Antigen-binding proteins and combinations thereof

Abstract

Compositions, and related methods, for the treatment of CD96-mediated diseases are provided.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 63 / 168,991, filed March 31, 2021, and U.S. Provisional Application No. 63 / 275,651, filed November 4, 2021, the entire contents of each of the foregoing applications being incorporated herein by reference. [Technical Field]

[0002] Electronically submitted sequence listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated by reference in its entirety. The ASCII copy, created on February 1, 2022, is named "PU67095_WO_SL_ASCII" and is 363KB in size.

[0003] Technical Field The present invention relates to antigen-binding proteins and fragments thereof that specifically bind to CD96, particularly human CD96. The present invention also relates to methods of treating diseases or disorders using the antigen-binding fragments, pharmaceutical compositions comprising the antigen-binding fragments, and methods of manufacture. Other embodiments of the invention will become apparent from the description below. [Background technology]

[0004] CD96 / TACTILE ("upregulated late in T cell activation") is a cell surface receptor belonging to the immunoglobulin superfamily, expressed primarily on T cells, natural killer (NK) cells, and natural killer T (NKT) cells. CD96 belongs to a receptor family that includes CD226 and TIGIT ("T cell immunoreceptor with Ig and ITIM domains," also known as WUCAM, Vstm3, and VSIG9), which are known to interact with nectin and nectin-like ligands. CD155 / NECL5 ("nectin-like protein-5") is the primary ligand for all three receptors (CD96, TIGIT, and CD226). TIGIT binds to CD155 with higher affinity (3.15 nM) than CD226 (119 nM), whereas CD96 binding is intermediate (37.6 nM) (Martinet L. & Smyth MJ Nat Rev Immunol. 2015 Apr; 15(4): 243-54). In addition to CD155, TIGIT and CD226 also bind to another ligand, CD112, but with much lower affinity. Recently, a new receptor, CD112R, which also binds to CD112, was discovered (Zhu Y., et al. 2016 Feb 8; 213(2): 167-76).

[0005] Among the receptors in this axis, CD226 (DNAM-1) is one of the major activating receptors for NK cells. CD226 has been reported to enhance NK cell cytotoxicity against cancer cells and is important for tumor immunosurveillance (Lakshmikanth T., et al., 2009; 119(5): 1251-63; Chan CJ et al., 2010; 184(2): 902-11; Gilfillan S., et al., 2008; 205(13): 2965-73; Iguchi Manaka et al., J Exp Med. 2008; 205(13): 2959-64). Conversely, CD96 (Chan CJ et al., Nat Immunol. 2014; 15(5): 431-8) and TIGIT (Lozano E., et al., 2012; 188(8): 3869-75) are known to attenuate immune responses by inhibiting the function of NK cells and / or T cells. TIGIT expression is associated with T cell exhaustion (Lozano E. et al., 2015; 125(11): 4053-62) and NK cell exhaustion (Zhang Q., et al., Nat Immunol. 2018; 19(7): 723-32), and several anti-TIGIT antibodies are in clinical development.

[0006] Overall, CD226 and TIGIT have a much larger literature base and a better understanding of their mechanisms than CD96. CD226 does not possess the classical ITAM motifs found in other immune activation receptors. Upon ligand binding and receptor dimerization, positive signaling occurs through a series of phosphorylation events involving PKC and Vav1 proteins. The cytoplasmic tail of TIGIT contains an ITT motif and a classical inhibitory ITIM motif. Upon CD155 binding, the ITT motif is tyrosine phosphorylated, transducing downstream immunosuppressive signals involving SHIP1. On the other hand, the signaling pathway of CD96 remains unclear. The cytoplasmic tail of CD96 is known to contain both potentially inhibitory ITIM motifs and potentially activating YXXM motifs, which are present in several immune activation receptors (e.g., ICOS and CD28) (Georgiev H., et al., Front Immunol.).

[0007] Although CD96 was discovered over 25 years ago (Wang PL, et al., 1992; 148(8): 2600-8), little was known about its function other than the fact that it is a member of the immunoglobulin family that shares the ligand CD155 with CD226 and TIGIT (Fuchs A., et al., 2004; 172(7): 3994-8). Subsequently, most papers linking CD96 to cancer focused on CD96 as a leukemia stem cell (LSC) marker. The first paper to suggest CD96 as a potential cancer immunotherapy target was published in 2014 by Professor Mark Smyth's laboratory; it was shown that CD96 competes with CD226 for CD155 binding on NK cells and negatively regulates the production of inflammatory cytokines, including IFNγ, in mice after activation with LPS (Chan CJ, et al.). CD96 knockout mice and mice treated with anti-CD96 antibodies were less susceptible to MCA-induced sarcoma formation (ibid.). In the same study, blockade of CD226 or CD155 resulted in a worse outcome, which is speculated to be due to loss of the CD155:CD226 activation pathway (ibid.).

[0008] Subsequently, additional in vivo studies have been published supporting the inhibition of CD96 in cancer therapy (e.g., Blake SJ et al., Cancer Discov. 2016; 6(4): 446-59; Brooks J., et al.: 475-88; Harjunpaa H., et al., 2018; 7(7): e1445949). Thus, there is a need for improved antigen-binding proteins and fragments thereof that target CD96 for use in the treatment of disease. Such compositions and related methods are provided in the present disclosure. Summary of the Invention

[0009] In a first aspect, the present invention provides a CD96 binding protein. In a second aspect, the present invention also provides a nucleic acid construct encoding the CD96 binding protein. In a third aspect, the present invention provides an expression vector comprising a nucleic acid according to the second aspect. In a fourth aspect, the present invention provides a recombinant host cell comprising the nucleic acid or expression vector described in the previous aspect. In a fifth aspect, the present invention further provides a method comprising culturing a host cell described in the previous aspect under conditions suitable for expression of the nucleic acid sequence or vector, thereby producing a polypeptide comprising the CD96 binding protein. In a sixth aspect, the present disclosure provides a CD96 binding protein produced by the production method described in the previous aspect. In a seventh aspect, the present disclosure also provides a pharmaceutical composition comprising the CD96 binding protein described in any one of the previous aspects and a pharmaceutically acceptable excipient. Another aspect of the present disclosure is a method of treating a disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a CD96 binding protein or pharmaceutical composition described in any one of the preceding aspects. A further aspect of the present disclosure is a method of treatment according to the previous aspect, further comprising determining whether the subject expresses CD96. Another aspect of the present disclosure is a CD96 binding protein or pharmaceutical composition according to any one of the preceding aspects for use in therapy or for use in treating a disease.

[0010] The following detailed description of preferred embodiments of the invention will be better understood when read in conjunction with the accompanying drawings. For the purpose of illustrating the invention, there are shown in the drawings embodiments which are presently preferred. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities of the embodiments shown in the drawings. [Brief explanation of the drawings]

[0011] [Figure 1] Shown is the binding of CD96 binding protein to human CD3+ T cells (A) and the ability of CD96 binding protein to inhibit binding of CD155 to CHO cells expressing human CD96 (B). [Figure 2] Solution equilibrium titration (SET) data for binding of CD96 binding proteins to human (a), cynomolgus monkey (b) or mouse (c) CD96 are shown. [Figure 3] Binding of CD96 binding proteins to HEK cells transiently transfected with human or cynomolgus CD96 isoforms is shown. [Figure 4] Binding of CD96 binding proteins (vs. isotype control) to primary human T cells (total CD3+ T cells vs. CD4+ or CD8+ subsets) is shown. [Figure 5] Binding of CD96 binding proteins to activated primary cynomolgus monkey T cells is shown. [Figure 6] Showing internalization of CD96 using imaging cytometry in CD8+ T cells after binding to human PBMCs; representative cell imaging of CD8+ T cells (grey = CD8 staining, white = CD96 binding protein-PE staining) [Figure 7] We show that CD96-binding proteins, when pre-complexed to membrane CD96 in primary human T cells, prevent binding of CD155:Fc to these T cells. [Figure 8] 1 shows the displacement of CD155:Fc pre-bound to human T cells by CD96 binding protein. [Figure 9-1] 1 shows human Fcγ reporter assay data demonstrating that binding of CD96 binding proteins to CD96 on primary human T cells does not induce cross-linking and / or signaling through Fcγ receptors. [Figure 9-2] 1 shows human Fcγ reporter assay data demonstrating that binding of CD96 binding proteins to CD96 on primary human T cells does not induce cross-linking and / or signaling through Fcγ receptors. [Figure 10] Human ADCC target cell killing assay data in CD4+ and CD8+ T cells are shown; no evidence of increased cell death was observed in either CD4+ or CD8+ T cells in the presence of CD96 binding protein. [Figure 11] Figure 1 shows a human CD4+ target cell killing assay in CD4+ T cells; no evidence of complement-dependent cytotoxicity derived from CD96-binding proteins is observed. [Figure 12] EC50 data for IFNγ release of CD96 binding proteins (expressed from CHO or HEK cells) in a mixed PMBC-MLR assay are shown. [Figure 13] The activity of CD96 binding proteins (expressed from HEK cells) on IFNγ production in a mixed PBMC-MLR assay in the presence or absence of CD4+ (A) or CD8+ (B) T cells is shown. [Figure 14] 1 shows the effect of CD96 binding proteins on IFNγ and granzyme B secretion in a mixed PBMC-MLR assay. [Figure 15] 1 shows the frequency of IFNγ+ cells in different cell populations on day 3 in the presence of CD96 binding proteins and controls in a mixed PBMC-MLR assay. [Figure 16] The frequency of CD96+ cells in CD4+, CD8+ and NK cell populations in a mixed PBMC-MLR assay is shown upon treatment with CD96 binding proteins and controls. [Figure 17] 1 shows the expression levels of CD96 in CD4+, CD8+, and NK cell populations in control and treated with CD96 binding proteins in a mixed PBMC-MLR assay. [Figure 18] 1 shows the characterization of FACs showing the effect of CD96 binding proteins on the ratio of CD226+ single positive versus CD226+CD96+ double positive NK cells in a mixed PBMC-MLR assay. [Figure 19] FIG. 1 shows FACs characteristics showing the effect of CD96-binding proteins on IFNγ+GrzB+ double-positive cells among the total NK cell population in a mixed PBMC-MLR assay. [Figure 20] 1 shows the inhibitory effect of plate-bound CD155-Fc on IFNγ production in a human PBMC assay. [Figure 21] 1 shows the activity of CD96-binding proteins in a renal cancer TIL functional assay alone or in combination with anti-PD1 or anti-TIGIT antibodies. [Figure 22A] 1 shows bioluminescence imaging study data for CD96-binding proteins in an NK cell-dependent B16F10 melanoma lung colonization model, showing representative bioluminescence images acquired approximately 15 minutes after injection of B16F10 RFluc melanoma cells. [Figure 22B] 1 shows bioluminescence imaging study data for CD96-binding proteins in an NK cell-dependent B16F10 melanoma lung colonization model, showing representative bioluminescence images acquired approximately 15 minutes after injection of B16F10 RFluc melanoma cells. [Figure 23] FIG. 1 shows lung bioluminescence signals 14 days after B16F10 cell injection in mice with and without depletion of CD4, CD8, or NK cells. [Figure 24] 1 shows in vivo bioluminescent lung signals at days 14 and 20 showing the effect of CD96 binding proteins (vs. control) on lung metastases in various groups. [Figure 25] Images of CD96 binding protein-treated CD4+ / CD8+ depleted mouse lungs versus controls are shown on day 20 (end of study). [Figure 26] IFNγ production in CD155-coated PBMC assays in the presence of CD96-binding protein or isotype control in the presence of anti-TIGIT mAb is shown and assessed by MSD. [Figure 27] TNFα production in the presence of CD96-binding proteins or isotype control in the presence of anti-TIGIT mAb in a CD155-coated PBMC assay is shown (assessed by MSD). [Figure 28] IFNγ production in CD155-coated PBMC assays over 3 days in the presence or absence of anti-TIGIT mAb, CD96 binding protein or isotype control is shown and assessed by MSD. [Figure 29A]Figure 29A shows CD226 axis expression across immune subsets in human tumors, as determined by CyTOF as described in Example 11. Figure 29A: Live CD45+ cells from a subset of donors (61 concatenated and analyzed by Uniform Manifold Approximation Projection (UMAP) analysis). N=12 cell subsets were gated, and expression of canonical immune markers was used to define the two-axis gating strategy. [Figure 29B] Figure 29B shows CD226 axis expression across immune subsets in human tumors as determined by CyTOF as described in Example 11. Figure 29B: Frequency of dual-axis gated populations among samples across N=14 tumor indications and all samples (n=104). [Figure 29C] Figure 29C shows CD226 axis expression across immune subsets in human tumors as determined by CyTOF as described in Example 11. Figure 29C: UMAP highlighting expression of CD226 axis members, color-coded for signal intensity (median mass intensity, MMI). [Figure 29D] Figure 29D shows CD226 axis expression across immune subsets in human tumors as determined by CyTOF as described in Example 11. Figure 29D: Collation of percent (%) expression of CD226 axis members across major immune cell subsets. Each symbol represents a single sample. [Figure 30A] Figure 30A shows CD226 axis expression on NK cell subsets across tumor indications, as determined by CyTOF as described in Example 11. Figure 30A: NK cells from all donors with a minimum of 30 NK cells (76 identified by dual-axis gating) were combined for UMAP analysis. The dual-axis gating definition of NK cells (informed by the UMAP analysis in Figure 29A) includes CD56+ and / or NKG2D+ cells that are also CD3-CD19-CD15-CD11b-CD11c-. Regions of interest (ROIs) with unique protein expression patterns are shown in Figures 30A-30B. [Figure 30B]Figures 30A-30B show CD226 axis expression on NK cell subsets across tumor indications, as determined by CyTOF as described in Example 11. Regions of interest (ROIs) with unique protein expression patterns are shown in Figures 30A-30B. Figure 30B: NK cell UMAP highlighting expression of CD226 axis members, color-coded by signal intensity (MMI). [Figure 30C] Figure 30C shows CD226 axis expression on NK cell subsets across tumor indications as determined by CyTOF as described in Example 11. Figure 30C shows the frequency of NK cells contained within each ROI (gated on the UMAP) in each sample across tumor indications. [Figure 30D] Figure 30D shows CD226 axis expression on NK cell subsets across tumor indications, as determined by CyTOF as described in Example 11. Figure 30D: Signal intensity (median metal intensity, MMI) of various markers across NK ROIs. Different clusters are highlighted (boxed). Markers with an MMI below 5 across all ROIs and CD226 axis ligands (CD155 and CD112) were removed. PVRIG-based analysis was performed on N=61 samples. [Figure 31A] Figure 31A shows CD226 axial expression on CD4+ T cell subsets in whole human tumors, as determined by CyTOF as described in Example 11. Figure 31A: CD4+ T cells from all donors with at least 30 CD4+ T cells (n=97), identified by dual-axis gating, were combined for UMAP analysis. The dual-axis gating definition for tumor-infiltrating CD4+ T cells included CD8-CD19-CD56-CD15-CD14-CD11b- CD3+CD4+ cells with FoxP3 expression, which defines Treg cells. Regions of interest (ROIs) with unique protein expression patterns on the resulting CD4+ T cell UMAP are shown in Figures 31A and 31B. [Figure 31B]Figures 31A and 31B show CD226 axis expression on CD4+ T cell subsets in whole human tumors, as determined by CyTOF as described in Example 11. Regions of interest (ROIs) with unique protein expression patterns are shown on the resulting CD4+ T cell UMAP. Figure 31B: CD4+ T cell UMAP highlighting expression of CD226 axis members, color-coded by signal intensity (MMI). [Figure 31C] Figure 31C shows CD226 axis expression on CD4+ T cell subsets across human tumors as determined by CyTOF as described in Example 11. Figure 31C: Frequency of CD4+ T cells contained within each ROI (gated on UMAP) among samples across tumor indications. [Figure 31D] Figure 31D shows CD226 axis expression on CD4+ T cell subsets across human tumors, as determined by CyTOF as described in Example 11. Figure 31D: Signal intensity (MMI) of various markers among CD4+ T cell ROIs. Different clusters are highlighted (boxed). Markers with minimal expression (MMI < 5 in all ROIs) and CD226 axis ligands (CD155 and CD112) were removed. PVRIG-based analysis was performed on N = 61 samples. [Figure 32A] Figure 32A shows CD226 axial expression on CD8+ T cell subsets across human tumors, as determined by CyTOF as described in Example 11. Figure 32A: CD8+ T cells from all donors with a minimum of 30 CD8+ T cells (n=90), identified by dual-axis gating, were combined for UMAP analysis. The dual-axis gating definition for tumor-infiltrating CD8+ T cells included CD3+ CD8+ cells that were also CD4-CD19-CD56-CD15-CD14-CD11b-. Regions of interest (ROIs) with unique protein expression patterns on the resulting CD8+ T cell UMAP are shown in Figures 32A-32B. [Figure 32B]Figures 32A-32B show CD226 axis expression on CD8+ T cell subsets across human tumors, as determined by CyTOF as described in Example 11. Regions of interest (ROIs) with unique protein expression patterns are shown on the resulting CD8+ T cell UMAP. Figure 32B: CD8+ T cell UMAP highlighting expression of CD226 axis members, color-coded by signal intensity (MMI). [Figure 32C] Figure 32C shows CD226 axis expression on CD8+ T cell subsets across human tumors as determined by CyTOF as described in Example 11. Figure 32C: Frequency of CD8+ T cells contained within each ROI (gated on UMAP) in each sample across tumor indications. [Figure 32D] Figure 32D shows CD226 axis expression on CD8+ T cell subsets across human tumors, as determined by CyTOF as described in Example 11. Figure 32D: Signal intensity (MMI) of various markers within CD8+ T cell ROIs. Different clusters are highlighted (boxed). Markers with minimal expression (MMI < 5 in all ROIs) and CD226 axis ligands (CD155 and CD112) were removed. PVRIG-based analysis was performed on N=61 samples. [Figure 33] Figure 1 shows a summary of CD226 axis members (CD96, PVRIG, TIGIT, CD226) and PD-1 expression on human tumor-infiltrating lymphocytes (TILs) as determined by CyTOF as described in Example 11. Expression levels are shown as relative expression ranging from - (no expression) to +++ (very high). Relative expression compares overall total expression across all relevant immune subsets. Specific Description of the Invention

[0012] The present disclosure provides CD96 binding proteins, nucleic acids encoding such proteins, and related subject matter.

[0013] As used in the specification and claims, the singular forms "a," "and," and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to a "peptide chain" is a reference to one or more peptide chains and includes equivalents thereof known to those skilled in the art.

[0014] As used in this specification and claims, the term "comprising" encompasses "including" or "consisting." For example, a composition "comprising" X may consist of only X, or may include additional items such as X+Y.

[0015] The term "consisting essentially of" limits the scope of a feature to the specified materials or steps, and those that do not materially affect the basic characteristics of the described feature.

[0016] The term "consisting of" excludes the presence of additional components.

[0017] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Although any compositions and methods similar or equivalent to those described herein can be used in practicing or testing the methods of the present disclosure, exemplary compositions and methods are described herein. Any of the aspects and embodiments of the present disclosure described herein can also be combined. For example, the subject matter of any dependent or independent claim disclosed herein can be combined in multiple ways (e.g., one or more statements from each dependent claim can be combined into a single claim based on the independent claim to which it depends).

[0018] The ranges provided herein include all values ​​within the particular ranges described, as well as values ​​related to the endpoints of the particular ranges. Additionally, the figures and tables of this disclosure list ranges and discrete values ​​that may comprise any element of the methods disclosed herein.

[0019] The concentrations described herein are determined at ambient temperature and pressure. This may be, for example, room temperature or the temperature and pressure within a particular portion of the process stream. Preferably, the concentrations are determined at standard conditions of 25°C and 1 bar pressure.

[0020] The term "about" means a value within two standard deviations of the mean for a particular measurement.

[0021] "Affinity" refers to the strength of binding between a molecule and another molecule. The binding affinity of an antigen-binding protein to a target can be determined by equilibrium methods (such as enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay (RIA)) or kinetic methods (such as surface plasmon resonance analysis using a BIACORE device).

[0022] As used herein, the term "antigen" refers to a macromolecular structure selectively recognized by an antigen-binding protein. Antigens include, but are not limited to, proteins (with or without polysaccharides) or protein compositions containing one or more T-cell epitopes. As contemplated herein, the target-binding domain of an antigen-binding protein may recognize the sugar side chains of a glycoprotein rather than a specific amino acid sequence or polymer. Thus, the sugar moiety or sulfated sugar moiety functions as the antigen.

[0023] As used herein, the term "antigen-binding protein" refers to isolated proteins, antibodies, antibody fragments (e.g., Fabs), and other antibody-derived protein constructs, including domains capable of binding to CD96 (e.g., domain antibodies). Such alternative antibody formats include triabodies, tetrabodies, miniantibodies, and minibodies. Also included are alternative scaffolds in which one or more CDRs of any molecule according to the present disclosure can be placed on a suitable non-immunoglobulin protein scaffold or framework, such as an affibody, an SpA scaffold, an LDL receptor class A domain, an avimer (see, e.g., U.S. Patent Application Publication Nos. 2005 / 0053973, 2005 / 0089932, and 2005 / 0164301), or an EGF domain. ABPs also include antigen-binding fragments of such antibodies and other molecules. Furthermore, ABPs may comprise the VH regions of the present invention formatted into full-length antibodies, (Fab')2 fragments, Fab fragments, bispecific or biparatopic molecules, or their equivalents (e.g., scFVs, bibodies, tribodies, or tetrabodies, Tandabs, etc.) when paired with an appropriate light chain. ABPs may comprise antibodies that are IgG1, IgG2, IgG3, or IgG4, or IgM, IgA, IgE, or IgD, or modified variants thereof. The constant domain of the antibody heavy chain can be selected appropriately. The light chain constant domain may be a kappa or lambda constant domain. ABPs may also be chimeric antibodies of the type described in WO 86 / 01533, comprising an antigen-binding region and a non-immunoglobulin region. The antigen-binding proteins of the present disclosure may be provided as lyophilized powders containing the antibody and excipients, which can be reconstituted with a pharmaceutically acceptable carrier (e.g., sterile water). This reconstituted pharmaceutical composition can then be administered either subcutaneously or intravenously (e.g., with further dilution). The antigen binding proteins of the present disclosure may also be provided as a liquid formulation comprising the antibody, excipients, and a pharmaceutically acceptable carrier. This liquid pharmaceutical composition can be administered subcutaneously or intravenously (e.g., with further dilution).The terms "ABP," "antigen-binding protein," and "binding protein" are used interchangeably herein. As used herein, the terms "peptide," "polypeptide," and "protein" are used interchangeably and refer to compounds containing amino acid residues covalently linked by peptide bonds. A protein or peptide must contain at least two amino acids, and there is no limit to the maximum number of amino acids that may comprise a protein or peptide sequence. A polypeptide includes peptides or proteins containing two or more amino acids linked to each other by peptide bonds. As used herein, the term refers to both short chains, commonly referred to in the art as peptides, oligopeptides, and oligomers, and longer chains, which are numerous and commonly referred to in the art as proteins. "Polypeptide" includes, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, polypeptide variants, modified polypeptides, derivatives, analogs, fusion proteins, and the like. A polypeptide includes natural peptides, recombinant peptides, synthetic peptides, or combinations thereof.

[0024] As used herein, the term "antibody variant" refers to an antibody that differs from a parent antibody by at least one amino acid modification (e.g., by having a different amino acid side chain), post-translational modification, or other modification in at least one heavy chain, light chain, or combination thereof, resulting in a structural change (e.g., a different amino acid side chain, a different post-translational modification, or other modification) compared to the parent antibody. Structural changes can be determined directly by various methods well known in the art, such as LC-MS or direct sequencing, or indirectly via methods such as isoelectric focusing. Such methods are well known to those skilled in the art.

[0025] As used herein, the term "epitope" refers to the portion of an antigen that contacts a specific binding domain. Epitopes can be linear or conformational / discontinuous. Conformational or discontinuous epitopes contain amino acid residues that are separated by other sequences, i.e., that are not contiguous in the primary sequence of the antigen. These residues may originate from different regions of the peptide chain but are adjacent in the three-dimensional structure of the antigen. In the case of multimeric antigens, conformational or discontinuous epitopes may include residues from different peptide chains. Specific residues contained within an epitope can be determined by computer modeling programs or by three-dimensional structures obtained by methods known in the art, such as X-ray crystallography. As contemplated herein, the term epitope also includes post-translational modifications to polypeptides that can be recognized by antigen-binding proteins or domains, such as sugar moieties of glycosylated proteins.

[0026] As used herein, the term "isolated" means changed or removed from its natural state. For example, a nucleic acid or peptide naturally occurring in a living animal is not "isolated," but the same nucleic acid or peptide partially or completely separated from the coexisting materials of its natural state is "isolated." An isolated nucleic acid or protein can exist in a substantially purified form, or it can exist in a non-native environment, such as a host cell.

[0027] CD96 (cluster of differentiation 96), also known as TACTILE, is a receptor expressed on T cells and NK cells. It shares sequence similarity with CD226 (DNAM01) and is a type 1 transmembrane glycoprotein belonging to the immunoglobulin superfamily.

[0028] Human CD96 has three isoforms: two membrane forms (V1 and V2) and a soluble form. The longer V1 isoform is a 585-amino acid protein with a molecular weight of 65,634 Da. The shorter isoform V2 (569 aa) has a molecular weight of 63,888 Da. V2 differs from V1 by a short deletion of the Ig fold in the second domain. The first domain of CD96 contains the epitope required for CD155 binding, while the second domain is reported to regulate the magnitude / strength of binding. CD96V2 binds to CD155 much more strongly than CD96V1 and is the predominant form expressed in all but acute myeloid leukemia (AML) cells. Little is known about soluble CD96 (sCD96). sCD96 has been detected in healthy donor blood (1–3 ng / ml), with higher levels reported in patients with hepatitis B virus (HBV) and cirrhosis.

[0029] mRNA analysis of normal human tissues revealed that hematopoietic cells expressed the highest levels of CD96 (probes detecting both V1 and V2 of CD96). CD96 expression is also observed in lymphocyte-rich tissues such as the spleen, lung, thyroid, and small intestine. Among hematopoietic cells, CD96 is most abundant on T cells and NK cells, with lower expression on some B cells. Like CD96, TIGIT and CD226 are most abundant on hematopoietic cells and are expressed on both T cells and NK cells. CD226 is also expressed on conventional DC cells. The ligand CD155 shows a broad expression pattern in normal human tissues and is also expressed on DC cells and macrophages (antigen-presenting cells). CD155 is not expressed on T cells or NK cells.

[0030] As used herein, the term "CD96 antagonist" or "CD96 binding protein" refers to a chemical compound or biological molecule that inhibits the binding of CD96 expressed on T cells or NK cells to CD155.

[0031] The binding affinity (KD) of the antigen-binding protein-target antigen interaction may be 1 mM or less, 100 nM or less, 10 nM or less, 2 nM or less, or 1 nM or less. Alternatively, the KD may be 5 to 10 nM; or 1 to 2 nM. The KD may be 1 pM to 500 pM; or 500 pM to 1 nM. For example, certain useful such variants have a binding affinity (KD) of at least about 40 nM, or at least about 35 nM, or at least about 30 nM, e.g., about 10 pM to about 30 nM.

[0032] The binding affinity of an antigen-binding protein is determined by the association constant (Ka) and dissociation constant (Kd) (KD = Kd / Ka). Binding affinity can be measured by surface plasmon resonance (e.g., using a BIACORE instrument). For example, the test antibody can be captured on a protein-A coated sensor surface and the target antigen can be flowed over this surface. Alternatively, binding affinity can be measured by FORTEBIO. For example, the test antibody receptor can be captured on a protein-A coated needle and the target antigen can be flowed over this surface. Alternatively, binding affinity (KD) can be measured using MSD-SET analysis (MSD solution equilibrium titration) (e.g., using the test antibody titrated on a standard binding MSD plate and detected using an MSD SECT or IMAGER). MSD-SET determines the solution-phase equilibrium affinity of an antibody. This known method relies on the detection of free antigen at equilibrium with a titrated series of antibody concentrations.

[0033] Kd is 1 x 10 -3 Ms -1 Below, 1×10 -4 Ms -1 or less, or 1 x 10 -5 Ms -1 Kd can be 1 × 10 or less. -5 Ms -1 ~1×10 -4 Ms -1 , or 1 × 10 -4 Ms -1 ~1×10 -3 Ms -1A slow Kd may slow the dissociation of the antigen-binding protein-target antigen complex, potentially improving neutralization of the target antigen.

[0034] The term "specific antigen binding activity" as used herein refers to antigen binding activity measured, for example, by surface plasmon resonance (SPR). CD96 specific binding activity can be measured, for example, by SPR using a BIACORE instrument in binding mode. This is the binding activity divided by the total protein content in the sample.

[0035] The terms "VH" and "VL" are used herein to refer to the heavy and light chain variable regions, respectively, of an antigen binding protein.

[0036] "CDR" is defined as the complementarity-determining region amino acid sequence of an antigen-binding protein. These are the hypervariable regions of immunoglobulin heavy and light chains. The variable region of an immunoglobulin has three CDRs (or CDR regions) in each of the heavy and light chains. Therefore, as used herein, "CDR" refers to all three heavy chain CDRs, all three light chain CDRs, all heavy and light chain CDRs, or at least one CDR, where at least one CDR is CDRH3. A framework region follows each of these CDR regions. Acceptable framework 1, framework 2, and framework 3 regions of heavy and light chain variable regions are readily recognized by those skilled in the art. Acceptable heavy chain constant regions (including hinge regions) and light chain constant regions are also readily recognized by those skilled in the art. Acceptable antibody isotypes are also readily recognized by those skilled in the art.

[0037] Throughout this specification, amino acid residues in variable domain sequences and full-length antibody sequences are numbered according to the Kabat numbering convention. Similarly, the terms "CDR," "CDRL1," "CDRL2," "CDRL3," "CDRH1," "CDRH2," and "CDRH3" used herein refer to the Kabat numbering convention.

[0038] Those skilled in the art will appreciate that there are alternative numbering conventions for amino acid residues in variable domain sequences and full-length antibody sequences. Alternative numbering conventions also exist for CDR sequences, such as those established according to the Chothia numbering convention. Antibody structure and protein folding may mean that other residues are considered part of the CDR sequences, and this will be understood by those skilled in the art.

[0039] Other numbering methods for CDR sequences available to those skilled in the art include the "AbM" (University of Bath) method and the "contact" (University College London) method. At least two of the Kabat, Chothia, AbM, and contact methods can be used to determine the minimum overlapping region to provide a "minimum binding unit." The minimum binding unit may be a portion of a CDR.

[0040] Table 1 below provides one definition for each CDR or binding unit using the respective numbering conventions. Table 1 uses the Kabat numbering scheme for numbering variable domain amino acid sequences. It should be noted that some of the CDR definitions may vary depending on the individual reference used.

