WO2024191807A1

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Publication number: WO2024191807A1
Application number: PCT/US2024/019082
Authority: WO
Inventors: John Harrold; Sahar ANSARI; Shyra Jane Gardai; Gabriela PATILEA-VRANA; Alyson Jessica SMITH; Haley Denise NEFF-LAFORD
Original assignee: Seagen Inc.
Priority date: 2023-03-10
Filing date: 2024-03-08
Publication date: 2024-09-19

Abstract

Provided herein are methods of treating cancer with an anti-TIGIT antibody.

Description

where + indicates the sugar molecule can be present or absent, and the numbers indicate the position of linkages between the sugar molecules. In the above structure, the sugar chain terminal which binds to asparagine is called a reducing terminal (at right), and the opposite side is called a non-reducing terminal. Fucose is usually bound to N-acetylglucosamine (“GlcNAc”) of the reducing terminal, typically by an α1,6 bond (the 6-position of GlcNAc is linked to the 1- position of fucose). “Gal” refers to galactose, and “Man” refers to mannose. [00149] A “complex N-glycoside-linked sugar chain” includes 1) a complex type, in which the non-reducing terminal side of the core structure has zero, one or more branches of galactose- N-acetylglucosamine (also referred to as “gal-GlcNAc”) and the non-reducing terminal side of gal-GlcNAc optionally has a sialic acid, bisecting N-acetylglucosamine or the like; and 2) a hybrid type, in which the non-reducing terminal side of the core structure has both branches of a high mannose N-glycoside-linked sugar chain and complex N-glycoside-linked sugar chain. [00150] In some methods as provided herein, only a minor amount of fucose is incorporated into the complex N-glycoside-linked sugar chain(s) of the anti-TIGIT antibodies. For example, in various embodiments, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3% of the anti-TIGIT antibodies in a composition have core fucosylation by fucose. For example, in various embodiments, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 3% of the anti-TIGIT antibodies in a composition have core fucosylation by fucose. In some embodiments, about 2% of the anti-TIGIT antibodies in the composition have core fucosylation by fucose. In various embodiments, when less than 60% of the anti-TIGIT antibodies in a composition have core fucosylation by fucose, the antibodies of the composition may be referred to as “nonfucosylated” or “afucosylated.” In some embodiments, at least 90%, at least 91%, at least Attorney Docket No.01218-0031-00PCT 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the anti-TIGIT antibodies in the composition are nonfucosylated. [00151] In certain embodiments, only a minor amount of a fucose analog (or a metabolite or product of the fucose analog) is incorporated into the complex N-glycoside-linked sugar chain(s). For example, in various embodiments, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3% of the anti-TIGIT antibodies have core fucosylation by a fucose analog or a metabolite or product of the fucose analog. For example, in various embodiments, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 3% of the anti-TIGIT antibodies have core fucosylation by a fucose analog or a metabolite or product of the fucose analog. In some embodiments, about 2% of the anti-TIGIT antibodies have core fucosylation by a fucose analog or a metabolite or product of the fucose analog. [00152] In some embodiments, less that about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, or less than about 3% of the anti-TIGIT antibodies in a composition have a fucose residue on a G0, G1, or G2 glycan structure. (See, e.g., Raju et al., 2012, MAbs 4: 385- 391, Figure 3.) In some embodiments, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 15%, less than 10%, less than 5%, or less than 3% of the anti- TIGIT antibodies in a composition have a fucose residue on a G0, G1, or G2 glycan structure. In some embodiments, about 2% of the anti-TIGIT antibodies in the composition have a fucose residue on a G0, G1, or G2 glycan structure. In various embodiments, when less than 60% of the anti-TIGIT antibodies in a composition have a fucose residue on a G0, G1, or G2 glycan structure, the antibodies of the composition may be referred to as “nonfucosylated.” In some embodiments, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the anti-TIGIT antibodies in the composition lack fucose on a G0, G1, or G2 glycan structure. It should be noted that G0 glycans include G0-GN glycans. G0-GN glycans are monoantenary glycans with one terminal GlcNAc residue. G1 glycans include G1-GN glycans. G1-GN glycans are monoantenary glycans with one terminal galactose residue. G0-GN and G1-GN glycans can be fucosylated or nonfucosylated. [00153] A variety of methods for generating nonfucosylated antibodies can be utilized. Exemplary strategies include the use of cell lines lacking certain biosynthetic enzymes involved in fucosylation pathways or the inhibition or the knockout of certain genes involved in the Attorney Docket No.01218-0031-00PCT fucosylation pathway. A review of such approaches is provided by Pereira, et al. (2018) mAbs 10:693-711, which is incorporated herein by reference in its entirety. [00154] For example, methods of making nonfucosylated antibodies, such as the nonfucosylated anti-TIGIT antibodies disclosed herein, by incubating antibody-producing cells with a fucose analogue are described, e.g., in WO2009/135181 and US 8,163,551. Briefly, cells that have been engineered to express the antibodies are incubated in the presence of a fucose analogue or an intracellular metabolite or product of the fucose analog. An intracellular metabolite can be, for example, a GDP-modified analog or a fully or partially de-esterified analog. A product can be, for example, a fully or partially de-esterified analog. In some embodiments, a fucose analogue can inhibit an enzyme(s) in the fucose salvage pathway. For example, a fucose analog (or an intracellular metabolite or product of the fucose analog) can inhibit the activity of fucokinase, or GDP-fucose-pyrophosphorylase. In some embodiments, a fucose analog (or an intracellular metabolite or product of the fucose analog) inhibits fucosyltransferase (preferably a 1,6-fucosyltransferase, e.g., the FUT8 protein). In some embodiments, a fucose analog (or an intracellular metabolite or product of the fucose analog) can inhibit the activity of an enzyme in the de novo synthetic pathway for fucose. For example, a fucose analog (or an intracellular metabolite or product of the fucose analog) can inhibit the activity of GDP-mannose 4,6-dehydratase or/or GDP-fucose synthetase. In some embodiments, the fucose analog (or an intracellular metabolite or product of the fucose analog) can inhibit a fucose transporter (e.g., GDP-fucose transporter). [00155] In one embodiment, the fucose analogue is 2-flurofucose. Methods of using fucose analogues in growth medium and other fucose analogues are disclosed, e.g., in WO 2009/135181, which is herein incorporated by reference. [00156] Other methods for engineering cell lines to reduce core fucosylation included gene knock-outs, gene knock-ins and RNA interference (RNAi). See, e.g., Pereira et al., 2018, mAbs, 10(5): 693-711. In gene knock-outs, the gene encoding FUT8 (alpha 1,6- fucosyltransferase enzyme) is inactivated. FUT8 catalyzes the transfer of a fucosyl residue from GDP-fucose to position 6 of Asn-linked (N-linked) GlcNac of an N-glycan. FUT8 is reported to be the only enzyme responsible for adding fucose to the N-linked biantennary carbohydrate at Asn297. Gene knock-ins add genes encoding enzymes such as GNTIII or a golgi alpha mannosidase II. An increase in the levels of such enzymes in cells diverts monoclonal antibodies from the fucosylation pathway (leading to decreased core fucosylation), and having increased amount of bisecting N-acetylglucosamines. RNAi typically also targets FUT8 gene expression, leading to decreased mRNA transcript levels or knocking out gene expression entirely. Attorney Docket No.01218-0031-00PCT [00157] Other strategies that may be used include GlycoMAb^® (US Patent No.6,602,684) and Potelligent^® (BioWa). [00158] Any of these methods can be used to generate a cell line that would be able to produce a nonfucosylated antibody. [00159] Various engineering approaches can also be utilized to obtain Fc regions with the desired FcγR activity and effector function. In some embodiments, the Fc is engineered to have the following combination of mutations: S239D, A330L and I332E, which increases the affinity of the Fc domain for FcγRIIIA and consequently increases ADCC. Additional substitutions that enhance affinity for FcγRIIIa include, for example, T256A, K290A, S298A, E333A, and K334A. Substitutions that enhance binding to activating FcγRIIIa and reduced binding to inhibitory FcγRIIIb include, for example, F243L/R292P/Y300L/V305I/P396L and F243L/R292P/Y300L/L235V/P396L. In some embodiments, the substitutions are in an IgG1 Fc backbone. [00160] Oligosaccharides covalently attached to the conserved Asn297 are involved in the ability of the Fc region of an IgG to bind FcγR (Lund et al., 1996, J. Immunol.157:4963-69; Wright and Morrison, 1997, Trends Biotechnol.15:26-31). Engineering of this glycoform on IgG can significantly improve IgG-mediated ADCC. Addition of bisecting N- acetylglucosamine modifications (Umana et al., 1999, Nat. Biotechnol.17:176-180; Davies et al., 2001, Biotech. Bioeng.74:288-94) to this glycoform or removal of fucose (Shields et al., 2002, J. Biol. Chem.277:26733-40; Shinkawa et al., 2003, J. Biol. Chem.278:6591-604; Niwa et al., 2004, Cancer Res.64:2127-33) from this glycoform are two examples of IgG Fc engineering that improves the binding between IgG Fc and FcγR, thereby enhancing Ig- mediated ADCC activity. [00161] A systemic substitution of solvent-exposed amino acids of human IgG1 Fc region has generated IgG variants with altered FcγR binding affinities (Shields et al., 2001, J. Biol. Chem. 276:6591-604). When compared to parental IgG1, a subset of these variants involving substitutions at Thr256/Ser298, Ser298/Glu333, Ser298/Lys334, or Ser298/Glu333/Lys334 to Ala demonstrate increased in both binding affinity toward FcγR and ADCC activity (Shields et al., 2001, J. Biol. Chem.276:6591-604; Okazaki et al., 2004, J. Mol. Biol.336:1239-49). [00162] Many methods are available to determine the amount of fucosylation on an antibody. Methods include, e.g., LC-MS via PLRP-S chromatography, electrospray ionization quadrupole TOF MS, Capillary Electrophoresis with Laser-Induced Fluorescence (CE−LIF), and Hydrophilic Interaction Chromatography with Fluorescence Detection (HILIC). Attorney Docket No.01218-0031-00PCT Exemplary Additional Therapeutic Agents [00163] In some embodiments, the methods provided herein comprise administering an anti- TIGIT antibody and an additional therapeutic agent, such as a checkpoint inhibitor or an antibody-drug conjugate, as a combination therapy. In some embodiments, the additional therapeutic agent is an immuno-oncology agent. In some embodiments, the immuno-oncology agent is an agent (e.g., an antibody, small molecule, or peptide) that antagonizes or inhibits a component of an immune checkpoint pathway, such as the PD-1 pathway, the CTLA-4 pathway, the Lag3 pathway, or the TIM-3 pathway. In some embodiments, the immuno-oncology agent is an agonist of a T cell coactivator (i.e., an agonist of a protein that stimulates T cell activation) by targeting the OX-40 pathway, the 4-1BB (CD137) pathway, the CD27 pathway, the ICOS pathway, or the GITR pathway. In some embodiments, the immuno-oncology agent is a PD-1 pathway inhibitor. [00164] In some embodiments, the immuno-oncology agent is an agonist of a T cell coactivator. In some embodiments, the immuno-oncology agent is an agonist of CD28, CD28H, CD3, 4-1BB (CD137), ICOS, OX40, GITR, CD27, or CD40. In some embodiments, the immuno-oncology agent is an immune stimulatory cytokine. In some embodiments, the immune stimulatory cytokine is granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), interleukin 1 (IL-1), interleukin 2 (IL-2), interleukin 3 (IL-3), interleukin 12 (IL-12), interleukin 15 (IL-15), or interferon gamma (IFN-γ). In some embodiments, the immuno-oncology agent is SGN-2FF (Seagen; see, e.g., WO 2009/135181 A2, WO 2012/019165 A2, and WO 2017/096274 A1). [00165] In some embodiments, the additional therapeutic agent is selected from an anti-CD25 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-Tim3 antibody, anti-Lag3 antibody, anti-CTLA4 antibody, anti-41BB antibody, anti-OX40 antibody, anti-CD3 antibody, anti-CD40 antibody, anti-CD47M antibody, anti-CSF1R antibody, TLR agonist, STING agonist, RIGI agonist, anti-TAM receptor kinase antibody, anti-NKG2A antibody, an anti-NKG2D antibody, an anti-GD2 antibody, an anti-HER2 antibody, an anti-EGFR antibody, an anti-PDGFR-α- antibody, an anti-SLAMF7 antibody, an anti-VEGF antibody, an anti-CTLA-4 antibody, an anti- CD20 antibody, an anti-cCLB8 antibody, an anti-KIR antibody, and an anti-CD52 antibody. In some embodiments, the additional therapeutic agent is selected from SEA-CD40 (Seattle Genetics; see, e.g., WO 2006/128103 A2 and WO 2016/069919 A1), avelumab, durvalumab, nivolumab, pembrolizumab, pidilizumab, atezolizumab, Hul4.18K322A (anti-GD2 antibody, St. Jude), Hu3F8 (anti-GD2 antibody, MSKCC), dinituximab, trastuzumab, cetuximab, olaratumab, Attorney Docket No.01218-0031-00PCT necitumumab, elotuzumab, ramucirumab, pertuzumab, ipilimumab, bevacizumab, rituximab, obinutuzumab, siltuximab, ofatumumab, and alemtuzumab. [00166] In some embodiments, the additional therapeutic agent is a PD-1 inhibitor or a PD- L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is AMP-224, CT-011, cemiplimab, camrelizumab, sintilimab, tislelizumab, TSR-042, PDR001, toripalimab, BGB-A317, nivolumab (also known as ONO-4538, BMS-936558, or MDX1106), pembrolizumab (also known as MK-3475, SCH 900475, or lambrolizumab), or dostarlimab. In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a human IgG4 anti-PD-1 monoclonal antibody, and is marketed under the trade name Opdivo^™. In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 antibody and is marketed under the trade name Keytruda™. In yet another embodiment, the anti-PD-1 antibody is CT-011, a humanized antibody. In yet another embodiment, the anti-PD-1 antibody is AMP-224, a fusion protein. In another embodiment, the anti-PD-1 antibody is BGB-A317. BGB-A317 is a monoclonal antibody in which the ability to bind Fc gamma receptor I is specifically engineered out, and which has a unique binding signature to PD-1 with high affinity and superior target specificity. In one embodiment, the PD-1 antibody is cemiplimab. In another embodiment, the anti-PD-1 antibody is camrelizumab. In a further embodiment, the anti-PD-1 antibody is sintilimab. In some embodiments, the anti-PD-1 antibody is tislelizumab. In certain embodiments, the anti- PD-1 antibody is TSR-042. In yet another embodiment, the anti-PD-1 antibody is PDR001. In yet another embodiment, the anti-PD-1 antibody is toripalimab. In yet another embodiment, the anti-PD-1 antibody is dostarlimab. [00167] In certain embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 antibody is MEDI4736 (also known as durvalumab or IMFINZI®), BMS-936559 (also known as MDX-1105-01), atezolizumab (also known as MPDL3280A, and Tecentriq^®), or avelumab (also known as BAVENCIO®). In one embodiment, the anti-PD-L1 antibody is MEDI4736 (durvalumab). In another embodiment, the anti-PD-L1 antibody is BMS-936559. In yet another embodiment, the PD-L1 inhibitor is atezolizumab. In a further embodiment, the PD-L1 inhibitor is avelumab. [00168] In some embodiments, the additional therapeutic agent is brentuximab vedotin. Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) having three components: (1) a chimeric IgG1 monoclonal antibody (cAC10), specific for human CD30; (2) monomethyl auristatin E (MMAE); and (3) a protease-cleavable linker that covalently attaches MMAE to cAC10. Attorney Docket No.01218-0031-00PCT Preparation of Antibodies [00169] For preparing an antibody, many techniques known in the art can be used. See, e.g., Kohler & Milstein, Nature 256:495-497 (1975); Kozbor et al., Immunology Today 4: 72 (1983); Cole et al., pp.77-96 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc. (1985); Coligan, Current Protocols in Immunology (1991); Harlow & Lane, Antibodies, A Laboratory Manual (1988); and Goding, Monoclonal Antibodies: Principles and Practice (2nd ed.1986)). [00170] The genes encoding the heavy and light chains of an antibody of interest can be cloned from a cell, e.g., the genes encoding a monoclonal antibody can be cloned from a hybridoma that expresses the antibody and used to produce a recombinant monoclonal antibody. Gene libraries encoding heavy and light chains of monoclonal antibodies can also be made from hybridoma or plasma cells. Additionally, phage or yeast display technology can be used to identify antibodies and heteromeric Fab fragments that specifically bind to selected antigens (see, e.g., McCafferty et al., Nature 348:552-554 (1990); Marks et al., Biotechnology 10:779- 783 (1992); Lou et al. (2010) PEDS 23:311; and Chao et al., Nature Protocols, 1:755-768 (2006)). Alternatively, antibodies and antibody sequences may be isolated and/or identified using a yeast-based antibody presentation system, such as that disclosed in, e.g., Xu et al., Protein Eng Des Sel, 2013, 26:663-670; WO 2009/036379; WO 2010/105256; and WO 2012/009568. Random combinations of the heavy and light chain gene products generate a large pool of antibodies with different antigenic specificity (see, e.g., Kuby, Immunology (3^rd ed. 1997)). Techniques for the production of single chain antibodies or recombinant antibodies (US Patent 4,946,778, US Patent No.4,816,567) can also be adapted to produce antibodies. Antibodies can also be made bispecific, i.e., able to recognize two different antigens (see, e.g., WO 93/08829, Traunecker et al., EMBO J.10:3655-3659 (1991); and Suresh et al., Methods in Enzymology 121:210 (1986)). Antibodies can also be heteroconjugates, e.g., two covalently joined antibodies, or antibodies covalently bound to immunotoxins (see, e.g., US Patent No. 4,676,980, WO 91/00360; and WO 92/200373). [00171] Antibodies can be produced using any number of expression systems, including prokaryotic and eukaryotic expression systems. In some embodiments, the expression system is a mammalian cell, such as a hybridoma, or a CHO cell. Many such systems are widely available from commercial suppliers. In embodiments in which an antibody comprises both a heavy chain and light chain, the heavy chain and heavy chain and light chain may be expressed using a single vector, e.g., in a di-cistronic expression unit, or be under the control of different promoters. In other embodiments, the heavy chain and light chain region may be expressed using separate vectors. Heavy chains and light chains as described herein may optionally comprise a methionine at the N-terminus. Attorney Docket No.01218-0031-00PCT [00172] In some embodiments, antibody fragments (such as a Fab, a Fab’, a F(ab’)₂, a scFv, or a diabody) are generated. Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were derived via proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., J. Biochem. Biophys. Meth., 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly using recombinant host cells. For example, antibody fragments can be isolated from antibody phage libraries. Alternatively, Fab’-SH fragments can be directly recovered from E. coli cells and chemically coupled to form F(ab’)₂ fragments (see, e.g., Carter et al., BioTechnology, 10:163-167 (1992)). According to another approach, F(ab’)₂ fragments can be isolated directly from recombinant host cell culture. Other techniques for the production of antibody fragments will be apparent to those skilled in the art. In other embodiments, the antibody of choice is a single chain Fv fragment (scFv). See, e.g., PCT Publication No. WO 93/16185; and US Patent Nos.5,571,894 and 5,587,458. The antibody fragment may also be a linear antibody as described, e.g., in US Patent No.5,641,870. [00173] In some embodiments, the antibody or antibody fragment can be conjugated to another molecule, e.g., polyethylene glycol (PEGylation) or serum albumin, to provide an extended half-life in vivo. Examples of PEGylation of antibody fragments are provided in Knight et al. Platelets 15:409, 2004 (for abciximab); Pedley et al., Br. J. Cancer 70:1126, 1994 (for an anti-CEA antibody); Chapman et al., Nature Biotech.17:780, 1999; and Humphreys, et al., Protein Eng. Des.20: 227, 2007). [00174] In some embodiments, multispecific antibodies are provided, e.g., a bispecific antibody. Multispecific antibodies are antibodies that have binding specificities for at least two different antigens or for at least two different epitopes of the same antigen. Methods for making multispecific antibodies include, but are not limited to, recombinant co-expression of two pairs of heavy chain and light chain in a host cell (see, e.g., Zuo et al., Protein Eng Des Sel, 2000, 13:361-367); “knobs-into-holes” engineering (see, e.g., Ridgway et al., Protein Eng Des Sel, 1996, 9:617-721); “diabody” technology (see, e.g., Hollinger et al., PNAS (USA), 1993, 90:6444-6448); and intramolecular trimerization (see, e.g., Alvarez-Cienfuegos et al., Scientific Reports, 2016, doi:/10.1038/srep28643); see also, Spiess et al., Molecular Immunology, 2015, 67(2), Part A:95-106. Selection of Constant Region [00175] Heavy and light chain variable regions of the antibodies described herein can be linked to at least a portion of a human constant region. The choice of constant region depends, in part, whether antibody-dependent cell-mediated cytotoxicity, antibody dependent cellular phagocytosis and/or complement dependent cytotoxicity are desired. For example, human Attorney Docket No.01218-0031-00PCT isotopes IgG1 and IgG3 have strong complement-dependent cytotoxicity, human isotype IgG2 weak complement-dependent cytotoxicity and human IgG4 lacks complement-dependent cytotoxicity. Human IgG1 and IgG3 also induce stronger cell mediated effector functions than human IgG2 and IgG4. Light chain constant regions can be lambda or kappa. Antibodies can be expressed as tetramers containing two light and two heavy chains, as separate heavy chains, light chains, as Fab, Fab', F(ab')₂, and Fv, or as single chain antibodies in which heavy and light chain variable domains are linked through a spacer. [00176] Human constant regions show allotypic variation and isoallotypic variation between different individuals, that is, the constant regions can differ in different individuals at one or more polymorphic positions. Isoallotypes differ from allotypes in that sera recognizing an isoallotype binds to a non-polymorphic region of one or more other isotypes. [00177] One or several amino acids at the amino or carboxy terminus of the light and/or heavy chain, such as the C-terminal lysine of the heavy chain, may be missing or derivatized in a proportion or all of the molecules. Substitutions can be made in the constant regions to reduce or increase effector function such as complement-mediated cytotoxicity or ADCC (see, e.g., Winter et al., US Patent No.5,624,821; Tso et al., US Patent No.5,834,597; and Lazar et al., Proc. Natl. Acad. Sci. USA 103:4005, 2006), or to prolong half-life in humans (see, e.g., Hinton et al., J. Biol. Chem.279:6213, 2004). [00178] For constructing desired antibodies, in some embodiments, exemplary substitution include the amino acid substitution of the native amino acid to a cysteine residue is introduced at amino acid position 234, 235, 237, 239, 267, 298, 299, 326, 330, or 332, preferably an S239C mutation in a human IgG1 isotype (numbering is according to the EU index (Kabat, Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, MD, 1987 and 1991); see US 20100158909, which is herein incorporated reference). The presence of an additional cysteine residue may allow interchain disulfide bond formation. Such interchain disulfide bond formation can cause steric hindrance, thereby reducing the affinity of the Fc region-FcγR binding interaction. Other substitutions at any of positions 234, 235, 236 and/or 237 reduce affinity for Fcγ receptors, particularly FcγRI receptor (see, e.g., US 6,624,821, US 5,624,821). [00179] The in vivo half-life of an antibody can also impact its effector functions. The half- life of an antibody can be increased or decreased to modify its therapeutic activities. FcRn is a receptor that is structurally similar to MHC Class I antigen that non-covalently associates with β2-microglobulin. FcRn regulates the catabolism of IgGs and their transcytosis across tissues (Ghetie and Ward, 2000, Annu. Rev. Immunol.18:739-766; Ghetie and Ward, 2002, Immunol. Res.25:97-113). The IgG-FcRn interaction takes place at pH 6.0 (pH of intracellular vesicles) Attorney Docket No.01218-0031-00PCT but not at pH 7.4 (pH of blood); this interaction enables IgGs to be recycled back to the circulation (Ghetie and Ward, 2000, Ann. Rev. Immunol.18:739-766; Ghetie and Ward, 2002, Immunol. Res.25:97-113). The region on human IgG1 involved in FcRn binding has been mapped (Shields et al., 2001, J. Biol. Chem.276:6591-604). Alanine substitutions at positions Pro238, Thr256, Thr307, Gln311, Asp312, Glu380, Glu382, or Asn434 of human IgG1 enhance FcRn binding (Shields et al., 2001, J. Biol. Chem.276:6591-604). IgG1 molecules harboring these substitutions have longer serum half-lives. Consequently, these modified IgG1 molecules may be able to carry out their effector functions, and hence exert their therapeutic efficacies, over a longer period of time compared to unmodified IgG1. Other exemplary substitutions for increasing binding to FcRn include a Gln at position 250 and/or a Leu at position 428. EU numbering is used for all positions in the constant region. [00180] Complement fixation activity of antibodies (both C1q binding and CDC activity) can be improved by substitutions at Lys326 and Glu333 (Idusogie et al., 2001, J. Immunol. 166:2571-2575). The same substitutions on a human IgG2 backbone can convert an antibody isotype that binds poorly to C1q and is severely deficient in complement activation activity to one that can both bind C1q and mediate CDC (Idusogie et al., 2001, J. Immunol.166:2571-75). Several other methods have also been applied to improve complement fixation activity of antibodies. For example, the grafting of an 18-amino acid carboxyl-terminal tail piece of IgM to the carboxyl-termini of IgG greatly enhances their CDC activity. This is observed even with IgG4, which normally has no detectable CDC activity (Smith et al., 1995, J. Immunol. 154:2226-36). Also, substituting Ser444 located close to the carboxy-terminal of IgG1 heavy chain with Cys induced tail-to-tail dimerization of IgG1 with a 200-fold increase of CDC activity over monomeric IgG1 (Shopes et al., 1992, J. Immunol.148:2918-22). In addition, a bispecific diabody construct with specificity for C1q also confers CDC activity (Kontermann et al., 1997, Nat. Biotech.15:629-31). [00181] Complement activity can be reduced by mutating at least one of the amino acid residues 318, 320, and 322 of the heavy chain to a residue having a different side chain, such as Ala. Other alkyl-substituted non-ionic residues, such as Gly, Ile, Leu, or Val, or such aromatic non-polar residues as Phe, Tyr, Trp and Pro in place of any one of the three residues also reduce or abolish C1q binding. Ser, Thr, Cys, and Met can be used at residues 320 and 322, but not 318, to reduce or abolish C1q binding activity. Replacement of the 318 (Glu) residue by a polar residue may modify but not abolish C1q binding activity. Replacing residue 297 (Asn) with Ala results in removal of lytic activity but only slightly reduces (about three-fold weaker) affinity for C1q. This alteration destroys the glycosylation site and the presence of carbohydrate that is required for complement activation. Any other substitution at this site also destroys the Attorney Docket No.01218-0031-00PCT glycosylation site. The following mutations and any combination thereof also reduce C1q binding: D270A, K322A, P329A, and P311S (see WO 06/036291). [00182] Reference to a human constant region includes a constant region with any natural allotype or any permutation of residues occupying polymorphic positions in natural allotypes. Also, up to 1, 2, 5, or 10 mutations may be present relative to a natural human constant region, such as those indicated above to reduce Fcγ receptor binding or increase binding to FcRN. Nucleic Acids, Vectors, and Host Cells [00183] In some embodiments, the antibodies described herein are prepared using recombinant methods. Accordingly, in some aspects, the invention provides isolated nucleic acids comprising a nucleic acid sequence encoding any of the antibodies described herein (e.g., any one or more of the CDRs described herein); vectors comprising such nucleic acids; and host cells into which the nucleic acids are introduced that are used to replicate the antibody-encoding nucleic acids and/or to express the antibodies. In some embodiments, the host cell is eukaryotic, e.g., a Chinese Hamster Ovary (CHO) cell; or a human cell. [00184] In some embodiments, a polynucleotide (e.g., an isolated polynucleotide) comprises a nucleotide sequence encoding an antibody described herein. In some embodiments, the polynucleotide comprises a nucleotide sequence encoding one or more amino acid sequences (e.g., CDR, heavy chain, light chain, and/or framework regions) disclosed herein. In some embodiments, the polynucleotide comprises a nucleotide sequence encoding an amino acid sequence having at least 85% sequence identity (e.g., at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity) to a sequence (e.g., a CDR, heavy chain, light chain, or framework region sequence) disclosed herein. [00185] In a further aspect, methods of making an antibody described herein are provided. In some embodiments, the method includes culturing a host cell as described herein (e.g., a host cell expressing a polynucleotide or vector as