proliferation, (ii) an increase in the subject's CD8+ T cell function, (iii) a decrease in CD8+ T cell exhaustion, or (iv) a combination thereof may be observed at least 1 week, at least 2 weeks, at least 3 weeks, or at least 4 weeks after administration of the anti-TIGIT antibody.In some embodiments, (i) an increase in the subject's CD8+ T cell expansion or proliferation, (ii) an increase in the subject's CD8+ T cell function, (iii) a decrease in CD8+ T cell exhaustion, or (iv) a combination thereof may be observed after one, two, three, four, or more administration cycles. In some embodiments, (i) an increase in the subject's CD8+ T cell expansion or proliferation, (ii) an increase in the subject's CD8+ T cell function, (iii) a decrease in CD8+ T cell exhaustion, or (iv) a combination thereof is greater than the corresponding measurement at the corresponding time in a patient treated with an Fc-addressed anti-TIGIT antibody, e.g., AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, larzapastzug, and JS006.

[0253] Additionally or alternatively, the present disclosure provides a method for treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR relative to WT IgG1, wherein after the initial administration of the anti-TIGIT antibody, there is expansion, proliferation, or activation of myeloid cells, lymphoid cells, or a combination thereof. In some embodiments, the reduction in Tregs or TIGIT+ Tregs is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% or less. In some embodiments, administration can include one or more (e.g., 1, 2, 3, or 4 or more) administration cycles in which an anti-TIGIT antibody is administered and then re-administered at a later time point (e.g., 1, 2, 3, 4, 5, 6, 7, or 8 or more weeks after the previous administration). For example, one or more administration cycles can include administering the anti-TIGIT antibody to the subject once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, or once every 8 weeks. In some embodiments, one or more administration cycles can include administering the anti-TIGIT antibody to the subject at a dose of about 10 mg / kg to about 20 mg / kg. In some embodiments, one or more administration cycles may include administering an anti-TIGIT antibody to a subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg. In some embodiments, expansion, proliferation, or activation of myeloid cells, lymphoid cells, or a combination thereof may be observed at least one day, at least one week, at least two weeks, at least three weeks, or at least four weeks after administration of the anti-TIGIT antibody. In some embodiments, expansion, proliferation, or activation of myeloid cells, lymphoid cells, or a combination thereof may be observed after one, two, three, four, or more administration cycles.In some embodiments, the expansion or proliferation or activation of myeloid cells, lymphoid cells, or a combination thereof, is greater than corresponding measurements at corresponding times in patients treated with an Fc-addressed anti-TIGIT antibody, such as AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, larzapastzug, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006.

[0254] c. One or more additional therapies For purposes of any of the foregoing methods, the method of treatment may further comprise the administration of one or more additional therapies. Suitable additional therapies are described in Section IV.

[0255] In some of the foregoing methods, the additional therapy can be an immunotherapeutic agent. Immunotherapeutic agents that can be suitably combined with the anti-TIGIT antibodies of the present disclosure having reduced or ablated Fc effector function include checkpoint inhibitors, e.g., antagonists of CTLA-4, PD-1, and PD-L1, and ATP-adenosine targeting agents, e.g., A 2a R and / or A 2bExamples of CPIs that can be combined with the disclosed anti-TIGIT antibodies (e.g., domvanalimab) include, but are not limited to, ipilimumab (YERVOY®), nivolumab (OPDIVO®), pembrolizumab (KEYTRUDA®), cemiplimab (LIBTAYO®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), atezolizumab (TECENTRIQ®), and zimbelemab (AB122). Treatment-related adverse events, including immune-related adverse events, have been observed with many immune checkpoint inhibitor CPIs, such as CTLA-4 antagonists and PD-1 / PD-L1 antagonists. For example, known risk effects of the PD-(L)1 class include identified risks such as Stevens-Johnson syndrome, myocarditis, pneumonia, immune-mediated pulmonary disease, and interstitial lung disease; and potential risks such as infusion-related reactions, immune-mediated hepatitis, and immune-mediated enterocolitis. For purposes of the present treatment methods, combining an anti-TIGIT antibody with reduced or ablated Fc effector function (e.g., domvanalimab) with a CPI (such as those listed above) is not expected to result in an increased likelihood, overall occurrence, or severity of one or more treatment-related adverse events (e.g., immune-related adverse events) that may occur when a given CPI is administered alone. Furthermore, the administration of the disclosed anti-TIGIT antibody with reduced or ablated Fc effector function (e.g., domvanalimab) is not expected to result in further loss, depletion, or inactivation of T cells (e.g., CD8+ T cells), Tregs, and / or other myeloid or lymphoid lineages beyond that expected for a given CPI.

[0256] In some of the aforementioned methods, the additional therapy may be one or more chemotherapeutic agents. Those skilled in the art can select an appropriate chemotherapy regimen, and this decision can be informed by the current standard of care for a particular cancer and / or the mutational status and / or disease stage of the target cancer. Detailed standard of care guidelines are published, for example, by the National Comprehensive Cancer Network (NCCN). It is understood in the art that many chemotherapeutic agents cause a depletion of T cells and other immune cells. For purposes of the disclosed methods, administration of the disclosed anti-TIGIT antibody with reduced or eliminated Fc effector function (e.g., domvanalimab) is not expected to result in further loss, depletion, or inactivation of T cells (e.g., CD8+ T cells), Tregs, and / or other myeloid or lymphoid lineages beyond that expected for a given chemotherapeutic agent.

[0257] In some embodiments, the one or more additional therapeutic agents include etramadenant. In some embodiments, the therapeutically effective amount of etramadenant is about 50 mg to about 250 mg orally administered per day, about 50 mg to about 225 mg orally administered per day, about 50 mg to about 150 mg orally administered per day, or about 100 mg to about 250 mg orally administered per day. In some embodiments, the therapeutically effective amount of etramadenant is about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg orally administered per day.

[0258] In some embodiments, the one or more additional therapeutic agents comprise dimmeremab and etramadenant. In some embodiments, the therapeutically effective amount of dimmeremab is about 360 mg administered intravenously every three weeks or about 480 mg administered intravenously every four weeks, and the therapeutically effective amount of etramadenant is about 50 mg to about 250 mg administered orally per day, or about 50 mg to about 150 mg administered orally per day. In some embodiments, the therapeutically effective amount of dimmeremab is about 720 mg administered intravenously every six weeks, about 760 mg administered intravenously every six weeks, about 960 mg administered intravenously every six weeks, or about 760 mg to about 960 mg administered intravenously every six weeks, and the therapeutically effective amount of etramadenant is about 50 mg to about 250 mg administered orally per day, or about 50 mg to about 150 mg administered orally per day.

[0259] In some embodiments, the one or more additional therapeutic agents comprise quemliculstat, hi some embodiments, the therapeutically effective amount of quemliculstat is about 100 mg to about 200 mg administered intravenously every two weeks, or about 300 mg administered intravenously every three weeks.

[0260] In some embodiments, the one or more additional therapeutic agents comprise dimvelemab and quemlicustat. In some embodiments, the therapeutically effective amount of dimvelemab is about 360 mg administered intravenously every 3 weeks or about 480 mg administered intravenously every 4 weeks, and the therapeutically effective amount of quemlicustat is about 300 mg administered intravenously every 3 weeks. In some embodiments, the therapeutically effective amount of dimvelemab is about 720 mg administered intravenously every 6 weeks, about 760 mg administered intravenously every 6 weeks, about 960 mg administered intravenously every 6 weeks, or about 760 mg to about 960 mg administered intravenously every 6 weeks, and the therapeutically effective amount of quemlicustat is about 300 mg administered intravenously every 3 weeks.

[0261] d. Administration cycle For purposes of any of the foregoing methods of treatment, a dosing cycle can include, for example, twice-weekly, once-weekly, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, or once every eight weeks. In some embodiments, a dosing cycle can include about 10 mg / kg to about 20 mg / kg of an antibody of the present disclosure (e.g., domvanalimab) administered Q2W, Q3W, or Q4W. In a particular example, a dosing cycle can include about 10 mg / kg of antibody administered Q2W. In another particular example, a dosing cycle can include about 15 mg / kg of antibody administered Q2W. In another particular example, a dosing cycle can include about 15 mg / kg of antibody administered Q3W. In another particular example, a dosing cycle can include about 20 mg / kg of antibody administered Q3W. In another particular example, a dosing cycle can include about 20 mg / kg of antibody administered Q4W. In some embodiments, a dosage cycle can include about 500 mg to about 2000 mg of antibody administered Q2W, Q3W, or Q4W. In some embodiments, a dosage cycle can include about 600 mg to about 1600 mg of antibody administered Q2W, Q3W, or Q4W. In some embodiments, a dosage cycle can include about 1000 mg to about 1500 mg of antibody administered Q2W, Q3W, or Q4W. In particular examples, a dosage cycle can include about 600 mg to about 800 mg of antibody administered Q2W, Q3W, or Q4W. In particular examples, a dosage cycle can include about 900 mg to about 1200 mg of antibody administered Q2W, Q3W, or Q4W. In particular examples, a dosage cycle can include about 1200 mg to about 1600 mg of antibody administered Q2W, Q3W, or Q4W. In a specific example, a dosage cycle can include about 600 mg to about 800 mg of antibody administered Q2W. In a specific example, a dosage cycle can include about 900 mg to about 1200 mg of antibody administered Q3W. In a specific example, a dosage cycle can include about 1200 mg to about 1600 mg of antibody administered Q4W. In a specific example, a dosage cycle can include about 1000 mg of antibody administered Q2W. In another specific example, a dosage cycle can include about 1200 mg of antibody administered Q2W.In another specific example, a dosage cycle can include about 1200 mg of antibody administered Q3W. In another specific example, a dosage cycle can include about 1500 mg of antibody administered Q3W. In another specific example, a dosage cycle can include about 1500 mg of antibody administered Q4W.