[0041] [Table 1]

[0042] One embodiment of the present disclosure comprises: (a) any one CDR or combination of CDRs selected from (i) CDRH1, CDRH2, CDRH3 from SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, and 94, and / or CDRL1, CDRL2, CDRL3 from SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, and 93; or (ii) a variant of the CDR of (i) having one, two, or three amino acid modifications; or (b) a variant of the CDR of SEQ ID NO: 1, 2, or 3; a VH region comprising a sequence with at least 80% identity (or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% identity) to the sequence of SEQ ID NO: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90 or 94, and / or a VL region comprising a sequence with at least 80% identity to the sequence of SEQ ID NO: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89 or 93; is a CD96-binding protein comprising:

[0043] In another embodiment, the CD96 binding protein is (a) (i) any one CDR or combination of CDRs selected from CDRH1, CDRH2, CDRH3 from SEQ ID NOs: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, and 94, and / or CDRL1, CDRL2, CDRL3 from SEQ ID NOs: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89, and 93; or (ii) a variant of the CDR of (i) having one, two, or three amino acid modifications. a variant; or (b) a VH region comprising the sequence of SEQ ID NO: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 42, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90 or 94, and / or a VL region comprising a sequence with at least 80% identity (or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% identity) to the sequence of SEQ ID NO: 1, 5, 9, 13, 17, 21, 25, 29, 33, 37, 41, 45, 49, 53, 57, 61, 65, 69, 73, 77, 81, 85, 89 or 93; Includes.

[0044] Another embodiment of the present disclosure is a CDRH1 selected from SEQ ID NOs: 105-125; a CDRH2 selected from SEQ ID NOs: 126-146; and / or a CDRH3 selected from SEQ ID NOs: 147-150; a CDRL1 selected from SEQ ID NOs: 97-98; a CDRL2 selected from SEQ ID NOs: 99-100; and / or a CDRL3 selected from SEQ ID NOs: 101-104.

[0023] The CD96 binding protein of the preceding embodiment, comprising:

[0045] In another embodiment of the disclosure, the binding protein is a CD96 binding protein of any preceding aspect, comprising a CDRH3 that is 100% identical to SEQ ID NO: 147, 148, 149, or 150.

[0046] Another embodiment of the disclosure is a CDRH1 that is 100% identical to the sequence of SEQ ID NO: 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, or 125; 146, and / or CDRH3 that is 100% identical to SEQ ID NO: 147, 148, 149 or 150; CDRL1 that is 100% identical to SEQ ID NO: 97 or 98, CDRL2 that is 100% identical to SEQ ID NO: 99 or 100, and / or CDRL3 that is 100% identical to SEQ ID NO: 101, 102, 103 or 104.

[0047] Another embodiment of the present disclosure is a CD96 binding protein according to any preceding aspect, wherein all six CDRs are present in said binding protein.

[0048] Another embodiment of the disclosure is a CD96 binding protein according to any preceding aspect, comprising a CDRH1 of SEQ ID NO: 115; a CDRH2 of SEQ ID NO: 145; and a CDRH3 of SEQ ID NO: 147; and / or a CDRL1 of SEQ ID NO: 97; a CDRL2 of SEQ ID NO: 99; and a CDRL3 of SEQ ID NO: 101.

[0049]

[0023] Another embodiment of the disclosure is a CD96 binding protein according to any preceding embodiment, wherein the binding protein comprises a VH region that is 75% identical to SEQ ID NO: 86; and / or a VL region that is 75% identical to SEQ ID NO: 85 (or at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% identical to these sequences).

[0024] Another embodiment of the disclosure is a CD96 binding protein according to any preceding embodiment, wherein the binding protein comprises a VH region that is 100% identical to SEQ ID NO: 86; and / or a VL region that is 100% identical to SEQ ID NO: 85.

[0050] In one embodiment of the disclosure, the invention provides a CD96 binding protein comprising any of the CDRs described herein (alone or in any combination as described) and also comprising an Fc region capable of binding to an Fcγ receptor and / or promoting IFNγ release. Such an Fc region can be a wild-type IgG1 Fc.

[0051] In one embodiment of the disclosure, the invention provides a CD96 binding protein comprising any of the VH regions described herein (alone or in the combinations described) and also comprising an Fc region capable of binding to an Fcγ receptor and / or promoting IFNγ release. Such an Fc region may be a wild-type IgG1 Fc.

[0052] In one embodiment of the present disclosure, the invention provides CD96 binding proteins comprising any of the VL regions described herein (alone or in the combinations described) and also comprising an Fc region capable of binding to an Fcγ receptor and / or promoting IFNγ release. Such an Fc region may be a wild-type IgG1 Fc.

[0053] Another embodiment of the present disclosure is a CD96 binding protein according to any preceding aspect, which is an antibody, wherein said binding protein comprises a (complete) heavy chain that is 75% identical (or at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% identical) to SEQ ID NO: 165; and / or a (complete) light chain that is 75% identical (or at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% identical) to SEQ ID NO: 166.

[0054] Another embodiment of the disclosure is the CD96 binding protein of any preceding embodiment, wherein the binding protein comprises a VH region that is 100% identical to SEQ ID NO: 86; and / or a VL region that is 100% identical to SEQ ID NO: 85.

[0055] Another embodiment of the disclosure is a CD96 binding protein according to any preceding embodiment, wherein the binding protein is an antibody, wherein the binding protein comprises a (complete) heavy chain that is 100% identical to SEQ ID NO: 165; and / or a (complete) light chain that is 100% identical to SEQ ID NO: 166 (CDRs are underlined in SEQ ID NOs: 165 and 166); or an antibody that binds to CD96, wherein the heavy chain is encoded by the nucleic acid sequence of SEQ ID NO: 167 and / or the light chain is encoded by the nucleic acid sequence of SEQ ID NO: 168.

[0056] Another embodiment of the disclosure is a CD96 binding protein according to any preceding embodiment, wherein the binding protein is an antibody, wherein the binding protein comprises a (complete) heavy chain that is 100% identical to SEQ ID NO: 170; and / or a (complete) light chain that is 100% identical to SEQ ID NO: 169 (CDRs are underlined); or the antibody binds to CD96, wherein the heavy chain is encoded by the nucleic acid sequence of SEQ ID NO: 172 and / or the light chain is encoded by the nucleic acid sequence of SEQ ID NO: 171.

[0057] Another embodiment of the disclosure is a CD96 binding protein according to any preceding embodiment, wherein the binding protein is an antibody, wherein the binding protein comprises a (complete) heavy chain that is 100% identical to SEQ ID NO: 174; and / or a (complete) light chain that is 100% identical to SEQ ID NO: 173 (CDRs are underlined); or the antibody binds to CD96, wherein the heavy chain is encoded by the nucleic acid sequence of SEQ ID NO: 176 and / or the light chain is encoded by the nucleic acid sequence of SEQ ID NO: 175.

[0058] The present invention includes binding proteins that are 100% identical to any of the amino acid sequences described herein, as well as proteins having variants of the amino acid sequences described herein (e.g., sequences that are at least 75% identical, or at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% identical to the sequences herein).

[0059] The present invention includes nucleic acid sequences encoding the binding proteins of the invention, including nucleic acid sequences that are 100% identical to any of the nucleic acid sequences described herein, as well as variants of the sequences described herein (e.g., sequences that are at least 75% identical, or at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5% identical to a sequence herein).

[0060] The CDRs and variable regions having the amino acid sequences provided in the present application are those that have a binding affinity for CD96 that is equal to or better than that of CD155, and / or that can prevent or displace CD155 from binding to CD96 (examples of binding assays that can be used to determine this are described in Examples 1 and 2 herein). Useful variants of the sequences described herein are those in which the variable regions have a binding affinity for CD96 that is equal to or better than that of CD155, or that can prevent or displace CD155 from binding to CD96 (examples of binding assays that can be used to determine this are described in Examples 1 and 2 herein). For example, certain useful such variants have a binding affinity (KD) of at least about 40 nM, or at least about 35 nM, or at least about 30 nM (e.g., about 10 pM to about 30 nM), as determined, for example, by the MSD-SET assay detailed herein.

[0061] Useful CD96 binding proteins (such as antibodies) according to the invention can comprise such a variable region and also an Fc region as described herein, wherein the Fc region is capable of binding to an Fcγ receptor and / or promoting IFNγ release. Such an Fc region according to the invention is a wild-type IgG1 Fc or a functional variant thereof (e.g., an Fc-null mutant, the region of which is capable of binding to an Fc gamma receptor and / or promoting IFNγ release). Thus, any of the CDRs and / or variable regions of the invention can be combined with an Fc region of the invention, e.g., a wild-type IgG1 Fc or a functional variant thereof.

[0062] Another embodiment of the present disclosure is a CD96 binding protein according to any of the preceding embodiments, wherein said binding protein comprises a synthetic peptide, a humanized sequence, or a chimeric sequence.

[0063] As used herein, the term "conservative sequence modifications" is intended to refer to amino acid modifications that do not significantly affect or alter the binding characteristics of the antibody or antibody fragment containing the amino acid sequence. Such conservative modifications include amino acid substitutions, additions, and deletions. Modifications can be introduced into the antibodies or antibody fragments of the invention by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. A conservative amino acid substitution is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[0064] The term "domain" refers to a folded protein structure that retains its tertiary structure independently of the rest of the protein. Generally, domains are responsible for distinct functional properties of the protein and can often be added, removed, or moved to other proteins without impairing the function of the rest of the protein and / or the domain.

[0065] The term "nucleic acid" or "polynucleotide" refers to single- or double-stranded deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and polymers thereof. Unless otherwise specified, the term encompasses nucleic acids containing known analogs of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides. Unless otherwise indicated, a particular nucleic acid sequence implicitly encompasses its conservatively modified variants (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences, as well as the explicitly indicated sequence. Specifically, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).

[0066] One embodiment of the present disclosure is a nucleic acid sequence encoding a CD96 binding protein as defined in any of the preceding embodiments.

[0067] A further embodiment of the disclosure is a nucleic acid sequence according to the preceding embodiments, comprising a heavy chain encoding SEQ ID NO: 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52, 56, 60, 64, 68, 72, 76, 80, 84, 88, 92 or 96; and / or a light chain encoding SEQ ID NO: 3, 7, 11, 15, 19, 23, 27, 31, 35, 39, 43, 47, 51, 55, 59, 63, 67, 71, 75, 79, 83, 87, 91 or 95. Another embodiment of the disclosure is an expression vector comprising a nucleic acid sequence according to any of the preceding embodiments.

[0068] The compositions described herein can be produced by any number of conventional techniques. For example, the compositions can be expressed in and purified from recombinant expression systems. In one embodiment, the compositions are produced by a method of culturing host cells under conditions suitable for expression of a CD96 binding protein described in any of the previous embodiments (wherein the composition is expressed), optionally purified, and optionally formulated into a pharmaceutical composition.

[0069] Many different expression systems and purification regimens can be used to produce the compositions. Generally, host cells are transformed with a recombinant expression vector encoding the antibody. A wide variety of host cells can be employed, including eukaryotic cell lines of mammalian origin (e.g., CHO, Perc6, HEK293, HeLa, NS0). Suitable host cells include mammalian cells such as CHO (CHOK1, CHO-DG44, etc.).

[0070] The host cell may be an isolated host cell. The host cell is not normally part of a multicellular organism (e.g., a plant or animal). The host cell may be a non-human host cell.

[0071] Suitable cloning and expression vectors for use with eukaryotic or mammalian cell hosts, as well as cloning methods, are known in the art.

[0072] The cells can be cultured under conditions that promote antibody expression. For example, the cells can be cultured in a production bioreactor. The capacity of the production bioreactor can be (i) about 20,000 liters, about 10,000 liters, about 5,000 liters, about 2,000 liters, about 1,000 liters, or about 500 liters, or (ii) 500 to 20,000 liters, 500 to 10,000 liters, 500 to 5,000 liters, 1,000 to 10,000 liters, or 2,000 to 10,000 liters. For example, the cells can be cultured in the production bioreactor at a pH of about 6.75 to 7.00. Alternatively, the cells can be cultured in the production bioreactor for about 12 to 18 days. Alternatively, the cells can be cultured in the production bioreactor at a pH of 6.75 to 7.00 for about 12 to 18 days. This incubation step may help to control, for example, the level of deamidated antibody variants.

[0073] The composition can be recovered and purified by standard protein purification procedures. For example, the composition can be harvested directly from the culture medium. Recovery of the cell culture medium can be achieved via clarification, for example, by centrifugation and / or depth filtration. Recovery of the composition can be followed by purification to ensure sufficient purity.

[0074] A further embodiment of the present disclosure is a recombinant host cell comprising the nucleic acid sequence or expression vector described in any of the preceding embodiments. Another embodiment of the present disclosure is a method of producing CD96, comprising culturing a host cell described in the preceding embodiments under conditions suitable for expression of the nucleic acid sequence or vector, thereby producing a polypeptide comprising a CD96 binding protein. A further embodiment of the present disclosure is a CD96 binding protein produced by the method described in the preceding Examples. Another embodiment of the present disclosure is a cell line engineered to express a CD96 binding protein described in any one of the preceding embodiments.

[0075] The "percent identity" between a query nucleic acid sequence and a subject nucleic acid sequence is the "identity" value, expressed as a percentage, calculated by the BLASTN algorithm after pairwise BLASTN alignment, when the subject nucleic acid sequence has 100% query coverage with the query nucleic acid sequence. Such pairwise BLASTN alignment between a query nucleic acid sequence and a subject nucleic acid sequence is performed using the default settings of the BLASTN algorithm available on the National Center for Biotechnology Institute website, with the filter for low complexity regions turned off. Importantly, the query nucleic acid sequence may be described by a nucleic acid sequence identified in one or more claims herein.

[0076] The "percent identity" between a query amino acid sequence and a subject amino acid sequence is the "identity" value calculated by the BLASTP algorithm after pairwise BLASTP alignment when the subject amino acid sequence has 100% query coverage with the query amino acid sequence, expressed as a percentage. Such pairwise BLASTP alignment between the query amino acid sequence and the subject amino acid sequence is performed using the default settings of the BLASTP algorithm available on the National Center for Biotechnology Institute website, with the filter for low complexity regions turned off. Importantly, the query amino acid sequence can be described by an amino acid sequence identified in one or more claims herein.

[0077] The query sequence may be 100% identical to the subject sequence, or may contain up to a certain integer number of amino acid or nucleotide changes compared to the subject sequence such that identity is less than 100%. For example, the query sequence may be at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the subject sequence. Such modifications include at least one amino acid deletion, substitution (including conservative and non-conservative substitution), or insertion, which may occur at the amino- or carboxy-terminal position of the query sequence, or anywhere between these terminal positions, and may be interspersed among amino acids or nucleotides in the query sequence, either individually, or in one or more contiguous groups within the query sequence.

[0078] As used herein, " sequence identity " refers to the degree of relatedness between two or more amino acid sequences or two or more nucleic acid sequences, as determined by comparing sequences. Sequence comparison and determination of sequence identity can be achieved using mathematical algorithms; those skilled in the art will recognize available computer programs for aligning two sequences and determining the percent identity between them. Those skilled in the art will understand that different algorithms may produce slightly different results.

[0079] As used herein, the term "specifically binds" and grammatical variations thereof with respect to antibodies refer to an antibody or antibody fragment that recognizes and binds to a specific antigen but does not substantially recognize or bind to other molecules in a sample. For example, an antibody that specifically binds to an antigen of one species may also bind to antigens of one or more species. However, such cross-species reactivity does not, in and of itself, change the specific classification of the antibody. In another example, an antibody that specifically binds to an antigen may also bind to different allelic forms of that antigen. However, such cross-reactivity does not, in and of itself, change the specific classification of the antibody. In some cases, the terms "specific binding" or "specifically binds" are used in reference to the interaction of an antibody, protein, or peptide with a second chemical species to mean that the interaction is dependent on the presence of a particular structure (e.g., an antigenic determinant or epitope) on the chemical species. If an antibody is specific for epitope "A," then in a reaction involving labeled "A" and the antibody, the presence of a molecule containing epitope "A" (or free, unlabeled "A") reduces the amount of labeled "A" that binds to the antibody.

[0080] As used herein, the term "pharmaceutical composition" means a composition suitable for administration to a patient.

[0081] The pharmaceutical compositions described herein may include purified preparations of the CD96 binding proteins described herein.

[0082] For example, a pharmaceutical formulation can include a purified preparation of a CD96 binder described herein in combination with a pharmaceutically acceptable carrier.

[0083] Typically, such pharmaceutical compositions will include a pharmaceutically acceptable carrier, as specified by known and accepted pharmaceutical practice, such as a sterile carrier such as saline, Ringer's solution, or dextrose solution, optionally buffered to a pH within the range of 5 to 8 with a suitable buffer.

[0084] The pharmaceutical composition may be administered by injection or infusion (e.g., intravenously, intraperitoneally, intradermally, subcutaneously, intramuscularly, or intraportally). Such compositions are preferably free of visible particulate matter. The pharmaceutical composition may comprise 1 mg to 10 g of antigen-binding protein, for example, 5 mg to 1 g of antigen-binding protein. Alternatively, the composition may comprise 5 mg to 500 mg of antigen-binding protein, for example, 5 mg to 50 mg of antigen-binding protein.

[0085] Methods for preparing such pharmaceutical compositions are well known to those skilled in the art. Pharmaceutical compositions can contain 1 mg to 10 g of antigen-binding protein in unit dosage form, optionally with instructions for use. Pharmaceutical compositions may be lyophilized (freeze-dried) for reconstitution prior to administration, according to methods known or apparent to those skilled in the art. If the antibody has the IgG1 isotype, a citrate salt (e.g., sodium citrate) or a copper chelator, such as EDTA or histidine, may be added to the pharmaceutical composition to reduce the extent of copper-mediated degradation of antibodies of this isotype. Pharmaceutical compositions may also contain solubilizing agents, such as arginine, surfactants / anti-aggregating agents, such as polysorbate 80, and inert gases, such as nitrogen, to displace oxygen from the vial headspace.

[0086] One embodiment of the present disclosure is a pharmaceutical composition comprising a CD96 binding protein according to any one of the preceding embodiments and a pharmaceutically acceptable excipient. A further embodiment of the present disclosure is a pharmaceutical composition comprising a therapeutically effective amount of a CD96 binding protein according to any one of the preceding embodiments and a pharmaceutically acceptable excipient.

[0087] As used herein, the term "anti-tumor effect" refers to a biological effect that can be manifested by a reduction in tumor growth rate, a reduction in tumor volume, a reduction in tumor cell number, a reduction in the number of metastases, an increase in life expectancy, or an improvement in various physiological symptoms associated with a cancerous condition. An "anti-tumor effect" can also be manifested by the ability of the peptides, polynucleotides, cells, and antibodies of the present invention to prevent the development of tumors in the first place.

[0088] As used herein, the terms "cancer," "neoplasm," and "tumor" are used interchangeably and refer, in either singular or plural, to cells that have undergone pathological malignant transformation in the host organism. Illustrative examples of cells that may be targeted by the contemplated compositions and methods in certain embodiments include, but are not limited to, the following cancers: synovial sarcoma, non-small cell lung cancer (NSCLC), myxoid round cell liposarcoma (MRCLS), and multiple myeloma (MM). Primary cancer cells can be easily distinguished from non-cancerous cells by established techniques, particularly histological examination. The definition of cancer cells, as used herein, includes not only primary cancer cells but also any cells derived from a cancer cell precursor. This includes metastatic cancer cells, in vitro cultures derived from cancer cells, and cell lines. A "clinically detectable" tumor, referring to a type of cancer that typically manifests as a solid tumor, is detectable based on tumor mass; for example, by procedures such as computed tomography (CT) scan, magnetic resonance imaging (MRI), x-ray, ultrasound, or physical examination, and / or by the expression of one or more cancer-specific antigens in a sample obtained from the patient. The tumor may also be a hematopoietic (or blood, hematology, or blood-related) cancer, such as a cancer derived from blood cells or immune cells, which are sometimes referred to as a "liquid tumor." Specific examples of clinical conditions based on hematopoietic tumors include leukemias, such as chronic myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia; plasma cell malignancies, such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia; and lymphomas, such as non-Hodgkin's lymphoma and Hodgkin's lymphoma.

[0089] The cancer may be one in which there is an abnormal number of blast cells or unwanted cell proliferation, or one diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic, or myelogenous, or myeloblastic) leukemia (undifferentiated or differentiated), acute promyelocytic (or promyelocytic, or promyelogenous, or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroid leukemia, and megakaryocytic (or megakaryoblastic) leukemia. These leukemias are sometimes collectively referred to as acute myeloid (or myelocytic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPDs), including, but not limited to, chronic myeloid (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndromes, MDS), sometimes referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformed form (RAEBT); and myelofibrosis (MFS), with or without asymptomatic myelodysplasia.

[0090] Hematopoietic cancers also include lymphoid malignancies, which can affect lymph nodes, spleen, bone marrow, peripheral blood, and / or extranodal sites. Lymphoid cancers include B-cell malignancies, including, but not limited to, B-cell non-Hodgkin's lymphoma (B-NHL). B-NHL can be low-grade, intermediate-grade, or high-grade. Low-grade B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL), including nodal MZL, extranodal MZL, splenic MZL, and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated lymphoid tissue (MALT or extranodal marginal zone) lymphoma. Intermediate-grade B-NHL includes mantle cell lymphoma (MCL) with or without leukemic infiltration, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3, or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHL includes Burkitt lymphoma (BL), Burkitt-like lymphoma, small noncleaved cell lymphoma (SNCCL), and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-associated (or AIDS-associated) lymphoma, post-transplant lymphoproliferative disorder (PTLD), or lymphoma. B-cell malignancies include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphocytic (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. Non-Hodgkin's lymphomas include, but are not limited to, T-cell non-Hodgkin's lymphoma (T-NHL), including, but not limited to, T-cell non-Hodgkin's lymphoma (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides, and Sézary syndrome.

[0091] Hematopoietic cancers also include Hodgkin lymphomas (or diseases) such as classical Hodgkin lymphoma, nodular sclerosing Hodgkin lymphoma, mixed cytology Hodgkin lymphoma, lymphocyte-predominant (LP) Hodgkin lymphoma, nodular LP Hodgkin lymphoma, and lymphocytopenic Hodgkin lymphoma. Hematopoietic cancers also include plasma cell dyscrasias or cancers such as multiple myeloma (MM), including smoldering MM, undefined (or unclear or ill-defined) monoclonal gammopathy (MGUS), plasmacytoma (bone, extramedullary), lymphoplasmacytic lymphoma (LPL), Waldenström's macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers also include cancers of hematopoietic cells, such as polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes, and natural killer cells. Tissues containing hematopoietic cells, referred to herein as "hematopoietic cell tissues," include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as the spleen, lymph nodes, lymphoid tissues associated with mucous membranes (such as gut-associated lymphoid tissue), tonsils, Peyer's patches, appendix, and lymphoid tissues associated with other mucous membranes, such as the lining of the bronchi.

[0092] In one embodiment, cancers that can be treated with the binding proteins of the invention can include solid tumors (e.g., recurrent, metastatic, or progressive solid tumors). Examples of such solid tumors include ovarian cancer, lung cancer (e.g., NSCLC), gastric cancer, bladder cancer, colorectal cancer, liver cancer (e.g., HCC), kidney cancer (e.g., RCC), and head and neck squamous cell carcinoma (HNSCC).

[0093] As used herein, the term "therapeutic" means treatment and / or prophylaxis. A therapeutic effect is achieved by suppressing, ameliorating, or eradicating a disease state.

[0094] As used herein, a "therapeutically effective amount" or "effective amount" refers to an amount that provides a therapeutic or prophylactic benefit or elicits the biological or medical response in a tissue, system, or subject that is desired by a researcher, veterinarian, medical doctor, or other clinician. Therapeutically effective amounts and treatment regimens are generally determined empirically and may depend on factors such as the patient's age, weight, and health, the disease or disorder being treated, and the like. Such factors are within the purview of the attending physician.

[0095] As used herein, the term "treat" and its grammatical variations refer to therapeutic therapy. With respect to a particular condition, treating means: (1) improving or preventing the condition of one or more biological manifestations of the condition; (2) inhibiting one or more points in (a) the condition or (b) the biological cascade responsible for one or more biological manifestations of the condition; (3) alleviating one or more symptoms, effects, or side effects associated with the condition or its treatment; (4) slowing the progression of the condition or one or more biological symptoms of the condition; and / or (5) curing the condition or one or more biological symptoms of the condition by eliminating or reducing to undetectable levels one or more biological symptoms of the condition without additional treatment for a period of time considered to be in remission of the symptoms. Those skilled in the art will understand the period of time considered to be in remission for a particular disease or condition. Prophylactic treatment is also contemplated hereby. Those skilled in the art will understand that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of an agent to substantially reduce the likelihood or severity of a condition or its biological manifestations, or to delay the onset of such a condition or its biological manifestations. Preventative treatment is appropriate when a subject is considered to be at high risk of developing cancer, for example, when the subject has a strong family history of cancer or when the subject has been exposed to a carcinogen.

[0096] As used herein, the terms "individual," "subject," and "patient" are used interchangeably. In one embodiment, the subject is a mammal, such as a primate, e.g., a marmoset or monkey, or a human. In a further embodiment, the subject is a human.

[0097] The dose of an antigen-binding protein administered to a subject is generally 1 μg / kg to 150 mg / kg, 0.1 mg / kg to 100 mg / kg, 0.5 mg / kg to 50 mg / kg, 1 to 25 mg / kg, about 0.3 mg / kg to about 3 mg / kg, or 1 to 10 mg / kg of the subject's body weight. For example, the dose may be 10 mg / kg, 30 mg / kg, or 60 mg / kg. The dose may also be 10 mg / kg to 110 mg / mg, 15 mg / kg to 25 mg / kg, or 15 mg / kg to 100 mg / kg. The antigen-binding protein can be administered, for example, parenterally, subcutaneously, intravenously, or intramuscularly. The dose can also be administered on a per-subject basis, such as about 20 mg to about 750 mg per subject, about 75 mg to about 750 mg per subject, or about 20 mg to about 200 mg per subject. The dosage can be any discrete subrange of these dosage ranges. For example, the dosage can also be about 100 mg per subject (e.g., once every four weeks), or about 300 mg per subject (or other doses administered subcutaneously, provided that bioavailability is achieved that is approximately the same as or comparable to that of intravenous administration—e.g., three 100 mg doses per subject to achieve a total subcutaneous dose of 300 mg per subject).

[0098] Ranges provided herein include all values ​​within the particular ranges stated, regardless of type, as well as values ​​relating to the endpoints of the particular ranges.

[0099] If desired, an effective daily amount of an antibody or antigen binding protein of the disclosure (e.g., as a pharmaceutical composition) can be administered as two, three, four, five, six or more doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form.

[0100] Administration can be by slow continuous infusion over a period of 2 to 24 hours, for example, 2 to 12 hours, or 2 to 6 hours, which may reduce side effects.

[0101] Administration can be repeated one or more times as needed, for example, three times a day, once a day, once every two days, once a week, once every 14 days, once a month, once every three months, once every four months, once every six months, or once every 12 months. The antigen-binding protein can be administered as a maintenance therapy, for example, once a week for a period of six months or more. The antigen-binding protein can also be administered intermittently, for example, in a cycle of administration for three to six months, followed by no administration for three to six months, and then again administering the antigen-binding protein for three to six months.

[0102] For example, it can be administered subcutaneously in multiple doses on the day of administration, for example, once every 14 or 28 days. In one embodiment, the dosage of the composition is 100 mg once every 4 weeks (28 days).

[0103] The antigen binding protein may be administered to a subject to target the treatment to a specific site.

[0104] The CD96 binding proteins in the disclosed methods can be used in combination with or co-administered with one or more other therapeutically active agents, such as antibodies, small molecule inhibitors, or in combination with cell therapy. As used herein, the term "co-administration" refers to either simultaneous administration or separate, sequential administration by any method of a CD96 binding protein described herein with an additional active agent or agent known to be useful in cancer treatment, including chemotherapy and radiation therapy. The term "additional active agent" as used herein includes any compound or therapeutic agent known to exhibit or exhibit advantageous properties when administered to a patient in need of cancer treatment. Preferably, if administration is not simultaneous, the compounds are administered in close temporal proximity to each other. Furthermore, it does not matter whether the compounds are administered in the same dosage form. For example, one compound can be administered by injection and another compound can be administered orally.

[0105] Typically, any anti-neoplastic agent active against the susceptible tumor being treated can be co-administered in the treatment of cancer in the present invention. Examples of such agents are described in "Cancer Principles and Practice of Oncology," 10th Edition (December 5, 2014), by VTDevita, T.S. Lawrence, and S.A. Rosenberg (Editors), Lippincott Williams & Wilkins Publishers. A person skilled in the art will be able to determine which drug combinations are useful based on the specific properties of the drugs and the cancer involved. Typical anti-neoplastic agents useful in cancer treatment include, but are not limited to, signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; heat shock protein inhibitors; cancer metabolism inhibitors; and cancer gene therapy agents.

[0106] Examples of additional active ingredients or components for use in combination or co-administration with the presently disclosed CD96 binding proteins are anti-neoplastic agents. Examples of anti-neoplastic agents include, but are not limited to, chemotherapeutic agents, immunomodulatory agents, and immunostimulatory adjuvants.

[0107] The presently disclosed CD96 binding proteins can also be used in combination with anti-TIGIT antibodies. Such combinations may further enhance CD155 / CD226 activation. Combinations with anti-TIGIT antibodies can be used to treat solid tumors, such as renal tumors, including renal cell carcinoma (RCC). An example of such an anti-TIGIT antibody is tiragolumab.

[0108] Anti-microtubule or anti-mitotic agents are phase-specific agents that exhibit activity against microtubules in tumor cells in the M or mitotic phase of the cell cycle. Examples of anti-microtubule agents include, but are not limited to, diterpenoids and vinca alkaloids.

[0109] Platinum coordination complexes are non-phase-specific anticancer agents that interact with DNA. Platinum complexes enter tumor cells, undergo activation, and form intra- and interstrand crosslinks with DNA, resulting in deleterious biological effects in tumors. Examples of platinum complexes include, but are not limited to, cisplatin and carboplatin.

[0110] Alkylating agents are non-specific anticancer drugs with strong electrophilicity. They typically form covalent bonds to DNA via alkylation through nucleophilic sites on the DNA molecule, such as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, or imidazole groups. This alkylation disrupts nucleic acid function and leads to cell death. Examples of alkylating agents include, but are not limited to, nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil; alkylsulfonates such as busulfan; nitrosoureas such as carmustine; and triazenes such as dacarbazine.

[0111] Antibiotic antineoplastic agents are non-phase specific agents that bind or intercalate with DNA. This action disrupts the normal function of nucleic acids, leading to cell death. Examples of antibiotic antineoplastic agents include, but are not limited to, actinomycins such as dactinomycin; anthrocyclines such as daunorubicin and doxorubicin; and bleomycin.