described herein) under conditions suitable for expression of the antibody. In some embodiments, the antibody is subsequently recovered from the host cell (or host cell culture medium). [00186] Suitable vectors containing polynucleotides encoding antibodies of the present disclosure, or fragments thereof, include cloning vectors and expression vectors. While the cloning vector selected may vary according to the host cell intended to be used, useful cloning vectors generally have the ability to self-replicate, may possess a single target for a particular restriction endonuclease, and/or may carry genes for a marker that can be used in selecting clones containing the vector. Examples include plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript (e.g., pBS SK+) and its derivatives, mpl8, mpl9, pBR322, pMB9, ColE1, Attorney Docket No.01218-0031-00PCT pCR1, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28. Cloning vectors are available from commercial vendors such as BioRad, Stratagene, and Invitrogen. [00187] Expression vectors generally are replicable polynucleotide constructs that contain a nucleic acid of the present disclosure. The expression vector may replicate in the host cells either as episomes or as an integral part of the chromosomal DNA. Suitable expression vectors include but are not limited to plasmids, viral vectors, including adenoviruses, adeno-associated viruses, retroviruses, and any other vector. Expression of Recombinant Antibodies [00188] Antibodies are typically produced by recombinant expression. Recombinant polynucleotide constructs typically include an expression control sequence operably linked to the coding sequences of antibody chains, including naturally-associated or heterologous promoter regions. Preferably, the expression control sequences are eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells. Once the vector has been incorporated into the appropriate host, the host is maintained under conditions suitable for high level expression of the nucleotide sequences, and the collection and purification of the cross-reacting antibodies. [00189] Mammalian cells are a preferred host for expressing nucleotide segments encoding immunoglobulins or fragments thereof. See Winnacker, From Genes to Clones, (VCH Publishers, NY, 1987). A number of suitable host cell lines capable of secreting intact heterologous proteins have been developed in the art, and include CHO cell lines (e.g., DG44), various COS cell lines, HeLa cells, HEK293 cells, L cells, and non-antibody-producing myelomas including Sp2/0 and NS0. Preferably, the cells are nonhuman. Expression vectors for these cells can include expression control sequences, such as an origin of replication, a promoter, an enhancer (Queen et al., Immunol. Rev.89:49 (1986)), and necessary processing information sites, such as ribosome binding sites, RNA splice sites, polyadenylation sites, and transcriptional terminator sequences. Preferred expression control sequences are promoters derived from endogenous genes, cytomegalovirus, SV40, adenovirus, bovine papillomavirus, and the like. See Co et al., J. Immunol.148:1149 (1992). [00190] Once expressed, antibodies can be purified according to standard procedures of the art, including HPLC purification, column chromatography, gel electrophoresis and the like (see generally, Scopes, Protein Purification (Springer-Verlag, NY, 1982)). Antibody Characterization [00191] Methods for analyzing binding affinity, binding kinetics, and cross-reactivity are known in the art. See, e.g., Ernst et al., Determination of Equilibrium Dissociation Constants, Therapeutic Monoclonal Antibodies (Wiley & Sons ed.2009). These methods include, but are Attorney Docket No.01218-0031-00PCT not limited to, solid-phase binding assays (e.g., ELISA assay), immunoprecipitation, surface plasmon resonance (SPR, e.g., Biacore™ (GE Healthcare, Piscataway, NJ)), kinetic exclusion assays (e.g., KinExA^®), flow cytometry, fluorescence-activated cell sorting (FACS), BioLayer interferometry (e.g., Octet™ (FortéBio, Inc., Menlo Park, CA)), and Western blot analysis. SPR techniques are reviewed, e.g., in Hahnfeld et al. Determination of Kinetic Data Using SPR Biosensors, Molecular Diagnosis of Infectious Diseases (2004). In a typical SPR experiment, one interactant (target or targeting agent) is immobilized on an SPR-active, gold-coated glass slide in a flow cell, and a sample containing the other interactant is introduced to flow across the surface. When light of a given wavelength is shined on the surface, the changes to the optical reflectivity of the gold indicate binding, and the kinetics of binding. In some embodiments, kinetic exclusion assays are used to determine affinity. This technique is described, e.g., in Darling et al., Assay and Drug Development Technologies Vol.2, number 6647-657 (2004). In some embodiments, BioLayer interferometry assays are used to determine affinity. This technique is described, e.g., in Wilson et al., Biochemistry and Molecular Biology Education, 38:400-407 (2010); Dysinger et al., J. Immunol. Methods, 379:30-41 (2012). IV. Expression Levels of PD-L1 [00192] The level of expression of PD-L1 in a cancer in a subject can be measured prior to administering any antibody, agent, or composition or utilizing any method disclosed herein. The level of expression can be determined by any methods known in the art. [00193] In order to assess the level of expression of PD-L1, in some embodiments, a cancer tissue sample can be obtained from the subject who is in need of the therapy. In another embodiment, the assessment of level of expression of PD-L1 can be achieved without obtaining a cancer tissue sample. In some embodiments, selecting a suitable subject includes (i) optionally providing a cancer tissue sample obtained from a subject, the cancer tissue sample comprising cancer cells and/or cancer-infiltrating inflammatory cells; and (ii) assessing the proportion of cells in the cancer tissue sample that express PD-L1 on the surface of the cells. [00194] In any of the methods comprising the measurement of PD-L1 expression in a cancer tissue sample, however, it should be understood that the step comprising the provision of a cancer tissue sample obtained from a subject is an optional step. It should also be understood that in certain embodiments the “measuring” or “assessing” step to identify, or determine the number or proportion of, cells in the cancer tissue sample that express PD-L1 on the cell surface is performed by a transformative method of assaying for PD-L1 expression, for example by performing a reverse transcriptase-polymerase chain reaction (RT-PCR) assay or an immunohistochemical (IHC) assay. In some embodiments, no transformative step is involved Attorney Docket No.01218-0031-00PCT and PD-L1 expression is assessed by, for example, reviewing a report of test results from a laboratory. In certain embodiments, the steps of the methods up to, and including, assessing PD- L1 expression provides an intermediate result that may be provided to a physician or other healthcare provider for use in selecting a suitable subject for treatment. In certain embodiments, the steps that provide the intermediate result is performed by a medical practitioner or someone acting under the direction of a medical practitioner. In other embodiments, these steps are performed by an independent laboratory or by an independent person such as a laboratory technician. [00195] In some embodiments, the proportion of cells that express PD-L1 is assessed by performing an assay to determine the presence of PD-L1 RNA. In some embodiments, the presence of PD-L1 RNA is determined by RT-PCR, in situ hybridization or RNase protection. In other embodiments, the proportion of cells that express PD-L1 is assessed by performing an assay to determine the presence of PD-L1 polypeptide. In some embodiments, the presence of PD-L1 polypeptide is determined by an IHC assay, an enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry. In some embodiments, PD-L1 expression is determined by an IHC assay. See Chen et al., (2013) Clin. Cancer Res.19(13): 3462-3473. [00196] Imaging techniques have provided important tools in cancer research and treatment. Recent developments in molecular imaging systems, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), fluorescence reflectance imaging (FRI), fluorescence-mediated tomography (FMT), bioluminescence imaging (BLI), laser-scanning confocal microscopy (LSCM) and multiphoton microscopy (MPM), may herald even greater use of these techniques in cancer research. Some of these molecular imaging systems allow clinicians to not only see where a cancer is located in the body, but also to visualize the expression and activity of specific molecules, cells, and biological processes that influence cancer behavior and/or responsiveness to therapeutic drugs (Condeelis and Weissleder, In vivo imaging in cancer, Cold Spring Harb. Perspect. Biol.2(12): a003848 (2010)). Antibody specificity, coupled with the sensitivity and resolution of PET, makes immunoPET imaging particularly attractive for monitoring and assaying expression of antigens in tissue samples (McCabe and Wu, Positive progress in immunoPET—not just a coincidence, Cancer Biother. Radiopharm.25(3):253-61 (2010); Olafsen et al., ImmunoPET imaging of B-cell lymphoma using 124I-anti-CD20 scFv dimers (diabodies), Protein Eng. Des. Sel.23(4):243-9 (2010)). In certain embodiments, PD-L1 expression is assayed by immunoPET imaging. In certain embodiments, the proportion of cells in a cancer tissue sample that express PD-L1 is assessed by performing an assay to determine the presence of PD-L1 polypeptide on the surface of cells in the cancer tissue sample. In certain embodiments, the cancer tissue sample is a formalin-fixed Attorney Docket No.01218-0031-00PCT paraffin-embedded (FFPE) tissue sample. In other embodiments, the presence of PD-L1 polypeptide is determined by an IHC assay. In further embodiments, the IHC assay is performed using an automated process. In some embodiments, the IHC assay is performed using an anti-PD-L1 monoclonal antibody to bind to the PD-L1 polypeptide. [00197] In some embodiments, an automated IHC method is used to assay the expression of PD-L1 on the surface of cells in FFPE tissue specimens. This disclosure provides methods for detecting the presence of human PD-L1 antigen in a cancer tissue sample, or quantifying the level of human PD-L1 antigen or the proportion of cells in the sample that express the antigen, which methods comprise contacting the test sample, and a negative control sample, with a monoclonal antibody that specifically binds to human PD-L1, under conditions that allow for formation of a complex between the antibody or portion thereof and human PD-L1. In certain embodiments, the test and control tissue samples are FFPE samples. The formation of a complex is then detected, wherein a difference in complex formation between the test sample and the negative control sample is indicative of the presence of human PD-L1 antigen in the sample. Various methods are used to quantify PD-L1 expression. [00198] In some embodiments, an automated IHC method comprises: (a) deparaffinizing and rehydrating mounted tissue sections in an autostainer; (b) retrieving antigen using a decloaking chamber and pH 6 buffer, heated to 110° C. for 10 min; (c) setting up reagents on an autostainer; and (d) running the autostainer to include steps of neutralizing endogenous peroxidase in the tissue specimen; blocking non-specific protein-binding sites on the slides; incubating the slides with primary antibody; incubating with a post primary blocking agent; incubating with NovoLink Polymer; adding a chromogen substrate and developing; and counterstaining with hematoxylin. [00199] For assessing PD-L1 expression in cancer tissue samples, a pathologist may examine the number of membrane PD-L1+ cancer cells in each field under a microscope and mentally estimates the percentage of cells that are positive, then averages them to come to the final percentage. The different staining intensities may be defined as 0/negative, 1+/weak, 2+/moderate, and 3+/strong. Percentage values may be first assigned to the 0 and 3+ buckets, and then the intermediate 1+ and 2+ intensities may be considered. For highly heterogeneous tissues, the specimen may be divided into zones, and each zone may be scored separately and then combined into a single set of percentage values. The percentages of negative and positive cells for the different staining intensities are determined from each area and a median value is given to each zone. A final percentage value may be given to the tissue for each staining intensity category: negative, 1+, 2+, and 3+. The sum of all staining intensities may be 100%. Attorney Docket No.01218-0031-00PCT [00200] Staining is also assessed in cancer-infiltrating inflammatory cells such as macrophages and lymphocytes. In most cases macrophages serve as an internal positive control since staining is observed in a large proportion of macrophages. While not required to stain with 3+ intensity, an absence of staining of macrophages may be taken into account to rule out any technical failure. Macrophages and lymphocytes may be assessed for plasma membrane staining and only recorded for all samples as being positive or negative for each cell category. Staining is also characterized according to an outside/inside cancer immune cell designation. “Inside” means the immune cell is within the cancer tissue and/or on the boundaries of the cancer region without being physically intercalated among the cancer cells. “Outside” means that there is no physical association with the cancer, the immune cells being found in the periphery associated with connective or any associated adjacent tissue. [00201] In certain embodiments of these scoring methods, the samples are scored by two pathologists operating independently, and the scores are subsequently consolidated. In certain other embodiments, the identification of positive and negative cells is scored using appropriate software. [00202] A histoscore is used as a more quantitative measure of the IHC data. In some embodiments, the histoscore may be calculated as follows: Histoscore = [(% cancer × 1 (low intensity)) + (% cancer × 2 (medium intensity)) + (% cancer × 3 (high intensity)] [00203] In some embodiment, to determine the histoscore, the pathologist may estimate the percentage of stained cells in each intensity category within a specimen. Because expression of most biomarkers is heterogeneous, the histoscore can be a truer representation of the overall expression. The final histoscore range is 0 (no expression) to 300 (maximum expression). [00204] In some embodiments, a means of quantifying PD-L1 expression in a cancer is to determine the adjusted inflammation score (AIS) score defined as the density of inflammation multiplied by the percent PD-L1 expression by cancer-infiltrating inflammatory cells. Taube et al., Colocalization of inflammatory response with B7-hl expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape, Sci. Transl. Med.