[0262] e. Anti-TIGIT antibody Suitable anti-TIGIT antibodies for the aforementioned methods are described in Section III. In some embodiments of the aforementioned methods, the anti-TIGIT antibody is an IgG4 or IgG1 with reduced ability to bind to FcγR. In some embodiments, the anti-TIGIT antibody is an IgG4 or IgG1 that does not bind to FcγR. Various modifications to IgG1 that can reduce or eliminate FcγR binding are described above.

[0263] In some embodiments of the aforementioned methods, the anti-TIGIT antibody is domvanalimab or an antigen-binding fragment of domvanalimab. In some embodiments, the anti-TIGIT antibody competitively inhibits the binding of domvanalimab to human TIGIT by at least 50% (e.g., at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%), as described in Section III. In some embodiments, the anti-TIGIT antibody binds to the same epitope of TIGIT as domvanalimab. In some embodiments of the aforementioned methods, the anti-TIGIT antibody is a variant domvanalimab.In some embodiments, the anti-TIGIT antibody comprises a heavy chain CDR1 comprising an amino acid sequence having 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%, at least 99%, or 100% sequence identity to SEQ ID NO:2; a heavy chain CDR2 comprising an amino acid sequence having 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%, at least 99%, or 100% sequence identity to SEQ ID NO:3; a heavy chain CDR2 comprising an amino acid sequence having 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%, at least 99%, or 100% sequence identity to SEQ ID NO:4; a heavy chain CDR3 comprising the amino acid sequence having 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%, at least 99%, or 100% sequence identity to SEQ ID NO:5; a light chain CDR2 comprising an amino acid sequence having 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%, at least 99%, or 100% sequence identity to SEQ ID NO:6; and a light chain CDR3 comprising an amino acid sequence having 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%, at least 99%, or 100% sequence identity to SEQ ID NO:7.

[0264] In some embodiments of the aforementioned methods, the anti-TIGIT antibody comprises a heavy chain variable region having 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%, at least 99%, or 100% sequence identity to SEQ ID NO: 8 or 10, and a light chain variable region having 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%, at least 99%, or 100% sequence identity to SEQ ID NO: 9 or 11. In some embodiments, the anti-TIGIT antibody comprises a heavy chain having 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%, at least 99%, or 100% sequence identity to SEQ ID NO: 12 and a light chain having 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%, at least 99%, or 100% sequence identity to SEQ ID NO: 13.

[0265] In some embodiments of the foregoing methods, the anti-TIGIT antibody may be formulated for injection as an aqueous solution containing about 10 mg / mL to about 100 mg / mL of antibody, or about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 to about 25 mM His / His-Cl, about 5% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, dextrose, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.1 mg / mL to about 0.3 mg / mL of polysorbate 80. Further embodiments are described in Section V.

[0266] f. Target A patient (or subject) in need of the treatment, prevention, or methods described herein may be a human subject with cancer. In some embodiments, the cancer or its tumor biopsy (which may include both tumor cells and immune cells) may be PD-1 positive or overexpressing. In some embodiments, the cancer may be PD-L1 positive or overexpressing. In some embodiments, the cancer may be CTLA positive or overexpressing. In some embodiments, the cancer may be CD73 positive or overexpressing. In some embodiments, the cancer may be DNAM-1 positive or overexpressing. In some embodiments, the cancer may be PVR positive or overexpressing. In some embodiments, the cancer may be TIGIT positive or overexpressing. In some embodiments, the cancer may be Ki67 positive or overexpressing, optionally CD8 positive and Ki67 positive or overexpressing. In some embodiments, the cancer may have a high tumor mutational burden (TMB). In some embodiments, the cancer may not have genomic alterations for which a targeted therapy has received regulatory approval for marketing. In some embodiments, the cancer may (i) be positive for, overexpress, or downregulated in a biomarker selected from the group consisting of CD73, DNAM-1, PVR, TIGIT, PD-L1, PD-1, CTLA, and CD8-Ki67, or any combination thereof; (ii) have a high TMB; (iii) not have a genomic alteration for which a targeted therapy has received regulatory marketing approval; or (iv) have any combination of (i)-(iii). Identification of biomarker-positive and / or overexpressing cancers may be performed using a suitable immunohistochemistry (IHC) assay and tumor biopsy samples. The criteria for biomarker-positive and biomarker-overexpressing or high cancers may be influenced by tumor site and / or type, the antibody used, and the assay conditions. Suitable antibodies for assessing PD-L1 expression include antibody clones 22C3, 28-8, SP142, SP263, and 73-10.PD-L1 expression may be reported as the tumor proportion score (TPS), combined positive score (CPS), the percentage of tumor cells with any PD-L1 membrane staining above background (%TC), the percentage of tumor area occupied by PD-L1-expressing tumor-infiltrating cells (%IC), or tumor area positivity (TAP) score. TPS is the percentage of viable tumor cells that show partial or complete membrane staining at any intensity. TPS or %TC is typically used to assess PD-L1 expression in NSCLC, although other measures may also be used. When TPS or %TC is used to assess PD-L1 expression, PD-L1-positive tumors may have a TPS or %TC score of 1% or greater, 5% or greater, 10% or greater, or 50% or greater, with a score of 50% or greater typically referred to as PD-L1-high. CPS and TAP are approaches used to quantify PD-L1 expression in tumors other than NSCLC (e.g., HNSCC, melanoma, UBC, TNBD, cervical, esophageal, gastric, GEJ, RCC, HCC, etc.). CPS is calculated by dividing the number of PD-L1-staining cells (tumor, lymphocytes, or macrophages) by the number of viable tumor cells and multiplying by 100. The TAP score is defined as the total percentage of tumor area covered by tumor cells with PD-L1 membrane staining at any intensity and tumor-associated immune cells with PD-L1 staining at any intensity. PD-L1-positive tumors can have a CPS of 1 or more, 5 or more, 10 or more, or 20 or more, or a TAP of 1%, 5%, 10% or more, or 20% or more. Suitable antibodies for assessing DNAM-1 include antibody clone R102 (Sino Biologicals). Suitable antibodies for assessing PVR include antibody clone D3G7H (Cell Signaling Technology). Suitable antibodies for assessing TIGIT include antibody clone SP410 (Spring Biosciences). Suitable antibodies for assessing Ki67 include antibody clone MIB-1. Tumor mutation burden (TMB) is defined as the number of mutations per megabase of DNA.TMB has historically been assessed using whole genome sequencing (WGS) or whole exome sequencing (WES) of tumor tissue, although good correlation between targeted next-generation sequencing (NGS) and WES has been reported. NGS can also be used simultaneously to detect specific genetic alterations. While not as established as measuring TMB from tumor tissue biopsies, TMB and genetic alterations can also be identified from circulating tumor DNA in plasma. In some embodiments, biomarker positivity, overexpression, or high cancer status and / or assessment of TMB and / or genetic alterations can be performed using FDA-approved tests such as PD-L1 IHC 22C3 (pharmDx), PD-L1 IHC 28-8 (pharmDx), PD-L1 SP142 assay (Ventana), PD-L1 SP263 assay (Ventana), FoundationOne CDx (to characterize an individual's genomic profile, including TMB status), and MSK-IMPACT tumor profiling (to characterize an individual's genomic profile, including TMB status).