[0112] Topoisomerase I inhibitors include, but are not limited to, camptothecins, the cytotoxic activity of which is believed to be related to their Topoisomerase I inhibitory activity.

[0113] Topoisomerase II inhibitors include, but are not limited to, epipodophyllotoxins. Epipodophyllotoxins are phase-specific antineoplastic agents derived from the mandrake plant. Epipodophyllotoxins typically affect cells in the S and G2 phases of the cell cycle by forming a ternary complex with topoisomerase II and DNA, causing DNA strand breaks. Strand breaks accumulate, leading to cell death. Examples of epipodophyllotoxins include, but are not limited to, etoposide and teniposide.

[0114] Antimetabolite antineoplastic agents are phase-specific antineoplastic agents that act on the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting the synthesis of purine or pyrimidine bases, thereby limiting DNA synthesis. As a result, S phase does not progress and cell death occurs. Examples of antimetabolite antineoplastic agents include, but are not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine, and gemcitabine.

[0115] Hormones and hormone analogs are compounds useful in the treatment of cancers where there is a relationship between hormones and the growth and / or lack of growth of the cancer. Examples of hormones and hormone analogs useful in cancer treatment include, but are not limited to, corticosteroids such as prednisone and prednisolone; aromatase inhibitors such as aminoglutethimide, anastrozole, letrazole, vorazole, and exemestane; progestrins such as megestrol acetate; progestrins such as megestrol acetate; estrogen, androgen, and anti-androgen compounds such as flutamide, nilutamide, bicalutamide, and cyproterone acetate. 5α-reductase inhibitors such as finasteride, dutasteride; antiestrogens such as tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, selective estrogen receptor modulators (SERMS); and gonadotropin-releasing hormone (GnRH) and analogs thereof that stimulate the release of leutinizing hormone (LH) and / or follicle-stimulating hormone (FSH), LHRH agonists, and antagonists such as goserelin acetate and leuprolide.

[0116] A signal transduction pathway inhibitor is an inhibitor that blocks or inhibits a chemical process that causes an intracellular change. As used herein, this change is cell proliferation or differentiation. Signal transduction inhibitors useful in the present invention include, but are not limited to, receptor tyrosine kinases, non-receptor tyrosine kinases, SH2 / SH3 domain blockers, serine / threonine kinases, phosphatidylinositol-3 kinases, myo-inositol signaling, and Ras oncogene inhibitors.

[0117] Several protein tyrosine kinases catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth. These protein tyrosine kinases are broadly classified into receptor kinases and non-receptor kinases.

[0118] Receptor tyrosine kinases are transmembrane proteins that contain an extracellular ligand-binding domain, a transmembrane domain, and a tyrosine kinase domain. Receptor tyrosine kinases are involved in the regulation of cell proliferation and are commonly referred to as growth factor receptors. Many of these kinases have been shown to exhibit inappropriate or uncontrolled activation, i.e., aberrant kinase growth factor receptor activity, due to overexpression or mutation, leading to uncontrolled cell proliferation. Therefore, the aberrant activity of such kinases is associated with the growth of malignant tissues. Therefore, inhibitors of such kinases may offer therapeutic options for cancer. Growth factor receptors include epidermal growth factor receptor (EGFr), platelet-derived growth factor receptor (PDGFr), erbB2, erbB4, vascular endothelial growth factor receptor (VEGFR), tyrosine kinase with immunoglobulin-like and epidermal growth factor homology domains (TIE-2), insulin growth factor I (IGFI) receptor, macrophage colony-stimulating factor (Cfms), BTK, ckit, cmet, fibroblast growth factor (FGF) receptor, Trk receptors (TrkA, TrkB, TrkC), ephrin (ef) receptor, and RET protogene. Growth receptor inhibitors, including ligand antagonists, antibodies, tyrosine kinase inhibitors, and antisense oligonucleotides, are currently under development. Growth factor receptors and drugs that inhibit the function of growth factor receptors are described, for example, in Kath JC, Exp. Opin. Ther. Patents, 10(6):803-818 (2000); Shawver LK, et al., Drug Discovery Today, 2(2):50-63 (1997); and Lofts, FJ and Gullick WJ, "Growth factor receptors as targets." in New Molecular Targets for Cancer Chemotherapy, Kerr DJ and Workman P. (editors), (June 27, 1994), CRC Press. Non-limiting examples of growth factor receptor inhibitors include pazopanib and sorafenib.

[0119] Tyrosine kinases that are not growth factor receptor kinases are called non-receptor tyrosine kinases. Non-receptor tyrosine kinases useful in the present invention are targets or potential targets of anti-cancer drugs, and include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons tyrosine kinase, Bcr-Abl, etc. Such non-receptor kinases and drugs that inhibit non-receptor tyrosine kinase function are described in Sinha S. and Corey SJ, J. Hematother. Stem Cell Res: 465-480 (2004) and Bolen, JB, Brugge, JS, Annu. Rev. Immunol., 15: 371-404 (1997).

[0120] SH2 / SH3 domain blockers are drugs that inhibit the binding of SH2 and SH3 domains in various enzymes and adaptor proteins, such as the PI3-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck, Grb2), and Ras-GAP. The SH2 / SH3 domain as a target for anticancer drugs is described in Smithgall TE, J. Pharmacol. Toxicol. Methods, 34(3): 125-32 (1995).

[0121] Inhibitors of serine / threonine kinases include, but are not limited to, MAP kinase cascade blockers, including blockers of Raf kinase (rafk), mitogen or extracellular regulated kinase (MEK), and extracellular regulated kinase (ERK); protein kinase C family member blockers, including blockers of PKC (α, β, γ, ε, μ, λ, ι, ζ); IkB kinase (IKKa, IKKb); PKB family kinases; AKT kinase family members; TGFβ receptor kinase; and mammalian target of rapamycin (mTOR) inhibitors (including but not limited to rapamycin (FK506) and rapalogs), RAD001 or everolimus (AFINITOR), CCI-779 or temsirolimus, AP23573, AZD8055, WYE-354, WYE-600, WYE-687, and Pp121. Examples of serine / threonine kinase inhibitors include, but are not limited to, trametinib, dabrafenib, the Akt inhibitor afuresertib, and N-{(1S)-2-amino-1-[(3,4-difluorophenyl)methyl]ethyl}-5-chloro-4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-furancarboxamide.

[0122] Inhibitors of the phosphatidylinositol 3-kinase family, including inhibitors of PI3-kinase, ATM, DNA-PK, and Ku, are also useful in the present invention. Such kinases are discussed in Abraham RT, Curr. Opin. Immunol: 412-418 (1996); Canman CE, and Lim DS, Oncogene, 17(25): 3301-3308 (1998); Jackson SP, Int. J. Biochem. Cell Biol: 935-938 (1997); and Zhong H. et al., Cancer Res., 60(6): 1541-1545 (2000).

[0123] Also useful in the present invention are myo-inositol signal inhibitors, such as phospholipase C blockers and myo-inositol analogs. Such signal inhibitors are described in Powis G. and Kozikowski A., "Inhibitors of Myo-Inositol Signaling," in New Molecular Targets for Cancer Chemotherapy, Kerr DJ and Workman P. (editors), (June 27, 1994), CRC Press.

[0124] Another group of signaling pathway inhibitors is inhibitors of the oncogene Ras. These inhibitors include inhibitors of farnesyltransferase, geranyl-geranyltransferase, and CAAX proteases, as well as antisense oligonucleotides, ribozymes, and other immunotherapies. These inhibitors have been shown to block Ras activation in cells containing wild-type or mutant Ras and act as antiproliferative agents. Ras oncogene inhibition is discussed in Scharovsky OG et al., J. Biomed. Sci., 7(4): 292-298 (2000); Ashby MN, Curr. Opin. Lipidol: 99-102 (1998); and Bennett CF and Cowsert LM, Biochem. Biophys. Acta., 1489(1): 19-30 (1999).

[0125] Antagonists of receptor kinase ligand binding also function as signal transduction inhibitors. This group of signal transduction pathway inhibitors includes the use of humanized antibodies or other antagonists against the extracellular ligand-binding domain of receptor tyrosine kinase. Examples of antibodies or other antagonists against receptor kinase ligand binding include, but are not limited to, cetuximab (ERBITUX), trastuzumab (HERCEPTIN); trastuzumab emtansine (KADCYLA); pertuzumab (PERJETA); ErbB inhibitors including lapatinib, erlotinib, and gefitinib; and 2C3 VEGFR2 specific antibody (Brekken R. et al., Cancer Res: 5117-5124 (2000)).

[0126] Non-receptor kinase angiogenesis inhibitors can also be used in the present invention. Inhibitors of angiogenesis-related VEGFR and TIE2 have been described above as signal transduction inhibitors (both receptors are receptor tyrosine kinases). Inhibitors of erbB2 and EGFR have been shown to inhibit angiogenesis, primarily VEGF expression, so angiogenesis is generally associated with erbB2 / EGFR signal transduction. Therefore, non-receptor tyrosine kinase inhibitors can be used in combination with the EGFR / erbB2 inhibitors of the present invention. For example, anti-VEGF antibodies that do not recognize VEGFR (receptor tyrosine kinase) but bind to its ligand; small molecule inhibitors of integrin (αβ3) that inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also prove useful in combination with the disclosed compounds (Bruns CJ et al., Cancer Res., 60(11): 2926-2935 (2000); Schreiber AB et al., Science, 232(4755): 1250-1253 (1986); Yen L., et al., Oncogene, 19(31): 3460-3469 (2000)).

[0127] Agents used in immunotherapy regimens are also useful in combination with the present invention. There are numerous immunological strategies for generating immune responses against erbB2 or EGFR. These strategies are generally in the field of tumor vaccination. Combined inhibition of the erbB2 / EGFR signaling pathway using small molecule inhibitors may significantly improve the efficacy of immunological approaches. Immunological / tumor vaccine approaches against erbB2 / EGFR are discussed in Reilly RT et al., Cancer Res., 60(13): 3569-3576(2000); and Chen Y., et al.: 1965-1971(1998).

[0128] Agents used in pro-apoptotic regimens (e.g., Bcl-2 antisense oligonucleotides) can also be used in the combinations of the present invention. Members of the Bcl-2 family of proteins block apoptosis. Therefore, upregulation of Bcl-2 is associated with chemotherapy resistance. Studies have shown that epidermal growth factor (EGF) stimulates anti-apoptotic members of the Bcl-2 family (i.e., Mcl-1). Therefore, strategies designed to downregulate Bcl-2 expression in tumors have shown clinical benefit. Such pro-apoptotic strategies using antisense oligonucleotides against Bcl-2 are discussed in Waters JS et al., J. Clin. Oncol: 1812-1823 (2000); and Kitada S. et al., Antisense Res. Dev., 4(2): 71-79 (1994).

[0129] Cell cycle signaling inhibitors inhibit molecules involved in cell cycle control. The interaction between a family of protein kinases called cyclin-dependent kinases (CDKs) and a family of proteins called cyclins regulates progression through the eukaryotic cell cycle. Normal progression through the cell cycle requires the coordinated activation and inactivation of different cyclin / CDK complexes. Several drugs that inhibit cell cycle signaling are currently under development. Examples of cyclin-dependent kinases, including CDK2, CDK4, and CDK6, and their inhibitors are described, for example, in Rosania GR, and Chang YT, Exp. Opin. Ther. Patents, 10(2): 215-230 (2000). Furthermore, p21WAF1 / CIP1 has been described as a potent and universal inhibitor of cyclin-dependent kinases (Cdks) (Ball KL, Prog. Cell Cycle Res., 3: 125-134 (1997)). Compounds known to induce the expression of p21WAF1 / CIP1 are involved in the inhibition of cell proliferation and tumor suppressor activity (Richon VM et al., Proc. Natl. Acad. Sci. USA, 97(18): 10014-10019 (2000)) and are included as cell cycle signaling inhibitors. Histone deacetylase (HDAC) inhibitors are involved in the transcriptional activation of p21WAF1 / CIP1 (Vigushin DM, and Coombes RC, Anticancer Drugs, 13(1): 1-13 (2002)) and are suitable cell cycle signaling inhibitors for use in combination herein. Examples of such HDAC inhibitors include, but are not limited to, vorinostat, romidepsin, panobinostat, valproic acid, and mocetinostat.

[0130] Proteasome inhibitors are drugs that inhibit the activity of proteasomes (cellular complexes that degrade proteins such as p53 protein). Some proteasome inhibitors are on the market or are being studied as cancer treatments. Suitable proteasome inhibitors for use in combination herein include, but are not limited to, bortezomib, disulfiram, epigallocatechin gallate, salinosporamide A, and carfilzomib.

[0131] The 70-kilodalton heat shock proteins (Hsp70s) and 90-kilodalton heat shock proteins (Hsp90s) are a family of ubiquitously expressed heat shock proteins. Hsp70s and Hsp90s are overexpressed in certain cancer types. Several Hsp70 and Hsp90 inhibitors are being investigated for the treatment of cancer. Examples of Hsp70 and Hsp90 inhibitors for use in combination herein include, but are not limited to, tanespimycin and radicicol.

[0132] Many tumor cells exhibit a metabolism that differs significantly from that of normal tissues. For example, the rate of glycolysis, the metabolic process that converts glucose to pyruvate, is increased, and the resulting pyruvate is reduced to lactate in the mitochondria rather than being further oxidized via the tricarboxylic acid (TCA) cycle. This effect, often observed even under aerobic conditions, is known as the Warburg effect.

[0133] Lactate dehydrogenase A (LDH-A), an isoform of lactate dehydrogenase expressed in muscle cells, plays a crucial role in tumor cell metabolism by reducing pyruvate to lactate and exporting it outside the cell. This enzyme has been shown to be upregulated in many tumor types. Alterations in glucose metabolism, described by the Warburg effect, are essential for cancer cell growth and proliferation, and knockdown of LDH-A using RNA-mediated induction has been shown to suppress cell proliferation and tumor growth in xenograft models (Tennant DA et al., Nat. Rev. Cancer, 10(4): 267-277 (2010); Fantin VR, et al., Cancer Cell, 9(6): 425-434 (2006)).

[0134] High levels of fatty acid synthase (FAS) have been found in cancer precursor lesions. Pharmacological inhibition of FAS affects the expression of key oncogenes involved in cancer development and maintenance. Alli PM, et al., Oncogene, 24(1): 39-46 (2005).

[0135] Cancer metabolism inhibitors, including LDH-A inhibitors and fatty acid biosynthesis inhibitors (or FAS inhibitors), are suitable for use in combination herein.

[0136] Cancer gene therapy involves the selective delivery of recombinant DNA / RNA using viral or non-viral gene transfer vectors to modify cancer progression for therapeutic purposes. Examples of cancer gene therapy include, but are not limited to, suicide gene therapy, oncolytic gene therapy, and adaptive T cell therapy.

[0137] As used herein, the term "immunomodulator" refers to any substance, including monoclonal antibodies, that acts on the immune system. The CD96-binding proteins of the present invention can be considered immunomodulators. Immunomodulators can be used as anti-neoplastic agents for the treatment of cancer. For example, immunomodulators include, but are not limited to, antibodies or other antagonists against CTLA-4, such as ipilimumab (YERVOY), and antibodies or other antagonists against PD-1, such as dostarimumab (JEMPERLI), nivolumab (OPDIVO), pembrolizumab (KEYTRUDA), and cemiplimumab (LIBTAYO). Other immunomodulators include, but are not limited to, antibodies or other antagonists against PD-L1, OX-40, LAG3, TIM-3, 41BB, and GITR.

[0138] As used herein, the term "PD-1 antagonist" refers to a chemical compound or biological molecule that inhibits the binding of PD-L1 expressed on cancer cells to PD-1 expressed on immune cells (T cells, B cells, or NKT cells), and preferably also inhibits the binding of PD-L2 expressed on cancer cells to PD-1 expressed on immune cells. Alternative names or synonyms for PD-1 and its ligands include: for PD-1, PDCD1, PD1, CD279, and SLEB2; for PD-L1, PDCD1L1, PDL1, B7H1, B7-4, CD274, and B7-H; and for PD-L2, PDCD1L2, PDL2, B7-DC, Btdc, and CD273. The amino acid sequence of human PD-1 can be found at NCBI Locus No. NP_005009. The human PD-L1 and PD-L2 amino acid sequences can be found at NCBI Locus Nos. NP_0548621 and NP_079515, respectively.

[0139] PD-1 antagonists useful in any embodiment of the present invention include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PD-1 or PD-L1, preferably those that specifically bind to human PD-1 or human PD-L1. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may comprise a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0140] In embodiments, the compound that is an inhibitor of PD-1 or PD-L1 is PCC0208025 (BMS202), BMS1166, BMS-8, BMS-37, BMS-202, BMS-230, BMS-242, BMS-1001, SB415286, vorinostat, panobinostat, azacitidine, decitabine, encitostat, JQ1, I-BET151, GSK503, or CA-170.

[0141] Examples of mAbs that bind to human PD-1 and are useful in various aspects and embodiments of the invention are described in U.S. Pat. Nos. 8,552,154; 8,354,509; 8,168,757; 8,008,449; 7,521,051; 7,488,802; WO 2004 / 072286; WO 2004 / 056875; and WO 2004 / 004771.

[0142] Other PD-1 antagonists useful in any aspect and embodiment of the invention include immunoadhesins that specifically bind to PD-1, preferably immunoadhesins that specifically bind to human PD-1, such as fusion proteins comprising the extracellular portion or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region, such as the Fc region, of an immunoglobulin molecule. Examples of immunoadhesin molecules that specifically bind to PD-1 are described in WO 2010 / 027827 and WO 2011 / 066342. Specific fusion proteins useful as PD-1 antagonists in the therapeutic methods, medicaments, and uses of the invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD-1.

[0143] Nivolumab is a humanized anti-PD-1 monoclonal antibody, marketed as OPDIVO. Nivolumab is indicated for the treatment of some unresectable or metastatic melanoma. Nivolumab binds to PD-1, a transmembrane protein of the Ig superfamily, and inhibits its activation by its ligands, PD-L1 and PD-L2, thereby activating T cells and inducing cell-mediated immune responses against tumor cells and pathogens. Activated PD-1 negatively regulates T cell activation and effector function by suppressing activation of the P13k / Akt pathway. Other names for nivolumab include BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence, methods of use, and methods of manufacture of nivolumab are disclosed in U.S. Patent No. 8,008,449.

[0144] Pembrolizumab is a humanized monoclonal anti-PD-1 antibody marketed as Keytruda. Pembrolizumab is indicated for the treatment of some unresectable or metastatic melanoma. The amino acid sequence and methods of use of pembrolizumab are disclosed in U.S. Patent No. 8,168,757.

[0145] In one embodiment, the PD-1 antagonist comprises any one or combination of the following CDRs: CDRH1:SYDMS (SEQ ID NO: 151) CDRH2: TISGGGSYTYYQDSVKG (SEQ ID NO: 152) CDRH3: PYYAMDY (SEQ ID NO: 153) CDRL1: KASQDVGTAVA (SEQ ID NO: 154) CDRL2: WASTLHT (SEQ ID NO: 155) CDRL3: QHYSSYPWT (SEQ ID NO: 156).

[0146] In one embodiment, the PD-1 antagonist comprises a heavy chain variable region CDR1 ("CDRH1") comprising an amino acid sequence having no more than two amino acid changes ("CDR variants") relative to the amino acid sequence set forth in SEQ ID NO: 151.

[0147] In one embodiment, the PD-1 antagonist comprises a heavy chain variable region CDR2 ("CDRH2") comprising an amino acid sequence that has no more than five (e.g., no more than four, no more than three, no more than two, or one) amino acid changes ("CDR variants") relative to the amino acid sequence set forth in SEQ ID NO: 152. In a further embodiment, CDRH2 comprises an amino acid sequence that has no more than two amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 152.

[0148] In one embodiment, the PD-1 antagonist comprises a heavy chain variable region CDR3 ("CDRH3") comprising an amino acid sequence having no more than two amino acid changes ("CDR variants") relative to the amino acid sequence set forth in SEQ ID NO: 153.

[0149] In one embodiment, the PD-1 antagonist comprises a light chain variable region CDR1 ("CDRL1") comprising an amino acid sequence having three or fewer (e.g., one or two) amino acid changes ("CDR variants") relative to the amino acid sequence set forth in SEQ ID NO: 154.

[0150] In one embodiment, the PD-1 antagonist comprises a light chain variable region CDR2 ("CDRL2") comprising an amino acid sequence having one or two amino acid alterations ("CDR variants") relative to the amino acid sequence set forth in SEQ ID NO: 155.

[0151] In one embodiment, the PD-1 antagonist comprises a light chain variable region CDR3 ("CDRL3") comprising an amino acid sequence that has no more than three (e.g., one or two) amino acid changes ("CDR variants") relative to the amino acid sequence set forth in SEQ ID NO: 156. In a particular embodiment, the CDRL3 comprises an amino acid sequence that has no more than two amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 156. In a further embodiment, the CDRL3 comprises the amino acid sequence set forth in SEQ ID NO: 157.

[0152] In one embodiment, the PD-1 antagonist comprises a CDRH1 comprising an amino acid sequence that has no more than one amino acid change relative to the amino acid sequence set forth in SEQ ID NO: 151; a CDRH2 comprising an amino acid sequence that has no more than five amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 152; a CDRH3 comprising an amino acid sequence that has no more than one amino acid change relative to the amino acid sequence set forth in SEQ ID NO: 153; a CDRL1 comprising an amino acid sequence that has no more than three amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 154; a CDRL2 comprising an amino acid sequence that has no more than one amino acid change relative to the amino acid sequence set forth in SEQ ID NO: 155; and / or a CDRL3 comprising an amino acid sequence that has no more than three amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 156.

[0153] In one embodiment of the invention, the PD-1 antagonist comprises a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 158, comprising CDRH1 (SEQ ID NO: 151), CDRH2 (SEQ ID NO: 152), and CDRH3 (SEQ ID NO: 153). In some embodiments, the PD-1 antibodies of the invention have at least 90% sequence identity to SEQ ID NO: 158. Suitably, the PD-1 antagonists of the invention may comprise a heavy chain variable region having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 158.

[0154] PD-1 antagonist heavy chain (V H ) Variable region: [ka]

[0155] In one embodiment, the PD-1 antagonist comprises a heavy chain variable region (“V”) comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 158. H In one embodiment, V H comprises an amino acid sequence having at least one amino acid change relative to the amino acid sequence set forth in SEQ ID NO: 158 (e.g., 1 to 5, e.g., 1 to 3, particularly 2 or less amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 158).

[0156] In one embodiment, the PD-1 antagonist comprises CDRL1 (SEQ ID NO: 154), CDRL2 (SEQ ID NO: 155), and CDRL3 (SEQ ID NO: 156) in a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 159. In one embodiment of the invention, a PD-1 antagonist of the invention comprises a heavy chain variable region of SEQ ID NO: 158 and a light chain variable region of SEQ ID NO: 159.

[0157] In some embodiments, the PD-1 antagonists of the invention comprise a light chain variable region having at least 90% sequence identity to SEQ ID NO: 159. Suitably, the PD-1 antagonists of the invention may comprise a light chain variable region having 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:159.

[0158] PD-1 antagonist light chain (V L ) Variable region: [ka]

[0159] In one embodiment, the PD-1 antagonist comprises a light chain variable region (“V”) comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 159. L In one embodiment, V L comprises an amino acid sequence having at least one amino acid change relative to the amino acid sequence set forth in SEQ ID NO: 159 (for example, 1 to 5, for example, 1 to 3, particularly 2 or less amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 159).

[0160] In one embodiment, the PD-1 antagonist comprises a V comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 158. H V comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO: 159 L In one embodiment, the PD-1 antagonist comprises a V having at least about 90% identity to SEQ ID NO: 158. H and V having at least about 90% identity to SEQ ID NO: 159L Includes.

[0161] In one embodiment, the PD-1 antagonist has the amino acid sequence set forth in SEQ ID NO:158. H and V having the amino acid sequence set forth in SEQ ID NO: 159 L Includes.

[0162] In one embodiment, the PD-1 antagonist is a monoclonal antibody and comprises a heavy chain (HC) amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:160.

[0163] [ka]

[0164] In one embodiment, the HC comprises an amino acid sequence having at least one amino acid change (e.g., 1 to 10, e.g., 1 to 7, in particular 6 or fewer amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 160) relative to the amino acid sequence set forth in SEQ ID NO: 160. In a further embodiment, the HC comprises 1, 2, 3, 4, 5, 6 or 7 amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 160.

[0165] In one embodiment, the HC chain comprises an alteration at positions 380 and / or 385 of SEQ ID NO: 160. The asparagine residues at these positions may be modified, for example, by deamidation (conversion of an asparagine (N) residue to an aspartic acid (D) residue). Thus, in one embodiment, the HC comprises the amino acid sequence of SEQ ID NO: 162 (N380D), SEQ ID NO: 163 (N385D), or SEQ ID NO: 164 (N380D and N385D).

[0166] In one embodiment, the PD-1 antagonist is a monoclonal antibody and comprises a light chain (LC) amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to SEQ ID NO:161.

[0167] [ka]

[0168] In one embodiment, the LC comprises an amino acid sequence having at least one amino acid change (e.g., 1 to 10, e.g., 1 to 5, in particular no more than 3 amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 161) relative to the amino acid sequence set forth in SEQ ID NO: 161. In a further embodiment, the LC comprises 1, 2 or 3 amino acid changes relative to the amino acid sequence set forth in SEQ ID NO: 161.

[0169] In one embodiment, the PD-1 antagonist comprises an HC comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 160; and an LC comprising an amino acid sequence having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 161. Thus, the antibody is an antibody having a heavy chain having at least about 90% identity to the amino acid sequence of SEQ ID NO: 160; and / or a light chain having at least about 90% identity to the amino acid sequence of SEQ ID NO: 161.

[0170] In one embodiment, the PD-1 antagonist comprises a heavy chain amino acid sequence having at least about 90% identity to the amino acid sequence of SEQ ID NO: 160; and / or a light chain amino acid sequence having at least about 90% identity to the amino acid sequence of SEQ ID NO: 161.

[0171] In one embodiment, the PD-1 antagonist comprises the heavy chain sequence of SEQ ID NO: 160 and the light chain sequence of SEQ ID NO: 161. In one embodiment, the antibody is dostarlimab, which comprises the heavy chain sequence of SEQ ID NO: 160 and the light chain sequence of SEQ ID NO: 161.

[0172] Anti-PD-L1 antibodies and methods for their production are known in the art. Such antibodies to PD-L1 may be polyclonal or monoclonal, and / or recombinant, and / or humanized. PD-L1 antibodies are being developed as immunomodulatory agents for the treatment of cancer.

[0173] Exemplary PD-L1 antibodies are disclosed in U.S. Patent No. 9,212,224; U.S. Patent No. 8,779,108; U.S. Patent No. 8,552,154; U.S. Patent No. 8,383,796; U.S. Patent No. 8,217,149; U.S. Patent Application Publication No. 2011 / 0280877; WO 2013 / 079174; and WO 2013 / 019906. Additional exemplary antibodies and methods of use against PD-L1 (also known as CD274 or B7-H1) are disclosed in U.S. Patent No. 8,168,179; U.S. Patent No. 7,943,743; U.S. Patent No. 7,595,048; WO 2014 / 055897; WO 2013 / 019906; and WO 2010 / 077634. ​​Particular anti-human PD-L1 monoclonal antibodies useful as PD-1 antagonists in the therapeutic methods, medicaments, and uses of the invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C.

[0174] Atezolizumab is a fully humanized anti-PD-L1 monoclonal antibody marketed as Tecentriq. Atezolizumab is indicated for the treatment of some locally advanced or metastatic urothelial carcinomas. Atezolizumab inhibits the interaction of PD-L1 with PD-1 and CD80. Other exemplary PD-L1 antibodies include avelumab (BAVENCIO) and durvalumab (IMFINZI).

[0175] CD134, also known as OX40, is a TNFR superfamily receptor that, unlike CD28, is not constitutively expressed on resting naive T cells. OX40 is a secondary costimulatory molecule that is expressed 24–72 hours after activation. Its ligand, OX40L, is also not expressed on resting antigen-presenting cells but is expressed after activation. OX40 expression is dependent on full T cell activation; in the absence of CD28, OX40 expression is delayed and its levels are fourfold lower. OX-40 antibodies, OX-40 fusion proteins, and methods of their use are disclosed in U.S. Pat. No. 7,504,101; U.S. Pat. No. 7,504,101; U.S. Pat. No. 7,758,852; U.S. Pat. No. 7,858,765; U.S. Pat. No. 7,550,140; U.S. Pat. No. 7,960,515; WO 2012 / 027328; WO 2013 / 028231.

[0176] Further examples of additional active ingredients or components (antineoplastic agents) for use in combination or co-administration with the presently disclosed CD96 binding proteins are antibodies or other antagonists to CD20, retinoids, or other kinase inhibitors. Examples of such antibodies or antagonists include, but are not limited to, rituximab (Rituxan and MABTHERA), ofatumumab (ARZERRA), and bexarotene (TARGRETIN).

[0177] Further examples of additional active ingredients or components (antineoplastic agents) for use in combination or co-administration with the presently disclosed CD96 binding proteins are Toll-like receptor 4 (TLR4) antagonists, including, but not limited to, aminoalkyl glucosaminide phosphates (AGPs).

[0178] AGP is known to be useful as a vaccine adjuvant and immunostimulant, stimulating cytokine production, activating macrophages, promoting innate immune responses, and enhancing antibody production in immunized animals. AGP is a synthetic ligand for TLR4. AGP and its immunomodulatory effects via TLR4 have been disclosed in patent publications such as WO 2006 / 016997, WO 2001 / 090129, and / or U.S. Patent No. 6,113,918, and have also been reported in the literature. Additional AGP derivatives are disclosed in U.S. Patent Nos. 7,129,219, 6,911,434, and 6,525,028. While certain AGPs act as TLR4 agonists, others are recognized as TLR4 antagonists.

[0179] An additional non-limiting example of an additional active ingredient or component (anti-neoplastic agent) for use in combination or co-administration with the presently disclosed CD96 binding proteins is an antibody against ICOS.

[0180] The CDRs of a murine antibody against human ICOS with agonistic activity are shown in PCT / EP2012 / 055735 (WO 2012 / 131004). Antibodies against ICOS are also disclosed in WO 2008 / 137915, WO 2010 / 056804, EP 1374902, EP 1374901, and EP 1125585.

[0181] Additional examples of additional active ingredients or components (anti-tumor agents) for use in combination or co-administration with the presently disclosed CD96 binding proteins are poly ADP-ribose polymerase (PARP) inhibitors. Non-limiting examples of such inhibitors include niraparib, olaparib, rucaparib, and talazoparib.

[0182] Further non-limiting examples of additional active ingredients or components (antineoplastic agents) for use in combination or co-administration with the presently disclosed CD96 binding proteins are STING-modulating compounds, CD39 inhibitors, and A2a and A2a adenosine antagonists.