[00205] In some embodiments, a means of quantifying PD-L1 expression in a cancer is to determine the Combined Positive Score (CPS), which as described above, is the number of PD- L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100. For some therapeutic treatments, a tumor sample is considered to have PD-L1 expression if CPS ≥ 1. [00206] In some embodiments, a means of quantifying PD-L1 expression in a cancer is to determine the Tumor Proportion Score (TPS), which as described above, is the percentage of Attorney Docket No.01218-0031-00PCT viable tumor cells showing partial or complete membrane staining at any intensity. For some therapeutic treatments, a tumor sample is considered to have PD-L1 expression if TPS ≥ 1% and high PD-L1 expression if TPS ≥ 50%. [00207] In some embodiments, a means for quantifying PD-L1 expression in a cancer is to determine a Tumor Cell (TC) score. For some therapeutic treatments, a tumor sample is considered to have PD-L1 expression if TC ≥50%. [00208] In some embodiments, a means for quantifying PD-L1 expression in a cancer is to determine a Tumor-Infiltrating Immune Cell (IC) score. For some therapeutic treatments, a tumor sample is considered to have PD-L1 expression if a specimen contains PD-L1 staining of any intensity in tumor infiltrating immune cells occupying ≥ 5% of tumor area. [00209] In some embodiments, a means of quantifying PD-L1 expression in a cancer is the Agilent (Dako) PD-L1 IHC 223 pharmDx Assay™, a description of which may be found in at least one of the following: 1) Physician Labeling, Dako PD-L1 IHC 22C3 pharmDx, Dako North America, Inc., Carpinteria, CA; 2) Keytruda package insert (2021) Merck & Co., Inc., Kenilworth, NJ; 3) PD-L1 IHC 22C3 pharmDx Instructions for Use (2020) Dako, Agilent Pathology Solutions, Carpinteria, CA; 4) Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer, N. Engl. J. Med.372(21):2018-2028 (2015); and 5) Roach C, Zhang N, Corigliano E, et al. Development of a companion diagnostic PD-L1 immunohistochemistry assay for pembrolizumab therapy in non-small-cell lung cancer, Appl Immunohistochem Mol. Morphol.24:392-397 (2016). [00210] In some embodiments, a means of quantifying PD-L1 expression in a cancer is the Agilent (Dako) PD-L1 IHC 28-8 pharmDx Assay™, a description of which may be found in at least one of the following: 1) Physician Labeling, Dako PD-L1 IHC 28-8 pharmDx (2020) Dako North America, Inc., Carpinteria, CA; 2) OPDIVO package insert (2021) Bristol Myers Squibb, New York, NY; 3) PD-L1 IHC 28-8 pharm Dx: Interpretation Manual (2021), Dako, Agilent Pathology Solutions, Carpinteria, CA; and 4) Phillips T, Simmons P, Inzunza HD, Cogswell J, Novotny J Jr, Taylor C, et al. Development of an automated PD-L1 immunohistochemistry (IHC) assay for non-small cell lung cancer, Appl. Immunohistochem. Mol. Morphol.23:541-9 (2015). [00211] In some embodiments, a means of quantifying PD-L1 expression in a cancer is the Agilent (Dako) PD-L1 IHC 73-10 Assay™, a description of which may be found in at least one of the following: 1) Hans, J.G. et al. PD-L1 Immunohistochemistry Assay Comparison Studies in Non-Small Cell Lung Cancer: Characterization of the 73-10 Assay, J. Thoracic Oncology 15:1306-1316 (2020); and 2) Bavencio package insert (2021) EMD Serono, Inc. Rockland, MA and Pfizer Inc., New York, NY. Attorney Docket No.01218-0031-00PCT [00212] In some embodiments, a means of quantifying PD-L1 expression in a cancer is the Ventana PD-L1 (SP142) Assay™, a description of which may be found in at least one of the following: 1) Physician Labeling: Ventana PD-L1 (SP142) Assay (2020) Ventana Medical Systems, Inc. and Roche Diagnostics International, Inc.; 2) Tecentriq package insert (2021) Genentech, Inc., South San Francisco, CA; 3) Ventana PD-L1 (SP142) Assay: Interpretation Guide (2019) Ventana Medical Systems, Inc. and Roche Diagnostics International, Inc.; and 4) Vennapusa et al., Development of a PD-L1 Complementary Diagnostic Immunochemistry Assay (SP142) for Atezolizumab, Appl. Immunohistochem. Mol. Morphol.27:92-100 (2019). [00213] In some embodiments, a means of quantifying PD-L1 expression in a cancer is the Ventana PD-L1 (SP263) Assay™, a description of which may be found in at least one of the following: 1) Physician Labeling: Ventana PD-L1 (SP263) Assay (2017) Ventana Medical Systems, Inc., Tucson, AZ; 2) Imfinzi package insert (2021), AstraZeneca Pharmaceuticals LP, Wilmington, DE; and 3) Ventana PD-L1 (SP263) Assay Staining: Interpretation Guide (2019) Roche Diagnostics GmbH, Munich, DE. [00214] Additionally, O’Malley et al., Immunohistochemical detection of PD-L1 among diverse human neoplasms in a reference laboratory: observations based upon 62,896 cases, Modern Pathology 32:929-942 (2019), provides a description evaluating PD-L1 expression using antibody clones 22C3, 28-8, SP142, or SP263, in various types of cancers. V. Therapeutic Methods [00215] In some embodiments, the methods are based in part on the surprising finding that cancers that are resistant or have become refractory to a PD-1 inhibitor or a PD-L1 inhibitor can be treated with an anti-TIGIT antibody as a monotherapy, or with an anti-TIGIT antibody and an additional therapeutic agent, such as a checkpoint inhibitor, as a combination therapy. In some embodiments, the methods are based in part on the surprising finding that a certain dose of an anti-TIGIT antibody, such as a dose of 0.3, 1, or 3 mg/kg and in particular a dose of 1 mg/kg, constitutes a superior dose of the anti-TIGIT antibody for treating a cancer in a subject. [00216] In some embodiments, a method for treating a cancer in a human subject is provided. In some embodiments, the method comprises administering to the subject an anti-TIGIT antibody, wherein the cancer is resistant or has become refractory to a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 0.01, 0.1, 0.3, 1, 3, or 6 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 0.3, 1, or 3 mg/kg. [00217] In some embodiments, a method for treating a cancer in a human subject is provided. In some embodiments, the method comprises administering to the subject an anti-TIGIT Attorney Docket No.01218-0031-00PCT antibody, and the anti-TIGIT antibody is administered to the subject at a dose of 0.01, 0.1, 0.3, 1, 3, or 6 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 0.01 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 0.01 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 0.1 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 0.1 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 0.3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 0.3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 1 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 6 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 6 mg/kg. [00218] In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 0.3, 1, or 3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 0.3, about 1, or about 3 mg/kg. In some embodiments, the anti- TIGIT antibody is administered to the subject at a dose of 1 or 3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 1 or about 3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 0.3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 0.3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 1 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of 3 mg/kg. In some embodiments, the anti-TIGIT antibody is administered to the subject at a dose of about 3 mg/kg. [00219] In some embodiments, the anti-TIGIT antibody is administered to the subject every three weeks (Q3W). In some embodiments, the anti-TIGIT antibody is administered to the subject intravenously. [00220] In some embodiments, the anti-TIGIT antibody is administered to the subject as a monotherapy. In some embodiments, the method further comprises administering to the subject an additional therapeutic agent. In some embodiments, the additional therapeutic agent is a checkpoint inhibitor. In some embodiments, the additional therapeutic agent is a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody. In Attorney Docket No.01218-0031-00PCT some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the additional therapeutic agent is brentuximab vedotin or other vedotin ADC. Subject [00221] In some embodiments, the subject receiving the method of treating a cancer has the cancer. In some embodiments, the subject is a human subject. In some embodiments, the subject has received a systemic therapy for the cancer. In some embodiments, the subject has received a platinum-based therapy. In some embodiments, the subject has received a PD-1 inhibitor or PD-L1 inhibitor. [00222] In some embodiments, the subject has received a therapy comprising ramucirumab and/or an anti-HER2/neu therapy. In some embodiments, the subject has received an anti-BRAF mutation therapy. In some embodiments, the subject has received an anti-EGFR therapy. In some embodiments, the subject has received a therapy comprising enfortumab vedotin. In some embodiments, the subject has received a therapy comprising bevacizumab. In some embodiments, the subject has received a therapy comprising bevacizumab or a poly(ADP- ribose) polymerase (PARP) inhibitor. In some embodiments, the subject has received a therapy comprising brentuximab vedotin. In some embodiments, the subject has received a therapy comprising two systemic chemo-immunotherapy regimens, optionally wherein the two systemic chemo-immunotherapy regimens comprise an anti-CD20 agent and a combination chemotherapy, or the subject has received a combination chemotherapy or autologous stem cell transplant. In some embodiments, the subject has received a therapy comprising cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), or CHOP-like therapy, or the subject has received a combination chemotherapy or autologous stem cell transplant. Cancers [00223] In some embodiments, the cancer is a refractory or relapsed cancer. In some embodiments, the cancer is an advanced or metastatic cancer. In some embodiments, the cancer is an unresectable cancer. [00224] In some embodiments, the cancer is non-small cell lung cancer (NSCLC), gastric/gastroesophageal (GE) junction carcinoma, gastric cancer, cutaneous melanoma, head and neck squamous cell carcinoma (HNSCC), bladder cancer, urothelial cancer, cervical cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, triple negative breast cancer (TNBC), classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), or peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS)). In some embodiments, the cancer is NSCLC. In some embodiments, the cancer is gastric/GE junction carcinoma. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is cutaneous melanoma. In some embodiments, the cancer is HNSCC. In some embodiments, the cancer is Attorney Docket No.01218-0031-00PCT bladder cancer. In some embodiments, the cancer is urothelial cancer. In some embodiments, the cancer is cervical cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is primary peritoneal cancer. In some embodiments, the cancer is fallopian tube cancer. In some embodiments, the cancer is TNBC. In some embodiments, the cancer is cHL. In some embodiments, the cancer is DLBCL. In some embodiments, the cancer is PTCL-NOS. [00225] In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is gastric cancer, and the anti-TIGIT antibody is administered to the subject at a dose of 0.3 mg/kg. In some embodiments, the cancer is gastric cancer, and the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. In some embodiments, the cancer is gastric cancer, and the anti-TIGIT antibody is administered to the subject at a dose of 3 mg/kg. In some embodiments, the cancer is gastric/GE junction carcinoma, and the subject has received a therapy comprising ramucirumab and/or an anti-HER2/neu therapy. [00226] In some embodiments, the cancer is cutaneous melanoma, and the subject has received an anti-BRAF mutation therapy. [00227] In some embodiments, the cancer is HNSCC, and the subject has received an anti- EGFR therapy. [00228] In some embodiments, the cancer is bladder cancer or urothelial cancer, and the subject has received a therapy comprising enfortumab vedotin. [00229] In some embodiments, the cancer is cervical cancer, and the subject has received a therapy comprising bevacizumab. [00230] In some embodiments, the cancer is ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, and the subject has received a therapy comprising bevacizumab or a poly(ADP-ribose) polymerase (PARP) inhibitor. [00231] In some embodiments, the cancer is cHL. In some embodiments, the cancer is cHL, and the subject has received a therapy comprising brentuximab vedotin. In some embodiments, the cancer is cHL, and the anti-TIGIT antibody is administered to the subject at a dose of 0.3 mg/kg. In some embodiments, the cancer is cHL, and the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. In some embodiments, the cancer is cHL, and the anti- TIGIT antibody is administered to the subject at a dose of 3 mg/kg. In some embodiments, the cancer is cHL, and the anti-TIGIT antibody is administered in combination with a therapy comprising brentuximab vedotin. In some embodiments, the cancer is cHL, and the anti-TIGIT antibody (at a dose of 1 mg/kg) is administered in combination with a therapy comprising brentuximab vedotin (at a dose of 1.8 mg/kg). Attorney Docket No.01218-0031-00PCT [00232] In some embodiments, the cancer is DLBCL, and the subject has received a therapy comprising two systemic chemo-immunotherapy regimens, optionally wherein the two systemic chemo-immunotherapy regimens comprise an anti-CD20 agent and a combination chemotherapy, or the subject has received a combination chemotherapy or autologous stem cell transplant. In some embodiments, the cancer is DLBCL, and the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. [00233] In some embodiments, the cancer is PTCL-NOS, and the subject has received a therapy comprising cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP), or CHOP- like therapy, or the subject has received a combination chemotherapy or autologous stem cell transplant. [00234] In some embodiments, the cancer is PTCL-NOS and is CD30-positive, and the subject has received a therapy comprising brentuximab vedotin. In some embodiments, the cancer is PTCL-NOS, and wherein the subject has received a therapy comprising brentuximab vedotin. [00235] In some embodiments, the cancer is resistant or refractory to a PD-1 inhibitor or a PD-L1 inhibitor. In some embodiments, the level of PD-L1 in a sample of the cancer is less than 10 as measured by Combined Positive Score (CPS), or less than 50% as measured by Total Proportion Score (TPS), or less than 50% as measured by a Tumor Cell score (TC), or less than 10% as measured by Tumor-Infiltrating Immune Cell staining (IC). In some embodiments, the level of PD-L1 in a sample of the cancer is less than 5, or less than 3, or less than 1, as measured by CPS. In some embodiments, the level of PD-L1 in a sample of the cancer is less than 40%, or less than 30%, or less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, as measured by TPS. In some embodiments, the level of PD-L1 in a sample of the cancer is less than 40%, or less than 30%, or less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, as measured by TC. In some embodiments, the level of PD-L1 in a sample of the cancer is less than 5%, or less than 3%, or less than 1%, as measured by IC. [00236] In some embodiments, the cancer comprises a level of PD-L1 that is less than 10, less than 5, or less than 3, or less than 1, as measured by CPS. In some embodiments, the cancer comprises a level of PD-L1 that is between 0 and 10, or between 1 and 10, or between 3 and 10, or between 5 and 10, or between 0 and 7, or between 1 and 7, or between 3 and 7, or between 0 and 5, or between 1 and 5, or between 3 and 5, or between 0 and 3, or between 1 and 3, as measured by CPS. [00237] In some embodiments, the cancer comprises a level of PD-L1 that is less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, as measured by TPS. In some embodiments, the cancer comprises a Attorney Docket No.01218-0031-00PCT level of PD-L1 that is between 0% and 50%, or between 1% and 50%, or between 3% and 50%, or between 5% and 50%, or between 10% and 50%, or between 20% and 50%, or between 0% and 30%, or between 1% and 30%, or between 3% and 30%, or between 5% and 30%, or between 10% and 30%, or between 0% and 20%, or between 3% and 20%, or between 5% and 20%, as measured by TPS. [00238] In some embodiments, the cancer comprises a level of PD-L1 that is less than 50%, or less than 40%, or less than 30%, or less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, as measured by TC. In some embodiments, the cancer comprises a level of PD-L1 that is between 0% and 50%, or between 1% and 50%, or between 3% and 50%, or between 5% and 50%, or between 10% and 50%, or between 20% and 50%, or between 0% and 30%, or between 1% and 30%, or between 3% and 30%, or between 5% and 30%, or between 10% and 30%, or between 0% and 20%, or between 3% and 20%, or between 5% and 20%, as measured by TC. [00239] In some embodiments, the cancer comprises a level of PD-L1 that is less than 10%, less than 5%, or less than 3%, or less than 1%, as measured by IC. In some embodiments, the cancer comprises a level of PD-L1 that is between 0% and 10%, or between 1% and 10%, or between 3% and 10%, or between 5% and 10%, or between 0% and 7%, or between 1% and 7%, or between 3% and 7%, or between 0% and 5%, or between 1% and 5%, or between 3% and 5%, or between 0% and 3%, or between 1% and 3%, as measured by IC. Administration [00240] The route of administration of a therapeutic agent (e.g., antibody, antibody-drug conjugate) disclosed herein can be oral, intraperitoneal, transdermal, subcutaneous, intravenous, intramuscular, inhalational, topical, intralesional, rectal, intrabronchial, nasal, transmucosal, intestinal, ocular or otic delivery, or any other methods known in the art. In some embodiments, one or more therapeutic agents are administered orally, intravenously, or intraperitoneally. In some embodiments, one or more therapeutic agents are administered intravenously. [00241] Co-administered therapeutic agents, such as any of the anti-TIGIT antibodies, anti- PD-1 antibodies, anti-PD-L1 antibodies, and/or brentuximab vedotin, can be administered together or separately, simultaneously or at different times. When administered, the therapeutic agents independently can be administered once, twice, three, four times daily or more or less often, as needed. In some embodiments, the administered therapeutic agents are administered once daily. In some embodiments, the administered therapeutic agents are administered at the same time or times, for instance as an admixture. In some embodiments, one or more of the therapeutic agents is administered in a sustained-release formulation. Attorney Docket No.01218-0031-00PCT [00242] In some embodiments, any of the therapeutic agents provided herein is administered to the subject over an extended period of time, e.g., for at least 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350 days or longer. Exemplary Efficacy Outcomes [00243] In some embodiments, the methods described herein have certain benefits. For example, in some embodiments, the subject has a partial metabolic response or two partial metabolic responses after the administering to the subject the anti-TIGIT antibody. In some embodiments, the subject has a partial response after the administering to the subject the anti- TIGIT antibody. VI. Compositions and Kits [00244] In another aspect, compositions and kits for use in treating or preventing a cancer in a subject are provided. Pharmaceutical Compositions [00245] In some embodiments, pharmaceutical compositions for use in the present methods are provided. In some embodiments, an anti-TIGIT antibody is administered in a pharmaceutical composition. In some embodiments, at least one of (1) an anti-TIGIT antibody and (2) an additional therapeutic agent is administered in a first pharmaceutical composition and at least another of (1) the anti-TIGIT antibody and (2) the additional therapeutic agent is administered in a second pharmaceutical composition. In some embodiments, (1) the anti- TIGIT antibody and (2) the additional therapeutic agent are administered in a single pharmaceutical composition. [00246] Guidance for preparing formulations for use in the methods disclosed is found in, for example, Remington: The Science and Practice of Pharmacy, 21^st Ed., 2006, supra; Martindale: The Complete Drug Reference, Sweetman, 2005, London: Pharmaceutical Press; Niazi, Handbook of Pharmaceutical Manufacturing Formulations, 2004, CRC Press; and Gibson, Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form, 2001, Interpharm Press, which are hereby incorporated herein by reference. The pharmaceutical compositions described herein can be manufactured in a manner that is known to those of skill in the art, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping or lyophilizing processes. The following methods and excipients are merely exemplary and are in no way limiting. [00247] In some embodiments, one or more therapeutic agents are prepared for delivery in a sustained-release, controlled release, extended-release, timed-release or delayed-release Attorney Docket No.01218-0031-00PCT formulation, for example, in semi-permeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various types of sustained-release materials have been established and are well known by those skilled in the art. Current extended-release formulations include film- coated tablets, multiparticulate or pellet systems, matrix technologies using hydrophilic or lipophilic materials and wax-based tablets with pore-forming excipients (see, for example, Huang, et al. Drug Dev. Ind. Pharm.29:79 (2003); Pearnchob, et al. Drug Dev. Ind. Pharm. 29:925 (2003); Maggi, et al. Eur. J. Pharm. Biopharm.55:99 (2003); Khanvilkar, et al., Drug Dev. Ind. Pharm.228:601 (2002); and Schmidt, et al., Int. J. Pharm.216:9 (2001)). Sustained- release delivery systems can, depending on their design, release the compounds over the course of hours or days, for instance, over 4, 6, 8, 10, 12, 16, 20, 24 hours or more. Usually, sustained release formulations can be prepared using naturally-occurring or synthetic polymers, for instance, polymeric vinyl pyrrolidones, such as polyvinyl pyrrolidone (PVP); carboxyvinyl hydrophilic polymers; hydrophobic and/or hydrophilic hydrocolloids, such as methylcellulose, ethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose; and carboxypolymethylene. [00248] For oral administration, a therapeutic agent can be formulated readily by combining with pharmaceutically acceptable carriers that are well known in the art. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, lipophilic and hydrophilic suspensions, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing the compounds with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents can be added, such as a cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. [00249] A therapeutic agent can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. For injection, the compound or compounds can be formulated into preparations by dissolving, suspending or emulsifying them in an aqueous or nonaqueous solvent, such as vegetable or other similar oils, synthetic aliphatic acid glycerides, esters of higher aliphatic acids or propylene glycol; and if desired, with conventional additives such as solubilizers, isotonic agents, suspending agents, emulsifying agents, stabilizers and preservatives. In some embodiments, compounds can be formulated in aqueous solutions, Attorney Docket No.01218-0031-00PCT preferably in physiologically compatible buffers such as Hanks’s solution, Ringer’s solution, or physiological saline buffer. Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. [00250] A therapeutic agent can be administered systemically by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. For topical administration, the agents are formulated into ointments, creams, salves, powders and gels. In one embodiment, the transdermal delivery agent can be DMSO. Transdermal delivery systems can include, e.g., patches. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Exemplary transdermal delivery formulations include those described in US Patent Nos.6,589,549; 6,544,548; 6,517,864; 6,512,010; 6,465,006; 6,379,696; 6,312,717 and 6,310,177. [00251] In some embodiments, a pharmaceutical composition comprises an acceptable carrier and/or excipients. A pharmaceutically acceptable carrier includes any solvents, dispersion media, or coatings that are physiologically compatible and that preferably does not interfere with or otherwise inhibit the activity of the therapeutic agent. In some embodiments, the carrier is suitable for intravenous, intramuscular, oral, intraperitoneal, transdermal, topical, or subcutaneous administration. Pharmaceutically acceptable carriers can contain one or more physiologically acceptable compound(s) that act, for example, to stabilize the composition or to increase or decrease the absorption of the active agent(s). Physiologically acceptable compounds can include, for example, carbohydrates, such as glucose, sucrose, or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, compositions that reduce the clearance or hydrolysis of the active agents, or excipients or other stabilizers and/or buffers. Other pharmaceutically acceptable carriers and their formulations are well-known and generally described in, for example, Remington: The Science and Practice of Pharmacy, 21st Edition, Philadelphia, PA. Lippincott Williams & Wilkins, 2005. Various pharmaceutically acceptable excipients are well-known in the art and can be found in, for example, Handbook of Pharmaceutical Excipients (5^th ed., Ed. Rowe et al., Pharmaceutical Press, Washington, D.C.). [00252] Dosages and desired concentration of pharmaceutical compositions of the disclosure may vary depending on the particular use envisioned. The determination of the appropriate dosage or route of administration is well within the skill of one in the art. Suitable dosages are also described herein. Attorney Docket No.01218-0031-00PCT Kits [00253] In some embodiments, kits for use in treating a subject having a cancer are provided. In some embodiments, the kit comprises an anti-TIGIT antibody, as provided herein. In some embodiments, the kit comprises (1) an anti-TIGIT antibody and (2) an additional therapeutic agent, as provided herein. [00254] In some embodiments, the kits can further comprise instructional materials containing directions (i.e., protocols) for the practice of the methods of this invention (e.g., instructions for using the kit for treating a cancer). While the instructional materials typically comprise written or printed materials, they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials. VII. Examples [00255] The examples discussed below are intended to be purely exemplary of the invention and should not be considered to limit the invention in any way. The examples are not intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (for example, amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric. Example 1: Dose Selection Based on Clinical Utility Index (CUI) Analysis 1.1 Materials and Methods [00256] To select doses for administering anti-TIGIT antibodies, such as SEA-TGT, a CUI analysis was performed. A CUI was determined for each candidate dose, ranging from 0.01 to 6 mg/kg, by mathematically integrating multiple mechanism-of-action-based, clinically meaningful pharmacokinetic (PK) and pharmacodynamic (PD) endpoints into a single readout. The CUI was determined using the following formula.