[0267] The antibodies described herein are useful for the treatment and / or prevention of cancer (e.g., carcinoma, sarcoma, leukemia, lymphoma, and myeloma). In some embodiments, the present disclosure provides methods for the treatment and / or prevention of cancer using an antibody of the present disclosure and at least one additional therapeutic agent, examples of which are described elsewhere herein. In certain embodiments, the present disclosure provides methods for the treatment and / or prevention of cancer using an antibody of the present disclosure and at least one additional therapeutic agent that is an immuno-oncology agent, optionally with one or more chemotherapeutic agents. In further embodiments, the immuno-oncology agent is an immune checkpoint inhibitor or an agent that targets the ATP-adenosine axis. In yet further embodiments, the ATP-adenosine axis targeting agent is an Adenosine axis targeting agent. 2a R antagonist, A 2b R antagonist, A 2a R and A 2bIn yet a further embodiment, the ATP-adenosine axis targeting agent is an antagonist of A R, a CD73 inhibitor, or a CD39 inhibitor, and the immune checkpoint inhibitor blocks the activity of at least one of PD-1, PD-L1, BTLA, LAG3, a B7 family member, TIM3, or CTLA-4. 2a R antagonist, A 2b R antagonist, A 2a R and A 2b In yet a further embodiment, the ATP-adenosine axis targeting agent is an antagonist of A R, a CD73 inhibitor, or a CD39 inhibitor, and the immune checkpoint inhibitor blocks the activity of at least one of PD-1, PD-L1, or CTLA-4. 2a R antagonist, A 2b R antagonist, A 2a R and A 2b R antagonist, CD73 inhibitor, or CD39 inhibitor, and the immune checkpoint inhibitor blocks the activity of at least one of PD-1 or PD-L1. To achieve treatment and / or prophylaxis, the antibodies and additional therapeutic agents of the present disclosure are administered in a "therapeutically effective amount."

[0268] The methods of the present disclosure can be carried out in an adjuvant setting. An "adjuvant setting" refers to a clinical setting in which a subject has a history of a proliferative disease, particularly cancer, and has generally (but not necessarily) responded to therapy, including, but not limited to, surgery, radiation therapy, and / or chemotherapy. However, due to the history of the proliferative disease, these subjects are considered to be at risk for recurrence and / or disease progression. Treatment or administration in an "adjuvant setting" refers to a subsequent form of treatment. Generally, adjuvant therapy is administered in addition to primary treatment to reduce the risk of the disease or condition recurring. In some embodiments, provided herein are methods of treating or effectively preventing cancer, comprising administering a therapeutically effective amount of any of the antibodies disclosed herein in an adjuvant setting to a subject having or at risk of cancer.

[0269] The methods provided herein can also be performed in a "neoadjuvant setting," i.e., the methods can be performed prior to primary therapy. In some aspects, the subject has been previously treated. In other aspects, the subject has not been previously treated. In some aspects, the primary treatment is a first-line therapy. In some embodiments, provided herein are methods of treating or effectively preventing cancer, comprising administering to a subject having or at risk of cancer a therapeutically effective amount of any of the antibodies disclosed herein in a neoadjuvant setting.

[0270] The methods provided herein can also be indicated as first-line, second-line, third-line, or higher-line treatments.

[0271] In some embodiments, the cancer may be locally advanced and / or unresectable, metastatic, or at risk of becoming metastatic. Alternatively, or in addition, the cancer may be recurrent or no longer responding to treatment, such as standard of care. In certain embodiments, the cancer may be (i) locally advanced, unresectable, locally advanced unresectable, or metastatic; (ii) no longer responding to treatment, such as standard of care, a CPI, or more specifically, a PD-1 or PD-L1 antagonist; or (iii) a combination of (i) and (ii). The determination of whether a subject is "no longer responding to treatment" may be made by the subject's healthcare provider, for example, based on response or stalled disease progression.

[0272] Exemplary types of cancer contemplated by the present disclosure include cancers of the genitourinary tract (e.g., bladder, kidney, renal cell, penis, prostate, testis, von Hippel-Lindau disease, etc.), uterus, cervix, ovary, breast, gastrointestinal tract (e.g., esophagus, oropharynx, stomach, small or large intestine, colon, or rectum), bone, bone marrow, skin (e.g., melanoma), head and neck, liver, gallbladder, bile duct, heart, lung, pancreas, salivary gland, adrenal gland, thyroid, brain (e.g., glioma), ganglia, central nervous system (CNS), peripheral nervous system (PNS), hematopoietic system (i.e., hematologic malignancies), and immune system (e.g., spleen or thymus).

[0273] In some embodiments, antibodies according to the present disclosure are useful for the treatment and / or prevention of solid tumors. The solid tumor may be ovarian cancer, endometrial cancer, breast cancer, lung cancer (small cell or non-small cell), colorectal cancer, prostate cancer, cervical cancer, biliary tract cancer, pancreatic cancer (e.g., pancreatic neuroendocrine tumor (pNET)), gastric cancer, esophageal cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer (e.g., renal cell carcinoma), head and neck tumors, mesothelioma, skin cancer (e.g., melanoma, Merkel cell carcinoma), sarcoma, central nervous system (CNS) hemangioblastoma, and brain tumors (e.g., gliomas such as astrocytoma, oligodendroglioma, and glioblastoma). The solid tumor may also be a locally advanced and / or unresectable solid tumor, a metastatic solid tumor, a recurrent solid tumor, a solid tumor that no longer responds to treatment, such as standard therapy, or a combination thereof.

[0274] In some embodiments, antibodies according to the present disclosure are useful for the treatment and / or prevention of lung cancer, genitourinary cancer, gastrointestinal cancer, cervical cancer, ovarian cancer, or a combination thereof, optionally wherein the tumor is a locally advanced and / or unresectable tumor, a metastatic tumor, a recurrent tumor, a tumor that no longer responds to treatment, such as standard of care, or any combination thereof.

[0275] In some embodiments, the cancer is lung cancer. In further embodiments, the lung cancer is non-small cell lung cancer (NSCLC), and optionally the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic; (ii) no longer responds to treatment, such as standard therapy; or (iii) a combination of (i) and (ii). In still further embodiments, the NSCLC can be lung squamous cell carcinoma or lung adenocarcinoma. For example, in one example, the lung cancer is locally advanced unresectable NSCLC, and the cancer has not progressed after definitive platinum-based concurrent chemoradiation therapy. In another example, the lung cancer is locally advanced or metastatic squamous or non-squamous NSCLC that is treatment-naive for locally advanced or metastatic disease.

[0276] In some embodiments, a patient in need of the treatment, prevention, or methods described herein may be a human subject with NSCLC (squamous or non-squamous disease), and in particular embodiments, a patient with unresectable locally advanced disease (stage IIIA, IIIB, IIIC) or metastatic disease (stage IV). In some embodiments, the NSCLC may be PD-L1 high, corresponding to a TPS of 50% or greater or a TC of 50% or greater, as measured by a clinically validated PD-L1 IHC assay or FDA-approved test, such as PharmDx 22C3, 28-8 pharmDx (Dako), SP263 assay (Ventana), or SP142 assay (Ventana). In some embodiments, the NSCLC may have PD-L1 expression corresponding to a TPS of less than 50% or a TC of less than 50%, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test, for example, about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 46%, about 47%, about 48%, about 49%, or a range thereof, for example, about 1-10%, about 10%-20%, about 20-30%, about 30-40%, about 40-49%, about 1-49%, about 1-25%, or about 25-49%. In some embodiments, the NSCLC may have PD-L1 expression corresponding to a TPS of 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, or a TC of 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, or 45% or more, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test. In some embodiments, the cancer may have tumor mutational burden-high (TMB-H; 10 mutations / megabase (mut / Mb) or more, as measured by an FDA-approved test). The cancer may or may not have genomic mutations for which targeted therapies have received regulatory approval for marketing; non-limiting examples of genes with such mutations include the ALK fusion oncogene, EGFR, ROS, BRAF, and NTRK.In the foregoing embodiments, the cancer may be positive for, or have overexpressed or downregulated biomarkers selected from the group consisting of CD73, DNAM-1, PVR, TIGIT, and CD8-Ki67, or any combination thereof.

[0277] In some embodiments, the cancer is gastrointestinal cancer. In various embodiments, the gastrointestinal cancer is esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, or liver cancer, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care.

[0278] In some embodiments, the cancer is an upper GI cancer, e.g., esophageal or gastric cancer, and optionally, the upper GI cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care. In further embodiments, the upper GI cancer is adenocarcinoma, squamous cell carcinoma, or any combination thereof. In still further embodiments, the upper GI cancer is esophageal adenocarcinoma (EAC), esophageal squamous cell carcinoma (ESCC), gastroesophageal junction adenocarcinoma (GEJ), gastric adenocarcinoma (also referred to herein as "gastric cancer"), or any combination thereof, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care. In still further embodiments, the upper GI cancer is esophageal adenocarcinoma (EAC), gastroesophageal junction adenocarcinoma (GEJ), gastric adenocarcinoma (GA), or any combination thereof, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care.

[0279] In some embodiments, a patient in need of the treatment, prevention, or methods described herein may be a human subject with gastrointestinal cancer, optionally, (i) upper GI cancer, (ii) GI cancer selected from the group consisting of GA, GEJ, ESCC, EAC, and any combination thereof, or (iii) GI cancer selected from the group consisting of GA, GEJ, EAC, and any combination thereof, and in certain embodiments, a patient with locally advanced unresectable or metastatic disease. The patient may or may not have been treated with prior systemic therapy and may be checkpoint inhibitor (CPI) naïve or CPI-experienced. In some embodiments, the cancer may express PD-L1 (e.g., TAP (tumor area positive) <1%, 1% or more, 5% or more, 10% or more, 1% to <5%, 5% to <10%, or more than 10% as measured by the Ventana PD-L1 (SP263) assay, or an equivalent value as measured by another clinically validated PD-L1 IHC assay). In some embodiments, the cancer may be tumor mutational burden-high (TMB-H; ≥10 mutations / megabase (mut / Mb) as measured by a clinically validated or FDA-approved test). The cancer may or may not harbor genomic mutations for which targeted therapies have received regulatory approval; non-limiting examples of genes harboring such mutations include ALK fusion oncogenes, EGFR, ROS, BRAF, and NTRK. In the foregoing embodiments, the cancer may be positive for, or have overexpressed or downregulated biomarkers selected from the group consisting of CD73, DNAM-1, PVR, TIGIT, and CD8-Ki67, or any combination thereof.