[0183] Selective antineoplastic agents that may be used in combination with a CD96 binding protein or a pharmaceutically acceptable salt thereof include, but are not limited to, abarelix, abemaciclib, abiraterone, afatinib, aflibercept, aldoxorubicin, alectinib, alemtuzumab, arsenic trioxide, asparaginase, axitinib, AZD-9291, belinstat, bendamustine, bevacizumab, blinatumomab, bolusamphone ... sutinib, brentuximab vedotin, cabazitaxel, cabozantinib, capecitabine, ceritinib, clofarabine, cobimetinib, crizotinib, daratumumab, dasatinib, degarelix, denosumab, dinutuximab, docetaxel, elotuzumab, entinostat, enzalutamide, epirubicin, eribulin, filgrastim, flumatinib, fulvestrant, fruquintinib, gemtuzumab ozogamicin, ibritumomab, ibuprofen Brutinib, idelalisib, imatinib, irinotecan, ixabepilone, ixazomib, lenalidomide, lenvatinib, leucovorin, mechlorethamine, necitumumab, nelarabine, netupitant, nilotinib, obinutuzumab, olaparib, omacetaxine, osimertinib, oxaliplatin, paclitaxel, palbociclib, palonosetron, panitumumab, pegfilgrastim, peginterferon, alfa-2b, pemetrexed, Plerixafor, pomalidomide, ponatinib, pralatrexate, quizartinib, radium-223, ramucirumab, regorafenib, rolapitant, rucaparib, sipuleucel-T, sonidegib, sunitinib, talimogen laherparepvec, tipiracil, topotecan, trabectedin, trifluridine, triptorelin, uridine, vandetanib, velaparib, vemurafenib, venetoclax, vincristine, vismodegib, zoledronic acid.

[0184] As used herein, a "PVRIG antagonist" refers to a chemical compound or biological molecule that inhibits the binding of PVRL2 (e.g., PVRL2 expressed on cancer cells) to PVRIG (e.g., PVRIG expressed on immune cells (T cells, B cells, or NKT cells)). Alternative names or synonyms for PVRIG and its ligands include the following: for PVRIG, C7orf15, C7orf15MGC138295, CD112R, MGC104322, MGC138297, MGC2463, poliovirus receptor-related immunoglobulin domain-containing protein, poliovirus receptor-related immunoglobulin domain-containing protein, and transmembrane protein PVRIG; for PVRL2, NECTIN2, CD112, HVEB, PRR2, PVRR2, and nectin cell adhesion molecule 2.

[0185] PVRIG antagonists useful in any aspect of the invention include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to PVRIG or PVRL2, preferably specifically bind to human PVRI or PVRL2. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody and may comprise a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0186] Examples of mAbs that bind to human PVRIG and are useful in various aspects and embodiments of the present disclosure are described, for example, in WO 2020 / 018879 and WO 2016 / 134333.

[0187] Thus, an additional example of an additional active ingredient or component (antineoplastic agent) for use in combination or co-administration with the presently disclosed CD96 binding proteins is an antibody or other antagonist to PVRIG. Examples of such antibodies or antagonists include, but are not limited to, anti-PVRIG antibodies such as SRF813 (Surface Oncology) or COM701 (CGEN-15029) (Compugen).

[0188] In one embodiment, the anti-PVRIG antibody comprises: (a) a CDRH1 comprising SEQ ID NO: 181, a CDRH2 comprising SEQ ID NO: 182, a CDRH3 comprising SEQ ID NO: 183, a CDRL1 comprising SEQ ID NO: 184, a CDRL2 comprising SEQ ID NO: 185, and a CDRL3 comprising SEQ ID NO: 186; (b) a CDRH1 comprising SEQ ID NO: 187, a CDRH2 comprising SEQ ID NO: 188, a CDRH3 comprising SEQ ID NO: 189, a CDRL1 comprising SEQ ID NO: 190, a CDRL2 comprising SEQ ID NO: 191, and a CDRL3 comprising SEQ ID NO: 192; (c) a CDRH1 comprising SEQ ID NO: 1 (d) CDRH1 comprising SEQ ID NO: 199, CDRH2 comprising SEQ ID NO: 200, CDRH3 comprising SEQ ID NO: 201, CDRL1 comprising SEQ ID NO: 202, CDRL2 comprising SEQ ID NO: 203, and CDRL3 comprising SEQ ID NO: 204; (e) CDRH1 comprising SEQ ID NO: 205, CDRH2 comprising SEQ ID NO: 206, CDRL3 comprising SEQ ID NO: (f) CDRH1 comprising SEQ ID NO:211, CDRH2 comprising SEQ ID NO:212, CDRH3 comprising SEQ ID NO:213, CDRL1 comprising SEQ ID NO:214, CDRL2 comprising SEQ ID NO:215, and CDRL3 comprising SEQ ID NO:216; (g) CDRH1 comprising SEQ ID NO:217, CDRH2 comprising SEQ ID NO:218, CDRH3 comprising SEQ ID NO:219, CDRL1 comprising SEQ ID NO:220, CDRL2 comprising SEQ ID NO:221 (h) CDRH1 comprising SEQ ID NO:223, CDRH2 comprising SEQ ID NO:224, CDRH3 comprising SEQ ID NO:225, CDRH1 comprising SEQ ID NO:226, CDRL2 comprising SEQ ID NO:227, and CDRL3 comprising SEQ ID NO:228; (i) CDRH1 comprising SEQ ID NO:229, CDRH2 comprising SEQ ID NO:230, CDRH3 comprising SEQ ID NO:231, CDRL1 comprising SEQ ID NO:232, CDRL2 comprising SEQ ID NO:233, and CDRL3 comprising SEQ ID NO:234;(j) CDRH1 comprising SEQ ID NO:235, CDRH2 comprising SEQ ID NO:236, CDRH3 comprising SEQ ID NO:237, CDRL1 comprising SEQ ID NO:238, CDRL2 comprising SEQ ID NO:239, and CDRL3 comprising SEQ ID NO:240; (k) CDRH1 comprising SEQ ID NO:241, CDRH2 comprising SEQ ID NO:242, CDRH3 comprising SEQ ID NO:243, CDRL1 comprising SEQ ID NO:244, CDRL2 comprising SEQ ID NO:245, and CDRL3 comprising SEQ ID NO:246; (l) CDRH1 comprising SEQ ID NO:247, CDRH2 comprising SEQ ID NO:248, CDRH3 comprising SEQ ID NO:249, CDRL1 comprising SEQ ID NO:250, CDRL2 comprising SEQ ID NO:251, and CDRL3 comprising SEQ ID NO:252; (m) a CDRH1 comprising SEQ ID NO:253, a CDRH2 comprising SEQ ID NO:254, a CDRH3 comprising SEQ ID NO:255, a CDRL1 comprising SEQ ID NO:256, a CDRH2 comprising SEQ ID NO:257, and a CDRL3 comprising SEQ ID NO:258; or (n) a CDRH1 comprising SEQ ID NO:259, a CDRH2 comprising SEQ ID NO:260, a CDRH3 comprising SEQ ID NO:261, a CDRL1 comprising SEQ ID NO:262, a CDRL2 comprising SEQ ID NO:263, and a CDRL3 comprising SEQ ID NO:264.

[0189] In one embodiment, the anti-PVRIG antibody comprises: (a) a VH comprising SEQ ID NO: 265 and a VL comprising SEQ ID NO: 266; (b) a VH comprising SEQ ID NO: 267 and a VL comprising SEQ ID NO: 268; (c) a VH comprising SEQ ID NO: 269 and a VL comprising SEQ ID NO: 270; (d) a VH comprising SEQ ID NO: 271 and a VL comprising SEQ ID NO: 272; (e) a VH comprising SEQ ID NO: 273 and a VL comprising SEQ ID NO: 274; (f) a VH comprising SEQ ID NO: 275 and a VL comprising SEQ ID NO: 276; (g) a VH comprising SEQ ID NO: 277 and a VL comprising SEQ ID NO: 278; (h) a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280; (i) a VH comprising SEQ ID NO: 281 and a VL comprising SEQ ID NO: 282; (j) a VH comprising SEQ ID NO: 283 and a VL comprising SEQ ID NO: 284; (k) a VH comprising SEQ ID NO: 285 and a VL comprising SEQ ID NO: 286; (l) a VH comprising SEQ ID NO: 287 and a VL comprising SEQ ID NO: 288; (m) a VH comprising SEQ ID NO: 289 and a VL comprising SEQ ID NO: 290; or (n) a VH comprising SEQ ID NO: 291 and a VL comprising SEQ ID NO: 292.

[0190] In one embodiment, the anti-PVRIG antibody comprises: CDRH1 comprising SEQ ID NO: 293, CDRH2 comprising SEQ ID NO: 294, CDRH3 comprising SEQ ID NO: 294, CDRL1 comprising SEQ ID NO: 296, CDRL2 comprising SEQ ID NO: 297, and CDRL3 comprising SEQ ID NO: 298.

[0191] In one embodiment, the anti-PVRIG antibody comprises: (a) a VH comprising SEQ ID NO: 299 and a VL comprising SEQ ID NO: 300; or (b) a VH comprising SEQ ID NO: 301 and a VL comprising SEQ ID NO: 302.

[0192] As used herein, the term "TIGIT antagonist" refers to a chemical compound or biological molecule that inhibits the activity of TIGIT by inhibiting the ligand binding and / or signal transduction activity of TIGIT. In embodiments, the TIGIT antagonist of the present disclosure inhibits the binding of TIGIT to CD155 / NECL5 and / or the signal transduction induced by CD155 / NECL5.

[0193] TIGIT antagonists useful in any aspect of the present invention include monoclonal antibodies (mAbs) or antigen-binding fragments thereof that specifically bind to TIGIT, e.g., TIGIT expressed on the surface of T cells, NK cells, or NKT cells. The mAb may be a human antibody, a humanized antibody, or a chimeric antibody, and may contain a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in preferred embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0194] In one embodiment, the anti-TIGIT antibody comprises a heavy chain sequence comprising SEQ ID NO: 392 and a light chain sequence comprising SEQ ID NO: 393. In a further embodiment, the anti-TIGIT antibody comprises: (a) a CDRH1 comprising SEQ ID NO: 320, a CDRH2 comprising SEQ ID NO: 321, a CDRH3 comprising SEQ ID NO: 322, a CDRL1 comprising SEQ ID NO: 317, a CDRL2 comprising SEQ ID NO: 318, and a CDRL3 comprising SEQ ID NO: 319. In another further embodiment, the anti-TIGIT antibody comprises: (a) a CDRH1 comprising SEQ ID NO: 326, a CDRH2 comprising SEQ ID NO: 327, a CDRH3 comprising SEQ ID NO: 328, a CDRL1 comprising SEQ ID NO: 323, a CDRL2 comprising SEQ ID NO: 324, and a CDRL3 comprising SEQ ID NO: 325. In another further embodiment, the anti-TIGIT antibody comprises a heavy chain variable sequence comprising a sequence selected from SEQ ID NO: 315 and SEQ ID NO: 316, and a light chain variable sequence comprising a sequence selected from SEQ ID NO: 313 and SEQ ID NO: 314.

[0195] In one embodiment, the anti-TIGIT antibody comprises a heavy chain variable sequence comprising SEQ ID NO: 329 and a light chain variable sequence comprising SEQ ID NO: 330. In another embodiment, the anti-TIGIT antibody comprises: (a) a CDRH1 comprising SEQ ID NO: 334, a CDRH2 comprising SEQ ID NO: 335, a CDRH3 comprising SEQ ID NO: 336, a CDRL1 comprising SEQ ID NO: 331, a CDRL2 comprising SEQ ID NO: 332, and a CDRL3 comprising SEQ ID NO: 333. In yet another embodiment, the anti-TIGIT antibody comprises a heavy chain variable sequence comprising a sequence selected from SEQ ID NO: 337, SEQ ID NO: 339, and SEQ ID NO: 341, and a light chain variable sequence comprising a sequence selected from SEQ ID NO: 338, SEQ ID NO: 340, and SEQ ID NO: 342.

[0196] In one embodiment, the anti-TIGIT antibody comprises a CDRH1 sequence comprising a sequence selected from SEQ ID NO: 320, SEQ ID NO: 326, and SEQ ID NO: 334, a CDRH2 sequence comprising a sequence selected from SEQ ID NO: 321, SEQ ID NO: 327, and SEQ ID NO: 335, and a CDRH3 sequence comprising a sequence selected from SEQ ID NO: 322, SEQ ID NO: 328, and SEQ ID NO: 336.

[0197] In one embodiment, the anti-TIGIT antibody comprises a CDRL1 sequence comprising a sequence selected from SEQ ID NO: 317, SEQ ID NO: 323, and SEQ ID NO: 331, a CDRL2 sequence comprising a sequence selected from SEQ ID NO: 318, SEQ ID NO: 324, and SEQ ID NO: 332, and a CDRL3 sequence comprising a sequence selected from SEQ ID NO: 319, SEQ ID NO: 325, and SEQ ID NO: 333.

[0198] In one embodiment, the anti-TIGIT antibody is selected from the group consisting of SEQ ID NO:315, SEQ ID NO:316, SEQ ID NO:329, SEQ ID NO:352, SEQ ID NO:354, SEQ ID NO:356, SEQ ID NO:358, SEQ ID NO:360, SEQ ID NO:362, SEQ ID NO:364, SEQ ID NO:366, SEQ ID NO:368, SEQ ID NO:370, SEQ ID NO:372, SEQ ID NO:374, SEQ ID NO:376, SEQ ID NO:378, SEQ ID NO:380, SEQ ID NO:382, SEQ ID NO:384, SEQ ID NO:386, SEQ ID NO:388, SEQ ID NO:390, SEQ ID NO:395, SEQ ID NO:402, SEQ ID NO:404, SEQ ID NO:406, SEQ ID NO:408, SEQ ID NO: SEQ ID NO:410, SEQ ID NO:411, SEQ ID NO:412, SEQ ID NO:413, SEQ ID NO:414, SEQ ID NO:415, SEQ ID NO:416, SEQ ID NO:417, SEQ ID NO:418, SEQ ID NO:419, SEQ ID NO:420, SEQ ID NO:421, SEQ ID NO:422, SEQ ID NO:423, SEQ ID NO:424, SEQ ID NO:425, SEQ ID NO:426, SEQ ID NO:427, SEQ ID NO:428, SEQ ID NO:429, SEQ ID NO:437, SEQ ID NO:439, SEQ ID NO:441, SEQ ID NO:443, SEQ ID NO:445, SEQ ID NO:446, SEQ ID NO:447 and SEQ ID NO:448.

[0199] In yet another embodiment, the anti-TIGIT antibody comprises a light chain variable sequence comprising a sequence selected from SEQ ID NO:330, SEQ ID NO:313, SEQ ID NO:314, SEQ ID NO:338, SEQ ID NO:340, SEQ ID NO:342, SEQ ID NO:345, SEQ ID NO:353, SEQ ID NO:355, SEQ ID NO:357, SEQ ID NO:359, SEQ ID NO:361, SEQ ID NO:363, SEQ ID NO:365, SEQ ID NO:367, SEQ ID NO:369, SEQ ID NO:371, SEQ ID NO:373, SEQ ID NO:375, SEQ ID NO:377, SEQ ID NO:379, SEQ ID NO:381, SEQ ID NO:383, SEQ ID NO:385, SEQ ID NO:387, SEQ ID NO:389, SEQ ID NO:391, SEQ ID NO:394, SEQ ID NO:403, SEQ ID NO:405, SEQ ID NO:407, SEQ ID NO:409, SEQ ID NO:430, SEQ ID NO:431, SEQ ID NO:432, SEQ ID NO:433, SEQ ID NO:434, SEQ ID NO:435, SEQ ID NO:436, SEQ ID NO:438, SEQ ID NO:440, SEQ ID NO:442, and SEQ ID NO:444.

[0200] In another further embodiment, the anti-TIGIT antibody comprises the heavy and light chain variable sequences shown in Table X: [Table 2]

[0201] In one embodiment, the chemical compound that is a TIGIT antagonist is liothyronine, OMP-313M32, or MTIG7192A.

[0202] Combinations of two or more of the PD-1 antagonists, TIGIT antagonists, PVRIG antagonists, and / or CD96 antagonists disclosed herein are provided by the present disclosure.

[0203] In one embodiment, the combination may comprise a PD-1 antagonist and a TIGIT antagonist. In another embodiment, the combination may comprise a PD-1 antagonist and a PVRIG antagonist. In another preferred embodiment, the combination may comprise a PD-1 antagonist and a CD96 antagonist. In another embodiment, the combination may comprise a TIGIT antagonist and a PVRIG antagonist. In another embodiment, the combination may comprise a TIGIT antagonist and a CD96 antagonist. In another embodiment, the combination may comprise a PVRIG antagonist and a CD96 antagonist.

[0204] Combinations of two or more of the antagonists disclosed herein may be expressed as a ratio of two or more antagonists. For example, combinations of the antagonists disclosed herein may be provided as a ratio of a fixed dose of one antagonist to a fixed dose of another antagonist (e.g., a fixed dose of a TIGIT antagonist to a fixed dose of a PD-1 antagonist).

[0205] In one embodiment, the ratio of TIGIT antagonist to PD-1 antagonist can be at least about 1:0.25 to at least about 1:2. In further embodiments, the ratio of TIGIT antagonist to PD-1 antagonist can be at least about 1:0.25, at least about 1:0.30, at least about 1:0.35, at least about 1:0.40, at least about 1:0.45, at least about 1:0.50, at least about 1:0.55, at least about 1:0.60, at least about 1:0.65, at least about 1:0.70, at least about 1:0.75, at least about 1:0.80, at least about 1:0.85, at least about 1:0.90, at least about 1:0.95, at least about 1:1, or at least about 1: 1:1.05, at least about 1:1.10, at least about 1:1.15, at least about 1:1.20, at least about 1:1.25, at least about 1:1.30, at least about 1:1.35, at least about 1:1.40, at least about 1:1.45, at least about 1:1.50, at least about 1:1.55, at least about 1:1.60, at least about 1:1.65, at least about 1:1.70, at least about 1:1.75, at least about 1:1.80, at least about 1:1.85, at least about 1:1.90, at least about 1:1.95, or at least about 1:2. In another further embodiment, the ratio of TIGIT antagonist to PD-1 antagonist is 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, 1:0.31, 1:0.32, 1:0.33, 1:0.34, 1:0.35, 1:0.36, 1:0.37, 1:0.38, 1:0.39, 1:0.40, 1:0.41, 1:0.42, 1:0.43, 1:0.44, 1:0.45, 1:0.46, 1:0.47, 1:0. 48, 1:0.49, 1:0.50, 1:0.51, 1:0.52, 1:0.53, 1:0.54, 1:0.55, 1:0.56, 1:0.57, 1:0.58, 1:0.59, 1:0.60, 1:0.61, 1:0.62, 1:0.63, 1:0.64, 1:0.65, 1:0.66, 1:0.67, 1:0.68, 1:0.69, 1:0.70, 1:0.71, 1:0.72, 1:0.73, 1:0.74, 1:0.75, 1:0.76, 1:0.77, 1:0.78, 1:0.79, 1:0.80, 1:0.81, 1:0.82, 1:0.83, 1:0.84, 1:0.85, 1:0.86, 1:0.87, 1:0.88, 1:0.89, 1:0.90, 1:0.91, 1:0.92, 1:0.93, 1:0.94, 1:0.95, 1:0.96, 1:0.97, 1:0.98, 1:0.99, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1. 09, 1:1.10, 1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20, 1:1.21, 1:1.22, 1:1.23, 1:1.24, 1:1.25, 1:1.26, 1:1.27, 1:1.28, 1:1.29, 1:1.30, 1:1.31, 1:1.32, 1:1.33, 1:1.34, 1:1.35, 1:1.36, 1:1.37, 1:1.38, 1:1.39, 1: 1.40, 1:1.41, 1:1.42, 1:1.43, 1:1.44, 1:1.45, 1:1.46, 1:1.47, 1:1.48, 1:1.49, 1:1.50, 1:1.51, 1:1.52, 1:1.53, 1:1.54, 1:1.55, 1:1.56, 1:1.57, 1:1.58, 1:1.59, 1:1.60, 1:1.61, 1:1.62, 1:1.63, 1:1.64, 1:1.65, 1:1.66, 1:1.67, 1:1.68, 1:1.69, 1:1.70, The ratio may be 1:1.71, 1:1.72, 1:1.73, 1:1.74, 1:1.75, 1:1.76, 1:1.77, 1:1.78, 1:1.79, 1:1.80, 1:1.81, 1:1.82, 1:1.83, 1:1.84, 1:1.85, 1:1.86, 1:1.87, 1:1.88, 1:1.89, 1:1.90, 1:1.91, 1:1.92, 1:1.93, 1:1.94, 1:1.95, 1:1.96, 1:1.97, 1:1.98, 1:1.99, or 1:2.

[0206] In one embodiment, the ratio of PVRIG antagonist to PD-1 antagonist may be at least about 1:0.25 to at least about 1:2. In further embodiments, the ratio of PVRIG antagonist to PD-1 antagonist is at least about 1:0.25, at least about 1:0.30, at least about 1:0.35, at least about 1:0.40, at least about 1:0.45, at least about 1:0.50, at least about 1:0.55, at least about 1:0.60, at least about 1:0.65, at least about 1:0.70, at least about 1:0.75, at least about 1:0.80, at least about 1:0.85, at least about 1:0.90, at least about 1:0.95, at least about 1:1, or at least about 1:1. 0.05, at least about 1:1.10, at least about 1:1.15, at least about 1:1.20, at least about 1:1.25, at least about 1:1.30, at least about 1:1.35, at least about 1:1.40, at least about 1:1.45, at least about 1:1.50, at least about 1:1.55, at least about 1:1.60, at least about 1:1.65, at least about 1:1.70, at least about 1:1.75, at least about 1:1.80, at least about 1:1.85, at least about 1:1.90, at least about 1:1.95, or at least about 1:2. In another further embodiment, the ratio of PVRIG antagonist to PD-1 antagonist is 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, 1:0.31, 1:0.32, 1:0.33, 1:0.34, 1:0.35, 1:0.36, 1:0.37, 1:0.38, 1:0.39, 1:0.40, 1:0.41, 1:0.42, 1:0.43, 1:0.44, 1:0.45, 1:0.46, 1:0.47, 1:0.48, 1:0.49, 1:0.50, 1:0.51, 1:0.52, 1:0.53, 1:0.54, 1:0.55, 1:0.56, 1:0.57, 1:0.58, 1:0.59, 1:0.60, 1:0.61, 1:0.62, 1:0.63, 1:0.64, 1:0.65, 1:0.66, 1:0.67, 1:0.68, 1:0.69, 1:0.70, 1:0.71, 1:0.72, 1:0.73, 1:0.74, 1:0.75, 1:0.76, 1:0.77, 1:0.78, 1:0.79, 1:0.80, 1:0.81, 1:0.82, 1:0.83, 1:0.84, 1:0.85, 1:0.86, 1:0.87, 1:0.88, 1:0.89, 1:0.90, 1:0.91, 1:0.92, 1:0.93, 1:0.94, 1:0.95, 1:0.96, 1:0.97, 1:0.98, 1:0.99, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08 , 1:1.09, 1:1.10, 1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20, 1:1.21, 1:1.22, 1:1.23, 1:1.24, 1:1.25, 1:1.26, 1:1.27, 1:1.28, 1:1.29, 1:1.30, 1:1.31, 1:1.32, 1:1.33, 1:1.34, 1:1.35, 1:1.36, 1:1.37, 1:1.38, 1:1.39 ,1:1.40,1:1.41,1:1.42,1:1.43,1:1.44,1:1.45,1:1.46,1:1.47,1:1.48,1:1.49,1:1.50,1:1.51,1:1.52,1:1.53,1:1.54,1:1.55,1:1.56,1:1.57,1:1.58,1:1.59,1:1.60,1:1.61,1:1.62,1:1.63,1:1.64,1:1.65,1:1.66,1:1.67,1:1.68,1:1.69,1:1.7 The ratio may be 0, 1:1.71, 1:1.72, 1:1.73, 1:1.74, 1:1.75, 1:1.76, 1:1.77, 1:1.78, 1:1.79, 1:1.80, 1:1.81, 1:1.82, 1:1.83, 1:1.84, 1:1.85, 1:1.86, 1:1.87, 1:1.88, 1:1.89, 1:1.90, 1:1.91, 1:1.92, 1:1.93, 1:1.94, 1:1.95, 1:1.96, 1:1.97, 1:1.98, 1:1.99, or 1:2.

[0207] In one embodiment, the ratio of CD96 antagonist to PD-1 antagonist can be at least about 1:0.25 to at least about 1:2. In further embodiments, the ratio of CD96 antagonist to PD-1 antagonist is at least about 1:0.25, at least about 1:0.30, at least about 1:0.35, at least about 1:0.40, at least about 1:0.45, at least about 1:0.50, at least about 1:0.55, at least about 1:0.60, at least about 1:0.65, at least about 1:0.70, at least about 1:0.75, at least about 1:0.80, at least about 1:0.85, at least about 1:0.90, at least about 1:0.95, at least about 1:1, or at least about 1:1. The ratio may be at least about 1:1.05, at least about 1:1.10, at least about 1:1.15, at least about 1:1.20, at least about 1:1.25, at least about 1:1.30, at least about 1:1.35, at least about 1:1.40, at least about 1:1.45, at least about 1:1.50, at least about 1:1.55, at least about 1:1.60, at least about 1:1.65, at least about 1:1.70, at least about 1:1.75, at least about 1:1.80, at least about 1:1.85, at least about 1:1.90, at least about 1:1.95, or at least about 1:2. In another further embodiment, the ratio of CD96 antagonist to PD-1 antagonist is 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, 1:0.31, 1:0.32, 1:0.33, 1:0.34, 1:0.35, 1:0.36, 1:0.37, 1:0.38, 1:0.39, 1:0.40, 1:0.41, 1:0.42, 1:0.43, 1:0.44, 1:0.45, 1:0.46, 1:0.47, 1:0. 48, 1:0.49, 1:0.50, 1:0.51, 1:0.52, 1:0.53, 1:0.54, 1:0.55, 1:0.56, 1:0.57, 1:0.58, 1:0.59, 1:0.60, 1:0.61, 1:0.62, 1:0.63, 1:0.64, 1:0.65, 1:0.66, 1:0.67, 1:0.68, 1:0.69, 1:0.70, 1:0.71, 1:0.72, 1:0.73, 1:0.74, 1:0.75, 1:0.76, 1:0.77, 1:0.78, 1:0.79, 1:0.80, 1:0.81, 1:0.82, 1:0.83, 1:0.84, 1:0.85, 1:0.86, 1:0.87, 1:0.88, 1:0.89, 1:0.90, 1:0.91, 1:0.92, 1:0.93, 1:0.94, 1:0.95, 1:0.96, 1:0.97, 1:0.98, 1:0.99, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1. 09, 1:1.10, 1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20, 1:1.21, 1:1.22, 1:1.23, 1:1.24, 1:1.25, 1:1.26, 1:1.27, 1:1.28, 1:1.29, 1:1.30, 1:1.31, 1:1.32, 1:1.33, 1:1.34, 1:1.35, 1:1.36, 1:1.37, 1:1.38, 1:1.39, 1: 1.40, 1:1.41, 1:1.42, 1:1.43, 1:1.44, 1:1.45, 1:1.46, 1:1.47, 1:1.48, 1:1.49, 1:1.50, 1:1.51, 1:1.52, 1:1.53, 1:1.54, 1:1.55, 1:1.56, 1:1.57, 1:1.58, 1:1.59, 1:1.60, 1:1.61, 1:1.62, 1:1.63, 1:1.64, 1:1.65, 1:1.66, 1:1.67, 1:1.68, 1:1.69, 1:1.70, The ratio may be 1:1.71, 1:1.72, 1:1.73, 1:1.74, 1:1.75, 1:1.76, 1:1.77, 1:1.78, 1:1.79, 1:1.80, 1:1.81, 1:1.82, 1:1.83, 1:1.84, 1:1.85, 1:1.86, 1:1.87, 1:1.88, 1:1.89, 1:1.90, 1:1.91, 1:1.92, 1:1.93, 1:1.94, 1:1.95, 1:1.96, 1:1.97, 1:1.98, 1:1.99, or 1:2.

[0208] In one embodiment, the ratio of PVRIG antagonist to TIGIT antagonist can be at least about 1:0.25 to at least about 1:2. In a further embodiment, the ratio of PVRIG antagonist to TIGIT antagonist is at least about 1:0.25, at least about 1:0.30, at least about 1:0.35, at least about 1:0.40, at least about 1:0.45, at least about 1:0.50, at least about 1:0.55, at least about 1:0.60, at least about 1:0.65, at least about 1:0.70, at least about 1:0.75, at least about 1:0.80, at least about 1:0.85, at least about 1:0.90, at least about 1:0.95, at least about 1:1, or at least about 1: 1:1.05, at least about 1:1.10, at least about 1:1.15, at least about 1:1.20, at least about 1:1.25, at least about 1:1.30, at least about 1:1.35, at least about 1:1.40, at least about 1:1.45, at least about 1:1.50, at least about 1:1.55, at least about 1:1.60, at least about 1:1.65, at least about 1:1.70, at least about 1:1.75, at least about 1:1.80, at least about 1:1.85, at least about 1:1.90, at least about 1:1.95, or at least about 1:2. In another further embodiment, the ratio of PVRIG antagonist to TIGIT antagonist is 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, 1:0.31, 1:0.32, 1:0.33, 1:0.34, 1:0.35, 1:0.36, 1:0.37, 1:0.38, 1:0.39, 1:0.40, 1:0.41, 1:0.42, 1:0.43, 1:0.44, 1:0.45, 1:0.46, 1:0.47, 1:0.48, 1:0.49, 1:0.50, 1:0.51, 1:0.52, 1:0.53, 1:0.54, 1:0.55, 1:0.56, 1:0.57, 1:0.58, 1:0.59, 1:0.60, 1:0.61, 1:0.62, 1:0.63, 1:0.64, 1:0.65, 1:0.66, 1:0.67, 1:0.68, 1:0.69, 1:0.70, 1:0.71, 1:0.72, 1:0.73, 1:0.74, 1:0.75, 1:0.76, 1:0.77, 1:0.78, 1:0.79, 1:0.80, 1:0.81, 1:0.82, 1:0.83, 1:0.84, 1:0.85, 1:0.86, 1:0.87, 1:0.88, 1:0.89, 1:0.90, 1:0.91, 1:0.92, 1:0.93, 1:0.94, 1:0.95, 1:0.96, 1:0.97, 1:0.98, 1:0.99, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08 , 1:1.09, 1:1.10, 1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20, 1:1.21, 1:1.22, 1:1.23, 1:1.24, 1:1.25, 1:1.26, 1:1.27, 1:1.28, 1:1.29, 1:1.30, 1:1.31, 1:1.32, 1:1.33, 1:1.34, 1:1.35, 1:1.36, 1:1.37, 1:1.38, 1:1.39 ,1:1.40,1:1.41,1:1.42,1:1.43,1:1.44,1:1.45,1:1.46,1:1.47,1:1.48,1:1.49,1:1.50,1:1.51,1:1.52,1:1.53,1:1.54,1:1.55,1:1.56,1:1.57,1:1.58,1:1.59,1:1.60,1:1.61,1:1.62,1:1.63,1:1.64,1:1.65,1:1.66,1:1.67,1:1.68,1:1.69,1:1.7 The ratio may be 0, 1:1.71, 1:1.72, 1:1.73, 1:1.74, 1:1.75, 1:1.76, 1:1.77, 1:1.78, 1:1.79, 1:1.80, 1:1.81, 1:1.82, 1:1.83, 1:1.84, 1:1.85, 1:1.86, 1:1.87, 1:1.88, 1:1.89, 1:1.90, 1:1.91, 1:1.92, 1:1.93, 1:1.94, 1:1.95, 1:1.96, 1:1.97, 1:1.98, 1:1.99, or 1:2.