[00257] The endpoints, selected a priori, included (i) NK and CD8+ T cell proliferation (assigned 30% weight), (ii) maintenance of overall peripheral CD8+ T cells (assigned 30% weight), (iii) depletion of peripheral regulatory T cells (Treg) (assigned 30% weight), (iv) Attorney Docket No.01218-0031-00PCT peripheral target engagement and pharmacokinetic linearity of the antibody (assigned 5% weight), and (v) simulated tumor receptor occupancy (RO) and formation of the TIGIT:anti- TIGIT antibody:Fc receptor gamma (FcγRIIIa) trimer complexes in the tumor (assigned 5% weight). The endpoints reflected various properties of the anti-TIGIT antibody. For example, target engagement, pharmacokinetic linearity, and peripheral CD8+ T cell count reflect the antibody’s ability to block inhibitory TIGIT-mediated checkpoint signal to memory CD8+ T cells; Treg cell depletion and NK cell proliferation reflect the antibody’s ability to deplete Treg cells, which inhibit CD8+ cells by increasing activation of NK cells; and CD8+ T cell proliferation reflects the antibody’s ability to bind activating FcγRIIIa on myeloid cells and induce new antigen+ CD8+ T cells. [00258] The peripheral target engagement, peripheral total Treg depletion, peripheral total CD8 depletion, and peripheral NK and CD8+ T cell proliferation were assessed using flow cytometric evaluation of whole blood samples (immunophenotyping) obtained from some of the participants in Part A of the study described in Example 3 below (2, 4, 5, 11, 11, and 6 participants in the 0.01, 0.1, 0.3, 1, 3, and 6 mg/kg cohorts, respectively). On-treatment values were compared to those determined pre-treatment (at baseline) to characterize changes over time. Pre-determined thresholds for the CUI were set based on preclinical (in vitro, mouse, and/or cynomolgus monkey) data for what the superior effects should be (i.e., strong biologic activity vs. weak or no activity vs. detrimental activity). Where available, published literature data of anti-TIGIT monoclonal antibodies were used to check if the set thresholds were appropriate and/or clinically meaningful. [00259] The simulated tumor RO and formation of TIGIT:anti-TIGIT antibody:FcγR complex (trimer) was determined using a semi-mechanistic PK/PD model based on preclinical SEA-TGT in vitro activity assays and cynomolgus monkey PK and literature data, and then translated to humans using physiologically relevant parameters. [00260] Circulating SEA-TGT concentrations were assessed using a sandwich ELISA with an anti-idiotype (anti-ID)-TIGIT monoclonal antibody to capture SEA-TGT from plasma of the participants. Bound SEA-TGT was detected using a second anti-ID TIGIT mAb conjugated with biotin. Detection was facilitated by addition of a polymeric horseradish peroxidase (HRP) conjugated to streptavidin (poly-HRP-SA) and 3,3’,5,5’-tetramethylbenzidine (TMB) substrate. Pharmacokinetic parameters were determined using Phoenix WinNonlin software. [00261] Tables 1-5 show the utility scores assigned to the different results for different endpoints, respectively—(i) peripheral NK and CD8+ cell proliferation (shown by Ki67 staining); (ii) total CD8+ T cells (shown by percentage of live cells); (iii) total Treg cells (shown Attorney Docket No.01218-0031-00PCT by percentage of live cells); (iv) target engagement; and (v) tumor RO and formation of trimer complex. [00262] Table 1: Utility scores for NK and CD8+ cell proliferation