[0280] In some embodiments, antibodies according to the present disclosure are useful for the treatment and / or prevention of NSCLC, head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma (RCC), breast cancer, colorectal cancer (CRC), melanoma, bladder cancer, ovarian cancer, endometrial cancer, Merkel cell, and gastroesophageal cancer.

[0281] The present disclosure also provides methods for treating or preventing other cancer-related diseases, disorders, or conditions. The use of the terms cancer-related diseases, disorders, and conditions is meant to broadly refer to conditions directly or indirectly related to cancer, including, for example, angiogenesis and precancerous conditions, such as dysplasia, as well as non-cancerous proliferative diseases, disorders, or conditions, such as benign proliferative breast disease and papilloma. For clarity, the term cancer-related diseases, disorders, and conditions does not include cancer itself. In some embodiments, the present disclosure provides methods for treating cancer-related diseases, disorders, or conditions using an antibody of the present disclosure and at least one additional therapeutic agent, examples of which are described elsewhere herein.

[0282] The following embodiments are given to illustrate the present disclosure, and it should be understood that the present invention is not limited to the following embodiments.

[0283] Embodiment 1: A method of treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to WT human IgG1, wherein the subject's percent change from baseline in a T cell measurement is different by a smaller margin than corresponding measurements in a population of subjects treated with an Fc-matched anti-TIGIT antibody or is not statistically different from corresponding measurements in a population of healthy subjects, and wherein the CD8+ T cell measurement is: (i) a greater than or equal to 100% of the CD8+ T cell count measured in a first sample at baseline and in a second sample obtained one or more days or one or more weeks after administration of the anti-TIGIT antibody; + or (ii) the absolute number of Tregs, CD8+ T cells, or a combination thereof measured in a first sample at baseline and in a second sample obtained one or more days or one or more weeks after administration of the anti-TIGIT antibody.

[0284] Embodiment 2: (i) the ratio of total CD8+ T cells to Tregs measured in a subject in a first sample at baseline and in a second sample obtained one or more weeks after the first dose of an anti-TIGIT antibody differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%; or ii) The method of embodiment 1, wherein the subject's Tregs, CD8+ T cells, or a combination thereof measured in a first sample at baseline and in a second sample one week or more after the first dose of administration of the anti-TIGIT antibody differ by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%.

[0285] Embodiment 3: The method of embodiment 1 or 2, wherein the administration comprises one or more administration cycles.

[0286] Embodiment 4: The method of embodiment 3, wherein the administration cycle comprises administering the anti-TIGIT antibody to the subject once every two weeks, once every three weeks, or once every four weeks.

[0287] Embodiment 5: The method of any one of embodiments 1 to 4, wherein the anti-TIGIT antibody is administered to the subject at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg.

[0288] Embodiment 6: The method of any one of embodiments 1 to 5, wherein the anti-TIGIT antibody is administered to the subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg.

[0289] Embodiment 7: The method of any one of embodiments 1-6, further comprising administering one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are optionally an immunotherapeutic agent, a chemotherapeutic agent, a chemotherapy regimen, or a combination thereof.

[0290] Embodiment 8: The method of any one of embodiments 1 to 7, wherein the first sample and the second sample are selected from a blood sample, a tumor sample, and a combination thereof.

[0291] Embodiment 9: The method of any one of embodiments 1 to 8, wherein the second sample is obtained 2, 3, 4, 5, or 6 weeks after the first administration of the anti-TIGIT antibody.

[0292] Embodiment 10: The method of any one of embodiments 1 to 9, wherein the Fc-targeted anti-TIGIT antibody is selected from AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, larzapastzug, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006.

[0293] Embodiment 11: The method of any one of embodiments 1 to 10, wherein the subject is not experiencing an immune-related adverse event.

[0294] Embodiment 12: The method of any one of embodiments 1 to 10, wherein the subject is less likely to experience an immune-related adverse event, or optionally an immune-related adverse event of Grade 3 or higher, than a subject being treated with an Fc-addressed anti-TIGIT antibody.

[0295] Embodiment 13: The method of embodiment 1 or 12, wherein the immune-related adverse event is selected from (i) skin or subcutaneous tissue disorder, gastrointestinal disorder, hepatic biliary disorder, endocrine disorder, or respiratory, thoracic, or mediastinal disorder; (ii) skin or subcutaneous tissue disorder; (iii) rash, oral mucositis, dry mouth, colitis, diarrhea, hepatitis, pneumonitis, endocrine disorder, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, or a combination thereof; (iv) arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reaction, maculopapular rash, pneumonitis, pruritus, psoriasis, rash, facial swelling, or a combination thereof; or (v) infusion-related reaction, maculopapular rash, pruritus, psoriasis, rash, or a combination thereof.

[0296] Embodiment 14: A method of treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR compared to WT IgG1, wherein after the first administration of the anti-TIGIT antibody, there is (i) an increase in CD8+ T cell proliferation in the subject, (ii) an increase in CD8+ T cell function in the subject, (iii) a decrease in CD8+ T cell exhaustion in the subject, or (iv) a combination thereof, and the decrease in Tregs or TIGIT+ Tregs is less than corresponding measurements in a population of similar patients treated with an Fc-capable anti-TIGIT antibody or is not statistically different from corresponding measurements in a population of healthy subjects.

[0297] Embodiment 15: The method of embodiment 14, wherein the increase in CD8+ T cell proliferation, the increase in CD8+ T cell function, the decrease in CD8+ T cell exhaustion, and the decrease in total Tregs or TIGIT+ Tregs in the subject are determined by measuring a first sample obtained at baseline and a second sample obtained at least one week after the first administration of the anti-TIGIT antibody.

[0298] Embodiment 16: The method of embodiment 15, wherein the first sample and the second sample are selected from a blood sample, a tumor sample, and a combination thereof.

[0299] Embodiment 17: The method of embodiment 15 or 16, wherein the second sample is obtained 2, 3, 4, 5, or 6 weeks after the first administration of the anti-TIGIT antibody.

[0300] Embodiment 18: The method of any one of embodiments 14 to 17, further comprising two or more administration cycles of the anti-TIGIT antibody.

[0301] Embodiment 19: The method of embodiment 18, wherein the administration cycle comprises administering the anti-TIGIT antibody to the subject once every two weeks, once every three weeks, or once every four weeks.

[0302] Embodiment 20: The method of any one of embodiments 14 to 19, wherein the anti-TIGIT antibody is administered to the subject at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg.

[0303] Embodiment 21: The method of any one of embodiments 14 to 20, wherein the anti-TIGIT antibody is administered to the subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg.

[0304] Embodiment 22: The method of any one of embodiments 14 to 21, wherein any decrease in total Tregs or TIGIT+ Tregs is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% or less throughout treatment with the anti-TIGIT antibody.

[0305] Embodiment 23: The method of any one of embodiments 14 to 22, further comprising administering one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are optionally an immunotherapeutic agent, a chemotherapeutic agent, a chemotherapy regimen, or a combination thereof.

[0306] Embodiment 24: The method of any one of embodiments 14 to 23, wherein the ratio of CD8+ T cells to Tregs differs by a smaller margin than the corresponding ratio at the corresponding time in patients treated with an Fc-targeted anti-TIGIT antibody.

[0307] Embodiment 25: The method of embodiment 14, wherein the Fc-enabled anti-TIGIT antibody is selected from AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, larzapastzug, EOS-448, SEA-TGT, AGEN1777, AGEN1327, and JS006.

[0308] Embodiment 26: The method of any one of embodiments 14 to 25, wherein the subject is not experiencing an immune-related adverse event.

[0309] Embodiment 27: The method of any one of embodiments 14 to 25, wherein the subject is less likely to experience an immune-related adverse event, or optionally an immune-related adverse event of Grade 3 or higher, than a subject being treated with an Fc-addressed anti-TIGIT antibody.

[0310] Embodiment 28: The method of embodiment 26 or 27, wherein the immune-related adverse event is selected from (i) skin or subcutaneous tissue disorder, gastrointestinal disorder, hepatobiliary disorder, endocrine disorder, or respiratory, thoracic, or mediastinal disorder; (ii) skin or subcutaneous tissue disorder; (iii) arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reaction, maculopapular rash, pneumonia, pruritus, psoriasis, rash, facial swelling, or a combination thereof; or (iv) infusion-related reaction, maculopapular rash, pruritus, psoriasis, rash, or a combination thereof.