[0209] In one embodiment, the ratio of CD96 antagonist to TIGIT antagonist can be at least about 1:0.25 to at least about 1:2. In further embodiments, the ratio of CD96 antagonist to TIGIT antagonist is at least about 1:0.25, at least about 1:0.30, at least about 1:0.35, at least about 1:0.40, at least about 1:0.45, at least about 1:0.50, at least about 1:0.55, at least about 1:0.60, at least about 1:0.65, at least about 1:0.70, at least about 1:0.75, at least about 1:0.80, at least about 1:0.85, at least about 1:0.90, at least about 1:0.95, at least about 1:1, or at least about 1: 1:1.05, at least about 1:1.10, at least about 1:1.15, at least about 1:1.20, at least about 1:1.25, at least about 1:1.30, at least about 1:1.35, at least about 1:1.40, at least about 1:1.45, at least about 1:1.50, at least about 1:1.55, at least about 1:1.60, at least about 1:1.65, at least about 1:1.70, at least about 1:1.75, at least about 1:1.80, at least about 1:1.85, at least about 1:1.90, at least about 1:1.95, or at least about 1:2. In another further embodiment, the ratio of CD96 antagonist to TIGIT antagonist is 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, 1:0.31, 1:0.32, 1:0.33, 1:0.34, 1:0.35, 1:0.36, 1:0.37, 1:0.38, 1:0.39, 1:0.40, 1:0.41, 1:0.42, 1:0.43, 1:0.44, 1:0.45, 1:0.46, 1:0.47, 1:0. 48, 1:0.49, 1:0.50, 1:0.51, 1:0.52, 1:0.53, 1:0.54, 1:0.55, 1:0.56, 1:0.57, 1:0.58, 1:0.59, 1:0.60, 1:0.61, 1:0.62, 1:0.63, 1:0.64, 1:0.65, 1:0.66, 1:0.67, 1:0.68, 1:0.69, 1:0.70, 1:0.71, 1:0.72, 1:0.73, 1:0.74, 1:0.75, 1:0.76, 1:0.77, 1:0.78, 1:0.79, 1:0.80, 1:0.81, 1:0.82, 1:0.83, 1:0.84, 1:0.85, 1:0.86, 1:0.87, 1:0.88, 1:0.89, 1:0.90, 1:0.91, 1:0.92, 1:0.93, 1:0.94, 1:0.95, 1:0.96, 1:0.97, 1:0.98, 1:0.99, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1. 09, 1:1.10, 1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20, 1:1.21, 1:1.22, 1:1.23, 1:1.24, 1:1.25, 1:1.26, 1:1.27, 1:1.28, 1:1.29, 1:1.30, 1:1.31, 1:1.32, 1:1.33, 1:1.34, 1:1.35, 1:1.36, 1:1.37, 1:1.38, 1:1.39, 1: 1.40, 1:1.41, 1:1.42, 1:1.43, 1:1.44, 1:1.45, 1:1.46, 1:1.47, 1:1.48, 1:1.49, 1:1.50, 1:1.51, 1:1.52, 1:1.53, 1:1.54, 1:1.55, 1:1.56, 1:1.57, 1:1.58, 1:1.59, 1:1.60, 1:1.61, 1:1.62, 1:1.63, 1:1.64, 1:1.65, 1:1.66, 1:1.67, 1:1.68, 1:1.69, 1:1.70, The ratio may be 1:1.71, 1:1.72, 1:1.73, 1:1.74, 1:1.75, 1:1.76, 1:1.77, 1:1.78, 1:1.79, 1:1.80, 1:1.81, 1:1.82, 1:1.83, 1:1.84, 1:1.85, 1:1.86, 1:1.87, 1:1.88, 1:1.89, 1:1.90, 1:1.91, 1:1.92, 1:1.93, 1:1.94, 1:1.95, 1:1.96, 1:1.97, 1:1.98, 1:1.99, or 1:2.

[0210] In one embodiment, the ratio of CD96 antagonist to PVRIG antagonist can be at least about 1:0.25 to at least about 1:2. In a further embodiment, the ratio of CD96 antagonist to PVRIG antagonist is at least about 1:0.25, at least about 1:0.30, at least about 1:0.35, at least about 1:0.40, at least about 1:0.45, at least about 1:0.50, at least about 1:0.55, at least about 1:0.60, at least about 1:0.65, at least about 1:0.70, at least about 1:0.75, at least about 1:0.80, at least about 1:0.85, at least about 1:0.90, at least about 1:0.95, at least about 1:1, or at least about 1: 1:1.05, at least about 1:1.10, at least about 1:1.15, at least about 1:1.20, at least about 1:1.25, at least about 1:1.30, at least about 1:1.35, at least about 1:1.40, at least about 1:1.45, at least about 1:1.50, at least about 1:1.55, at least about 1:1.60, at least about 1:1.65, at least about 1:1.70, at least about 1:1.75, at least about 1:1.80, at least about 1:1.85, at least about 1:1.90, at least about 1:1.95, or at least about 1:2. In another further embodiment, the ratio of CD96 antagonist to PVRIG antagonist is 1:0.25, 1:0.26, 1:0.27, 1:0.28, 1:0.29, 1:0.30, 1:0.31, 1:0.32, 1:0.33, 1:0.34, 1:0.35, 1:0.36, 1:0.37, 1:0.38, 1:0.39, 1:0.40, 1:0.41, 1:0.42, 1:0.43, 1:0.44, 1:0.45, 1:0.46, 1:0.47, 1:0. 48, 1:0.49, 1:0.50, 1:0.51, 1:0.52, 1:0.53, 1:0.54, 1:0.55, 1:0.56, 1:0.57, 1:0.58, 1:0.59, 1:0.60, 1:0.61, 1:0.62, 1:0.63, 1:0.64, 1:0.65, 1:0.66, 1:0.67, 1:0.68, 1:0.69, 1:0.70, 1:0.71, 1:0.72, 1:0.73, 1:0.74, 1:0.75, 1:0.76, 1:0.77, 1:0.78, 1:0.79, 1:0.80, 1:0.81, 1:0.82, 1:0.83, 1:0.84, 1:0.85, 1:0.86, 1:0.87, 1:0.88, 1:0.89, 1:0.90, 1:0.91, 1:0.92, 1:0.93, 1:0.94, 1:0.95, 1:0.96, 1:0.97, 1:0.98, 1:0.99, 1:1, 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1. 09, 1:1.10, 1:1.11, 1:1.12, 1:1.13, 1:1.14, 1:1.15, 1:1.16, 1:1.17, 1:1.18, 1:1.19, 1:1.20, 1:1.21, 1:1.22, 1:1.23, 1:1.24, 1:1.25, 1:1.26, 1:1.27, 1:1.28, 1:1.29, 1:1.30, 1:1.31, 1:1.32, 1:1.33, 1:1.34, 1:1.35, 1:1.36, 1:1.37, 1:1.38, 1:1.39, 1: 1.40, 1:1.41, 1:1.42, 1:1.43, 1:1.44, 1:1.45, 1:1.46, 1:1.47, 1:1.48, 1:1.49, 1:1.50, 1:1.51, 1:1.52, 1:1.53, 1:1.54, 1:1.55, 1:1.56, 1:1.57, 1:1.58, 1:1.59, 1:1.60, 1:1.61, 1:1.62, 1:1.63, 1:1.64, 1:1.65, 1:1.66, 1:1.67, 1:1.68, 1:1.69, 1:1.70, The ratio may be 1:1.71, 1:1.72, 1:1.73, 1:1.74, 1:1.75, 1:1.76, 1:1.77, 1:1.78, 1:1.79, 1:1.80, 1:1.81, 1:1.82, 1:1.83, 1:1.84, 1:1.85, 1:1.86, 1:1.87, 1:1.88, 1:1.89, 1:1.90, 1:1.91, 1:1.92, 1:1.93, 1:1.94, 1:1.95, 1:1.96, 1:1.97, 1:1.98, 1:1.99, or 1:2.

[0211] In one embodiment, a combination may comprise a PD-1 antagonist and a TIGIT antagonist, wherein the PD-1 antagonist comprises a CDRH1 comprising SEQ ID NO: 151, a CDRH2 comprising SEQ ID NO: 152, a CDRH3 comprising SEQ ID NO: 153, a CDRH1 comprising SEQ ID NO: 154, a CDRL2 comprising SEQ ID NO: 155, and a CDRL3 comprising SEQ ID NO: 156, and the TIGIT antagonist comprises a CDRH1 comprising SEQ ID NO: 334, a CDRH2 comprising SEQ ID NO: 335, a CDRH3 comprising SEQ ID NO: 336, a CDRL1 comprising SEQ ID NO: 331, a CDRL2 comprising SEQ ID NO: 332, and a CDRL3 comprising SEQ ID NO: 333. In one embodiment, a combination may comprise a PD-1 antagonist and a TIGIT antagonist, wherein the PD-1 antagonist comprises a VH comprising SEQ ID NO: 158 and a VL comprising SEQ ID NO: 159, and the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330. In one embodiment, a combination may comprise a PD-1 antagonist and a TIGIT antagonist, wherein the PD-1 antagonist comprises an HC comprising SEQ ID NO: 160 and an LC comprising SEQ ID NO: 161, and the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330. In one embodiment, a combination may comprise a PD-1 antagonist and a TIGIT antagonist, wherein the PD-1 antagonist is dostarlimab and the TIGIT antagonist is vibostolimab. In one embodiment, a combination may comprise a PD-1 antagonist and a TIGIT antagonist, wherein the PD-1 antagonist is dostarlimab and the TIGIT antagonist comprises an anti-TIGIT antibody comprising the heavy and light chain variable sequences set forth in Table X.

[0212] In one embodiment, a combination may comprise a PD-1 antagonist and a PVRIG antagonist, wherein the PD-1 antagonist comprises a CDRH1 comprising SEQ ID NO: 151, a CDRH2 comprising SEQ ID NO: 152, a CDRH3 comprising SEQ ID NO: 153, a CDRH1 comprising SEQ ID NO: 154, a CDRL2 comprising SEQ ID NO: 155, and a CDRL3 comprising SEQ ID NO: 156, and the PVRIG antagonist comprises a CDRH1 comprising SEQ ID NO: 223, a CDRH2 comprising SEQ ID NO: 224, a CDRH3 comprising SEQ ID NO: 225, a CDRL1 comprising SEQ ID NO: 226, a CDRL2 comprising SEQ ID NO: 227, and a CDRL3 comprising SEQ ID NO: 228. In one embodiment, a combination may comprise a PD-1 antagonist and a PVRIG antagonist, wherein the PD-1 antagonist comprises a VH comprising SEQ ID NO: 158 and a VL comprising SEQ ID NO: 159, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280. In one embodiment, a combination may comprise a PD-1 antagonist and a PVRIG antagonist, wherein the PD-1 antagonist comprises an HC comprising SEQ ID NO: 160 and an LC comprising SEQ ID NO: 161, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280. In one embodiment, a combination may comprise a PD-1 antagonist and a PVRIG antagonist, wherein the PD-1 antagonist is dostarlimab and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280.

[0213] In one embodiment, a combination may comprise a PD-1 antagonist and a CD96 antagonist, wherein the PD-1 antagonist comprises a CDRH1 comprising SEQ ID NO: 151, a CDRH2 comprising SEQ ID NO: 152, a CDRH3 comprising SEQ ID NO: 153, a CDRH1 comprising SEQ ID NO: 154, a CDRL2 comprising SEQ ID NO: 155, and a CDRL3 comprising SEQ ID NO: 156, and the CD96 antagonist comprises a CDRH1 comprising SEQ ID NO: 115, a CDRH2 comprising SEQ ID NO: 145, a CDRH3 comprising SEQ ID NO: 147, a CDRL1 comprising SEQ ID NO: 97, a CDRL2 comprising SEQ ID NO: 99, and a CDRL3 comprising SEQ ID NO: 101. In one embodiment, a combination may comprise a PD-1 antagonist and a CD96 antagonist, wherein the PD-1 antagonist comprises a VH comprising SEQ ID NO: 158 and a VL comprising SEQ ID NO: 159, and the CD96 antagonist comprises a VH comprising SEQ ID NO: 86 and a VL comprising SEQ ID NO: 85. In one embodiment, a combination may comprise a PD-1 antagonist and a CD96 antagonist, wherein the PD-1 antagonist comprises a HC comprising SEQ ID NO: 160 and a LC comprising SEQ ID NO: 161, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166. In one embodiment, a combination may comprise a PD-1 antagonist and a CD96 antagonist, wherein the PD-1 antagonist is dostarlimab and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166.

[0214] In one embodiment, the combination may comprise a TIGIT antagonist and a PVRIG antagonist, wherein the TIGIT antagonist comprises a CDRH1 comprising SEQ ID NO: 334, a CDRH2 comprising SEQ ID NO: 335, a CDRH3 comprising SEQ ID NO: 336, a CDRL1 comprising SEQ ID NO: 331, a CDRL2 comprising SEQ ID NO: 332, and a CDRL3 comprising SEQ ID NO: 333, and the PVRIG antagonist comprises a CDRH1 comprising SEQ ID NO: 223, a CDRH2 comprising SEQ ID NO: 224, a CDRH3 comprising SEQ ID NO: 225, a CDRL1 comprising SEQ ID NO: 226, a CDRL2 comprising SEQ ID NO: 227, and a CDRL3 comprising SEQ ID NO: 228. In one embodiment, the combination may comprise a TIGIT antagonist and a PVRIG antagonist, wherein the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280. In one embodiment, a combination may comprise a TIGIT antagonist and a PVRIG antagonist, wherein the TIGIT antagonist is an anti-TIGIT antibody comprising the heavy and light chain variable sequences set forth in Table X, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280. In one embodiment, a combination may comprise a TIGIT antagonist and a PVRIG antagonist, wherein the TIGIT antagonist is vibostolimab, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280.

[0215] In one embodiment, the combination may comprise a TIGIT antagonist and a CD96 antagonist, wherein the TIGIT antagonist comprises a CDRH1 comprising SEQ ID NO: 334, a CDRH2 comprising SEQ ID NO: 335, a CDRH3 comprising SEQ ID NO: 336, a CDRL1 comprising SEQ ID NO: 331, a CDRL2 comprising SEQ ID NO: 332, and a CDRL3 comprising SEQ ID NO: 333, and the CD96 antagonist comprises a CDRH1 comprising SEQ ID NO: 115, a CDRH2 comprising SEQ ID NO: 145, a CDRH3 comprising SEQ ID NO: 147, a CDRL1 comprising SEQ ID NO: 97, a CDRL2 comprising SEQ ID NO: 99, and a CDRL3 comprising SEQ ID NO: 101. In one embodiment, the combination may comprise a TIGIT antagonist and a CD96 antagonist, wherein the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, and the CD96 antagonist comprises a VH comprising SEQ ID NO: 86 and a VL comprising SEQ ID NO: 85. In one embodiment, the combination may comprise a TIGIT antagonist and a CD96 antagonist, wherein the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166. In one embodiment, the combination may comprise a TIGIT antagonist and a CD96 antagonist, wherein the TIGIT antagonist is an anti-TIGIT antibody comprising heavy and light chain variable sequences as set forth in Table X, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166. In one embodiment, the combination may comprise a TIGIT antagonist and a CD96 antagonist, wherein the TIGIT antagonist is vibostolimab, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166.

[0216] In one embodiment, a combination may comprise a PVRIG antagonist and a CD96 antagonist, wherein the PVRIG antagonist comprises a CDRH1 comprising SEQ ID NO: 223, a CDRH2 comprising SEQ ID NO: 224, a CDRH3 comprising SEQ ID NO: 225, a CDRH1 comprising SEQ ID NO: 226, a CDRL2 comprising SEQ ID NO: 227, and a CDRL3 comprising SEQ ID NO: 228, and the CD96 antagonist comprises a CDRH1 comprising SEQ ID NO: 115, a CDRH2 comprising SEQ ID NO: 145, a CDRH3 comprising SEQ ID NO: 147, a CDRL1 comprising SEQ ID NO: 97, a CDRL2 comprising SEQ ID NO: 99, and a CDRL3 comprising SEQ ID NO: 101. In one embodiment, a combination may comprise a PVRIG antagonist and a CD96 antagonist, wherein the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a VH comprising SEQ ID NO: 86 and a VL comprising SEQ ID NO: 85. In one embodiment, a combination may comprise a PVRIG antagonist and a CD96 antagonist, wherein the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166.

[0217] In another embodiment, the combination may comprise a PD1 antagonist, a TIGIT antagonist, and a PVRIG antagonist. In another embodiment, the combination may comprise a PD1 antagonist, a TIGIT antagonist, and a CD96 antagonist. In another embodiment, the combination may comprise a PD1 antagonist, a PVRIG antagonist, and a CD96 antagonist. In another embodiment, the combination may comprise a TIGIT antagonist, a PVRIG antagonist, and a CD96 antagonist.

[0218] In one embodiment, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist can be at least about 1:0.25:0.25 to at least about 1:2:2. In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist can be at least about 1:0.25:0.25, at least about 1:0.30:0.30, at least about 1:0.35:0.35, at least about 1:0.40:0.40, at least about 1:0.45:0.45, at least about 1:0.50:0.50, or at least about 1:0.55:0. 0.55, at least about 1:0.60:0.60, at least about 1:0.65:0.65, at least about 1:0.70:0.70, at least about 1:0.75:0.75, at least about 1:0.80:0.80, at least about 1:0.85:0.85, at least about 1:0.90:0.90, at least about 1:0.95:0.95, at least about 1:1:1, at least about 1:1.05: 1.05, at least about 1:1.10:1.10, at least about 1:1.15:1.15, at least about 1:1.20:1.20, at least about 1:1.25:1.25, at least about 1:1.30:1.30, at least about 1:1.35:1.35, at least about 1:1.40:1.40, at least about 1:1.45:1.45, at least about 1:1.50:1.50, at least about 1 :1.55:1.55, at least about 1:1.60:1.60, at least about 1:1.65:1.65, at least about 1:1.70:1.70, at least about 1:1.75:1.75, at least about 1:1.80:1.80, at least about 1:1.85:1.85, at least about 1:1.90:1.90, at least about 1:1.95:1.95 or at least about 1:2:2.

[0219] In one embodiment, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist can be at least about 1:0.25:0.25 to at least about 1:2:2. In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist can be at least about 1:0.25:0.25, at least about 1:0.30:0.30, at least about 1:0.35:0.35, at least about 1:0.40:0.40, at least about 1:0.45:0.45, at least about 1:0.50:0.50, or at least about 1:0.55:0. 0.55, at least about 1:0.60:0.60, at least about 1:0.65:0.65, at least about 1:0.70:0.70, at least about 1:0.75:0.75, at least about 1:0.80:0.80, at least about 1:0.85:0.85, at least about 1:0.90:0.90, at least about 1:0.95:0.95, at least about 1:1:1, at least about 1:1.05: 1.05, at least about 1:1.10:1.10, at least about 1:1.15:1.15, at least about 1:1.20:1.20, at least about 1:1.25:1.25, at least about 1:1.30:1.30, at least about 1:1.35:1.35, at least about 1:1.40:1.40, at least about 1:1.45:1.45, at least about 1:1.50:1.50, at least about 1 :1.55:1.55, at least about 1:1.60:1.60, at least about 1:1.65:1.65, at least about 1:1.70:1.70, at least about 1:1.75:1.75, at least about 1:1.80:1.80, at least about 1:1.85:1.85, at least about 1:1.90:1.90, at least about 1:1.95:1.95 or at least about 1:2:2.

[0220] In one embodiment, the ratio of PD-1 antagonist to PVRIG antagonist to CD96 antagonist can be at least about 1:0.25:0.25 to at least about 1:2:2. In further embodiments, the ratio of PD-1 antagonist to PVRIG antagonist to CD96 antagonist can be at least about 1:0.25:0.25, at least about 1:0.30:0.30, at least about 1:0.35:0.35, at least about 1:0.40:0.40, at least about 1:0.45:0.45, at least about 1:0.50:0.50, or at least about 1:0.55:0. 0.55, at least about 1:0.60:0.60, at least about 1:0.65:0.65, at least about 1:0.70:0.70, at least about 1:0.75:0.75, at least about 1:0.80:0.80, at least about 1:0.85:0.85, at least about 1:0.90:0.90, at least about 1:0.95:0.95, at least about 1:1:1, at least about 1:1.05: 1.05, at least about 1:1.10:1.10, at least about 1:1.15:1.15, at least about 1:1.20:1.20, at least about 1:1.25:1.25, at least about 1:1.30:1.30, at least about 1:1.35:1.35, at least about 1:1.40:1.40, at least about 1:1.45:1.45, at least about 1:1.50:1.50, at least about 1 :1.55:1.55, at least about 1:1.60:1.60, at least about 1:1.65:1.65, at least about 1:1.70:1.70, at least about 1:1.75:1.75, at least about 1:1.80:1.80, at least about 1:1.85:1.85, at least about 1:1.90:1.90, at least about 1:1.95:1.95 or at least about 1:2:2.

[0221] In one embodiment, the ratio of TIGIT antagonist to PVRIG antagonist to CD96 antagonist can be at least about 1:0.25:0.25 to at least about 1:2:2. In further embodiments, the ratio of TIGIT antagonist to PVRIG antagonist to CD96 antagonist can be at least about 1:0.25:0.25, at least about 1:0.30:0.30, at least about 1:0.35:0.35, at least about 1:0.40:0.40, at least about 1:0.45:0.45, at least about 1:0.50:0.50, or at least about 1:0.55:0. 0.55, at least about 1:0.60:0.60, at least about 1:0.65:0.65, at least about 1:0.70:0.70, at least about 1:0.75:0.75, at least about 1:0.80:0.80, at least about 1:0.85:0.85, at least about 1:0.90:0.90, at least about 1:0.95:0.95, at least about 1:1:1, at least about 1:1.05: 1.05, at least about 1:1.10:1.10, at least about 1:1.15:1.15, at least about 1:1.20:1.20, at least about 1:1.25:1.25, at least about 1:1.30:1.30, at least about 1:1.35:1.35, at least about 1:1.40:1.40, at least about 1:1.45:1.45, at least about 1:1.50:1.50, at least about 1 :1.55:1.55, at least about 1:1.60:1.60, at least about 1:1.65:1.65, at least about 1:1.70:1.70, at least about 1:1.75:1.75, at least about 1:1.80:1.80, at least about 1:1.85:1.85, at least about 1:1.90:1.90, at least about 1:1.95:1.95 or at least about 1:2:2.In one embodiment, the combination may comprise a PD-1 antagonist, a TIGIT antagonist and a PVRIG antagonist, wherein the PD-1 antagonist comprises a CDRH1 comprising SEQ ID NO: 151, a CDRH2 comprising SEQ ID NO: 152, a CDRH3 comprising SEQ ID NO: 153, a CDRH1 comprising SEQ ID NO: 154, a CDRL2 comprising SEQ ID NO: 155, and a CDRL3 comprising SEQ ID NO: 156; the TIGIT antagonist comprises a CDRH1 comprising SEQ ID NO: 334, a CDRH2 comprising SEQ ID NO: 335, a CDRH3 comprising SEQ ID NO: 336, a CDRL1 comprising SEQ ID NO: 331, a CDRL2 comprising SEQ ID NO: 332, and a CDRL3 comprising SEQ ID NO: 333; and the PVRIG antagonist comprises a CDRH1 comprising SEQ ID NO: 223, a CDRH2 comprising SEQ ID NO: 224, a CDRH3 comprising SEQ ID NO: 225, a CDRL1 comprising SEQ ID NO: 226, a CDRL2 comprising SEQ ID NO: 227, and a CDRL3 comprising SEQ ID NO: 228. In one embodiment, a combination may comprise a PD-1 antagonist, a TIGIT antagonist, and a PVRIG antagonist, wherein the PD-1 antagonist comprises a VH comprising SEQ ID NO: 158 and a VL comprising SEQ ID NO: 159, the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280. In one embodiment, a combination may comprise a PD-1 antagonist, a TIGIT antagonist, and a PVRIG antagonist, wherein the PD-1 antagonist comprises a HC comprising SEQ ID NO: 160 and a LC comprising SEQ ID NO: 161, the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280. In one embodiment, a combination may comprise a PD-1 antagonist, a TIGIT antagonist, and a PVRIG antagonist, wherein the PD-1 antagonist is dostarlimab, the TIGIT antagonist is an anti-TIGIT antibody comprising heavy and light chain variable sequences set forth in Table X, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280.In one embodiment, a combination may comprise a PD-1 antagonist, a TIGIT antagonist and a PVRIG antagonist, wherein the PD-1 antagonist is dostarlimab, the TIGIT antagonist is vibostolimab, and the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280.

[0222] In one embodiment, the combination may comprise a PD-1 antagonist, a TIGIT antagonist and a CD96 antagonist, wherein the PD-1 antagonist comprises a CDRH1 comprising SEQ ID NO: 151, a CDRH2 comprising SEQ ID NO: 152, a CDRH3 comprising SEQ ID NO: 153, a CDRH1 comprising SEQ ID NO: 154, a CDRL2 comprising SEQ ID NO: 155, and a CDRL3 comprising SEQ ID NO: 156; the TIGIT antagonist comprises a CDRH1 comprising SEQ ID NO: 334, a CDRH2 comprising SEQ ID NO: 335, a CDRH3 comprising SEQ ID NO: 336, a CDRL1 comprising SEQ ID NO: 331, a CDRL2 comprising SEQ ID NO: 332, and a CDRL3 comprising SEQ ID NO: 333; and the CD96 antagonist comprises a CDRH1 comprising SEQ ID NO: 115, a CDRH2 comprising SEQ ID NO: 145, a CDRH3 comprising SEQ ID NO: 147, a CDRL1 comprising SEQ ID NO: 97, a CDRL2 comprising SEQ ID NO: 99, and a CDRL3 comprising SEQ ID NO: 101. In one embodiment, the combination may comprise a PD-1 antagonist, a TIGIT antagonist, and a CD96 antagonist, wherein the PD-1 antagonist comprises a VH comprising SEQ ID NO: 158 and a VL comprising SEQ ID NO: 159, the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, and the CD96 antagonist comprises a VH comprising SEQ ID NO: 86 and a VL comprising SEQ ID NO: 85. In one embodiment, the combination may comprise a PD-1 antagonist, a TIGIT antagonist, and a CD96 antagonist, wherein the PD-1 antagonist comprises a HC comprising SEQ ID NO: 160 and a LC comprising SEQ ID NO: 161, the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166. In one embodiment, the combination may comprise a PD-1 antagonist, a TIGIT antagonist, and a CD96 antagonist, wherein the PD-1 antagonist is dostarlimab, the TIGIT antagonist is an anti-TIGIT antibody comprising heavy and light chain variable sequences set forth in Table X, and the CD96 antagonist comprises an HC comprising SEQ ID NO: 165 and an LC comprising SEQ ID NO: 166.In one embodiment, the combination may comprise a PD-1 antagonist, a TIGIT antagonist and a CD96 antagonist, wherein the PD-1 antagonist is dostarlimab, the TIGIT antagonist is vibostolimab, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166.

[0223] In one embodiment, the combination may comprise a PD-1 antagonist, a PVRIG antagonist and a CD96 antagonist, wherein the PD-1 antagonist comprises a CDRH1 comprising SEQ ID NO: 151, a CDRH2 comprising SEQ ID NO: 152, a CDRH3 comprising SEQ ID NO: 153, a CDRH1 comprising SEQ ID NO: 154, a CDRL2 comprising SEQ ID NO: 155, and a CDRL3 comprising SEQ ID NO: 156; the PVRIG antagonist comprises a CDRH1 comprising SEQ ID NO: 223, a CDRH2 comprising SEQ ID NO: 224, a CDRH3 comprising SEQ ID NO: 225, a CDRH1 comprising SEQ ID NO: 226, a CDRL2 comprising SEQ ID NO: 227, and a CDRL3 comprising SEQ ID NO: 228; and the CD96 antagonist comprises a CDRH1 comprising SEQ ID NO: 115, a CDRH2 comprising SEQ ID NO: 145, a CDRH3 comprising SEQ ID NO: 147, a CDRL1 comprising SEQ ID NO: 97, a CDRL2 comprising SEQ ID NO: 99, and a CDRL3 comprising SEQ ID NO: 101. In one embodiment, a combination may comprise a PD-1 antagonist, a PVRIG antagonist, and a CD96 antagonist, wherein the PD-1 antagonist comprises a VH comprising SEQ ID NO: 158 and a VL comprising SEQ ID NO: 159, the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a VH comprising SEQ ID NO: 86 and a VL comprising SEQ ID NO: 85. In one embodiment, a combination may comprise a PD-1 antagonist, a PVRIG antagonist, and a CD96 antagonist, wherein the PD-1 antagonist comprises a HC comprising SEQ ID NO: 160 and a LC comprising SEQ ID NO: 161, the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166. In one embodiment, a combination may comprise a PD-1 antagonist, a PVRIG antagonist, and a CD96 antagonist, wherein the PD-1 antagonist is dostarlimab, the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166.