[00263] Table 2: Utility scores for total CD8+ T cells (percentage of live cells)

[00264] Table 3: Utility scores for total Treg cells (percentage of live cells)

[00265] Table 4: Utility scores for target engagement

[00266] Table 5: Utility scores for tumor RO and formation of trimer complex

1.2 Results [00267] Fig.1 shows the CUI of different doses of SEA-TGT, obtained by integrating the weighted utility scores for the above endpoints. An increase in the CUI, representing an Attorney Docket No.01218-0031-00PCT increase in biological activity, was observed during dose escalation, with an apparent plateau between the 0.3 and 6 mg/kg doses. Based on safety signals at higher doses and PK variability at lower doses, 1 and 3 mg/kg were selected for further evaluation. Both 1 and 3 mg/kg represented biologically active dose levels as they showed PK and PD activity that were within desirable ranges and had similarly high overall CUI relative to all doses evaluated. Monte Carlo simulations were performed, which showed a high likelihood that the 1 mg/kg dose would be superior to the 0.1, 0.3, 3, and 6 mg/kg doses. The superiority of the 1 mg/kg dose is further supported by the results described in the clinical trial examples below. Example 2: Anti-PD-1 Resistant Tumor Mouse Model 2.1 Materials and Methods [00268] To develop a syngeneic murine CT26 colorectal tumor model that is resistant to anti- PD-1 therapy, CT26 tumors were implanted in mice. When the tumors grew to about 100 mm³ in size, they were subjected to three three-day cycles of increasing levels of anti-PD-1 antibody therapy (Q3D×3; cycle 1: 1.5 mpk; cycle 2: 2.5 mpk; cycle 3: 5 mpk). At the end of each cycle, the tumors were harvested, placed in cell culture, and then re-implanted into mice after several passages ex vivo/in vitro. [00269] To demonstrate the acquired resistance, mice bearing anti-PD-1 resistant CT26 tumors were treated with 5 mg/kg anti-PD-1 antibody, Q3D×4. To demonstrate the activity of SEA-TGT against the resistant tumors, in addition to or instead of being treated with the anti- PD-1 antibody, some mice bearing the resistant tumors were treated with 0.3, 1, or 3 mg/kg SEA-TGT, Q3D×4. Survival of mice and tumor volumes were measured, and an RNAseq analysis of the tumors treated with SEA-TGT was performed. 2.2 Results [00270] Figs.2A and 2B show tumor growth curves of parental CT26 tumors and the anti- PD-1 resistant CT26 (PD1R) tumors implanted in mice, after being untreated or treated with 5 mg/kg anti-PD-1 antibody, Q3D×4. The anti-PD-1 resistant CT26 tumor showed robust resistance to anti-PD-1 antibody treatment, showing similar growth kinetics to the parental tumor not treated with the anti-PD-1 antibody. [00271] Fig.3A shows tumor growth curves of the anti-PD-1 resistant CT26 tumors implanted in mice, after being untreated or treated with 0.3 mg/kg SEA-TGT (left) or 1 mg/kg of the same anti-TIGIT monoclonal antibody with an intact, wild type mIgG2a backbone (right). Treatment with SEA-TGT at a dose of 0.3 mg/kg demonstrated good tumor growth delay, and curative responses were observed in three of eight mice treated with SEA-TGT at a dose of 0.3 mg/kg. Slightly less tumor growth delay and the same number of complete responses (3/8) were seen with the mIgG2a backbone anti-TIGIT antibody at a dose of 1 mg/kg. Fig.3B shows areas Attorney Docket No.01218-0031-00PCT under the growth curve (AUC.3; per Guo et al. (BMC Cancer 19, 718 (2019)) of the anti-PD-1 resistant CT26 tumor implanted in mice, after being untreated or treated with a range of doses of SEA-TGT, 0.3, 1, or 3 mg/kg, or with 1 mg/kg of the mIgG2a anti-TIGIT antibody. [00272] Consistent with Fig.3A, Fig.3B shows that treatment with the mIgG2a backbone anti-TIGIT antibody reduced tumor growth, whereas treatment with SEA-TGT resulted in potent antitumor activity slightly above what was seen with the mIgG2a wild type version (not statistically significant). These results demonstrate that in certain tumors that are resistant or refractory to anti-PD-1 treatment, SEA-TGT can still generate efficacious responses. [00273] Figs.4A-4C show overall survival (Fig.4A), tumor growth curves (Fig.4B), and average area under the tumor growth curves (AUC.3) (Fig.4C) of the anti-PD-1 resistant CT26 tumors implanted in mice, after being untreated or treated with 5 mg/kg (mpk) anti-PD-1 antibody and/or 0.1 or 1 mg/kg SEA-TGT. Despite the resistant tumor being unresponsive to the anti-PD-1 antibody alone, the tumor was responsive to SEA-TGT treatment alone as was seen previously. Furthermore, treatment with SEA-TGT sensitized the tumor to the anti-PD-1 antibody, as the combination treatment showed further increased responsiveness both in terms of increased tumor growth delay and survival benefit. These data suggest that treatment with SEA- TGT could re-program certain anti-PD-1 resistant tumor microenvironments and allow them to be responsive to anti-PD-1 treatments, either alone or in combination with SEA-TGT. [00274] Fig.5 shows RNAseq data of the anti-PD-1 resistant CT26 tumors in the mice treated with 5 mg/kg anti-PD-1 antibody and/or 0.1 or 1 mg/kg SEA-TGT (five mice in each group), as shown in Figs.4A-4C, demonstrating that the treatment with SEA-TGT drives upregulation of genes associated with clinical response to anti-PD-1 agents. The upregulation was very similar between the groups treated with 0.1 mg/kg SEA-TGT and the groups treated with 1 mg/kg SEA-TGT. The RNAseq analysis of the tumors, excised 3 days post third dose, revealed upregulation of genes associated with IFNγ signaling, antigen presentation, and chemoattractants that mediate recruitment and activation of CD8⁺ T cells in animals treated with SEA-TGT alone or in combination with the anti-PD-1 antibody. Expression of these genes has been associated with clinical response to anti-PD-1 agents (Ayers, Mark, et al. "IFN-γ–related mRNA profile predicts clinical response to PD-1 blockade." The Journal of clinical investigation 127.8 (2017): 2930-2940). Example 3: Clinical Study of an Anti-TIGIT Antibody as a Monotherapy 3.1 Study Design [00275] A Phase 1 non-randomized, open-label, multicenter, dose-escalation, and dose- expansion study designed to evaluate the safety and tolerability of SEA-TGT as a monotherapy in adults with advanced malignancies is undertaken. Attorney Docket No.01218-0031-00PCT [00276] The participants are patients with histologically-confirmed or cytologically- confirmed advanced or metastatic malignancy. Eligible diagnoses include non-small cell lung cancer (NSCLC), gastric/gastroesophageal (GE) junction carcinoma, cutaneous melanoma, head and neck squamous cell carcinoma (HNSCC), bladder cancer, cervical cancer, ovarian cancer, triple negative breast cancer (TNBC), and selected lymphomas including classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). The participants must have relapsed, refractory, or progressive disease (PD). [00277] SEA-TGT is administered intravenously (IV) on Day 1 of each 21-day cycle (Q3W). During Part A of the study, SEA-TGT is administered at escalating doses (ranging from 0.01 to 6.0 mg/kg of body weight) to determine maximum tolerated dose (MTD), maximum administered dose (MAD), or recommended dose. During Part B of the study, SEA-TGT is administered IV on Day 1 of every 21-day cycle (Q3W) at or below the MTD, MAD, or recommended dose. [00278] Participants receive study treatment until confirmed disease progression (based on RECIST (solid tumor) and Lugano with the incorporation of LYRIC (lymphoma) criteria), loss of clinical benefit, unacceptable toxicity, withdrawal of consent, or study termination, whichever occurs first. [00279] The inclusion criteria for the study are as follows. 1. Participants must have a histologically-confirmed or cytologically-confirmed advanced or metastatic malignancy, defined as: a. One of the following tumor types: o Unresectable locally-advanced or metastatic NSCLC, gastric/GE junction carcinoma, cutaneous melanoma, HNSCC, bladder cancer, cervical cancer, ovarian cancer, or TNBC o Lymphomas, including: − cHL − DLBCL, as defined by the World Health Organization (WHO) criteria − PTCL-NOS b. Relapsed, refractory or PD, specifically: o Solid tumors: Following at least 1 prior systemic therapy and for which, in the judgment of the investigator, no further standard therapy is available at the time of enrollment, and with the specific prior therapies as listed below. − NSCLC: Participants must have received platinum-based therapy, unless clinically contraindicated. Participants must have received anti-PD-1 or anti-PD-L1 Attorney Docket No.01218-0031-00PCT therapy, unless clinically contraindicated. − Gastric/GE junction Carcinoma: Participants must have received prior platinum chemotherapy, unless clinically contraindicated. If appropriate, participants must also have received ramucirumab. In addition, participants should have received HER2/neu-targeted therapy if appropriate. Participants must have received anti-PD-1 or anti-PD-L1 therapy if indicated. − Cutaneous Melanoma: Participants must have received at least one anti-PD-1 therapy unless clinically contraindicated. Participants with specific, targetable mutations (such as BRAF) should have received at least one therapy targeting that mutation unless clinically contraindicated. − HNSCC: Participants must have received prior therapy with a platinum-based regimen and a PD-1 or PD-L1 inhibitor, if eligible. Participants eligible to receive anti-epithelial growth factor receptor (anti-EGFR) therapy must have received anti- EGFR therapy prior to study entry. − Bladder cancer: Participants must have histologically documented locally advanced or metastatic urothelial (previously known as transitional cell) cancer (cancer of the bladder, renal pelvis, ureter, or urethra). Participants with locally advanced disease that is resectable with curative intent are ineligible. Participants must have received platinum-based chemotherapy. If eligible, participants must have received enfortumab vedotin. If eligible and consistent with standard of care, participants must have received an anti-PD-1 or PD-L1 therapy. − Cervical cancer: Participants with squamous cell, adenocarcinoma, or adenosquamous histology must have experienced disease progression on standard of care systemic therapy in combination with bevacizumab, if eligible. − Ovarian cancer: Participants must have epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Participants must have received platinum- based chemotherapy and considered not eligible for retreatment. If eligible, participants must have received a bevacizumab-containing regimen and/or a poly(ADP-ribose) polymerase (PARP) inhibitor. − TNBC: Participants must have received 1 or more prior lines of therapy for locally advanced or metastatic disease. Participants must have received a taxane and PD-1 or PD-L1 inhibitor, in any setting, administered either as single agents or in combination unless contraindicated. o Lymphoma: Participants must have disease progression on or after treatment with standard therapies expected to provide benefit in the judgement of the investigator. − cHL: Participants should have had disease recurrence or progression Attorney Docket No.01218-0031-00PCT following brentuximab vedotin therapy or have been ineligible to receive brentuximab vedotin. Participants who have not received autologous stem cell transplant (SCT) must have refused or been deemed ineligible (e.g., due to age, co-morbid conditions). Participants should have received or not be eligible to have received an anti-PD-1 agent. − DLBCL: Participants must have received at least 2 prior systemic chemo-immunotherapy regimens, including an anti-CD20 agent and combination chemotherapy. Unless clinically contraindicated, participants should have had disease that has relapsed after or be refractory to intensive salvage chemotherapy, including autologous SCT. − PTCL-NOS: Participants must have had at least 1 prior systemic therapy. Participants must have received or have been ineligible to receive the combination of cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or CHOP-like therapy. Participants with CD30-positive disease must have received or be ineligible to receive brentuximab vedotin. Participants must have also received intensive salvage therapy (defined as combination chemotherapy ± autologous SCT) unless they refused or were deemed ineligible. 2. Participants must have measurable disease defined as: a. Solid tumors: Measurable disease according to RECIST V1.1. b. Lymphomas: Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and measurable disease of ≥15 mm in the greatest transverse diameter by computed tomography (CT) scan, as assessed by the site radiologist. 3. Participants should be able to provide adequate tumor tissue for biomarker analysis, if available and feasible to obtain: a. Part A: Archival tumor tissue from the most recent biopsy and collected within 12 months of enrollment is requested for all participants, if available b. Part B: Archival tumor tissue from the most recent biopsy and collected within 12 months of enrollment is required, if available. If archived tissue is not available, a fresh baseline tumor biopsy that has not been previously irradiated is requested for any participant whose tumors are considered accessible and appropriate in the opinion of the investigator. For all melanoma and lymphoma participants, and for the 11th participant and beyond in each disease specific cohort, fresh baseline and on-treatment tumor biopsies are required, if feasible. c. Part B (biology cohort only): Participants must have an accessible tumor for multiple (up to 3) fresh biopsies. Fresh baseline and on-treatment biopsy from same lesion as the pre-dose biopsy are required. A third biopsy at the time of progression and/or end of treatment (EOT) may be obtained if feasible (optional). 4. PD-L1 expression for participants with NSCLC that will be enrolled in Part B will be based on historical local laboratory (central confirmation is not required for enrollment). Attorney Docket No.01218-0031-00PCT 5. Participants must be age 18 years or older. 6. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. 7. Participants must have the following baseline laboratory data (in the absence of growth factor or platelet transfusion support): • lymphocyte count ≥ 500 cells/μL • hemoglobin ≥ 9 g/dL or 5.6 mmol/L • ANC ≥ 1,500 cells/μL • platelets ≥ 100,000/μL • serum total bilirubin ≤ 1.5 × upper limit of normal (ULN) or ≤ 3 × ULN for participants with Gilbert’s disease • ALT (alanine aminotransferase) and AST (aspartate aminotransferase) ≤ 1.5 × ULN (or ALT and AST ≤ 5 × ULN if there is evidence of hepatic involvement by malignant disease) • estimated glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m² using the Modification of Diet in Renal Disease (MDRD) study equation All baseline laboratory requirements are assessed and should be obtained within 7 days prior to Cycle 1 Day 1. 8. Participants of childbearing potential must meet the following conditions: a. Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 3 days prior to the first dose of SEA-TGT. Participants with false positive results and documented verification that the participant is not pregnant are eligible for participation. b. Must agree not to try to become pregnant during the study and for at least 3 months after the final dose of study drug. c. Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 3 months after the final dose of study drug. d. If sexually active in a way that could lead to pregnancy, must consistently use the acceptable combinations of contraceptive methods starting at time of informed consent and continuing throughout the study and for at least 3 months after the final dose of study drug. 9. Participants born male must meet the following conditions: a. Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 60 days after the dose of final study drug. b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use the acceptable combination of contraceptive methods starting at time of informed consent and continuing throughout the study and for at least 60 days Attorney Docket No.01218-0031-00PCT after the final dose of study drug. c. If sexually active with a person who is pregnant or breastfeeding, must consistently use contraception starting at time of informed consent and continuing throughout the study and for at least 60 days after the final dose of study drug. 10. Participants must provide written informed consent. 11. Participants must be willing and able to comply with the scheduled visits, treatment schedule, laboratory tests, and other requirements of the study [00280] Participants are excluded from the study if any of the following criteria apply: 1. Participants have a history of another malignancy within 2 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. 2. Participants received chemotherapy, radiotherapy, biologics, and/or other antitumor treatment that has not been completed before the first dose of study drug within the timeframe as follows: a. Chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): 2 weeks o Palliative radiotherapy (≤ 2 weeks of radiotherapy to non-central nervous system [CNS] disease): ≤ 7 days prior to start of SEA-TGT. b. Immune-checkpoint inhibitors (i.e., anti-PD-1, anti-PD-L1, anti-cytotoxic T- lymphocyte-associated antigen 4 [CTLA-4]): 4 weeks c. Monoclonal antibodies, ADC, or radioimmunoconjugates: 4 weeks (2 weeks with documented disease progression) d. T-cell or other cell-based therapies: 12 weeks 3. Participants have known active CNS metastases. a. Participants with a history of CNS metastases are allowed if they have undergone treatment for the CNS disease, symptoms have resolved, and steroids have been discontinued. b. Leptomeningeal involvement by malignant disease is excluded regardless of prior treatment. 4. Participants have recent or serious ongoing infection, including: a. Any uncontrolled Grade 3 or higher (per the National Cancer Institute’s Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 5) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of SEA-TGT. Routine antimicrobial prophylaxis is permitted. b. Known seropositivity for, or active infection, by human immunodeficiency virus Attorney Docket No.01218-0031-00PCT (HIV). c. Known to be positive for hepatitis B by surface antigen expression, or any other positive test for hepatitis B virus indicating acute or chronic infection. d. Known active hepatitis C infection (positive by serology and confirmed by polymerase chain reaction [PCR]) or on antiviral therapy for hepatitis C within 6 months of the first dose of study drug. Participants who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks. 5. Participants have known active or latent tuberculosis. 6. Participants have received a live or live-attenuated vaccine within 30 days prior to Cycle 1 Day 1. 7. Participants have had previous allogeneic SCT. Participants with prior autologous SCT may be eligible if they are > 100 days from autologous SCT and fulfill all other inclusion criteria. 8. Participants have a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV heart failure 6 months prior to their first dose of SEA-TGT. 9. Participants receive current therapy with other systemic anti-neoplastic or investigational agents. 10. Participants had prior use of any anti-TIGIT mAb. 11. Participants have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone or equivalents are permitted in the absence of active immune disease. 12. Participants have other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study. 13. Participants are breastfeeding, pregnant, or planning to become pregnant from time of informed consent until 4 months after final dose of study drug. 14. Participants have known hypersensitivity to any excipient contained in the drug formulation of SEA-TGT. 15. Participants have a history of interstitial lung disease. Participants with focal asymptomatic radiation-induced fibrosis may be permitted upon consultation with the medical monitor. 16. Participants have a known or suspected autoimmune disease or significant autoimmune- related toxicity from prior immuno-oncology-based therapy (prior autoimmune colitis, Attorney Docket No.01218-0031-00PCT pneumonitis, transaminitis) that is currently active, has not fully resolved, or is at risk of recurrence; participants with vitiligo, controlled type-1 diabetes mellitus, residual hypothyroidism requiring hormone replacement, or conditions not expected to recur in the absence of an external trigger are permitted to enroll. 17. Participants have other serious underlying medical condition that, in the opinion of the investigator, would impair the participant’s ability to receive or tolerate the planned treatment and follow-up. [00281] Specific objectives and corresponding endpoints for the study are summarized in Table 6 below. [00282] Table 6: Objectives and corresponding endpoints

Attorney Docket No.01218-0031-00PCT

3.2 Results [00283] In Part A of the study, from June 12, 2020, to October 5, 2022, 41 participants were enrolled (2, 4, 5, 11, 12, and 7 participants in the 0.01, 0.1, 0.3, 1, 3, and 6 mg/kg cohorts, respectively). Among the 39 participants who were treated, 23 participants had solid tumors, and 16 had lymphomas. The median number of prior therapies across all cohorts was 5.0. [00284] Treatment-emergent adverse events (TEAEs) of any grade were reported in 100% of the participants, and treatment-related adverse events (TRAEs) of any grade were reported in 69.2% of the participants. TRAEs seen in ≥ 10% of the participants were infusion-related reaction (38.5%), chills (25.6%), pyrexia (17.9%), fatigue (12.8%), maculopapular rash (12.8%), and rash (10.3%). Seven participants (17.9%) reported TRAEs Grade ≥ 3, and rash (5.1%) was the most frequently reported. No Grade 4 or 5 TRAEs were reported. One dose-limiting toxicity, pruritic rash, was observed in one participant in the 6 mg/kg cohort, and MTD was not exceeded. [00285] Overall TEAEs are summarized in Table 7 below. TRAEs are summarized in Table 8 below. Grade 3 or higher TRAEs are summarized in Table 9 below. TEAEs for immune- mediated, infusion-related reaction, and rash are summarized in Table 10 below. Treatment- related severe adverse events (TR SAEs) are summarized in Table 11 below. Dose modifications are summarized in Table 12 below. One subject enrolled at 0.3 mg/kg and was treated at this dose for Cycles 1-4 before switching to 3 mg/kg for Cycles 5+.