[0311] Embodiment 29: The method of any one of embodiments 1 to 28, wherein the treatment results in a decrease in tumor size, a decrease in tumor number, a decrease in metastases, stable disease (SD), a partial response (PR), a complete response (CR), or a combination thereof.

[0312] Embodiment 30: The method of any one of embodiments 1 to 29, wherein the treatment results in improved overall survival (OS), progression-free survival (PFS), disease control rate (DCR), overall response rate (ORR), or a combination thereof, compared to placebo or standard of care.

[0313] Embodiment 31: A method for blocking or preventing binding of TIGIT to CD155 in a human subject without significantly reducing Tregs, CD8+ T cells, CD4+ T cells, or a combination thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to FcγR compared to WT IgG1.

[0314] Embodiment 32: The method of embodiment 31, wherein the reduction in Tregs, CD8+ T cells, CD4+ T cells, or a combination thereof differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% from the baseline measurement before administration of the anti-TIGIT antibody.

[0315] Embodiment 33: The method of embodiment 31 or 32, wherein any potential reduction in Tregs, CD8+ T cells, CD4+ T cells, or a combination thereof is assessed 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks after administration of the anti-TIGIT antibody.

[0316] Embodiment 34: The method of any one of embodiments 31 to 33, wherein the subject has cancer.

[0317] Embodiment 35: The method of any one of embodiments 31 to 34, wherein the anti-TIGIT antibody is administered in 1, 2, 3, or 4 administration cycles.

[0318] Embodiment 36: The method of embodiment 35, wherein the administration cycle comprises administering the anti-TIGIT antibody to the subject once every two weeks, once every three weeks, or once every four weeks.

[0319] Embodiment 37: The method of any one of embodiments 31 to 36, wherein the anti-TIGIT antibody is administered to the subject at a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg.

[0320] Embodiment 38: The method of any one of embodiments 31 to 37, wherein the anti-TIGIT antibody is administered to the subject at a dose ranging from about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg.

[0321] Embodiment 39: The method of any one of embodiments 31 to 38, wherein the method does not result in immune-related adverse events.

[0322] Embodiment 40: The method of any one of embodiments 31 to 38, wherein the subject is less likely to experience an immune-related adverse event, or optionally an immune-related adverse event of Grade 3 or higher, than a subject being treated with an Fc-addressed anti-TIGIT antibody.

[0323] Embodiment 41: The method of embodiment 39 or 40, wherein the immune-related adverse event is selected from (i) skin or subcutaneous tissue disorder, gastrointestinal disorder, hepatobiliary disorder, endocrine disorder, or respiratory, thoracic, or mediastinal disorder; (ii) skin or subcutaneous tissue disorder; (iii) arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reaction, maculopapular rash, pneumonia, pruritus, psoriasis, rash, facial swelling, or a combination thereof; or (iv) infusion-related reaction, maculopapular rash, pruritus, psoriasis, rash, or a combination thereof.

[0324] Embodiment 42: The method of any one of embodiments 31 to 41, further comprising administering to the subject one or more additional therapeutic agents, wherein the one or more additional therapeutic agents are optionally an immunotherapeutic agent, a chemotherapeutic agent, a chemotherapy regimen, or a combination thereof.

[0325] Embodiment 43: The method of any one of embodiments 31 to 42, wherein the reduction in Tregs is 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15% or less throughout treatment with the anti-TIGIT antibody.

[0326] Embodiment 44: The method of any one of embodiments 31 to 43, wherein after the initial administration of an anti-TIGIT antibody, there may be (i) an increase in proliferation of the subject's CD8+ T cells, (ii) an increase in the subject's CD8+ T cell function, (iii) a decrease in CD8+ T cell exhaustion, or (iv) a combination thereof.

[0327] Embodiment 45: (i) the ratio of total CD8+ T cells to Tregs in the subject measured in a first sample at baseline and in a second sample obtained one or more weeks after the first administration of an anti-TIGIT antibody differs by no more than 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30%, and (ii) in the first sample at baseline 45. The method of any one of embodiments 31-44, wherein the amount of CD8+ T cells, Tregs, or a combination thereof measured in the first sample and in the second sample one week or more after the first dose of administration of the anti-TIGIT antibody differs by 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, or 30% or less, or (iii) a combination thereof.

[0328] Embodiment 46: The method of any one of embodiments 1 to 45, wherein the anti-TIGIT antibody having reduced binding to one or more activating human FcγRs comprises an Fc region that has a reduced ability to bind to one or more activating human FcγRs, and is optionally an IgG4 or IgG1.

[0329] Embodiment 47: The method of any one of embodiments 1 to 46, wherein the anti-TIGIT having reduced binding to one or more activating human FcγR does not bind to one or more activating human FcγR.

[0330] Embodiment 48: The method of any one of embodiments 1 to 47, wherein the anti-TIGIT antibody comprises a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO: 3, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO: 4, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 6, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 7.

[0331] Embodiment 49: The method of any one of embodiments 1 to 48, wherein the anti-TIGIT antibody comprises a heavy chain variable region having at least 90% sequence identity to SEQ ID NO: 8 or 10 and a light chain variable region having at least 90% sequence identity to SEQ ID NO: 9 or 11.

[0332] Embodiment 50: The method of any one of embodiments 1 to 49, wherein the anti-TIGIT antibody comprises a heavy chain having at least 90% sequence identity to SEQ ID NO: 12 and a light chain having at least 90% sequence identity to SEQ ID NO: 13.

[0333] Embodiment 51: The method of any one of embodiments 1 to 50, wherein the anti-TIGIT antibody binds to the same epitope of TIGIT as domvanalimab or competes with domvanalimab for binding to TIGIT.

[0334] Embodiment 52: The method of any one of embodiments 1 to 51, wherein the cancer is a solid tumor, and optionally the tumor is a locally advanced and / or unresectable tumor, a metastatic tumor, a recurrent tumor, a tumor that no longer responds to treatment, and optionally the treatment is standard of care, a checkpoint inhibitor, a PD-1 antagonist, or a PD-L1 antagonist, or any combination thereof.

[0335] Embodiment 53: The method of embodiment 52, wherein the cancer is lung cancer, genitourinary cancer, or gastrointestinal cancer.

[0336] Embodiment 54: The method of embodiment 53, wherein the cancer is lung cancer.

[0337] Embodiment 55: The method of embodiment 54, wherein the lung cancer is non-small cell lung cancer (NSCLC), and optionally the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic; and (ii) no longer responds to treatment, and optionally the treatment is standard of care, a checkpoint inhibitor, a PD-1 antagonist, or a PD-L1 antagonist, or (iii) a combination of (i) and (ii).

[0338] Embodiment 56: The method of embodiment 54, wherein the lung cancer is squamous or non-squamous, unresectable locally advanced or metastatic disease.

[0339] Embodiment 57: The method of embodiment 53, wherein the cancer is gastrointestinal cancer.

[0340] Embodiment 58: The method of embodiment 57, wherein the gastrointestinal cancer is esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, or liver cancer, and optionally the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care.

[0341] Embodiment 59: The method of embodiment 57, wherein the gastrointestinal cancer is esophageal cancer or gastric cancer, and optionally the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care, checkpoint inhibitors, PD-1 antagonists, or PD-L1 antagonists.

[0342] Embodiment 60: The method of embodiment 57, wherein the gastrointestinal cancer is esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastroesophageal junction adenocarcinoma, or gastric adenocarcinoma, and optionally the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and / or (ii) no longer responds to treatment, such as standard of care.

[0343] Embodiment 61: The method of embodiment 52, wherein the cancer is NSCLC, head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma (RCC), breast cancer, colorectal cancer (CRC), melanoma, bladder cancer, ovarian cancer, endometrial cancer, Merkel cell, or gastroesophageal cancer.

[0344] Embodiment 62: The method of any one of embodiments 1 to 61, wherein the PD-L1 expression of the cancer is a TPS of 50% or greater, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

[0345] Embodiment 63: The method of any one of embodiments 1 to 61, wherein the PD-L1 expression of the cancer is a TPS of less than 50%, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

[0346] Embodiment 64: The method of embodiment 63, wherein PD-L1 expression is about 1-10%, about 10%-20%, about 20-30%, about 30-40%, about 40-49%, about 1-49%, about 1-25%, or about 25-49%, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

[0347] Embodiment 65: The method of any one of embodiments 1 to 64, wherein the cancer may be tumor mutation burden-high (TMB-H; 10 mutations / megabase (mut / Mb) or more as measured by an FDA-approved test).

[0348] Embodiment 66: The method of any one of embodiments 1 to 64, wherein the cancer is not TMB-H.

[0349] Embodiment 67: The method of any one of embodiments 1 to 66, wherein the cancer does not have an actionable oncogenic mutation in ALK, EGFR, ROS, BRAF, or NTRK, and / or has wild-type ALK, EGFR, ROS, BRAF, and / or NTRK.