[0224] In one embodiment, the combination may comprise a TIGIT antagonist, a PVRIG antagonist and a CD96 antagonist, wherein the TIGIT antagonist comprises a CDRH1 comprising SEQ ID NO: 334, a CDRH2 comprising SEQ ID NO: 335, a CDRH3 comprising SEQ ID NO: 336, a CDRL1 comprising SEQ ID NO: 331, a CDRL2 comprising SEQ ID NO: 332, and a CDRL3 comprising SEQ ID NO: 333; the PVRIG antagonist comprises a CDRH1 comprising SEQ ID NO: 223, a CDRH2 comprising SEQ ID NO: 224, a CDRH3 comprising SEQ ID NO: 225, a CDRL1 comprising SEQ ID NO: 226, a CDRL2 comprising SEQ ID NO: 227, and a CDRL3 comprising SEQ ID NO: 228; and the CD96 antagonist comprises a CDRH1 comprising SEQ ID NO: 115, a CDRH2 comprising SEQ ID NO: 145, a CDRH3 comprising SEQ ID NO: 147, a CDRL1 comprising SEQ ID NO: 97, a CDRL2 comprising SEQ ID NO: 99, and a CDRL3 comprising SEQ ID NO: 101. In one embodiment, the combination may comprise a TIGIT antagonist, a PVRIG antagonist and a CD96 antagonist, wherein the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a VH comprising SEQ ID NO: 86 and a VL comprising SEQ ID NO: 85. In one embodiment, the combination may comprise a TIGIT antagonist, a PVRIG antagonist and a CD96 antagonist, wherein the TIGIT antagonist comprises a VH comprising SEQ ID NO: 329 and a VL comprising SEQ ID NO: 330, the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166. In one embodiment, the combination may comprise a TIGIT antagonist, a PVRIG antagonist and a CD96 antagonist, wherein the TIGIT antagonist is an anti-TIGIT antibody comprising heavy and light chain variable sequences shown in Table X, the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166.

[0225] In one embodiment, the combination may comprise a TIGIT antagonist, a PVRIG antagonist and a CD96 antagonist, wherein the TIGIT antagonist is vibostolimab, the PVRIG antagonist comprises a VH comprising SEQ ID NO: 279 and a VL comprising SEQ ID NO: 280, and the CD96 antagonist comprises a HC comprising SEQ ID NO: 165 and a LC comprising SEQ ID NO: 166.

[0226] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.25, at least about 1:0.30:0.30, at least about 1:0.35:0.35, at least about 1:0.40:0.40, at least about 1:0.45:0.45, at least about 1:0.50:0.50, or at least about 1:0.55:0. 0.55, at least about 1:0.60:0.60, at least about 1:0.65:0.65, at least about 1:0.70:0.70, at least about 1:0.75:0.75, at least about 1:0.80:0.80, at least about 1:0.85:0.85, at least about 1:0.90:0.90, at least about 1:0.95:0.95, at least about 1:1:1, at least about 1:1.05: 1.05, at least about 1:1.10:1.10, at least about 1:1.15:1.15, at least about 1:1.20:1.20, at least about 1:1.25:1.25, at least about 1:1.30:1.30, at least about 1:1.35:1.35, at least about 1:1.40:1.40, at least about 1:1.45:1.45, at least about 1:1.50:1.50, at least about 1 :1.55:1.55, at least about 1:1.60:1.60, at least about 1:1.65:1.65, at least about 1:1.70:1.70, at least about 1:1.75:1.75, at least about 1:1.80:1.80, at least about 1:1.85:1.85, at least about 1:1.90:1.90, at least about 1:1.95:1.95 or at least about 1:2:2.

[0227] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.30, at least about 1:0.25:0.35, at least about 1:0.25:0.40, at least about 1:0.25:0.45, at least about 1:0.25:0.50, at least about 1:0.25:0.55, or at least about 1:0. 25:0.60, at least about 1:0.25:0.65, at least about 1:0.25:0.70, at least about 1:0.25:0.75, at least about 1:0.25:0.80, at least about 1:0.25:0.85, at least about 1:0.25:0.90, at least about 1:0.25:0.95, at least about 1:0.25:1, at least about 1:0.25:1.05, at least Also about 1:0.25:1.10, at least about 1:0.25:1.15, at least about 1:0.25:1.20, at least about 1:0.25:1.25, at least about 1:0.25:1.30, at least about 1:0.25:1.35, at least about 1:0.25:1.40, at least about 1:0.25:1.45, at least about 1:0.25:1.50, at least about 1:0.25: 1.55, at least about 1:0.25:1.60, at least about 1:0.25:1.65, at least about 1:0.25:1.70, at least about 1:0.25:1.75, at least about 1:0.25:1.80, at least about 1:0.25:1.85, at least about 1:0.25:1.90, at least about 1:0.25:1.95 or at least about 1:0.25:2.

[0228] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.30:0.25, at least about 1:0.30:0.30, at least about 1:0.30:0.35, at least about 1:0.30:0.40, at least about 1:0.30:0.45, at least about 1:0.30:0.50, at least about 1:0.30:0. .55, at least about 1:0.30:0.60, at least about 1:0.30:0.65, at least about 1:0.30:0.70, at least about 1:0.30:0.75, at least about 1:0.30:0.80, at least about 1:0.30:0.85, at least about 1:0.30:0.90, at least about 1:0.30:0.95, at least about 1:0.30:1, at least about 1:0.30: 1.05, at least about 1:0.30:1.10, at least about 1:0.30:1.15, at least about 1:0.30:1.20, at least about 1:0.30:1.25, at least about 1:0.30:1.30, at least about 1:0.30:1.35, at least about 1:0.30:1.40, at least about 1:0.30:1.45, at least about 1:0.30:1.50, at least about 1: 0.30:1.55, at least about 1:0.30:1.60, at least about 1:0.30:1.65, at least about 1:0.30:1.70, at least about 1:0.30:1.75, at least about 1:0.30:1.80, at least about 1:0.30:1.85, at least about 1:0.30:1.90, at least about 1:0.30:1.95 or at least about 1:0.30:2.

[0229] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.35:0.25, at least about 1:0.35:0.30, at least about 1:0.35:0.35, at least about 1:0.35:0.40, at least about 1:0.35:0.45, at least about 1:0.35:0.50, at least about 1:0.35:0.60, at least about 1:0.35:0.70, at least about 1:0.35:0.80, at least about 1:0.35:0.90, at least about 1:0.35:0.10, at least about 1:0.35:0.11, at least about 1:0.35:0.25, at least about 1:0.35:0.30, at least about 1:0.35:0.35, at least about 1:0.35:0.40, at least about 1:0.35:0.45, at least about 1:0.35:0.50, at least about 1:0.35:0.60, at least about 1:0.35:0.70, at least about 1:0.35:0.80, at least about 1:0.35:0.90, at least about 1:0.35:0.12 .55, at least about 1:0.35:0.60, at least about 1:0.35:0.65, at least about 1:0.35:0.70, at least about 1:0.35:0.75, at least about 1:0.35:0.80, at least about 1:0.35:0.85, at least about 1:0.35:0.90, at least about 1:0.35:0.95, at least about 1:0.35:1, at least about 1:0.35: 1.05, at least about 1:0.35:1.10, at least about 1:0.35:1.15, at least about 1:0.35:1.20, at least about 1:0.35:1.25, at least about 1:0.35:1.30, at least about 1:0.35:1.35, at least about 1:0.35:1.40, at least about 1:0.35:1.45, at least about 1:0.35:1.50, at least about 1: 0.35:1.55, at least about 1:0.35:1.60, at least about 1:0.35:1.65, at least about 1:0.35:1.70, at least about 1:0.35:1.75, at least about 1:0.35:1.80, at least about 1:0.35:1.85, at least about 1:0.35:1.90, at least about 1:0.35:1.95 or at least about 1:0.35:2.

[0230] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.40:0.25, at least about 1:0.40:0.30, at least about 1:0.40:0.35, at least about 1:0.40:0.40, at least about 1:0.40:0.45, at least about 1:0.40:0.50, at least about 1:0.40:0.50, at least about 1:0.40:0.60, at least about 1:0.40:0.70, at least about 1:0.40:0.80, at least about 1:0.40:0.90, at least about 1:0.40:0.10, at least about 1:0.40:0.12, at least about 1:0.40:0.14, at least about 1:0.40:0.16, at least about 1:0.40:0.18, at least about 1:0.40:0.20, at least about 1:0.40:0.25, at least about 1:0.40:0.30, at least about 1:0.40:0.35, at least about 1:0.40:0.40, at least about 1:0.40:0.45, at least about 1:0.40:0.50, at least about 1:0.40:0.18 .55, at least about 1:0.40:0.60, at least about 1:0.40:0.65, at least about 1:0.40:0.70, at least about 1:0.40:0.75, at least about 1:0.40:0.80, at least about 1:0.40:0.85, at least about 1:0.40:0.90, at least about 1:0.40:0.95, at least about 1:0.40:1, at least about 1:0.40: 1.05, at least about 1:0.40:1.10, at least about 1:0.40:1.15, at least about 1:0.40:1.20, at least about 1:0.40:1.25, at least about 1:0.40:1.30, at least about 1:0.40:1.35, at least about 1:0.40:1.40, at least about 1:0.40:1.45, at least about 1:0.40:1.50, at least about 1:0.40:1.60, at least about 1:0.40:1.70, at least about 1:0.40:1.80, at least about 1:0.40:1.90, at least about 1:0.40:1.10, at least about 1:0.40:1.11 0.40:1.55, at least about 1:0.40:1.60, at least about 1:0.40:1.65, at least about 1:0.40:1.70, at least about 1:0.40:1.75, at least about 1:0.40:1.80, at least about 1:0.40:1.85, at least about 1:0.40:1.90, at least about 1:0.40:1.95 or at least about 1:0.40:2.

[0231] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.45:0.25, at least about 1:0.45:0.30, at least about 1:0.45:0.35, at least about 1:0.45:0.40, at least about 1:0.45:0.45, at least about 1:0.45:0.50, at least about 1:0.45:0.50, at least about 1:0.45:0.60, at least about 1:0.45:0.70, at least about 1:0.45:0.80, at least about 1:0.45:0.9 ... .55, at least about 1:0.45:0.60, at least about 1:0.45:0.65, at least about 1:0.45:0.70, at least about 1:0.45:0.75, at least about 1:0.45:0.80, at least about 1:0.45:0.85, at least about 1:0.45:0.90, at least about 1:0.45:0.95, at least about 1:0.45:1, at least about 1:0.45: 1.05, at least about 1:0.45:1.10, at least about 1:0.45:1.15, at least about 1:0.45:1.20, at least about 1:0.45:1.25, at least about 1:0.45:1.30, at least about 1:0.45:1.35, at least about 1:0.45:1.40, at least about 1:0.45:1.45, at least about 1:0.45:1.50, at least about 1: 0.45:1.55, at least about 1:0.45:1.60, at least about 1:0.45:1.65, at least about 1:0.45:1.70, at least about 1:0.45:1.75, at least about 1:0.45:1.80, at least about 1:0.45:1.85, at least about 1:0.45:1.90, at least about 1:0.45:1.95 or at least about 1:0.45:2.

[0232] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.50:0.25, at least about 1:0.50:0.30, at least about 1:0.50:0.35, at least about 1:0.50:0.40, at least about 1:0.50:0.45, at least about 1:0.50:0.50, at least about 1:0.50:0. .55, at least about 1:0.50:0.60, at least about 1:0.50:0.65, at least about 1:0.50:0.70, at least about 1:0.50:0.75, at least about 1:0.50:0.80, at least about 1:0.50:0.85, at least about 1:0.50:0.90, at least about 1:0.50:0.95, at least about 1:0.50:1, at least about 1:0.50:0. 1.05, at least about 1:0.50:1.10, at least about 1:0.50:1.15, at least about 1:0.50:1.20, at least about 1:0.50:1.25, at least about 1:0.50:1.30, at least about 1:0.50:1.35, at least about 1:0.50:1.40, at least about 1:0.50:1.45, at least about 1:0.50:1.50, at least about 1: It can be 0.50:1.55, at least about 1:0.50:1.60, at least about 1:0.50:1.65, at least about 1:0.50:1.70, at least about 1:0.50:1.75, at least about 1:0.50:1.80, at least about 1:0.50:1.85, at least about 1:0.50:1.90, at least about 1:0.50:1.95 or at least about 1:0.50:2.

[0233] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.55:0.25, at least about 1:0.55:0.30, at least about 1:0.55:0.35, at least about 1:0.55:0.40, at least about 1:0.55:0.45, at least about 1:0.55:0.50, at least about 1:0.55:0.60, at least about 1:0.55:0.70, at least about 1:0.55:0.80, at least about 1:0.55:0.90, at least about 1:0.55:0.10, at least about 1:0.55:0.11, at least about 1:0.55:0.25, at least about 1:0.55:0.30, at least about 1:0.55:0.35, at least about 1:0.55:0.40, at least about 1:0.55:0.45, at least about 1:0.55:0.50, at least about 1:0.55:0.60, at least about 1:0.55:0.70, at least about 1:0.55:0.80 0.55, at least about 1:0.55:0.60, at least about 1:0.55:0.65, at least about 1:0.55:0.70, at least about 1:0.55:0.75, at least about 1:0.55:0.80, at least about 1:0.55:0.85, at least about 1:0.55:0.90, at least about 1:0.55:0.95, at least about 1:0.55:1, at least about 1:0.55:1. 55:1.05, at least about 1:0.55:1.10, at least about 1:0.55:1.15, at least about 1:0.55:1.20, at least about 1:0.55:1.25, at least about 1:0.55:1.30, at least about 1:0.55:1.35, at least about 1:0.55:1.40, at least about 1:0.55:1.45, at least about 1:0.55:1.50, at least or at least about 1:0.55:1.55, at least about 1:0.55:1.60, at least about 1:0.55:1.65, at least about 1:0.55:1.70, at least about 1:0.55:1.75, at least about 1:0.55:1.80, at least about 1:0.55:1.85, at least about 1:0.55:1.90, 1:0.55:1.95 or at least about 1:0.55:2.

[0234] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.60:0.25, at least about 1:0.60:0.30, at least about 1:0.60:0.35, at least about 1:0.60:0.40, at least about 1:0.60:0.45, at least about 1:0.60:0.50, at least about 1:0.60:0. .55, at least about 1:0.60:0.60, at least about 1:0.60:0.65, at least about 1:0.60:0.70, at least about 1:0.60:0.75, at least about 1:0.60:0.80, at least about 1:0.60:0.85, at least about 1:0.60:0.90, at least about 1:0.60:0.95, at least about 1:0.60:1, at least about 1:0.60: 1.05, at least about 1:0.60:1.10, at least about 1:0.60:1.15, at least about 1:0.60:1.20, at least about 1:0.60:1.25, at least about 1:0.60:1.30, at least about 1:0.60:1.35, at least about 1:0.60:1.40, at least about 1:0.60:1.45, at least about 1:0.60:1.50, at least about 1:0.60:1.60 0.60:1.55, at least about 1:0.60:1.60, at least about 1:0.60:1.65, at least about 1:0.60:1.70, at least about 1:0.60:1.75, at least about 1:0.60:1.80, at least about 1:0.60:1.85, at least about 1:0.60:1.90, at least about 1:0.60:1.95 or at least about 1:0.60:2.

[0235] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.65:0.25, at least about 1:0.65:0.30, at least about 1:0.65:0.35, at least about 1:0.65:0.40, at least about 1:0.65:0.45, at least about 1:0.65:0.50, at least about 1:0.65:0.65 .55, at least about 1:0.65:0.60, at least about 1:0.65:0.65, at least about 1:0.65:0.70, at least about 1:0.65:0.75, at least about 1:0.65:0.80, at least about 1:0.65:0.85, at least about 1:0.65:0.90, at least about 1:0.65:0.95, at least about 1:0.65:1, at least about 1:0.65: 1.05, at least about 1:0.65:1.10, at least about 1:0.65:1.15, at least about 1:0.65:1.20, at least about 1:0.65:1.25, at least about 1:0.65:1.30, at least about 1:0.65:1.35, at least about 1:0.65:1.40, at least about 1:0.65:1.45, at least about 1:0.65:1.50, at least about 1: 0.65:1.55, at least about 1:0.65:1.60, at least about 1:0.65:1.65, at least about 1:0.65:1.70, at least about 1:0.65:1.75, at least about 1:0.65:1.80, at least about 1:0.65:1.85, at least about 1:0.65:1.90, at least about 1:0.65:1.95 or at least about 1:0.65:2.

[0236] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.70:0.25, at least about 1:0.70:0.30, at least about 1:0.70:0.35, at least about 1:0.70:0.40, at least about 1:0.70:0.45, at least about 1:0.70:0.50, at least about 1:0.70:0.60, at least about 1:0.70:0.75, at least about 1:0.70:0.80, at least about 1:0.70:0.90, at least about 1:0.70:0.10, at least about 1:0.70:0.11, at least about 1:0.70:0.12, at least about 1:0.70:0.13, at least about 1:0.70:0.14, at least about 1:0.70:0.15, at least about 1:0.70:0.16, at least about 1:0.70:0.17, at least about 1:0.70:0.18, at least about 1:0.70:0.19, at least about 1:0.70:0.20, at least about 1:0.70:0.21, at least about 1:0.70:0.22, at least about 1:0.70:0.23, at least about 1:0.70:0.24, at least about 1:0.70:0.25, at least about 1:0.70:0.30, at least about 1:0.70:0.35, at least about 1:0.70:0.40, at least about 1:0.70:0.45, at least about 1:0. .55, at least about 1:0.70:0.60, at least about 1:0.70:0.65, at least about 1:0.70:0.70, at least about 1:0.70:0.75, at least about 1:0.70:0.80, at least about 1:0.70:0.85, at least about 1:0.70:0.90, at least about 1:0.70:0.95, at least about 1:0.70:1, at least about 1:0.70: 1.05, at least about 1:0.70:1.10, at least about 1:0.70:1.15, at least about 1:0.70:1.20, at least about 1:0.70:1.25, at least about 1:0.70:1.30, at least about 1:0.70:1.35, at least about 1:0.70:1.40, at least about 1:0.70:1.45, at least about 1:0.70:1.50, at least about 1: 0.70:1.55, at least about 1:0.70:1.60, at least about 1:0.70:1.65, at least about 1:0.70:1.70, at least about 1:0.70:1.75, at least about 1:0.70:1.80, at least about 1:0.70:1.85, at least about 1:0.70:1.90, at least about 1:0.70:1.95 or at least about 1:0.70:2.

[0237] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.75:0.25, at least about 1:0.75:0.30, at least about 1:0.75:0.35, at least about 1:0.75:0.40, at least about 1:0.75:0.45, at least about 1:0.75:0.50, at least about 1:0.75:0.60, at least about 1:0.75:0.75 .55, at least about 1:0.75:0.60, at least about 1:0.75:0.65, at least about 1:0.75:0.70, at least about 1:0.75:0.75, at least about 1:0.75:0.80, at least about 1:0.75:0.85, at least about 1:0.75:0.90, at least about 1:0.75:0.95, at least about 1:0.75:1, at least about 1:0.75: 1.05, at least about 1:0.75:1.10, at least about 1:0.75:1.15, at least about 1:0.75:1.20, at least about 1:0.75:1.25, at least about 1:0.75:1.30, at least about 1:0.75:1.35, at least about 1:0.75:1.40, at least about 1:0.75:1.45, at least about 1:0.75:1.50, at least about 1: It can be 0.75:1.55, at least about 1:0.75:1.60, at least about 1:0.75:1.65, at least about 1:0.75:1.70, at least about 1:0.75:1.75, at least about 1:0.75:1.80, at least about 1:0.75:1.85, at least about 1:0.75:1.90, at least about 1:0.75:1.95 or at least about 1:0.75:2.

[0238] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.80:0.25, at least about 1:0.80:0.30, at least about 1:0.80:0.35, at least about 1:0.80:0.40, at least about 1:0.80:0.45, at least about 1:0.80:0.50, at least about 1:0.80:0.60, at least about 1:0.80:0.70, at least about 1:0.80:0.85, at least about 1:0.80:0.90, at least about 1:0.80:0.10, at least about 1:0.80:0.11, at least about 1:0.80:0.12, at least about 1:0.80:0.13, at least about 1:0.80:0.14, at least about 1:0.80:0.15, at least about 1:0.80:0.16, at least about 1:0.80:0.17, at least about 1:0.80:0.18, at least about 1:0.80:0.19, at least about 1:0.80:0.20, at least about 1:0.80:0.21, at least about 1:0.80:0.22, at least about 1:0.80:0.23, at least about 1:0.80:0.24, at least about 1:0.80:0.25, at least about 1:0.80:0.30, at least about 1:0.80:0.35, at least about 1:0.80:0.40, at least about 1:0.80:0.45, at least about 1:0. .55, at least about 1:0.80:0.60, at least about 1:0.80:0.65, at least about 1:0.80:0.70, at least about 1:0.80:0.75, at least about 1:0.80:0.80, at least about 1:0.80:0.85, at least about 1:0.80:0.90, at least about 1:0.80:0.95, at least about 1:0.80:1, at least about 1:0.80: 1.05, at least about 1:0.80:1.10, at least about 1:0.80:1.15, at least about 1:0.80:1.20, at least about 1:0.80:1.25, at least about 1:0.80:1.30, at least about 1:0.80:1.35, at least about 1:0.80:1.40, at least about 1:0.80:1.45, at least about 1:0.80:1.50, at least about 1:0.80:1.60 0.80:1.55, at least about 1:0.80:1.60, at least about 1:0.80:1.65, at least about 1:0.80:1.70, at least about 1:0.80:1.75, at least about 1:0.80:1.80, at least about 1:0.80:1.85, at least about 1:0.80:1.90, at least about 1:0.80:1.95 or at least about 1:0.80:2.

[0239] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.85:0.25, at least about 1:0.85:0.30, at least about 1:0.85:0.35, at least about 1:0.85:0.40, at least about 1:0.85:0.45, at least about 1:0.85:0.50, at least about 1:0.85:0.60, at least about 1:0.85:0.70, at least about 1:0.85:0.85 .55, at least about 1:0.85:0.60, at least about 1:0.85:0.65, at least about 1:0.85:0.70, at least about 1:0.85:0.75, at least about 1:0.85:0.80, at least about 1:0.85:0.85, at least about 1:0.85:0.90, at least about 1:0.85:0.95, at least about 1:0.85:1, at least about 1:0.85: 1.05, at least about 1:0.85:1.10, at least about 1:0.85:1.15, at least about 1:0.85:1.20, at least about 1:0.85:1.25, at least about 1:0.85:1.30, at least about 1:0.85:1.35, at least about 1:0.85:1.40, at least about 1:0.85:1.45, at least about 1:0.85:1.50, at least about 1: 0.85:1.55, at least about 1:0.85:1.60, at least about 1:0.85:1.65, at least about 1:0.85:1.70, at least about 1:0.85:1.75, at least about 1:0.85:1.80, at least about 1:0.85:1.85, at least about 1:0.85:1.90, at least about 1:0.85:1.95 or at least about 1:0.85:2.

[0240] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.90:0.25, at least about 1:0.90:0.30, at least about 1:0.90:0.35, at least about 1:0.90:0.40, at least about 1:0.90:0.45, at least about 1:0.90:0.50, at least about 1:0.90:0.60, at least about 1:0.90:0.70, at least about 1:0.90:0.80, at least about 1:0.90:0.95, at least about 1:0.90:0.96, at least about 1:0.90:0.97, at least about 1:0.90:0.99 .55, at least about 1:0.90:0.60, at least about 1:0.90:0.65, at least about 1:0.90:0.70, at least about 1:0.90:0.75, at least about 1:0.90:0.80, at least about 1:0.90:0.85, at least about 1:0.90:0.90, at least about 1:0.90:0.95, at least about 1:0.90:1, at least about 1:0.90: 1.05, at least about 1:0.90:1.10, at least about 1:0.90:1.15, at least about 1:0.90:1.20, at least about 1:0.90:1.25, at least about 1:0.90:1.30, at least about 1:0.90:1.35, at least about 1:0.90:1.40, at least about 1:0.90:1.45, at least about 1:0.90:1.50, at least about 1: 0.90:1.55, at least about 1:0.90:1.60, at least about 1:0.90:1.65, at least about 1:0.90:1.70, at least about 1:0.90:1.75, at least about 1:0.90:1.80, at least about 1:0.90:1.85, at least about 1:0.90:1.90, at least about 1:0.90:1.95 or at least about 1:0.90:2.

[0241] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.95:0.25, at least about 1:0.95:0.30, at least about 1:0.95:0.35, at least about 1:0.95:0.40, at least about 1:0.95:0.45, at least about 1:0.95:0.50, at least about 1:0.95:0.60, at least about 1:0.95:0.70, at least about 1:0.95:0.80, at least about 1:0.95:0.95 .55, at least about 1:0.95:0.60, at least about 1:0.95:0.65, at least about 1:0.95:0.70, at least about 1:0.95:0.75, at least about 1:0.95:0.80, at least about 1:0.95:0.85, at least about 1:0.95:0.90, at least about 1:0.95:0.95, at least about 1:0.95:1, at least about 1:0.95: 1.05, at least about 1:0.95:1.10, at least about 1:0.95:1.15, at least about 1:0.95:1.20, at least about 1:0.95:1.25, at least about 1:0.95:1.30, at least about 1:0.95:1.35, at least about 1:0.95:1.40, at least about 1:0.95:1.45, at least about 1:0.95:1.50, at least about 1: It can be 0.95:1.55, at least about 1:0.95:1.60, at least about 1:0.95:1.65, at least about 1:0.95:1.70, at least about 1:0.95:1.75, at least about 1:0.95:1.80, at least about 1:0.95:1.85, at least about 1:0.95:1.90, at least about 1:0.95:1.95 or at least about 1:0.95:2.

[0242] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1:0.25, at least about 1:1:0.30, at least about 1:1:0.35, at least about 1:1:0.40, at least about 1:1:0.45, at least about 1:1:0.50, at least about 1:1:0.55, at least about 1:1:0.60, at least about 1:1:0.65, at least about 1:1:0.70, at least about 1:1:0.75, at least about 1:1:0.80, at least about 1:1:0.85, at least about 1:1:0.90, at least about 1:1:0.95, at least about 1:1:1, at least about 1:1:1, or at least about 1:1:1. 1:1:1.05, at least about 1:1:1.10, at least about 1:1:1.15, at least about 1:1:1.20, at least about 1:1:1.25, at least about 1:1:1.30, at least about 1:1:1.35, at least about 1:1:1.40, at least about 1:1:1.45, at least about 1:1:1.50, at least about 1:1:1.55, at least about 1:1:1.60, at least about 1:1:1.65, at least about 1:1:1.70, at least about 1:1:1.75, at least about 1:1:1.80, at least about 1:1:1.85, at least about 1:1:1.90, at least about 1:1:1.95 or at least about 1:1:2.

[0243] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.05:0.25, at least about 1:1.05:0.30, at least about 1:1.05:0.35, at least about 1:1.05:0.40, at least about 1:1.05:0.45, at least about 1:1.05:0.50, at least about 1:1.05:0.60, at least about 1:1.05:0.70, at least about 1:1.05:0.80, at least about 1:1.05:0.90, at least about 1:1.05:0.10, at least about 1:1.05:0.11, at least about 1:1.05:0.25, at least about 1:1.05:0.30, at least about 1:1.05:0.35, at least about 1:1.05:0.40, at least about 1:1.05:0.45, at least about 1:1.05:0.50, at least about 1:1.05:0.60, at least about 1:1.05:0.70, at least about 1:1.05:0.80, at least about 1:1.05:0.90, at least about 1:1.05:0.12 .55, at least about 1:1.05:0.60, at least about 1:1.05:0.65, at least about 1:1.05:0.70, at least about 1:1.05:0.75, at least about 1:1.05:0.80, at least about 1:1.05:0.85, at least about 1:1.05:0.90, at least about 1:1.05:0.95, at least about 1:1.05:1, at least about 1:1.05: 1.05, at least about 1:1.05:1.10, at least about 1:1.05:1.15, at least about 1:1.05:1.20, at least about 1:1.05:1.25, at least about 1:1.05:1.30, at least about 1:1.05:1.35, at least about 1:1.05:1.40, at least about 1:1.05:1.45, at least about 1:1.05:1.50, at least about 1: 1.05:1.55, at least about 1:1.05:1.60, at least about 1:1.05:1.65, at least about 1:1.05:1.70, at least about 1:1.05:1.75, at least about 1:1.05:1.80, at least about 1:1.05:1.85, at least about 1:1.05:1.90, at least about 1:1.05:1.95 or at least about 1:1.05:2.

[0244] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.10:0.25, at least about 1:1.10:0.30, at least about 1:1.10:0.35, at least about 1:1.10:0.40, at least about 1:1.10:0.45, at least about 1:1.10:0.50, at least about 1:1.10:0.60, at least about 1:1.10:0.70, at least about 1:1.10:0.80, at least about 1:1.10:0.90, at least about 1:1.10:0.10, at least about 1:1.10:0.11 .55, at least about 1:1.10:0.60, at least about 1:1.10:0.65, at least about 1:1.10:0.70, at least about 1:1.10:0.75, at least about 1:1.10:0.80, at least about 1:1.10:0.85, at least about 1:1.10:0.90, at least about 1:1.10:0.95, at least about 1:1.10:1, at least about 1:1.10: 1.05, at least about 1:1.10:1.10, at least about 1:1.10:1.15, at least about 1:1.10:1.20, at least about 1:1.10:1.25, at least about 1:1.10:1.30, at least about 1:1.10:1.35, at least about 1:1.10:1.40, at least about 1:1.10:1.45, at least about 1:1.10:1.50, at least about 1: 1.10:1.55, at least about 1:1.10:1.60, at least about 1:1.10:1.65, at least about 1:1.10:1.70, at least about 1:1.10:1.75, at least about 1:1.10:1.80, at least about 1:1.10:1.85, at least about 1:1.10:1.90, at least about 1:1.10:1.95 or at least about 1:1.10:2.

[0245] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.15:0.25, at least about 1:1.15:0.30, at least about 1:1.15:0.35, at least about 1:1.15:0.40, at least about 1:1.15:0.45, at least about 1:1.15:0.50, at least about 1:1.15:0.60, at least about 1:1.15:0.70, at least about 1:1.15:0.80, at least about 1:1.15:0.90, at least about 1:1.15:0.10, at least about 1:1.15:0.11 .55, at least about 1:1.15:0.60, at least about 1:1.15:0.65, at least about 1:1.15:0.70, at least about 1:1.15:0.75, at least about 1:1.15:0.80, at least about 1:1.15:0.85, at least about 1:1.15:0.90, at least about 1:1.15:0.95, at least about 1:1.15:1, at least about 1:1.15: 1.05, at least about 1:1.15:1.10, at least about 1:1.15:1.15, at least about 1:1.15:1.20, at least about 1:1.15:1.25, at least about 1:1.15:1.30, at least about 1:1.15:1.35, at least about 1:1.15:1.40, at least about 1:1.15:1.45, at least about 1:1.15:1.50, at least about 1: 1.15:1.55, at least about 1:1.15:1.60, at least about 1:1.15:1.65, at least about 1:1.15:1.70, at least about 1:1.15:1.75, at least about 1:1.15:1.80, at least about 1:1.15:1.85, at least about 1:1.15:1.90, at least about 1:1.15:1.95 or at least about 1:1.15:2.