Attorney Docket No.01218-0031-00PCT

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^o_it^a_e_u^d_.^e_s^e_{3 r}^p D_{o x} n_i^h_{t s}_{t ti}^a_d^{n 1}^e_R C^{S n e}^{o e}ⁿ_{e o}^p_l^b_{, ,}^e t s_h^t o^w^c_s m_s^e_a^s_e^l_sⁿ_r^e_r^o s_i^ei^d_r^a^{t o}_{s r}_e^c_i^T_b lⁿ i^a_o_t^p_f_s^{e .}_{) f} e_r¹_{9 e}^s n_g e^e_t^h t_o^{b d} n^{a n}_a^t_{e e} z_i^h_{t r} c_R_i⁹_o l m₁t^d^e^o_{c o e}^r p_e^v_d^{e ml}_aⁿ_{I o} m_.^{b N} a_{, t}^e^{t d}_{l h}^t e^l_{o s} m_i_o^c_{s r}_t^{u r} l_{u a} cⁱt_r^m w u^o_e^t^s_l^{e m}_a^u_l^C₍^a^d_e^t^{n c} e_{x c} e^{o a}^s_{p s b l} m_oⁱ_{) 4}^{ai a} t^{y 1}_t^r_{v d} e^o_{h c} t^e_l^e^a_{ll n}^{o w} t¹_.^e_a^{p t}_{o e s}_e^{r a} i_t_{t u}^{t a}_c^{d 1}ⁱ_{n v l}_T^b_a^o t^{n m s}_a s^o tⁿ_o^w^d_u_n^a m f_i^a_,^{r S T}_r^{e s}_r^s_r^W^,_n^d_{o e I} Cⁿ_{i f}^{e e}_f^a_{e 3}_n^o m^c_n^{. E d}_{e r}^e_r^P-_r^Q^o_i^{t d} c_e^s_e^{r a}_{c a R}^z^u_{a o c i R E}^{e g}^{i m}_n^{o r}_a m^N_p^p_k^/_g_d^{b m} r e_r^s_{t o}^{h P} a^r_o^s_{a p}^d_e m^{, ,} e^s m_e^s_e^s_o_a^l C^m¹^s w o^d_{n o}^g m o^{w h}t i t_i^y_{l a}^u_{s n} w_l^b l^{s o}_p^e_{si e ,} d^h_t¹^{e d}_{e i}^{) s}_e^c_{g e}^l^,_t^{a f}_{i t c}^s_{s C}^r_{l i}^{l n}_{i p}_y^a_{l c} eⁱ_f^, d_{i n}ⁿ^o_a^p_B^e e_s^I^s_R^a_{it o}^s^{r b}_{a u} m d^a_x_e^d_{it i}^{c g}_a⁽ Y_a^t_e^e^s_o^a_{u it}_o mⁿi^r_r^a_{l s}_{t a e}^{r L p} o^h_t m_t_i^o_{t e}^{u E} pⁿ_i d^d_e_e^s_oⁿ_o^p^{e s}_u m^{w s}_r^{vi m}_o^d_e d_u^d^l_t^cs_n^{o f}f_i^u_t d⁴₁^e_f^e_s_r^s_e^c_,^b^l_i^r_c_c^sⁿ_{r i} i i_f^d^{d n}_i^d i h_l⁰ t^o_{s 2}^r_{g a}^s o_R^{P o}_r^v_{r e}^d^{s f} n_{o n}^a_d ,^e_i_v o^{r wt}_n^{i n}_,^{p e}_t^sⁱ_{y ) a}^{g e}_s^o tⁿ iⁱ_s_t^r^a_{a n}^o_{i e}_c^{t s}_n_b^a_p^R_uⁿ R^L_o^{s e y}_l p_r^e_c^{n a}_n i m_a_fi mⁿ_i^{o i}^s_c_a^it_r^O₍ⁿ_{o s}^e_f r^e_{r e}^{d a}ⁱ_{f I} d_o^u_s^m m^e i h_l w^{a e}_{t d}^{e c}^e_i_{e p}_a^a_{r s}^{a l} D o mⁿ_o^U^c_C_e_e^{s T} o_.^{, s}_n d⁾_n^{o o}_d^eⁿ_sⁿ_b_d^b^e_a^{t P} e^,_e^t_c^h^a_t_n ,_e₂^s_i_a^t_p_p^s_{a o} u_e^r_a^p_{s s} m^s_{a x}^{e o}^{1 e e s}_{e e}^e_{s t}^r^e_s_l^{i r}_r^e_l^m t^ai_{t o}^h_r_e^s_s^t^a_{( e}ⁱ^l_d^%_a_{p e 5}^{9 p}^b_d_{a e}ⁿ^v i^r_{a p}^v_i^{s v}i^{d n}_i T i_s^,_n^p m^y_t^c_a^m_{o s}^s_{e d} n_I^s_e^o^r_i^e l_e^{j m c} g^t_n_cⁿ_e u O_{i b o} k^{h o} t^{r d} gⁱ_s^e^-_s_o^a g O_p^o_B m^s_{r r}^w ]^o³_{r d}^e_]^d_]^y l^e_f^p t o^o_]₉^p^{2 o}_r_t^,_y⁴_o H^{5 n e}_r t 0_e^a₉_l²₀^h₉_t²_i₀^e_R^s t r^{s 6}^e_r^e₉²^{0 u e}_{i t}^m_{f f 0}_{[ d d}⁰_[ w⁰_[^a_{r C}^e_r^e_r⁰_[ Attorney Docket No.01218-0031-00PCT

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1^.₌^%_{( , ,}¹_,^m_{y =}^%_{( ,}^{5 2}_.⁷_.₀^N_{( n 0}⁰_{( 0}⁰_{( 0 (}_{2 0 0}⁰₍^L₁^.₀^N_{( n}⁰₍^{1 8}ⁿ_{0 ( 1 ( 9 0} g_{k i} /_e^g_k_g⁾^m_{) ) 5}^{. )}₅^.₎^{) t}⁰₅^._a^/^R_g⁾^m_{) ) 5}⁾^.₅^.¹₀¹₇⁹₇⁹_{0 7}^{9 e 1}₇⁹₇⁹^.₌^% 0^N_{( ,}_{( n 0}⁰_,_{( 0}^{0 1}_{( ,}_{( 0 1 0 0}⁰_s₍^{n 1}₌^% o₀^._{( , ,} p₀^N_{( n 0}⁰_{( 0}⁰_{( 0}_s₎^e^R_R_{P e} +^vi R_t^c^C_{( e}^j e^e_b s_n^e_t^{O e e} t^e_t^a_r^:_{e t}^a_{r t}^a_r o^a_r^a_r^e p_s_e^{n R}₄_R^{1 s}_n_e^o_{R R} s_{R R} r^{Cr P}_o^l_p m m p^O_b^s^a_e^{r C P} l^l_{a o}^r_{o s}^{e r}_o r^f_{T l}^r_o^r_o_{e I}^f^v_o^C_{I r}^f^C_e^v_I^l_a^{r f}_I^f_I i^C_{] e}^{C C} D^S t_s % e⁵ %_t 5^c_e^j %⁸⁵₉^v²_ot_{s R}%⁵_R%^/⁵_R_B^R₉_C^R₉_P^D_S^D_{P E} N_{b 9} O₀⁰_[^e B^m_{9 9}_C^m_P m N Attorney Docket No.01218-0031-00PCT

)₉⁶₍⁾₃^{, )}¹₅⁵₅³¹_{( . .}_{1 0 2}¹₍⁸₃ )₇⁾⁶₃^,₄⁾₇₍³₍⁸_.⁵_._{2 0 1}⁰₍⁰₉₎⁴⁾₂₅^.⁷₀₍⁶_,_{3 0 0}⁰₍₎⁴⁾₂₅^.⁷₀₍⁶_,_{3 0 0}⁰₍₎⁹⁾₁₀^.⁵₄₍⁸_,_{1 0 0}⁰₍ )₀^{) , )}⁵_{0 4}₍⁵₆²_.⁷_._{1 0 (}₁¹₍⁸₉₎⁾⁰₅₀^.¹₇₍⁹_,_{1 0 0}⁰₍ e_t^a_r e_s^{n R} o_R p_s^{) O}^e_{r R}^r^m_o^f D^P_e_/^v_I i_{t P}^C D^{c +} e_R% m_{P E}^j m⁵₉ N_b O^C₍ Attorney Docket No.01218-0031-00PCT Example 4: Clinical Study of an Anti-TIGIT Antibody in Combination with Brentuximab Vedotin for Treatment of Classical Hodgkin Lymphoma (cHL) 4.1 Study Design [00299] A Phase 1 non-randomized, open-label, multicenter study designed to evaluate the safety and tolerability of SEA-TGT in combination with brentuximab vedotin for the treatment of cHL is undertaken. [00300] Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) having three components: (1) a chimeric IgG1 monoclonal antibody (cAC10), specific for human CD30; (2) monomethyl auristatin E (MMAE); and (3) a protease-cleavable linker that covalently attaches MMAE to cAC10. [00301] The participants are patients with relapsed, refractory, or PD cHL that has failed the standard of care; prior treatment with brentuximab vedotin does not exclude participation. Subjects must have measurable disease (measurable fluorodeoxyglucose [FDG]-avid disease by positron emission tomography [PET] of ≥ 15 mm in the greatest transverse diameter by computed tomography [CT]), and qualifying baseline laboratory data. [00302] On Day 1 of each 21-day cycle (Q3W), SEA-TGT (at 1 mg/kg) and brentuximab vedotin (at 1.8 mg/kg, up to a maximum of 180 mg) are administered intravenously (IV). [00303] Aggregate safety data are reviewed after the first 6 subjects have completed 1 full cycle (21 days) of study treatment. If the combination is deemed safe, an additional 20 subjects may be enrolled to further evaluate the combination of SEA-TGT and brentuximab vedotin. If 2 or more of the initial 6 subjects experience a dose limiting toxicity, an additional 6 subjects with cHL may be enrolled to evaluate SEA-TGT at 0.3 mg/kg plus brentuximab vedotin before starting the expansion cohort. [00304] Participants receive study treatment until confirmed disease progression (based on Lugano with the incorporation of LYRIC criteria), loss of clinical benefit, unacceptable toxicity, withdrawal of consent, or study termination, whichever occurs first. [00305] The inclusion criteria for the study are as follows. 1. Participants must have histologically-confirmed or cytologically-confirmed advanced stage cHL. 2. Participants must be cHL patients that have failed standard of care for relapsed or refractory disease. Participants with prior brentuximab vedotin exposure require an objective response and subsequent disease progression or relapse are eligible. Participants that have not been previously exposed to brentuximab vedotin may be eligible for enrollment if they have failed other therapies considered standard of care for relapsed or refractory disease. 3. Participants must have FDG-PET avid and bidimensional measurable disease of at least 1.5 Attorney Docket No.01218-0031-00PCT cm in longest axis as documented by radiographic technique (spiral CT preferred). 4. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status score ≤ 2. 5. Participants must have the following baseline laboratory data: • ANC ≥ 1000 cells/μL (unless documented bone marrow involvement with lymphoma) • platelets ≥ 75,000/μL (unless documented bone marrow involvement with lymphoma) • serum bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN for subjects with Gilbert’s disease • serum creatinine (Scr) ≤ 1.5 x ULN • ALT and AST ≤ 3 x ULN for subjects with documented hepatic involvement with lymphoma • estimated GFR (glomerular filtration rate) ≥ 30 mL/min/1.73m² using the Modification of Diet in Renal Disease study equation 6. Participants of childbearing potential must meet the following conditions: a. Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 3 days prior to the first dose of SEA-TGT. Participants with false positive results and documented verification that the participant is not pregnant are eligible for participation. b. Must agree not to try to become pregnant during the study and for at least 3 months after the final dose of study drug. c. Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 3 months after the final dose of study drug. d. If sexually active in a way that could lead to pregnancy, must consistently use the acceptable combinations of contraceptive methods starting at time of informed consent and continuing throughout the study and for at least 3 months after the final dose of study drug. 7. Participants born male must meet the following conditions: a. Must agree not to donate sperm starting at time of informed consent and continuing throughout the study period and for at least 60 days after the dose of final study drug. b. If sexually active with a person of childbearing potential in a way that could lead to pregnancy, must consistently use the acceptable combination of contraceptive methods starting at time of informed consent and continuing throughout the study and for at least 60 days after the final dose of study drug. c. If sexually active with a person who is pregnant or breastfeeding, must consistently use contraception starting at time of informed consent and continuing throughout the study and Attorney Docket No.01218-0031-00PCT for at least 60 days after the final dose of study drug. 8. Participants must be age 18 years or older. 9. Participants must provide written informed consent. 10. Participants are required to have tumor tissue, if available, from the most recent biopsy (≤ 12 months from screening) prior to start of study treatment. If archival tissue is not available, a fresh screening tumor biopsy is required for any participant whose tumors are considered accessible and appropriate in the opinion of the investigator. [00306] Participants are excluded from the study if any of the following criteria apply: 1. Participants have a history of another malignancy within 2 years before the first dose of study drug, or any evidence of residual disease from a previously diagnosed malignancy. Exceptions are malignancies with a negligible risk of metastasis or death (e.g., 5-year overall survival [OS] ≥90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer. 2. Participants received chemotherapy, radiotherapy, biologics, and/or other antitumor treatment that has not been completed before the first dose of study drug within the timeframe as follows: a. Chemotherapy, small molecule inhibitors, radiation, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): 2 weeks o Palliative radiotherapy (≤ 2 weeks of radiotherapy to non-central nervous system [CNS] disease): ≤ 7 days prior to start of SEA-TGT. b. Immune-checkpoint inhibitors (i.e., anti-PD-1, anti-PD-L1, anti-cytotoxic T- lymphocyte-associated antigen 4 [CTLA-4]): 4 weeks c. Monoclonal antibodies, ADC (except brentuximab vedotin), or radioimmunoconjugates: 4 weeks (2 weeks with documented disease progression) d. T-cell or other cell-based therapies: 12 weeks 3. Participants have known active CNS involvement by lymphoma. 4. Participants have recent or serious ongoing infection, including: a. Any uncontrolled Grade 3 or higher (per the National Cancer Institute’s Common Terminology Criteria for Adverse Events [NCI CTCAE], Version 5) viral, bacterial, or fungal infection within 2 weeks prior to the first dose of SEA-TGT. Routine antimicrobial prophylaxis is permitted. b. Known seropositivity for, or active infection, by human immunodeficiency virus (HIV). c. Known to be positive for hepatitis B by surface antigen expression, or any other positive test for hepatitis B virus indicating acute or chronic infection. d. Known active hepatitis C infection (positive by serology and confirmed by Attorney Docket No.01218-0031-00PCT polymerase chain reaction [PCR]) or on antiviral therapy for hepatitis C within 6 months of the first dose of study drug. Participants who have been treated for hepatitis C infection are permitted if they have documented sustained virologic response of 12 weeks. 5. Participants have known active or latent tuberculosis. 6. Participants have received a live or live-attenuated vaccine within 30 days prior to Cycle 1 Day 1. 7. Participants have had previous allogeneic SCT. Participants with prior autologous SCT may be eligible if they are > 100 days from autologous SCT and fulfill all other inclusion criteria. 8. Participants have a documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III-IV heart failure 6 months prior to their first dose of SEA-TGT. 9. Participants receive current therapy with other systemic anti-neoplastic or investigational agents. 10. Participants had prior use of any anti-TIGIT mAb. 11. Participants have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of enrollment. Inhaled or topical steroids and adrenal replacement steroid doses > 10 mg daily prednisone or equivalents are permitted in the absence of active immune disease. 12. Participants have other medical or psychiatric condition including recent (within the past year) or active suicidal ideation/behavior or laboratory abnormality that may increase the risk of study participation or, in the investigator’s judgment, make the participant inappropriate for the study. 13. Participants are breastfeeding, pregnant, or planning to become pregnant from time of informed consent until 4 months after final dose of study drug. 14. Participants have known hypersensitivity to any excipient contained in the drug formulation of SEA-TGT or brentuximab vedotin. 15. Participants have a history of interstitial lung disease. Participants with focal asymptomatic radiation-induced fibrosis may be permitted upon consultation with the medical monitor. 16. Participants previously discontinued brentuximab vedotin due to any Grade 3 or higher toxicity. 17. Participants have existing Grade 2 or higher peripheral neuropathy. 18. Participants were previously refractory to treatment with brentuximab vedotin. 19. Participants have acute or chronic graft-versus-host-disease (GvHD) or received immunosuppressive therapy as treatment for or prophylaxis agent against GvHD. Attorney Docket No.01218-0031-00PCT 20. Participants have active cerebral/meningeal disease, including history of progressive multifocal leukoencephalopathy (PML). Participants with a history of cerebral/meningeal disease related to the underlying malignancy are allowed if prior CNS disease has been treated. 21. Participants have a history of progressive multifocal leukoencephalopathy (PML). 22. Participants have known hypersensitivity to any excipient contained in the drug formulation. 23. Participants had an allogeneic transplant with any detectable level of cytomegalovirus by polymerase chain reaction (PCR). Prior PCR positivity that was successfully treated is acceptable provided the baseline PCR result is negative prior to first dose of study drug. 24. Participants received prior donor lymphocyte infusion < 8 weeks prior to first dose of study drug. 25. Participants have other serious underlying medical condition that, in the opinion of the investigator, would impair the participant’s ability to receive or tolerate the planned treatment and follow-up. 26. Participants who enrolled and treated in this study cannot enroll in this study again. [00307] Specific objectives and corresponding endpoints for the study are summarized in Table 15 below. [00308] Table 15: Objectives and corresponding endpoints