[0350] Embodiment 68: The method of any one of embodiments 1 to 67, wherein the cancer expresses or overexpresses one or more biomarkers selected from CD73, DNAM-1, PVR, TIGIT, and CD8-Ki67.

[0351] Embodiment 71: The immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimbelemab; or, optionally, A 2a R antagonist, A 2b R antagonist, A 2a R and A 2b 43. The method of any one of embodiments 7, 23, or 42, wherein the ATP-adenosine axis targeting agent is selected from an R antagonist, a CD73 inhibitor, and a CD39 inhibitor.

[0352] Embodiment 72: The method of embodiment 71, wherein the chemotherapy regimen is a fluoropyrimidine-containing chemotherapy or a platinum-containing chemotherapy.

[0353] Embodiment 73: The method of embodiment 72, wherein the fluoropyrimidine is a fluorouracil-containing chemotherapy and the platinum-containing chemotherapy is carboplatin, cisplatin, or oxaliplatin.

[0354] Embodiment 74: The method of embodiment 72, wherein the chemotherapy regimen is FOLFOX, CAPOX, cisplatin and pemetrexed, carboplatin and pemetrexed, carboplatin and paclitaxel, or carboplatin and nab-paclitaxel.

[0355] Embodiment 75: A method of treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, wherein the treatment results in a reduction in one or more adverse events compared to a similar treatment comprising an Fc-matched anti-TIGIT antibody.

[0356] Embodiment 76: A method of treating cancer in a human subject in need thereof, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, wherein the subject is less likely to experience one or more adverse events compared to treatment with an Fc-matched anti-TIGIT antibody.

[0357] Embodiment 77: The method of embodiment 75 or 76, wherein the Fc-enabled anti-TIGIT antibody is selected from AB308, BMS-986207, tiragolumab, vibostolimab, etiglimab, osipelimab, larzapastzug, EOS-448, SEA-TGT, AGEN1777, AGEN1327, JS006, and an Fc-enabled version of domvanalimab comprising a wild-type IgG1 Fc region.

[0358] Embodiment 78: A method of treating cancer in a human subject in need thereof without significantly increasing the likelihood of adverse events compared to standard of care, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγR compared to wild-type (WT) human IgG1, in combination with one or more additional therapies.

[0359] Embodiment 79: A method for reducing one or more adverse events experienced by a human subject being treated for cancer with an anti-TIGIT antibody, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1.

[0360] Embodiment 80: A method for reducing one or more adverse events experienced by a human subject being treated for cancer with an anti-TIGIT antibody and an additional immunotherapeutic agent, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1, and the additional immunotherapeutic agent.

[0361] Embodiment 81: The method of embodiment 80, wherein the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab.

[0362] Embodiment 82: The method of any one of embodiments 75 to 81, wherein the adverse event is a treatment-related adverse event, a treatment-emergent adverse event, an immune-related adverse event, a treatment-related immune-related adverse event, a treatment-related adverse event leading to treatment discontinuation, a treatment-related adverse event leading to treatment interruption, a serious adverse event leading to treatment discontinuation, a serious adverse event leading to treatment interruption, a serious adverse event, a serious adverse event of Grade 3 or higher, or a treatment-related adverse event of Grade 3 or higher.

[0363] Embodiment 83: The immune-related adverse event is (i) Skin or subcutaneous tissue disorders, gastrointestinal disorders, hepatic and biliary disorders, endocrine disorders, or respiratory, thoracic, or mediastinal disorders; (ii) skin or subcutaneous tissue disorders; (iii) rash, oral mucositis, dry mouth, colitis, diarrhea, hepatitis, pneumonia, endocrine disorders, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, or a combination thereof; (iv) arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reactions, maculopapular rash, pneumonitis, pruritus, psoriasis, rash, facial swelling, or any combination thereof; or (v) The method of embodiment 82, wherein the reaction is selected from an infusion-related reaction, a maculopapular rash, pruritus, psoriasis, a rash, or a combination thereof.

[0364] Embodiment 84: A method for reducing one or more dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with an anti-TIGIT antibody, comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1.

[0365] Embodiment 85: A method of reducing one or more dose reductions, temporary treatment interruptions, or treatment discontinuations experienced by a human subject being treated for cancer with an anti-TIGIT antibody and an additional immunotherapeutic agent, the method comprising administering to the subject an anti-TIGIT antibody that has reduced binding to one or more activating human FcγRs compared to wild-type (WT) human IgG1.

[0366] Embodiment 86: The method of embodiment 87, wherein the immunotherapeutic agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, durvalumab, atezolizumab, and zimvelemab.

[0367] Embodiment 87: The method of any one of embodiments 84 to 86, wherein the method further comprises reducing one or more immune-related adverse events compared to a similar treatment comprising an Fc-targeted anti-TIGIT antibody.

[0368] Embodiment 88: The immune-related adverse event is (i) Skin or subcutaneous tissue disorders, gastrointestinal disorders, hepatic and biliary disorders, endocrine disorders, or respiratory, thoracic, or mediastinal disorders; (ii) skin or subcutaneous tissue disorders; (iii) rash, oral mucositis, dry mouth, colitis, diarrhea, hepatitis, pneumonia, endocrine disorders, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, or a combination thereof; (iv) arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reactions, maculopapular rash, pneumonitis, pruritus, psoriasis, rash, facial swelling, or any combination thereof; or (v) The method of embodiment 87, wherein the reaction is selected from an infusion-related reaction, a maculopapular rash, pruritus, psoriasis, a rash, or a combination thereof.

[0369] Embodiment 89: The method of any one of embodiments 75 to 88, wherein the administration comprises one or more administration cycles.

[0370] Embodiment 90: The method of embodiment 89, wherein the administration cycle comprises administering the anti-TIGIT antibody to the subject once every two weeks, once every three weeks, or once every four weeks.

[0371] Embodiment 91: The method of any one of embodiments 75 to 90, wherein the anti-TIGIT antibody is administered to the subject at a dose of about 5 mg / kg, about 10 mg / kg, about...

Claims

1. A composition for treating cancer in human subjects requiring cancer treatment, comprising an anti-TIGIT antibody having reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1, wherein the treatment results in a reduction of one or more adverse events compared to a similar treatment comprising an Fc-responsive anti-TIGIT antibody.

2. A composition for treating cancer in human subjects requiring cancer treatment, comprising an anti-TIGIT antibody having reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1, wherein the subject is less likely to experience one or more adverse events compared to treatment with an Fc-corresponding anti-TIGIT antibody.

3. The composition according to claim 1 or 2, wherein the Fc-responsive anti-TIGIT antibody is selected from AB308, BMS-986207, tilagolumab, vivostrimab, etiglimab, osperimab, EOS-448, SEA-TGT, AGEN1777, AGEN1327, JS006, ralzapastutug, and an Fc-responsive version of domvanalimab containing a wild-type IgG1 Fc region.

4. A composition for treating cancer in human subjects requiring cancer treatment without significantly increasing the likelihood of adverse events compared to standard treatment, comprising an anti-TIGIT antibody having reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1, and characterized in that the composition is administered in combination with one or more additional therapies.

5. A composition for reducing one or more adverse events experienced by human subjects being treated for cancer with an anti-TIGIT antibody, comprising an anti-TIGIT antibody having reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1.

6. A composition for reducing one or more adverse events experienced by human subjects being treated for cancer with an anti-TIGIT antibody and an additional immunotherapy agent, comprising an anti-TIGIT antibody having reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1, wherein the composition is administered in combination with an additional immunotherapy agent.

7. The composition according to claim 6, wherein the immunotherapy agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, semiprimab, avelumab, durvalumab, atezolizumab, and zimberemab.

8. The composition according to any one of claims 1, 2, 4 to 6, wherein the adverse event is a treatment-related adverse event, an adverse event occurring under treatment, an immune-related adverse event, a treatment-related immune-related adverse event, a treatment-related adverse event leading to discontinuation of treatment, a treatment-related adverse event leading to interruption of treatment, a serious adverse event leading to discontinuation of treatment, a serious adverse event leading to interruption of treatment, a serious adverse event, a serious adverse event of grade 3 or higher, or a treatment-related adverse event of grade 3 or higher.

9. The aforementioned immune-related adverse events are (i) Skin or subcutaneous tissue disorders, gastrointestinal disorders, hepatobiliary disorders, endocrine disorders, or respiratory, thoracic or mediastinal disorders, (ii) Skin or subcutaneous tissue disorders, (iii) Rash, oral mucositis, dry mouth, colitis, diarrhea, hepatitis, pneumonia, endocrine disorders, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, or combination thereof, (iv) Arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reactions, maculopapular rash, pneumonia, itching, psoriasis, rash, facial swelling, or any combination thereof, (v) The composition according to claim 8, selected from injection-related reactions, maculopapular rash, pruritus, psoriasis, rash, or a combination thereof.