[0246] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.20:0.25, at least about 1:1.20:0.30, at least about 1:1.20:0.35, at least about 1:1.20:0.40, at least about 1:1.20:0.45, at least about 1:1.20:0.50, at least about 1:1.20:0.60, at least about 1:1.20:0.70, at least about 1:1.20:0.80, at least about 1:1.20:0.90, at least about 1:1.20:0.10, at least about 1:1.20:0.11, at least about 1:1.20:0.25, at least about 1:1.20:0.30, at least about 1:1.20:0.35, at least about 1:1.20:0.40, at least about 1:1.20:0.45, at least about 1:1.20:0.50, at least about 1:1.20:0.60, at least about 1:1.20:0.70, at least about 1:1.20:0.80, at least about 1:1.20:0.90, at least about 1:1.20:0.12 .55, at least about 1:1.20:0.60, at least about 1:1.20:0.65, at least about 1:1.20:0.70, at least about 1:1.20:0.75, at least about 1:1.20:0.80, at least about 1:1.20:0.85, at least about 1:1.20:0.90, at least about 1:1.20:0.95, at least about 1:1.20:1, at least about 1:1.20: 1.05, at least about 1:1.20:1.10, at least about 1:1.20:1.15, at least about 1:1.20:1.20, at least about 1:1.20:1.25, at least about 1:1.20:1.30, at least about 1:1.20:1.35, at least about 1:1.20:1.40, at least about 1:1.20:1.45, at least about 1:1.20:1.50, at least about 1: 1.20:1.55, at least about 1:1.20:1.60, at least about 1:1.20:1.65, at least about 1:1.20:1.70, at least about 1:1.20:1.75, at least about 1:1.20:1.80, at least about 1:1.20:1.85, at least about 1:1.20:1.90, at least about 1:1.20:1.95 or at least about 1:1.20:2.

[0247] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.25:0.25, at least about 1:1.25:0.30, at least about 1:1.25:0.35, at least about 1:1.25:0.40, at least about 1:1.25:0.45, at least about 1:1.25:0.50, at least about 1:1.25:0.60, at least about 1:1.25:0.70, at least about 1:1.25:0.80, at least about 1:1.25:0.90, at least about 1:1.25:0.10, at least about 1:1.25:0.11, at least about 1:1.25:0.22, at least about 1:1.25:0.25, at least about 1:1.25:0.30, at least about 1:1.25:0.35, at least about 1:1.25:0.40, at least about 1:1.25:0.45, at least about 1:1.25:0.50, at least about 1:1.25:0.60, at least about 1:1.25:0.70, at least about 1:1.25:0.80, at least about 1:1.25:0.90, at least about 1:1.25:0.12 .55, at least about 1:1.25:0.60, at least about 1:1.25:0.65, at least about 1:1.25:0.70, at least about 1:1.25:0.75, at least about 1:1.25:0.80, at least about 1:1.25:0.85, at least about 1:1.25:0.90, at least about 1:1.25:0.95, at least about 1:1.25:1, at least about 1:1.25: 1.05, at least about 1:1.25:1.10, at least about 1:1.25:1.15, at least about 1:1.25:1.20, at least about 1:1.25:1.25, at least about 1:1.25:1.30, at least about 1:1.25:1.35, at least about 1:1.25:1.40, at least about 1:1.25:1.45, at least about 1:1.25:1.50, at least about 1: 1.25:1.55, at least about 1:1.25:1.60, at least about 1:1.25:1.65, at least about 1:1.25:1.70, at least about 1:1.25:1.75, at least about 1:1.25:1.80, at least about 1:1.25:1.85, at least about 1:1.25:1.90, at least about 1:1.25:1.95 or at least about 1:1.25:2.

[0248] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.30:0.25, at least about 1:1.30:0.30, at least about 1:1.30:0.35, at least about 1:1.30:0.40, at least about 1:1.30:0.45, at least about 1:1.30:0.50, at least about 1:1.30:0. .55, at least about 1:1.30:0.60, at least about 1:1.30:0.65, at least about 1:1.30:0.70, at least about 1:1.30:0.75, at least about 1:1.30:0.80, at least about 1:1.30:0.85, at least about 1:1.30:0.90, at least about 1:1.30:0.95, at least about 1:1.30:1, at least about 1:1.30: 1.05, at least about 1:1.30:1.10, at least about 1:1.30:1.15, at least about 1:1.30:1.20, at least about 1:1.30:1.25, at least about 1:1.30:1.30, at least about 1:1.30:1.35, at least about 1:1.30:1.40, at least about 1:1.30:1.45, at least about 1:1.30:1.50, at least about 1: 1.30:1.55, at least about 1:1.30:1.60, at least about 1:1.30:1.65, at least about 1:1.30:1.70, at least about 1:1.30:1.75, at least about 1:1.30:1.80, at least about 1:1.30:1.85, at least about 1:1.30:1.90, at least about 1:1.30:1.95 or at least about 1:1.30:2.

[0249] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.35:0.25, at least about 1:1.35:0.30, at least about 1:1.35:0.35, at least about 1:1.35:0.40, at least about 1:1.35:0.45, at least about 1:1.35:0.50, or at least about 1:1. 35:0.55, at least about 1:1.35:0.65, at least about 1:1.35:0.70, at least about 1:1.35:0.75, at least about 1:1.35:0.80, at least about 1:1.35:0.85, at least about 1:1.35:0.90, at least about 1:1.35:0.95, at least about 1:1.35:1, at least about 1:1.35:1.05, at least Also about 1:1.35:1.10, at least about 1:1.35:1.15, at least about 1:1.35:1.20, at least about 1:1.35:1.25, at least about 1:1.35:1.30, at least about 1:1.35:1.35, at least about 1:1.35:1.40, at least about 1:1.35:1.45, at least about 1:1.35:1.50, at least about 1:1.35: 1.55, at least about 1:1.35:1.60, at least about 1:1.35:1.65, at least about 1:1.35:1.70, at least about 1:1.35:1.75, at least about 1:1.35:1.80, at least about 1:1.35:1.85, at least about 1:1.35:1.90, at least about 1:1.35:1.95 or at least about 1:1.35:2.

[0250] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.40:0.25, at least about 1:1.40:0.30, at least about 1:1.40:0.35, at least about 1:1.40:0.40, at least about 1:1.40:0.45, at least about 1:1.40:0.50, at least about 1:1.40:0. .55, at least about 1:1.40:0.60, at least about 1:1.40:0.65, at least about 1:1.40:0.70, at least about 1:1.40:0.75, at least about 1:1.40:0.80, at least about 1:1.40:0.85, at least about 1:1.40:0.90, at least about 1:1.40:0.95, at least about 1:1.40:1, at least about 1:1.40: 1.05, at least about 1:1.40:1.10, at least about 1:1.40:1.15, at least about 1:1.40:1.20, at least about 1:1.40:1.25, at least about 1:1.40:1.30, at least about 1:1.40:1.35, at least about 1:1.40:1.40, at least about 1:1.40:1.45, at least about 1:1.40:1.50, at least about 1: 1.40:1.55, at least about 1:1.40:1.60, at least about 1:1.40:1.65, at least about 1:1.40:1.70, at least about 1:1.40:1.75, at least about 1:1.40:1.80, at least about 1:1.40:1.85, at least about 1:1.40:1.90, at least about 1:1.40:1.95 or at least about 1:1.40:2.

[0251] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.45:0.25, at least about 1:1.45:0.30, at least about 1:1.45:0.35, at least about 1:1.45:0.40, at least about 1:1.45:0.45, at least about 1:1.45:0.50, at least about 1:1.45:0. .55, at least about 1:1.45:0.60, at least about 1:1.45:0.65, at least about 1:1.45:0.70, at least about 1:1.45:0.75, at least about 1:1.45:0.80, at least about 1:1.45:0.85, at least about 1:1.45:0.90, at least about 1:1.45:0.95, at least about 1:1.45:1, at least about 1:1.45: 1.05, at least about 1:1.45:1.10, at least about 1:1.45:1.15, at least about 1:1.45:1.20, at least about 1:1.45:1.25, at least about 1:1.45:1.30, at least about 1:1.45:1.35, at least about 1:1.45:1.40, at least about 1:1.45:1.45, at least about 1:1.45:1.50, at least about 1: 1.45:1.55, at least about 1:1.45:1.60, at least about 1:1.45:1.65, at least about 1:1.45:1.70, at least about 1:1.45:1.75, at least about 1:1.45:1.80, at least about 1:1.45:1.85, at least about 1:1.45:1.90, at least about 1:1.45:1.95 or at least about 1:1.45:2.

[0252] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.50:0.25, at least about 1:1.50:0.30, at least about 1:1.50:0.35, at least about 1:1.50:0.40, at least about 1:1.50:0.45, at least about 1:1.50:0.50, at least about 1:1.50:0. .55, at least about 1:1.50:0.60, at least about 1:1.50:0.65, at least about 1:1.50:0.70, at least about 1:1.50:0.75, at least about 1:1.50:0.80, at least about 1:1.50:0.85, at least about 1:1.50:0.90, at least about 1:1.50:0.95, at least about 1:1.50:1, at least about 1:1.50: 1.05, at least about 1:1.50:1.10, at least about 1:1.50:1.15, at least about 1:1.50:1.20, at least about 1:1.50:1.25, at least about 1:1.50:1.30, at least about 1:1.50:1.35, at least about 1:1.50:1.40, at least about 1:1.50:1.45, at least about 1:1.50:1.50, at least about 1: 1.50:1.55, at least about 1:1.50:1.60, at least about 1:1.50:1.65, at least about 1:1.50:1.70, at least about 1:1.50:1.75, at least about 1:1.50:1.80, at least about 1:1.50:1.85, at least about 1:1.50:1.90, at least about 1:1.50:1.95 or at least about 1:1.50:2.

[0253] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.55:0.25, at least about 1:1.55:0.30, at least about 1:1.55:0.35, at least about 1:1.55:0.40, at least about 1:1.55:0.45, at least about 1:1.55:0.50, at least about 1:1.55:0.60, at least about 1:1.55:0.70, at least about 1:1.55:0.80, at least about 1:1.55:0.90, at least about 1:1.55:0.10, at least about 1:1.55:0.11, at least about 1:1.55:0.25, at least about 1:1.55:0.30, at least about 1:1.55:0.35, at least about 1:1.55:0.40, at least about 1:1.55:0.45, at least about 1:1.55:0.50, at least about 1:1.55:0.60, at least about 1:1.55:0.70, at least about 1:1.55:0.80, at least about 1:1.55:0.90, at least about 1:1.55:0.12 .55, at least about 1:1.55:0.60, at least about 1:1.55:0.65, at least about 1:1.55:0.70, at least about 1:1.55:0.75, at least about 1:1.55:0.80, at least about 1:1.55:0.85, at least about 1:1.55:0.90, at least about 1:1.55:0.95, at least about 1:1.55:1, at least about 1:1.55: 1.05, at least about 1:1.55:1.10, at least about 1:1.55:1.15, at least about 1:1.55:1.20, at least about 1:1.55:1.25, at least about 1:1.55:1.30, at least about 1:1.55:1.35, at least about 1:1.55:1.40, at least about 1:1.55:1.45, at least about 1:1.55:1.50, at least about 1: 1.55:1.55, at least about 1:1.55:1.60, at least about 1:1.55:1.65, at least about 1:1.55:1.70, at least about 1:1.55:1.75, at least about 1:1.55:1.80, at least about 1:1.55:1.85, at least about 1:1.55:1.90, at least about 1:1.55:1.95 or at least about 1:1.55:2.

[0254] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.60:0.25, at least about 1:1.60:0.30, at least about 1:1.60:0.35, at least about 1:1.60:0.40, at least about 1:1.60:0.45, at least about 1:1.60:0.50, at least about 1:1.60:0. .55, at least about 1:1.60:0.60, at least about 1:1.60:0.65, at least about 1:1.60:0.70, at least about 1:1.60:0.75, at least about 1:1.60:0.80, at least about 1:1.60:0.85, at least about 1:1.60:0.90, at least about 1:1.60:0.95, at least about 1:1.60:1, at least about 1:1.60: 1.05, at least about 1:1.60:1.10, at least about 1:1.60:1.15, at least about 1:1.60:1.20, at least about 1:1.60:1.25, at least about 1:1.60:1.30, at least about 1:1.60:1.35, at least about 1:1.60:1.40, at least about 1:1.60:1.45, at least about 1:1.60:1.50, at least about 1: 1.60:1.55, at least about 1:1.60:1.60, at least about 1:1.60:1.65, at least about 1:1.60:1.70, at least about 1:1.60:1.75, at least about 1:1.60:1.80, at least about 1:1.60:1.85, at least about 1:1.60:1.90, at least about 1:1.60:1.95 or at least about 1:1.60:2.

[0255] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.65:0.25, at least about 1:1.65:0.30, at least about 1:1.65:0.35, at least about 1:1.65:0.40, at least about 1:1.65:0.45, at least about 1:1.65:0.50, at least about 1:1.65:0.60, at least about 1:1.65:0.70, at least about 1:1.65:0.80, at least about 1:1.65:0.90, at least about 1:1.65:0.10, at least about 1:1.65:0.11, at least about 1:1.65:0.25, at least about 1:1.65:0.30, at least about 1:1.65:0.35, at least about 1:1.65:0.40, at least about 1:1.65:0.45, at least about 1:1.65:0.50, at least about 1:1.65:0.60 .55, at least about 1:1.65:0.60, at least about 1:1.65:0.65, at least about 1:1.65:0.70, at least about 1:1.65:0.75, at least about 1:1.65:0.80, at least about 1:1.65:0.85, at least about 1:1.65:0.90, at least about 1:1.65:0.95, at least about 1:1.65:1, at least about 1:1.65: 1.05, at least about 1:1.65:1.10, at least about 1:1.65:1.15, at least about 1:1.65:1.20, at least about 1:1.65:1.25, at least about 1:1.65:1.30, at least about 1:1.65:1.35, at least about 1:1.65:1.40, at least about 1:1.65:1.45, at least about 1:1.65:1.50, at least about 1: 1.65:1.55, at least about 1:1.65:1.60, at least about 1:1.65:1.65, at least about 1:1.65:1.70, at least about 1:1.65:1.75, at least about 1:1.65:1.80, at least about 1:1.65:1.85, at least about 1:1.65:1.90, at least about 1:1.65:1.95 or at least about 1:1.65:2.

[0256] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.70:0.25, at least about 1:1.70:0.30, at least about 1:1.70:0.35, at least about 1:1.70:0.40, at least about 1:1.70:0.45, at least about 1:1.70:0.50, at least about 1:1.70:0. .55, at least about 1:1.70:0.60, at least about 1:1.70:0.65, at least about 1:1.70:0.70, at least about 1:1.70:0.75, at least about 1:1.70:0.80, at least about 1:1.70:0.85, at least about 1:1.70:0.90, at least about 1:1.70:0.95, at least about 1:1.70:1, at least about 1:1.70: 1.05, at least about 1:1.70:1.10, at least about 1:1.70:1.15, at least about 1:1.70:1.20, at least about 1:1.70:1.25, at least about 1:1.70:1.30, at least about 1:1.70:1.35, at least about 1:1.70:1.40, at least about 1:1.70:1.45, at least about 1:1.70:1.50, at least about 1: 1.70:1.55, at least about 1:1.70:1.60, at least about 1:1.70:1.65, at least about 1:1.70:1.70, at least about 1:1.70:1.75, at least about 1:1.70:1.80, at least about 1:1.70:1.85, at least about 1:1.70:1.90, at least about 1:1.70:1.95 or at least about 1:1.70:2.

[0257] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.75:0.25, at least about 1:1.75:0.30, at least about 1:1.75:0.35, at least about 1:1.75:0.40, at least about 1:1.75:0.45, at least about 1:1.75:0.50, at least about 1:1.75:0.60, at least about 1:1.75:0.70, at least about 1:1.75:0.80, at least about 1:1.75:0.90, at least about 1:1.75:0.10, at least about 1:1.75:0.11, at least about 1:1.75:0.25, at least about 1:1.75:0.30, at least about 1:1.75:0.35, at least about 1:1.75:0.40, at least about 1:1.75:0.45, at least about 1:1.75:0.50, at least about 1:1.75:0.60, at least about 1:1.75:0.70 .55, at least about 1:1.75:0.60, at least about 1:1.75:0.65, at least about 1:1.75:0.70, at least about 1:1.75:0.75, at least about 1:1.75:0.80, at least about 1:1.75:0.85, at least about 1:1.75:0.90, at least about 1:1.75:0.95, at least about 1:1.75:1, at least about 1:1.75: 1.05, at least about 1:1.75:1.10, at least about 1:1.75:1.15, at least about 1:1.75:1.20, at least about 1:1.75:1.25, at least about 1:1.75:1.30, at least about 1:1.75:1.35, at least about 1:1.75:1.40, at least about 1:1.75:1.45, at least about 1:1.75:1.50, at least about 1: 1.75:1.55, at least about 1:1.75:1.60, at least about 1:1.75:1.65, at least about 1:1.75:1.70, at least about 1:1.75:1.75, at least about 1:1.75:1.80, at least about 1:1.75:1.85, at least about 1:1.75:1.90, at least about 1:1.75:1.95 or at least about 1:1.75:2.

[0258] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.80:0.25, at least about 1:1.80:0.30, at least about 1:1.80:0.35, at least about 1:1.80:0.40, at least about 1:1.80:0.45, at least about 1:1.80:0.50, at least about 1:1.80:0. .55, at least about 1:1.80:0.60, at least about 1:1.80:0.65, at least about 1:1.80:0.70, at least about 1:1.80:0.75, at least about 1:1.80:0.80, at least about 1:1.80:0.85, at least about 1:1.80:0.90, at least about 1:1.80:0.95, at least about 1:1.80:1, at least about 1:1.80: 1.05, at least about 1:1.80:1.10, at least about 1:1.80:1.15, at least about 1:1.80:1.20, at least about 1:1.80:1.25, at least about 1:1.80:1.30, at least about 1:1.80:1.35, at least about 1:1.80:1.40, at least about 1:1.80:1.45, at least about 1:1.80:1.50, at least about 1: 1.80:1.55, at least about 1:1.80:1.60, at least about 1:1.80:1.65, at least about 1:1.80:1.70, at least about 1:1.80:1.75, at least about 1:1.80:1.80, at least about 1:1.80:1.85, at least about 1:1.80:1.90, at least about 1:1.80:1.95 or at least about 1:1.80:2.

[0259] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.85:0.25, at least about 1:1.85:0.30, at least about 1:1.85:0.35, at least about 1:1.85:0.40, at least about 1:1.85:0.45, at least about 1:1.85:0.50, at least about 1:1.85:0.60, at least about 1:1.85:0.70, at least about 1:1.85:0.80, at least about 1:1.85:0.90, at least about 1:1.85:0.10, at least about 1:1.85:0.11, at least about 1:1.85:0.25, at least about 1:1.85:0.30, at least about 1:1.85:0.35, at least about 1:1.85:0.40, at least about 1:1.85:0.45, at least about 1:1.85:0.50, at least about 1:1.85:0.60, at least about 1:1.85:0.70, at least about 1:1.85:0.80 .55, at least about 1:1.85:0.60, at least about 1:1.85:0.65, at least about 1:1.85:0.70, at least about 1:1.85:0.75, at least about 1:1.85:0.80, at least about 1:1.85:0.85, at least about 1:1.85:0.90, at least about 1:1.85:0.95, at least about 1:1.85:1, at least about 1:1.85: 1.05, at least about 1:1.85:1.10, at least about 1:1.85:1.15, at least about 1:1.85:1.20, at least about 1:1.85:1.25, at least about 1:1.85:1.30, at least about 1:1.85:1.35, at least about 1:1.85:1.40, at least about 1:1.85:1.45, at least about 1:1.85:1.50, at least about 1: 1.85:1.55, at least about 1:1.85:1.60, at least about 1:1.85:1.65, at least about 1:1.85:1.70, at least about 1:1.85:1.75, at least about 1:1.85:1.80, at least about 1:1.85:1.85, at least about 1:1.85:1.90, at least about 1:1.85:1.95 or at least about 1:1.85:2.

[0260] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.90:0.25, at least about 1:1.90:0.30, at least about 1:1.90:0.35, at least about 1:1.90:0.40, at least about 1:1.90:0.45, at least about 1:1.90:0.50, at least about 1:1.90:0.60, at least about 1:1.90:0.70, at least about 1:1.90:0.80, at least about 1:1.90:0.90, at least about 1:1.90:0.10, at least about 1:1.90:0.11, at least about 1:1.90:0.25, at least about 1:1.90:0.30, at least about 1:1.90:0.35, at least about 1:1.90:0.40, at least about 1:1.90:0.45, at least about 1:1.90:0.50, at least about 1:1.90:0.60, at least about 1:1.90:0.70, at least about 1:1.90:0.80, at least about 1:1.90:0.90, at least about 1:1.90:0.12 .55, at least about 1:1.90:0.60, at least about 1:1.90:0.65, at least about 1:1.90:0.70, at least about 1:1.90:0.75, at least about 1:1.90:0.80, at least about 1:1.90:0.85, at least about 1:1.90:0.90, at least about 1:1.90:0.95, at least about 1:1.90:1, at least about 1:1.90: 1.05, at least about 1:1.90:1.10, at least about 1:1.90:1.15, at least about 1:1.90:1.20, at least about 1:1.90:1.25, at least about 1:1.90:1.30, at least about 1:1.90:1.35, at least about 1:1.90:1.40, at least about 1:1.90:1.45, at least about 1:1.90:1.50, at least about 1: 1.90:1.55, at least about 1:1.90:1.60, at least about 1:1.90:1.65, at least about 1:1.90:1.70, at least about 1:1.90:1.75, at least about 1:1.90:1.80, at least about 1:1.90:1.85, at least about 1:1.90:1.90, at least about 1:1.90:1.95 or at least about 1:1.90:2.

[0261] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:1.95:0.25, at least about 1:1.95:0.30, at least about 1:1.95:0.35, at least about 1:1.95:0.40, at least about 1:1.95:0.45, at least about 1:1.95:0.50, at least about 1:1.95:0.60, at least about 1:1.95:0.70, at least about 1:1.95:0.80, at least about 1:1.95:0.90 0.95:0.55, at least about 1:1.95:0.60, at least about 1:1.95:0.65, at least about 1:1.95:0.70, at least about 1:1.95:0.75, at least about 1:1.95:0.80, at least about 1:1.95:0.85, at least about 1:1.95:0.90, at least about 1:1.95:0.95, at least about 1:1.95:1, at least at least about 1:1.95:1.05, at least about 1:1.95:1.10, at least about 1:1.95:1.15, at least about 1:1.95:1.20, at least about 1:1.95:1.25, at least about 1:1.95:1.30, at least about 1:1.95:1.35, at least about 1:1.95:1.40, at least about 1:1.95:1.45, at least about 1:1. 95:1.50, at least about 1:1.95:1.55, at least about 1:1.95:1.60, at least about 1:1.95:1.65, at least about 1:1.95:1.70, at least about 1:1.95:1.75, at least about 1:1.95:1.80, at least about 1:1.95:1.85, at least about 1:1.95:1.90, at least about 1:1.95:1.95, or at least about 1:1.95:2.

[0262] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:2:0.25, at least about 1:2:0.30, at least about 1:2:0.35, at least about 1:2:0.40, at least about 1:2:0.45, at least about 1:2:0.50, at least about 1:2:0.55, at least about 1:2:0.60, at least about 1:2:0.65, at least about 1:2:0.70, at least about 1:2:0.75, at least about 1:2:0.80, at least about 1:2:0.85, at least about 1:2:0.90, at least about 1:2:0.95, at least about 1:2:1, at least about 1:2:1. 1:2:1.05, at least about 1:2:1.10, at least about 1:2:1.15, at least about 1:2:1.20, at least about 1:2:1.25, at least about 1:2:1.30, at least about 1:2:1.35, at least about 1:2:1.40, at least about 1:2:1.45, at least about 1:2:1.50, at least about 1:2:1.55, at least about 1:2:1.60, at least about 1:2:1.65, at least about 1:2:1.70, at least about 1:2:1.75, at least about 1:2:1.80, at least about 1:2:1.85, at least about 1:2:1.90, at least about 1:2:1.95 or at least about 1:2:2.

[0263] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.25, at least about 1:0.30:0.25, at least about 1:0.35:0.25, at least about 1:0.40:0.25, at least about 1:0.45:0.25, at least about 1:0.50:0.25, at least about 1:0.55:0.25, or at least about 1:0.60:0.25. .25, at least about 1:0.60:0.25, at least about 1:0.65:0.25, at least about 1:0.70:0.25, at least about 1:0.75:0.25, at least about 1:0.80:0.25, at least about 1:0.85:0.25, at least about 1:0.90:0.25, at least about 1:0.95:0.25, at least about 1:1:0.25, at least about 1:1.05: 0.25, at least about 1:1.10:0.25, at least about 1:1.15:0.25, at least about 1:1.20:0.25, at least about 1:1.25:0.25, at least about 1:1.30:0.25, at least about 1:1.35:0.25, at least about 1:1.40:0.25, at least about 1:1.45:0.25, at least about 1:1.50:0.25, at least about 1: 1.55:0.25, at least about 1:1.60:0.25, at least about 1:1.65:0.25, at least about 1:1.70:0.25, at least about 1:1.75:0.25, at least about 1:1.80:0.25, at least about 1:1.85:0.25, at least about 1:1.90:0.25, at least about 1:1.95:0.25 or at least about 1:2:0.25.

[0264] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.30, at least about 1:0.30:0.30, at least about 1:0.35:0.30, at least about 1:0.40:0.30, at least about 1:0.45:0.30, at least about 1:0.50:0.30, at least about 1:0.55:0.30, or at least about 1:0.60:0.30. .30, at least about 1:0.60:0.30, at least about 1:0.65:0.30, at least about 1:0.70:0.30, at least about 1:0.75:0.30, at least about 1:0.80:0.30, at least about 1:0.85:0.30, at least about 1:0.90:0.30, at least about 1:0.95:0.30, at least about 1:1:0.30, at least about 1:1.05: 0.30, at least about 1:1.10:0.30, at least about 1:1.15:0.30, at least about 1:1.20:0.30, at least about 1:1.25:0.30, at least about 1:1.30:0.30, at least about 1:1.35:0.30, at least about 1:1.40:0.30, at least about 1:1.45:0.30, at least about 1:1.50:0.30, at least about 1: 1.55:0.30, at least about 1:1.60:0.30, at least about 1:1.65:0.30, at least about 1:1.70:0.30, at least about 1:1.75:0.30, at least about 1:1.80:0.30, at least about 1:1.85:0.30, at least about 1:1.90:0.30, at least about 1:1.95:0.30 or at least about 1:2:0.30.

[0265] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.35, at least about 1:0.30:0.35, at least about 1:0.35:0.35, at least about 1:0.40:0.35, at least about 1:0.45:0.35, at least about 1:0.50:0.35, at least about 1:0.55:0.35, or at least about 1:0.60:0.35. .35, at least about 1:0.60:0.35, at least about 1:0.65:0.35, at least about 1:0.70:0.35, at least about 1:0.75:0.35, at least about 1:0.80:0.35, at least about 1:0.85:0.35, at least about 1:0.90:0.35, at least about 1:0.95:0.35, at least about 1:1:0.35, at least about 1:1.05: 0.35, at least about 1:1.10:0.35, at least about 1:1.15:0.35, at least about 1:1.20:0.35, at least about 1:1.25:0.35, at least about 1:1.30:0.35, at least about 1:1.35:0.35, at least about 1:1.40:0.35, at least about 1:1.45:0.35, at least about 1:1.50:0.35, at least about 1: 1.55:0.35, at least about 1:1.60:0.35, at least about 1:1.65:0.35, at least about 1:1.70:0.35, at least about 1:1.75:0.35, at least about 1:1.80:0.35, at least about 1:1.85:0.35, at least about 1:1.90:0.35, at least about 1:1.95:0.35 or at least about 1:2:0.35.

[0266] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.40, at least about 1:0.30:0.40, at least about 1:0.35:0.40, at least about 1:0.40:0.40, at least about 1:0.45:0.40, at least about 1:0.50:0.40, at least about 1:0.55:0.40, or at least about 1:0.65:0.40. .40, at least about 1:0.60:0.40, at least about 1:0.65:0.40, at least about 1:0.70:0.40, at least about 1:0.75:0.40, at least about 1:0.80:0.40, at least about 1:0.85:0.40, at least about 1:0.90:0.40, at least about 1:0.95:0.40, at least about 1:1:0.40, at least about 1:1.05: 0.40, at least about 1:1.10:0.40, at least about 1:1.15:0.40, at least about 1:1.20:0.40, at least about 1:1.25:0.40, at least about 1:1.30:0.40, at least about 1:1.35:0.40, at least about 1:1.40:0.40, at least about 1:1.45:0.40, at least about 1:1.50:0.40, at least about 1: 1.55:0.40, at least about 1:1.60:0.40, at least about 1:1.65:0.40, at least about 1:1.70:0.40, at least about 1:1.75:0.40, at least about 1:1.80:0.40, at least about 1:1.85:0.40, at least about 1:1.90:0.40, at least about 1:1.95:0.40 or at least about 1:2:0.40.

[0267] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.45, at least about 1:0.30:0.45, at least about 1:0.35:0.45, at least about 1:0.40:0.45, at least about 1:0.45:0.45, at least about 1:0.50:0.45, at least about 1:0.55:0.45, or at least about 1:0.60:0.65. .45, at least about 1:0.60:0.45, at least about 1:0.65:0.45, at least about 1:0.70:0.45, at least about 1:0.75:0.45, at least about 1:0.80:0.45, at least about 1:0.85:0.45, at least about 1:0.90:0.45, at least about 1:0.95:0.45, at least about 1:1:0.45, at least about 1:1.05: 0.45, at least about 1:1.10:0.45, at least about 1:1.15:0.45, at least about 1:1.20:0.45, at least about 1:1.25:0.45, at least about 1:1.30:0.45, at least about 1:1.35:0.45, at least about 1:1.40:0.45, at least about 1:1.45:0.45, at least about 1:1.50:0.45, at least about 1: 1.55:0.45, at least about 1:1.60:0.45, at least about 1:1.65:0.45, at least about 1:1.70:0.45, at least about 1:1.75:0.45, at least about 1:1.80:0.45, at least about 1:1.85:0.45, at least about 1:1.90:0.45, at least about 1:1.95:0.45 or at least about 1:2:0.45.

[0268] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.50, at least about 1:0.30:0.50, at least about 1:0.35:0.50, at least about 1:0.40:0.50, at least about 1:0.45:0.50, at least about 1:0.50:0.50, at least about 1:0.55:0.50, or at least about 1:0.55:0.50. .50, at least about 1:0.60:0.50, at least about 1:0.65:0.50, at least about 1:0.70:0.50, at least about 1:0.75:0.50, at least about 1:0.80:0.50, at least about 1:0.85:0.50, at least about 1:0.90:0.50, at least about 1:0.95:0.50, at least about 1:1:0.50, at least about 1:1.05: 0.50, at least about 1:1.10:0.50, at least about 1:1.15:0.50, at least about 1:1.20:0.50, at least about 1:1.25:0.50, at least about 1:1.30:0.50, at least about 1:1.35:0.50, at least about 1:1.40:0.50, at least about 1:1.45:0.50, at least about 1:1.50:0.50, at least about 1: 1.55:0.50, at least about 1:1.60:0.50, at least about 1:1.65:0.50, at least about 1:1.70:0.50, at least about 1:1.75:0.50, at least about 1:1.80:0.50, at least about 1:1.85:0.50, at least about 1:1.90:0.50, at least about 1:1.95:0.50 or at least about 1:2:0.50.