Attorney Docket No.01218-0031-00PCT

[00309] All publications, patents, patent applications or other documents cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication, patent, patent application, or other document was individually indicated to be incorporated by reference for all purposes.

Attorney Docket No.01218-0031-00PCT VIII. Table of Sequences

Attorney Docket No.01218-0031-00PCT

Attorney Docket No.01218-0031-00PCT

Claims

Attorney Docket No.01218-0031-00PCT WHAT IS CLAIMED IS: 1. A method of treating a cancer in a human subject, comprising administering to the subject an anti-TIGIT antibody, wherein the cancer is resistant or has become refractory to a PD-1 inhibitor or a PD-L1 inhibitor. 2. The method of the immediately preceding claim, wherein the anti-TIGIT antibody is administered to the subject at a dose of 0.3, 1, or 3 mg/kg. 3. A method of treating a cancer in a human subject, comprising administering to the subject an anti-TIGIT antibody, wherein the anti-TIGIT antibody is administered to the subject at a dose of 0.3, 1, or 3 mg/kg. 4. The method of any one of the preceding claims, wherein the anti-TIGIT antibody is administered to the subject at a dose of 1 or 3 mg/kg. 5. The method of any one of the preceding claims, wherein the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. 6. The method of any one of the preceding claims, wherein the anti-TIGIT antibody is administered to the subject every three weeks (Q3W). 7. The method of any one of the preceding claims, wherein the anti-TIGIT antibody is administered to the subject intravenously. 8. The method of any one of the preceding claims, wherein the subject has received a systemic therapy for the cancer. 9. The method of any one of the preceding claims, wherein the subject has received a platinum-based therapy. 10. The method of any one of the preceding claims, wherein the subject has received a PD-1 inhibitor or PD-L1 inhibitor. 11. The method of any one of the preceding claims, wherein the level of PD-L1 in a sample of the cancer is less than 10 as measured by Combined Positive Score (CPS), or less than 50% as measured by Total Proportion Score (TPS), or less than 50% as measured by a Tumor Cell score (TC), or less than 10% as measured by Tumor-Infiltrating Immune Cell staining (IC). Attorney Docket No.01218-0031-00PCT 12. The method of any one of the preceding claims, wherein the level of PD-L1 in a sample of the cancer is less than 5, or less than 3, or less than 1, as measured by CPS. 13. The method of any one of the preceding claims, wherein the level of PD-L1 in a sample of the cancer is less than 40%, or less than 30%, or less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, as measured by TPS. 14. The method of any one of the preceding claims, wherein the level of PD-L1 in a sample of the cancer is less than 40%, or less than 30%, or less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, as measured by TC. 15. The method of any one of the preceding claims, wherein the level of PD-L1 in a sample of the cancer is less than 5%, or less than 3%, or less than 1%, as measured by IC. 16. The method of any one of the preceding claims, wherein the cancer has relapsed or become refractory to a prior therapy for the cancer. 17. The method of any one of the preceding claims, wherein the cancer is an advanced or metastatic cancer. 18. The method of any one of the preceding claims, wherein the cancer is an unresectable cancer. 19. The method of any one of the preceding claims, wherein the cancer is non-small cell lung cancer (NSCLC), gastric/gastroesophageal (GE) junction carcinoma, gastric cancer, cutaneous melanoma, head and neck squamous cell carcinoma (HNSCC), bladder cancer, urothelial cancer, cervical cancer, ovarian cancer, primary peritoneal cancer, fallopian tube cancer, triple negative breast cancer (TNBC), classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), or peripheral T-cell lymphoma, not otherwise specified (PTCL- NOS)). 20. The method of any one of claims 1-19, wherein the cancer is gastric cancer. 21. The method of any one of claims 1-19, wherein the cancer is gastric cancer, and wherein the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. 22. The method of any one of claims 1-19 and 21, wherein the cancer is gastric/GE junction carcinoma, and wherein the subject has received a therapy comprising ramucirumab and/or an anti-HER2/neu therapy. Attorney Docket No.01218-0031-00PCT 23. The method of any one of claims 1-19, wherein the cancer is cutaneous melanoma, and wherein the subject has received an anti-BRAF mutation therapy. 24. The method of any one of claims 1-19, wherein the cancer is HNSCC, and wherein the subject has received an anti-EGFR therapy. 25. The method of any one of claims 1-19, wherein the cancer is bladder cancer or urothelial cancer, and wherein the subject has received a therapy comprising enfortumab vedotin. 26. The method of any one of claims 1-19, wherein the cancer is cervical cancer, and wherein the subject has received a therapy comprising bevacizumab. 27. The method of any one of claims 1-19, wherein the cancer is ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, and wherein the subject has received a therapy comprising bevacizumab or a poly(ADP-ribose) polymerase (PARP) inhibitor. 28. The method of any one of claims 1-19, wherein the cancer is cHL. 29. The method of any one of claims 1-19, wherein the cancer is cHL, and wherein the subject has received a therapy comprising brentuximab vedotin. 30. The method of any one of claims 1-19 and 29, wherein the cancer is cHL, and wherein the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. 31. The method of any one of claims 28-30, wherein the cancer is cHL, and wherein the anti-TIGIT antibody is administered in combination with a therapy comprising brentuximab vedotin. 32. The method of any one of claims 1-19, wherein the cancer is DLBCL, and wherein the subject has received a therapy comprising two systemic chemo-immunotherapy regimens, optionally wherein the two systemic chemo-immunotherapy regimens comprise an anti-CD20 agent and a combination chemotherapy, or wherein the subject has received a combination chemotherapy or autologous stem cell transplant. 33. The method of any one of claims 1-19 and 32, wherein the cancer is DLBCL, and wherein the anti-TIGIT antibody is administered to the subject at a dose of 1 mg/kg. 34. The method of any one of claims 1-19, wherein the cancer is PTCL-NOS, and wherein the subject has received a therapy comprising cyclophosphamide, doxorubicin, Attorney Docket No.01218-0031-00PCT vincristine, prednisone (CHOP), or CHOP-like therapy, or wherein the subject has received a combination chemotherapy or autologous stem cell transplant. 35. The method of any one of claims 1-19 and 34, wherein the cancer is PTCL-NOS and is CD30-positive, and wherein the subject has received a therapy comprising brentuximab vedotin. 36. The method of any one of claims 1-19 and 34, wherein the cancer is PTCL-NOS, and wherein the subject has received a therapy comprising brentuximab vedotin. 37. The method of any one of the preceding claims, wherein the anti-TIGIT antibody is administered to the subject as a monotherapy. 38. The method of any one of claims 1-36, wherein the method further comprises administering to the subject an additional therapeutic agent. 39. The method of the immediately preceding claim, wherein the additional therapeutic agent is a checkpoint inhibitor. 40. The method of the immediately preceding claim, wherein the checkpoint inhibitor is a PD-1 inhibitor or a PD-L1 inhibitor. 41. The method of the immediately preceding claim, wherein the PD-1 inhibitor is an anti-PD-1 antibody. 42. The method of claim 40 or claim 41, wherein the PD-L1 inhibitor is an anti-PD- L1 antibody. 43. The method of any one of the preceding claims, wherein the anti-TIGIT antibody comprises an Fc with enhanced binding to at least one of FcγRIIIa, FcγRIIa, and FcγRI. 44. The method of the immediately preceding claim, wherein the anti-TIGIT antibody comprises an Fc with enhanced binding to at least FcγRIIIa. 45. The method of claim 43, wherein anti-TIGIT antibody comprises an Fc with enhanced binding to at least FcγRIIIa and FcγRIIa. 46. The method of claim 43, wherein the anti-TIGIT antibody comprises an Fc with enhanced binding to at least FcγRIIIa and FcγRI. Attorney Docket No.01218-0031-00PCT 47. The method of claim 43, wherein the anti-TIGIT antibody comprises an Fc with enhanced binding to FcγRIIIa, FcγRIIa, and FcγRI. 48. The method of any one of claims 43-47, wherein the Fc of the anti-TIGIT antibody has reduced binding to FcγRIIb. 49. The method of any one of the preceding claims, wherein the anti-TIGIT antibody comprises substitutions S293D, A330L, and I332E in the heavy chain constant region. 50. The method of any one of the preceding claims, wherein the anti-TIGIT antibody is nonfucosylated. 51. The method of any one of the preceding claims, wherein the administering to the subject the anti-TIGIT antibody comprises administering a composition of anti-TIGIT antibodies, wherein at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% of the antibodies in the composition are nonfucosylated. 52. The method of any one of the preceding claims, wherein the Fc of the anti-TIGIT antibody comprises an Fc with enhanced ADCC and/or ADCP activity relative to a corresponding wild-type Fc of the same isotype. 53. The method of any one of the preceding claims, wherein the anti-TIGIT antibody comprises: a) a heavy chain CDR1 comprising an amino acid sequence selected from SEQ ID NOs: 7-9; b) a heavy chain CDR2 comprising an amino acid sequence selected from SEQ ID NOs: 10-13; c) a heavy chain CDR3 comprising an amino acid sequence selected from SEQ ID NOs: 14-16; d) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO: 17; e) a light chain CDR2 comprising the amino acid sequence of SEQ ID NO: 18; and f) a light chain CDR3 comprising the amino acid sequence of SEQ ID NO: 19. 54. The method of any one of the preceding claims, wherein the anti-TIGIT antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of: Attorney Docket No.01218-0031-00PCT a) SEQ ID NOs: 7, 10, 14, 17, 18, and 19, respectively; or SEQ ID NOs: 8, 11, 14, 17, 18, and 19, respectively; or SEQ ID NOs: 9, 12, 15, 17, 18, and 19, respectively; or SEQ ID NOs: 8, 13, 16, 17, 18, and 19, respectively; or SEQ ID NOs: 8, 12, 16, 17, 18, and 19, respectively. 55. The method of any one of the preceding claims, wherein the anti-TIGIT antibody comprises a heavy chain CDR1, CDR2, and CDR3 and a light chain CDR1, CDR2, and CDR3 comprising the sequences of SEQ ID NOs: 7, 10, 14, 17, 18, and 19, respectively. 56. The method of any one of claims 1-54, wherein the anti-TIGIT antibody comprises a heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: 1-5 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 6. 57. The method of any one of the preceding claims, wherein the anti-TIGIT antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 6. 58. The method of any one of claims 1-54 and 56, wherein the anti-TIGIT antibody comprises a heavy chain comprising an amino acid sequence selected from SEQ ID NOs: 20-24 and a light chain comprising the amino acid sequence of SEQ ID NO: 25. 59. The method of any one of the preceding claims, wherein the anti-TIGIT antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 20 and a light chain comprising the amino acid sequence of SEQ ID NO: 25. 60. The method of any one of the preceding claims, wherein the subject has a partial metabolic response or two partial metabolic responses after the administering to the subject the anti-TIGIT antibody. 61. The method of any one of the preceding claims, wherein the subject has a partial response after the administering to the subject the anti-TIGIT antibody.