10. A composition for use in a method of reducing one or more dose reductions, temporary interruptions, or discontinuations of treatment experienced by human subjects being treated for cancer with an anti-TIGIT antibody, comprising an anti-TIGIT antibody having reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1.

11. A composition for use in a method of reducing one or more dose reductions, temporary interruptions, or discontinuations of treatment experienced by human subjects being treated for cancer with an anti-TIGIT antibody and an additional immunotherapy agent, comprising an anti-TIGIT antibody having reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1.

12. The composition according to claim 11, wherein the immunotherapy agent is a checkpoint inhibitor optionally selected from ipilimumab, nivolumab, pembrolizumab, semiprimab, avelumab, durvalumab, atezolizumab, and zimberemab.

13. The composition according to any one of claims 10 to 12, further comprising the reduction of one or more immune-related adverse events compared to a similar treatment comprising an Fc-responsive anti-TIGIT antibody.

14. The aforementioned immune-related adverse events are (i) Skin or subcutaneous tissue disorders, gastrointestinal disorders, hepatobiliary disorders, endocrine disorders, or respiratory, thoracic or mediastinal disorders, (ii) Skin or subcutaneous tissue disorders, (iii) Rash, oral mucositis, dry mouth, colitis, diarrhea, hepatitis, pneumonia, endocrine disorders, hypophysitis, hypothyroidism, hyperthyroidism, adrenal insufficiency, diabetes, or combination thereof, (iv) Arthritis, hepatitis, hypothyroidism, hyperthyroidism, infusion-related reactions, maculopapular rash, pneumonia, itching, psoriasis, rash, facial swelling, or any combination thereof, (v) The composition according to claim 13, selected from injection-related reactions, maculopapular rash, pruritus, psoriasis, rash, or a combination thereof.

15. The composition according to any one of claims 1, 2, 4 to 6, 10, and 11, characterized in that the composition is administered in one or more administration cycles.

16. The composition according to claim 15, wherein the administration cycle comprises administering the composition to the subject once every two weeks, once every three weeks, or once every four weeks.

17. The composition according to any one of claims 1, 2, 4-6, 10, and 11, characterized in that the composition is administered to the subject at a dose of the anti-TIGIT antibody of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, or about 25 mg / kg.

18. The composition according to any one of claims 1, 2, 4-6, 10, and 11, characterized in that the composition is administered to the subject in a dose of the anti-TIGIT antibody of about 500 mg to about 2000 mg, about 600 mg to about 800 mg, about 900 mg to about 1200 mg, about 1200 mg to about 1600 mg, or about 1200 mg to about 1500 mg.

19. The composition according to claim 15, wherein the administration cycle comprises administering the composition to the subject at a dose of approximately 1200 mg of the anti-TIGIT antibody once every three weeks or at a dose of approximately 1600 mg of the anti-TIGIT antibody once every four weeks.

20. The composition according to any one of claims 1, 2, 4-6, 10, and 11, characterized in that the composition is further administered in combination with one or more additional therapeutic agents, the one or more additional therapeutic agents being optionally an immunotherapy agent, a chemotherapeutic agent, a chemotherapeutic regimen, or a combination thereof.

21. The aforementioned immunotherapy agent is A checkpoint inhibitor selected at will from ipilimumab, nivolumab, pembrolizumab, semiprimab, avelumab, durvalumab, atezolizumab, and zimberemab, or Optionally, A ２ａ R Antagonist, A ２ｂ R Antagonist, A ２ａ R and A ２ｂ The composition according to claim 20, which is an ATP-adenosine axis targeting agent selected from an R antagonist, a CD73 inhibitor, and a CD39 inhibitor.

22. The composition according to claim 20, wherein the chemotherapy regimen is a fluoropyrimidine-containing chemotherapy or a platinum-containing chemotherapy.

23. The composition according to claim 22, wherein the fluoropyrimidine-containing chemotherapy is fluorouracil, and the platinum-containing chemotherapy is carboplatin, cisplatin, or oxaliplatin.

24. The composition according to claim 22, wherein the chemotherapy regimen is FOLFOX, CAPOX, cisplatin and pemetrexed, carboplatin and pemetrexed, carboplatin and paclitaxel, or carboplatin and nab-paclitaxel.

25. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the anti-TIGIT antibody having reduced binding to one or more activated human FcγRs is a human IgG4 or human IgG1 having reduced ability to bind to one or more activated human FcγRs.

26. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the anti-TIGIT having reduced binding to one or more activated human FcγRs does not bind to one or more activated human FcγRs.

27. The composition according to any one of claims 1, 2, 4 to 6, 10, and 11, wherein the anti-TIGIT antibody comprises a heavy chain CDR1 containing the amino acid sequence of SEQ ID NO: 2, a heavy chain CDR2 containing the amino acid sequence of SEQ ID NO: 3, a heavy chain CDR3 containing the amino acid sequence of SEQ ID NO: 4, a light chain CDR1 containing the amino acid sequence of SEQ ID NO: 5, a light chain CDR2 containing the amino acid sequence of SEQ ID NO: 6, and a light chain CDR3 containing the amino acid sequence of SEQ ID NO:

7.

28. The composition according to any one of claims 1, 2, 4 to 6, 10, and 11, wherein the anti-TIGIT antibody comprises a heavy chain variable region having at least 90% sequence identity with SEQ ID NO: 8 or 10 and a light chain variable region having at least 90% sequence identity with SEQ ID NO: 9 or 11.

29. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the anti-TIGIT antibody comprises a heavy chain having at least 90% sequence identity with SEQ ID NO: 12 and a light chain having at least 90% sequence identity with SEQ ID NO:

13.

30. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the anti-TIGIT antibody binds to the same TIGIT epitope as domvanalimab, or the anti-TIGIT antibody competitively inhibits the binding of domvanalimab to human TIGIT by at least 50%.

31. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the cancer is a solid tumor, and optionally, the tumor is locally advanced and / or unresectable, metastatic, recurrent, or unresponsive to treatment, and optionally, the treatment is standard treatment, a checkpoint inhibitor, a PD-1 antagonist, or a PD-L1 antagonist, or any combination thereof.

32. The composition according to claim 31, wherein the cancer is lung cancer, genitourinary cancer, or gastrointestinal cancer.

33. The composition according to claim 32, wherein the cancer is lung cancer.

34. The composition according to claim 33, wherein the lung cancer is non-small cell lung cancer (NSCLC), and optionally, the cancer is (i) locally advanced, unresectable, locally advanced unresectable, or metastatic, and (ii) no longer responsive to treatment, and optionally, the treatment is standard treatment, a checkpoint inhibitor, a PD-1 antagonist, or a PD-L1 antagonist, or (iii) a combination of (i) and (ii).

35. The composition according to claim 34, wherein the lung cancer is an unresectable locally progressive or metastatic disease of squamous or non-squamous epithelium.

36. The subject is the composition according to claim 33, which has no prior experience with checkpoint inhibitors.

37. The composition according to claim 33, wherein the subject is a checkpoint inhibitor.

38. The composition according to claim 32, wherein the cancer is gastrointestinal cancer.

39. The gastrointestinal cancer is esophageal cancer, gastric cancer, colorectal cancer, pancreatic cancer, or liver cancer, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced and unresectable, or metastatic, and / or (ii) no longer responds to standard treatment, checkpoint inhibitors, PD-1 antagonists, or PD-L1 antagonists, according to claim 38.

40. The gastrointestinal cancer is esophageal cancer or gastric cancer, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced and unresectable, or metastatic, and / or (ii) no longer responsive to treatment such as standard therapy, according to claim 39.

41. The gastrointestinal cancer is esophageal adenocarcinoma, esophageal squamous cell carcinoma, gastroesophageal junction adenocarcinoma, or gastric adenocarcinoma, and optionally, the cancer is (i) locally advanced, unresectable, locally advanced and unresectable, or metastatic, and / or (ii) no longer responsive to treatment such as standard therapy, according to claim 40.

42. The composition according to claim 41, wherein the cancer is NSCLC, head and neck squamous cell carcinoma (HNSCC), renal cell carcinoma (RCC), breast cancer, colorectal cancer (CRC), melanoma, bladder cancer, ovarian cancer, endometrial cancer, Merkel cells, or gastroesophageal cancer.

43. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the PD-L1 expression of the cancer is measured by a clinically validated PD-L1 IHC assay or an FDA-approved test, and the TPS is 50% or higher.

44. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the PD-L1 corresponds to a TPS of less than 50% when measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

45. The composition according to claim 44, wherein the PD-L1 expression of the cancer is approximately 1-10%, approximately 10-20%, approximately 20-30%, approximately 30-40%, approximately 40-49%, approximately 1-49%, approximately 1-25%, or approximately 25-49% when measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

46. The composition according to claim 44, wherein the PD-L1 expression of the cancer is less than 1% as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

47. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the cancer has a tumor mutation burden of high (TMB-H; as measured by an FDA-approved test, 10 mutations / megabase (mut / Mb) or more.

48. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the cancer is not TMB-H.

49. The composition according to any one of claims 1, 2, 4 to 6, 10, and 11, wherein the cancer does not have an actionable oncogenic mutation in ALK, EGFR, ROS, BRAF, or NTRK, and / or has wild-type ALK, EGFR, ROS, BRAF, and / or NTRK.

50. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the cancer expresses or overexpresses one or more biomarkers selected from CD73, DNAM-1, PVR, TIGIT, and CD8-Ki67.

51. The composition according to any one of claims 1, 2, 5, or 10, wherein the anti-TIGIT antibody, which has reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1, is domvanalimab, and the subject is also administered a therapeutically effective dose of a PD-1 antagonist or a PD-L1 antagonist.

52. The composition according to any one of claims 4, 6, or 11, wherein the anti-TIGIT antibody, which has reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1, is domvanalimab, and the additional agent is a PD-1 antagonist or a PD-L1 antagonist.

53. The composition according to claim 51, wherein the cancer is locally advanced, metastatic, or unresectable non-small cell lung cancer (NSCLC), or locally advanced and unresectable NSCLC, and dombanalimab is optionally administered at a dose of about 1200 mg once every three weeks, or at a dose of about 1600 mg once every four weeks.

54. The composition according to claim 53, wherein the cancer is metastatic NSCLC, and domvanalimab and the PD-1 antagonist or PD-L1 antagonist are administered in combination with a chemotherapy agent or chemotherapy regimen as first-line treatment.

55. The aforementioned cancer is Metastatic non-squamous NSCLC, characterized in that dombanalimab and the PD-1 antagonist or PD-L1 antagonist are administered in combination with a chemotherapy regimen, which optionally includes pemetrexed and platinum-containing chemotherapy, or The composition according to claim 54, wherein the patient is metastatic squamous cell NSCLC, and domvanalimab and the PD-1 antagonist or PD-L1 antagonist are administered in combination with a chemotherapy regimen, wherein the chemotherapy regimen is optionally a taxane and platinum-containing chemotherapy regimen.

56. The composition according to claim 53, wherein the cancer is locally advanced or metastatic NSCLC, and domvanalimab and the PD-1 antagonist or PD-L1 antagonist are administered as first-line treatment without additional therapeutic agents.

57. The cancer is locally advanced or metastatic NSCLC, and dombanalimab and the PD-1 antagonist or PD-L1 antagonist are first-line treatments. ２ａ R and / or A ２ｂ The composition according to claim 53, characterized in that it is administered in combination with an R antagonist or a CD73 inhibitor.

58. The composition according to claim 53, wherein the cancer is metastatic NSCLC, and domvanalimab and the PD-1 antagonist or PD-L1 antagonist are administered as a second-line or higher treatment, optionally in combination with one or more additional therapeutic agents.

59. The composition according to claim 58, wherein the subject has disease progression during or after treatment with platinum-containing chemotherapy, checkpoint inhibitors, or targeted therapy, and optionally the checkpoint inhibitor is a PD-1 antagonist or a PD-L1 antagonist, and optionally the targeted therapy is a tyrosine kinase inhibitor.

60. The composition according to claim 58, characterized in that dombanalimab and the PD-1 antagonist or PD-L1 antagonist are administered without additional therapeutic agents.

61. An additional therapeutic agent is administered to the subject in combination with domvanalimab and the PD-1 antagonist or PD-L1 antagonist, and optionally, each additional therapeutic agent is A ２ａ R antagonist, A ２ｂ R antagonist, A ２ａ R / A ２ｂ The composition according to claim 58, selected from an R antagonist, a CD73 inhibitor, a chemotherapeutic agent, or a chemotherapy regimen

62. The composition according to claim 53, characterized in that the cancer is locally advanced, unresectable NSCLC, the disease of the subject has not progressed after chemoradiotherapy, and domvanalimab and the PD-1 antagonist or PD-L1 antagonist are administered selectively without additional therapeutic agents.

63. The composition according to claim 51, wherein the cancer is NSCLC of stage IB, stage II, or stage III, and dombanalimab and the PD-1 antagonist or PD-L1 antagonist are administered as adjuvant therapy after complete surgical resection, and optionally, dombanalimab is administered at a dose of about 1200 mg once every three weeks or at a dose of about 1600 mg once every four weeks.

64. The composition according to claim 51, wherein the cancer is resectable NSCLC, and domvanalimab and the PD-1 antagonist or PD-L1 antagonist are administered in a neoadjuvant environment in combination with a chemotherapy regimen including platinum-containing chemotherapy.

65. The composition according to claim 53, wherein the cancer does not have oncogenic mutations that can act on epidermal growth factor (EGFR) or anaplastic lymphoma kinase (ALK), and / or the PD-L1 expression of the cancer is 1% or more, 5% or more, 10% or more, or 50% or more, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

66. The composition according to claim 51, wherein the cancer is esophageal, gastroesophageal junction (GEJ), or gastric adenocarcinoma (GA), and dombanalimab is optionally administered at a dose of about 1200 mg once every three weeks, or at a dose of about 1600 mg once every four weeks.

67. The composition according to claim 66, characterized in that the esophageal, GEJ, or GA cancer is locally advanced, unresectable, or metastatic, and dombanalimab and the PD-1 antagonist or PD-L1 antagonist are administered in combination with a chemotherapy agent or chemotherapy regimen as first-line treatment.

68. The composition according to claim 67, characterized in that domvanalimab and the PD-1 antagonist or PD-L1 antagonist are administered in combination with a chemotherapy regimen comprising fluoropyrimidine-containing and platinum-containing chemotherapy.

69. The composition according to claim 66, characterized in that the esophageal, GEJ, or GA cancer is locally advanced, locally advanced and unresectable, or metastatic, and dombanalimab and the PD-1 antagonist or PD-L1 antagonist are administered as a second-line or higher treatment, optionally, without additional therapeutic agents.

70. The subject is a patient who has disease progression during or after first-line or higher therapy comprising platinum-containing chemotherapy, fluoropyrimidine-containing chemotherapy, checkpoint inhibitors, targeting agents, or any combination thereof, and optionally, the checkpoint inhibitor is a PD-1 antagonist or a PD-L1 antagonist, and optionally, the targeting agent is HER2 / neu targeted therapy, according to claim 69.

71. The composition according to claim 66, wherein the subject has completely resected esophageal or GEJ cancer with residual lesions and is undergoing neoadjuvant chemoradiotherapy.

72. The composition according to claim 66, wherein the PD-L1 expression of the cancer is 1% or more, 5% or more, 10% or more, or 50% or more, as measured by a clinically validated PD-L1 IHC assay or an FDA-approved test.

73. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the treatment results in a reduction in tumor size, a reduction in the number of tumors, a reduction in metastasis, stabilization, partial response, complete response, or a combination thereof.

74. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the treatment results in an improvement in overall survival, progression-free survival, disease control rate, overall response rate, or a combination thereof, compared to placebo or standard treatment.

75. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the treatment results in an extension of progression-free interval, an extension of disease-free survival, an extension of duration of response, an extension of duration of clinical benefit, an extension of time to treatment failure, or any combination thereof, compared to placebo or standard treatment.

76. The composition according to any one of claims 1, 2, 4-6, 10, and 11, wherein the anti-TIGIT antibody, which has reduced binding to one or more activated human FcγR compared to wild-type (WT) human IgG1, is formulated for dilution as an aqueous solution containing about 10 mg / mL to about 100 mg / mL of antibody or about 20 mg / mL to about 60 mg / mL of antibody, a buffer containing about 15 to about 30 mM histidine / histidine-Cl, about 5% to about 10% (weight / volume) of an excipient selected from the group consisting of sucrose, dextrose, trehalose, sorbitol, and mannitol, about 0 mg / mL to about 10 mg / mL of NaCl, and about 0.05 mg / mL to about 0.6 mg / mL of polysorbate 80.

77. The composition according to claim 52, wherein the cancer is locally advanced, metastatic, or unresectable non-small cell lung cancer (NSCLC), or locally advanced and unresectable NSCLC, and dombanalimab is optionally administered at a dose of about 1200 mg once every three weeks, or at a dose of about 1600 mg once every four weeks.

78. The composition according to claim 52, wherein the cancer is NSCLC of stage IB, stage II, or stage III, and dombanalimab and the PD-1 antagonist or PD-L1 antagonist are administered as adjuvant therapy after complete surgical resection, and optionally, dombanalimab is administered at a dose of about 1200 mg once every three weeks or at a dose of about 1600 mg once every four weeks.

79. The composition according to claim 52, wherein the cancer is resectable NSCLC, and domvanalimab and the PD-1 antagonist or PD-L1 antagonist are administered in a neoadjuvant environment in combination with a chemotherapy regimen including platinum-containing chemotherapy.

80. The composition according to claim 52, wherein the cancer is esophageal, gastroesophageal junction (GEJ), or gastric adenocarcinoma (GA), and dombanalimab is optionally administered at a dose of about 1200 mg once every three weeks or at a dose of about 1600 mg once every four weeks.

Images