[0269] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.55, at least about 1:0.30:0.55, at least about 1:0.35:0.55, at least about 1:0.40:0.55, at least about 1:0.45:0.55, at least about 1:0.50:0.55, at least about 1:0.55:0.55 .55, at least about 1:0.60:0.55, at least about 1:0.65:0.55, at least about 1:0.70:0.55, at least about 1:0.75:0.55, at least about 1:0.80:0.55, at least about 1:0.85:0.55, at least about 1:0.90:0.55, at least about 1:0.95:0.55, at least about 1:1:0.55, at least about 1:1.05: 0.55, at least about 1:1.10:0.55, at least about 1:1.15:0.55, at least about 1:1.20:0.55, at least about 1:1.25:0.55, at least about 1:1.30:0.55, at least about 1:1.35:0.55, at least about 1:1.40:0.55, at least about 1:1.45:0.55, at least about 1:1.50:0.55, at least about 1: 1.55:0.55, at least about 1:1.60:0.55, at least about 1:1.65:0.55, at least about 1:1.70:0.55, at least about 1:1.75:0.55, at least about 1:1.80:0.55, at least about 1:1.85:0.55, at least about 1:1.90:0.55, at least about 1:1.95:0.55 or at least about 1:2:0.55.

[0270] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.60, at least about 1:0.30:0.60, at least about 1:0.35:0.60, at least about 1:0.40:0.60, at least about 1:0.45:0.60, at least about 1:0.50:0.60, at least about 1:0.55:0.60, or at least about 1:0.65:0.60. .60, at least about 1:0.60:0.60, at least about 1:0.65:0.60, at least about 1:0.70:0.60, at least about 1:0.75:0.60, at least about 1:0.80:0.60, at least about 1:0.85:0.60, at least about 1:0.90:0.60, at least about 1:0.95:0.60, at least about 1:1:0.60, at least about 1:1.05: 0.60, at least about 1:1.10:0.60, at least about 1:1.15:0.60, at least about 1:1.20:0.60, at least about 1:1.25:0.60, at least about 1:1.30:0.60, at least about 1:1.35:0.60, at least about 1:1.40:0.60, at least about 1:1.45:0.60, at least about 1:1.50:0.60, at least about 1: 1.55:0.60, at least about 1:1.60:0.60, at least about 1:1.65:0.60, at least about 1:1.70:0.60, at least about 1:1.75:0.60, at least about 1:1.80:0.60, at least about 1:1.85:0.60, at least about 1:1.90:0.60, at least about 1:1.95:0.60 or at least about 1:2:0.60.

[0271] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.65, at least about 1:0.30:0.65, at least about 1:0.35:0.65, at least about 1:0.40:0.65, at least about 1:0.45:0.65, at least about 1:0.50:0.65, at least about 1:0.55:0.65, or at least about 1:0.65:0.65. .65, at least about 1:0.60:0.65, at least about 1:0.65:0.65, at least about 1:0.70:0.65, at least about 1:0.75:0.65, at least about 1:0.80:0.65, at least about 1:0.85:0.65, at least about 1:0.90:0.65, at least about 1:0.95:0.65, at least about 1:1:0.65, at least about 1:1.05: 0.65, at least about 1:1.10:0.65, at least about 1:1.15:0.65, at least about 1:1.20:0.65, at least about 1:1.25:0.65, at least about 1:1.30:0.65, at least about 1:1.35:0.65, at least about 1:1.40:0.65, at least about 1:1.45:0.65, at least about 1:1.50:0.65, at least about 1: 1.55:0.65, at least about 1:1.60:0.65, at least about 1:1.65:0.65, at least about 1:1.70:0.65, at least about 1:1.75:0.65, at least about 1:1.80:0.65, at least about 1:1.85:0.65, at least about 1:1.90:0.65, at least about 1:1.95:0.65 or at least about 1:2:0.65.

[0272] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.70, at least about 1:0.30:0.70, at least about 1:0.35:0.70, at least about 1:0.40:0.70, at least about 1:0.45:0.70, at least about 1:0.50:0.70, at least about 1:0.55:0.70, or at least about 1:0.60:0.70. .70, at least about 1:0.60:0.70, at least about 1:0.65:0.70, at least about 1:0.70:0.70, at least about 1:0.75:0.70, at least about 1:0.80:0.70, at least about 1:0.85:0.70, at least about 1:0.90:0.70, at least about 1:0.95:0.70, at least about 1:1:0.70, at least about 1:1.05: 0.70, at least about 1:1.10:0.70, at least about 1:1.15:0.70, at least about 1:1.20:0.70, at least about 1:1.25:0.70, at least about 1:1.30:0.70, at least about 1:1.35:0.70, at least about 1:1.40:0.70, at least about 1:1.45:0.70, at least about 1:1.50:0.70, at least about 1: 1.55:0.70, at least about 1:1.60:0.70, at least about 1:1.65:0.70, at least about 1:1.70:0.70, at least about 1:1.75:0.70, at least about 1:1.80:0.70, at least about 1:1.85:0.70, at least about 1:1.90:0.70, at least about 1:1.95:0.70 or at least about 1:2:0.70.

[0273] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.75, at least about 1:0.30:0.75, at least about 1:0.35:0.75, at least about 1:0.40:0.75, at least about 1:0.45:0.75, at least about 1:0.50:0.75, at least about 1:0.55:0.75, or at least about 1:0.60:0.75. .75, at least about 1:0.60:0.75, at least about 1:0.65:0.75, at least about 1:0.70:0.75, at least about 1:0.75:0.75, at least about 1:0.80:0.75, at least about 1:0.85:0.75, at least about 1:0.90:0.75, at least about 1:0.95:0.75, at least about 1:1:0.75, at least about 1:1.05: 0.75, at least about 1:1.10:0.75, at least about 1:1.15:0.75, at least about 1:1.20:0.75, at least about 1:1.25:0.75, at least about 1:1.30:0.75, at least about 1:1.35:0.75, at least about 1:1.40:0.75, at least about 1:1.45:0.75, at least about 1:1.50:0.75, at least about 1: 1.55:0.75, at least about 1:1.60:0.75, at least about 1:1.65:0.75, at least about 1:1.70:0.75, at least about 1:1.75:0.75, at least about 1:1.80:0.75, at least about 1:1.85:0.75, at least about 1:1.90:0.75, at least about 1:1.95:0.75 or at least about 1:2:0.75.

[0274] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.80, at least about 1:0.30:0.80, at least about 1:0.35:0.80, at least about 1:0.40:0.80, at least about 1:0.45:0.80, at least about 1:0.50:0.80, at least about 1:0.55:0.80, or at least about 1:0.60:0.80. .80, at least about 1:0.60:0.80, at least about 1:0.65:0.80, at least about 1:0.70:0.80, at least about 1:0.75:0.80, at least about 1:0.80:0.80, at least about 1:0.85:0.80, at least about 1:0.90:0.80, at least about 1:0.95:0.80, at least about 1:1:0.80, at least about 1:1.05: 0.80, at least about 1:1.10:0.80, at least about 1:1.15:0.80, at least about 1:1.20:0.80, at least about 1:1.25:0.80, at least about 1:1.30:0.80, at least about 1:1.35:0.80, at least about 1:1.40:0.80, at least about 1:1.45:0.80, at least about 1:1.50:0.80, at least about 1: 1.55:0.80, at least about 1:1.60:0.80, at least about 1:1.65:0.80, at least about 1:1.70:0.80, at least about 1:1.75:0.80, at least about 1:1.80:0.80, at least about 1:1.85:0.80, at least about 1:1.90:0.80, at least about 1:1.95:0.80 or at least about 1:2:0.80.

[0275] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.85, at least about 1:0.30:0.85, at least about 1:0.35:0.85, at least about 1:0.40:0.85, at least about 1:0.45:0.85, at least about 1:0.50:0.85, at least about 1:0.55:0.85, or at least about 1:0.60:0.85. .85, at least about 1:0.60:0.85, at least about 1:0.65:0.85, at least about 1:0.70:0.85, at least about 1:0.75:0.85, at least about 1:0.80:0.85, at least about 1:0.85:0.85, at least about 1:0.90:0.85, at least about 1:0.95:0.85, at least about 1:1:0.85, at least about 1:1.05: 0.85, at least about 1:1.10:0.85, at least about 1:1.15:0.85, at least about 1:1.20:0.85, at least about 1:1.25:0.85, at least about 1:1.30:0.85, at least about 1:1.35:0.85, at least about 1:1.40:0.85, at least about 1:1.45:0.85, at least about 1:1.50:0.85, at least about 1: 1.55:0.85, at least about 1:1.60:0.85, at least about 1:1.65:0.85, at least about 1:1.70:0.85, at least about 1:1.75:0.85, at least about 1:1.80:0.85, at least about 1:1.85:0.85, at least about 1:1.90:0.85, at least about 1:1.95:0.85 or at least about 1:2:0.85.

[0276] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.90, at least about 1:0.30:0.90, at least about 1:0.35:0.90, at least about 1:0.40:0.90, at least about 1:0.45:0.90, at least about 1:0.50:0.90, at least about 1:0.55:0.90, or at least about 1:0.60:0.90. .90, at least about 1:0.60:0.90, at least about 1:0.65:0.90, at least about 1:0.70:0.90, at least about 1:0.75:0.90, at least about 1:0.80:0.90, at least about 1:0.85:0.90, at least about 1:0.90:0.90, at least about 1:0.95:0.90, at least about 1:1:0.90, at least about 1:1.05: 0.90, at least about 1:1.10:0.90, at least about 1:1.15:0.90, at least about 1:1.20:0.90, at least about 1:1.25:0.90, at least about 1:1.30:0.90, at least about 1:1.35:0.90, at least about 1:1.40:0.90, at least about 1:1.45:0.90, at least about 1:1.50:0.90, at least about 1: 1.55:0.90, at least about 1:1.60:0.90, at least about 1:1.65:0.90, at least about 1:1.70:0.90, at least about 1:1.75:0.90, at least about 1:1.80:0.90, at least about 1:1.85:0.90, at least about 1:1.90:0.90, at least about 1:1.95:0.90 or at least about 1:2:0.90.

[0277] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:0.95, at least about 1:0.30:0.95, at least about 1:0.35:0.95, at least about 1:0.40:0.95, at least about 1:0.45:0.95, at least about 1:0.50:0.95, at least about 1:0.55:0.95, or at least about 1:0.60:0.95. .95, at least about 1:0.60:0.95, at least about 1:0.65:0.95, at least about 1:0.70:0.95, at least about 1:0.75:0.95, at least about 1:0.80:0.95, at least about 1:0.85:0.95, at least about 1:0.90:0.95, at least about 1:0.95:0.95, at least about 1:1:0.95, at least about 1:1.05: 0.95, at least about 1:1.10:0.95, at least about 1:1.15:0.95, at least about 1:1.20:0.95, at least about 1:1.25:0.95, at least about 1:1.30:0.95, at least about 1:1.35:0.95, at least about 1:1.40:0.95, at least about 1:1.45:0.95, at least about 1:1.50:0.95, at least about 1: 1.55:0.95, at least about 1:1.60:0.95, at least about 1:1.65:0.95, at least about 1:1.70:0.95, at least about 1:1.75:0.95, at least about 1:1.80:0.95, at least about 1:1.85:0.95, at least about 1:1.90:0.95, at least about 1:1.95:0.95 or at least about 1:2:0.95.

[0278] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1, at least about 1:0.30:1, at least about 1:0.35:1, at least about 1:0.40:1, at least about 1:0.45:1, at least about 1:0.50:1, at least about 1:0.55:1, at least about 1:0.60:1, at least about 1:0.65:1, at least about 1:0.70:1, at least about 1:0.75:1, at least about 1:0.80:1, at least about 1:0.85:1, at least about 1:0.90:1, at least about 1:0.95:1, at least about 1:1:1, or at least about 1:1. :1.05:1, at least about 1:1.10:1, at least about 1:1.15:1, at least about 1:1.20:1, at least about 1:1.25:1, at least about 1:1.30:1, at least about 1:1.35:1, at least about 1:1.40:1, at least about 1:1.45:1, at least about 1:1.50:1, at least about 1:1.55:1, at least about 1:1.60:1, at least about 1:1.65:1, at least about 1:1.70:1, at least about 1:1.75:1, at least about 1:1.80:1, at least about 1:1.85:1, at least about 1:1.90:1, at least about 1:1.95:1 or at least about 1:2:1.

[0279] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.05, at least about 1:0.30:1.05, at least about 1:0.35:1.05, at least about 1:0.40:1.05, at least about 1:0.45:1.05, at least about 1:0.50:1.05, at least about 1:0.55:1.05, or at least about 1:0.60:1.05. .05, at least about 1:0.60:1.05, at least about 1:0.65:1.05, at least about 1:0.70:1.05, at least about 1:0.75:1.05, at least about 1:0.80:1.05, at least about 1:0.85:1.05, at least about 1:0.90:1.05, at least about 1:0.95:1.05, at least about 1:1:1.05, at least about 1:1.05: 1.05, at least about 1:1.10:1.05, at least about 1:1.15:1.05, at least about 1:1.20:1.05, at least about 1:1.25:1.05, at least about 1:1.30:1.05, at least about 1:1.35:1.05, at least about 1:1.40:1.05, at least about 1:1.45:1.05, at least about 1:1.50:1.05, at least about 1: 1.55:1.05, at least about 1:1.60:1.05, at least about 1:1.65:1.05, at least about 1:1.70:1.05, at least about 1:1.75:1.05, at least about 1:1.80:1.05, at least about 1:1.85:1.05, at least about 1:1.90:1.05, at least about 1:1.95:1.05 or at least about 1:2:1.05.

[0280] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.10, at least about 1:0.30:1.10, at least about 1:0.35:1.10, at least about 1:0.40:1.10, at least about 1:0.45:1.10, at least about 1:0.50:1.10, at least about 1:0.55:1.10, or at least about 1:0.60:1.10. .10, at least about 1:0.60:1.10, at least about 1:0.65:1.10, at least about 1:0.70:1.10, at least about 1:0.75:1.10, at least about 1:0.80:1.10, at least about 1:0.85:1.10, at least about 1:0.90:1.10, at least about 1:0.95:1.10, at least about 1:1:1.10, at least about 1:1.05:1.10 1.10, at least about 1:1.10:1.10, at least about 1:1.15:1.10, at least about 1:1.20:1.10, at least about 1:1.25:1.10, at least about 1:1.30:1.10, at least about 1:1.35:1.10, at least about 1:1.40:1.10, at least about 1:1.45:1.10, at least about 1:1.50:1.10, at least about 1: 1.55:1.10, at least about 1:1.60:1.10, at least about 1:1.65:1.10, at least about 1:1.70:1.10, at least about 1:1.75:1.10, at least about 1:1.80:1.10, at least about 1:1.85:1.10, at least about 1:1.90:1.10, at least about 1:1.95:1.10 or at least about 1:2:1.10.

[0281] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.15, at least about 1:0.30:1.15, at least about 1:0.35:1.15, at least about 1:0.40:1.15, at least about 1:0.45:1.15, at least about 1:0.50:1.15, at least about 1:0.55:1.15, or at least about 1:0.60:1.15. .15, at least about 1:0.60:1.15, at least about 1:0.65:1.15, at least about 1:0.70:1.15, at least about 1:0.75:1.15, at least about 1:0.80:1.15, at least about 1:0.85:1.15, at least about 1:0.90:1.15, at least about 1:0.95:1.15, at least about 1:1:1.15, at least about 1:1.05: 1.15, at least about 1:1.10:1.15, at least about 1:1.15:1.15, at least about 1:1.20:1.15, at least about 1:1.25:1.15, at least about 1:1.30:1.15, at least about 1:1.35:1.15, at least about 1:1.40:1.15, at least about 1:1.45:1.15, at least about 1:1.50:1.15, at least about 1: 1.55:1.15, at least about 1:1.60:1.15, at least about 1:1.65:1.15, at least about 1:1.70:1.15, at least about 1:1.75:1.15, at least about 1:1.80:1.15, at least about 1:1.85:1.15, at least about 1:1.90:1.15, at least about 1:1.95:1.15 or at least about 1:2:1.15.

[0282] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.20, at least about 1:0.30:1.20, at least about 1:0.35:1.20, at least about 1:0.40:1.20, at least about 1:0.45:1.20, at least about 1:0.50:1.20, at least about 1:0.55:1.20, or at least about 1:0.60:1.20. .20, at least about 1:0.60:1.20, at least about 1:0.65:1.20, at least about 1:0.70:1.20, at least about 1:0.75:1.20, at least about 1:0.80:1.20, at least about 1:0.85:1.20, at least about 1:0.90:1.20, at least about 1:0.95:1.20, at least about 1:1:1.20, at least about 1:1.05:1.20 1.20, at least about 1:1.10:1.20, at least about 1:1.15:1.20, at least about 1:1.20:1.20, at least about 1:1.25:1.20, at least about 1:1.30:1.20, at least about 1:1.35:1.20, at least about 1:1.40:1.20, at least about 1:1.45:1.20, at least about 1:1.50:1.20, at least about 1: 1.55:1.20, at least about 1:1.60:1.20, at least about 1:1.65:1.20, at least about 1:1.70:1.20, at least about 1:1.75:1.20, at least about 1:1.80:1.20, at least about 1:1.85:1.20, at least about 1:1.90:1.20, at least about 1:1.95:1.20 or at least about 1:2:1.20.

[0283] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.25, at least about 1:0.30:1.25, at least about 1:0.35:1.25, at least about 1:0.40:1.25, at least about 1:0.45:1.25, at least about 1:0.50:1.25, at least about 1:0.55:1.25, or at least about 1:0.60:1.25. .25, at least about 1:0.60:1.25, at least about 1:0.65:1.25, at least about 1:0.70:1.25, at least about 1:0.75:1.25, at least about 1:0.80:1.25, at least about 1:0.85:1.25, at least about 1:0.90:1.25, at least about 1:0.95:1.25, at least about 1:1:1.25, at least about 1:1.05: 1.25, at least about 1:1.10:1.25, at least about 1:1.15:1.25, at least about 1:1.20:1.25, at least about 1:1.25:1.25, at least about 1:1.30:1.25, at least about 1:1.35:1.25, at least about 1:1.40:1.25, at least about 1:1.45:1.25, at least about 1:1.50:1.25, at least about 1: 1.55:1.25, at least about 1:1.60:1.25, at least about 1:1.65:1.25, at least about 1:1.70:1.25, at least about 1:1.75:1.25, at least about 1:1.80:1.25, at least about 1:1.85:1.25, at least about 1:1.90:1.25, at least about 1:1.95:1.25 or at least about 1:2:1.25.

[0284] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.30, at least about 1:0.30:1.30, at least about 1:0.35:1.30, at least about 1:0.40:1.30, at least about 1:0.45:1.30, at least about 1:0.50:1.30, at least about 1:0.55:1.30, or at least about 1:0.60:1.30. .30, at least about 1:0.60:1.30, at least about 1:0.65:1.30, at least about 1:0.70:1.30, at least about 1:0.75:1.30, at least about 1:0.80:1.30, at least about 1:0.85:1.30, at least about 1:0.90:1.30, at least about 1:0.95:1.30, at least about 1:1:1.30, at least about 1:1.05:1.30 1.30, at least about 1:1.10:1.30, at least about 1:1.15:1.30, at least about 1:1.20:1.30, at least about 1:1.25:1.30, at least about 1:1.30:1.30, at least about 1:1.35:1.30, at least about 1:1.40:1.30, at least about 1:1.45:1.30, at least about 1:1.50:1.30, at least about 1: 1.55:1.30, at least about 1:1.60:1.30, at least about 1:1.65:1.30, at least about 1:1.70:1.30, at least about 1:1.75:1.30, at least about 1:1.80:1.30, at least about 1:1.85:1.30, at least about 1:1.90:1.30, at least about 1:1.95:1.30 or at least about 1:2:1.30.

[0285] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.35, at least about 1:0.30:1.35, at least about 1:0.35:1.35, at least about 1:0.40:1.35, at least about 1:0.45:1.35, at least about 1:0.50:1.35, at least about 1:0.55:1.35, or at least about 1:0.60:1.35. .35, at least about 1:0.60:1.35, at least about 1:0.65:1.35, at least about 1:0.70:1.35, at least about 1:0.75:1.35, at least about 1:0.80:1.35, at least about 1:0.85:1.35, at least about 1:0.90:1.35, at least about 1:0.95:1.35, at least about 1:1:1.35, at least about 1:1.05: 1.35, at least about 1:1.10:1.35, at least about 1:1.15:1.35, at least about 1:1.20:1.35, at least about 1:1.25:1.35, at least about 1:1.30:1.35, at least about 1:1.35:1.35, at least about 1:1.40:1.35, at least about 1:1.45:1.35, at least about 1:1.50:1.35, at least about 1: 1.55:1.35, at least about 1:1.60:1.35, at least about 1:1.65:1.35, at least about 1:1.70:1.35, at least about 1:1.75:1.35, at least about 1:1.80:1.35, at least about 1:1.85:1.35, at least about 1:1.90:1.35, at least about 1:1.95:1.35 or at least about 1:2:1.35.

[0286] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.40, at least about 1:0.30:1.40, at least about 1:0.35:1.40, at least about 1:0.40:1.40, at least about 1:0.45:1.40, at least about 1:0.50:1.40, at least about 1:0.55:1.40, or at least about 1:0.60:1.40. .40, at least about 1:0.60:1.40, at least about 1:0.65:1.40, at least about 1:0.70:1.40, at least about 1:0.75:1.40, at least about 1:0.80:1.40, at least about 1:0.85:1.40, at least about 1:0.90:1.40, at least about 1:0.95:1.40, at least about 1:1:1.40, at least about 1:1.05:1.40 1.40, at least about 1:1.10:1.40, at least about 1:1.15:1.40, at least about 1:1.20:1.40, at least about 1:1.25:1.40, at least about 1:1.30:1.40, at least about 1:1.35:1.40, at least about 1:1.40:1.40, at least about 1:1.45:1.40, at least about 1:1.50:1.40, at least about 1: 1.55:1.40, at least about 1:1.60:1.40, at least about 1:1.65:1.40, at least about 1:1.70:1.40, at least about 1:1.75:1.40, at least about 1:1.80:1.40, at least about 1:1.85:1.40, at least about 1:1.90:1.40, at least about 1:1.95:1.40 or at least about 1:2:1.40.

[0287] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.45, at least about 1:0.30:1.45, at least about 1:0.35:1.45, at least about 1:0.40:1.45, at least about 1:0.45:1.45, at least about 1:0.50:1.45, at least about 1:0.55:1.45, or at least about 1:0.60:1.45. .45, at least about 1:0.60:1.45, at least about 1:0.65:1.45, at least about 1:0.70:1.45, at least about 1:0.75:1.45, at least about 1:0.80:1.45, at least about 1:0.85:1.45, at least about 1:0.90:1.45, at least about 1:0.95:1.45, at least about 1:1:1.45, at least about 1:1.05: 1.45, at least about 1:1.10:1.45, at least about 1:1.15:1.45, at least about 1:1.20:1.45, at least about 1:1.25:1.45, at least about 1:1.30:1.45, at least about 1:1.35:1.45, at least about 1:1.40:1.45, at least about 1:1.45:1.45, at least about 1:1.50:1.45, at least about 1: 1.55:1.45, at least about 1:1.60:1.45, at least about 1:1.65:1.45, at least about 1:1.70:1.45, at least about 1:1.75:1.45, at least about 1:1.80:1.45, at least about 1:1.85:1.45, at least about 1:1.90:1.45, at least about 1:1.95:1.45 or at least about 1:2:1.45.

[0288] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.50, at least about 1:0.30:1.50, at least about 1:0.35:1.50, at least about 1:0.40:1.50, at least about 1:0.45:1.50, at least about 1:0.50:1.50, at least about 1:0.55:1.50, or at least about 1:0.65:1.50. .50, at least about 1:0.60:1.50, at least about 1:0.65:1.50, at least about 1:0.70:1.50, at least about 1:0.75:1.50, at least about 1:0.80:1.50, at least about 1:0.85:1.50, at least about 1:0.90:1.50, at least about 1:0.95:1.50, at least about 1:1.05:1.50, at least about 1:1.05:1.50 1.50, at least about 1:1.10:1.50, at least about 1:1.15:1.50, at least about 1:1.20:1.50, at least about 1:1.25:1.50, at least about 1:1.30:1.50, at least about 1:1.35:1.50, at least about 1:1.40:1.50, at least about 1:1.45:1.50, at least about 1:1.50:1.50, at least about 1: 1.55:1.50, at least about 1:1.60:1.50, at least about 1:1.65:1.50, at least about 1:1.70:1.50, at least about 1:1.75:1.50, at least about 1:1.80:1.50, at least about 1:1.85:1.50, at least about 1:1.90:1.50, at least about 1:1.95:1.50 or at least about 1:2:1.50.

[0289] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.55, at least about 1:0.30:1.55, at least about 1:0.35:1.55, at least about 1:0.40:1.55, at least about 1:0.45:1.55, at least about 1:0.50:1.55, at least about 1:0.55:1.55 .55, at least about 1:0.60:1.55, at least about 1:0.65:1.55, at least about 1:0.70:1.55, at least about 1:0.75:1.55, at least about 1:0.80:1.55, at least about 1:0.85:1.55, at least about 1:0.90:1.55, at least about 1:0.95:1.55, at least about 1:1:1.55, at least about 1:1.05: 1.55, at least about 1:1.10:1.55, at least about 1:1.15:1.55, at least about 1:1.20:1.55, at least about 1:1.25:1.55, at least about 1:1.30:1.55, at least about 1:1.35:1.55, at least about 1:1.40:1.55, at least about 1:1.45:1.55, at least about 1:1.50:1.55, at least about 1: 1.55:1.55, at least about 1:1.60:1.55, at least about 1:1.65:1.55, at least about 1:1.70:1.55, at least about 1:1.75:1.55, at least about 1:1.80:1.55, at least about 1:1.85:1.55, at least about 1:1.90:1.55, at least about 1:1.95:1.55 or at least about 1:2:1.55.

[0290] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.60, at least about 1:0.30:1.60, at least about 1:0.35:1.60, at least about 1:0.40:1.60, at least about 1:0.45:1.60, at least about 1:0.50:1.60, at least about 1:0.55:1.60, or at least about 1:0.60:1.60. .60, at least about 1:0.60:1.60, at least about 1:0.65:1.60, at least about 1:0.70:1.60, at least about 1:0.75:1.60, at least about 1:0.80:1.60, at least about 1:0.85:1.60, at least about 1:0.90:1.60, at least about 1:0.95:1.60, at least about 1:1:1.60, at least about 1:1.05: 1.60, at least about 1:1.10:1.60, at least about 1:1.15:1.60, at least about 1:1.20:1.60, at least about 1:1.25:1.60, at least about 1:1.30:1.60, at least about 1:1.35:1.60, at least about 1:1.40:1.60, at least about 1:1.45:1.60, at least about 1:1.50:1.60, at least about 1: 1.55:1.60, at least about 1:1.60:1.60, at least about 1:1.65:1.60, at least about 1:1.70:1.60, at least about 1:1.75:1.60, at least about 1:1.80:1.60, at least about 1:1.85:1.60, at least about 1:1.90:1.60, at least about 1:1.95:1.60 or at least about 1:2:1.60.

[0291] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.65, at least about 1:0.30:1.65, at least about 1:0.35:1.65, at least about 1:0.40:1.65, at least about 1:0.45:1.65, at least about 1:0.50:1.65, at least about 1:0.55:1.65, or at least about 1:0.65:1.65. .65, at least about 1:0.60:1.65, at least about 1:0.65:1.65, at least about 1:0.70:1.65, at least about 1:0.75:1.65, at least about 1:0.80:1.65, at least about 1:0.85:1.65, at least about 1:0.90:1.65, at least about 1:0.95:1.65, at least about 1:1:1.65, at least about 1:1.05: 1.65, at least about 1:1.10:1.65, at least about 1:1.15:1.65, at least about 1:1.20:1.65, at least about 1:1.25:1.65, at least about 1:1.30:1.65, at least about 1:1.35:1.65, at least about 1:1.40:1.65, at least about 1:1.45:1.65, at least about 1:1.50:1.65, at least about 1: 1.55:1.65, at least about 1:1.60:1.65, at least about 1:1.65:1.65, at least about 1:1.70:1.65, at least about 1:1.75:1.65, at least about 1:1.80:1.65, at least about 1:1.85:1.65, at least about 1:1.90:1.65, at least about 1:1.95:1.65 or at least about 1:2:1.65.

[0292] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.70, at least about 1:0.30:1.70, at least about 1:0.35:1.70, at least about 1:0.40:1.70, at least about 1:0.45:1.70, at least about 1:0.50:1.70, at least about 1:0.55:1.70, or at least about 1:0.60:1.70. .70, at least about 1:0.60:1.70, at least about 1:0.65:1.70, at least about 1:0.70:1.70, at least about 1:0.75:1.70, at least about 1:0.80:1.70, at least about 1:0.85:1.70, at least about 1:0.90:1.70, at least about 1:0.95:1.70, at least about 1:1:1.70, at least about 1:1.05: 1.70, at least about 1:1.10:1.70, at least about 1:1.15:1.70, at least about 1:1.20:1.70, at least about 1:1.25:1.70, at least about 1:1.30:1.70, at least about 1:1.35:1.70, at least about 1:1.40:1.70, at least about 1:1.45:1.70, at least about 1:1.50:1.70, at least about 1: 1.55:1.70, at least about 1:1.60:1.70, at least about 1:1.65:1.70, at least about 1:1.70:1.70, at least about 1:1.75:1.70, at least about 1:1.80:1.70, at least about 1:1.85:1.70, at least about 1:1.90:1.70, at least about 1:1.95:1.70 or at least about 1:2:1.70.

[0293] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.75, at least about 1:0.30:1.75, at least about 1:0.35:1.75, at least about 1:0.40:1.75, at least about 1:0.45:1.75, at least about 1:0.50:1.75, at least about 1:0.55:1.75, or at least about 1:0.60:1.75. .75, at least about 1:0.60:1.75, at least about 1:0.65:1.75, at least about 1:0.70:1.75, at least about 1:0.75:1.75, at least about 1:0.80:1.75, at least about 1:0.85:1.75, at least about 1:0.90:1.75, at least about 1:0.95:1.75, at least about 1:1:1.75, at least about 1:1.05: 1.75, at least about 1:1.10:1.75, at least about 1:1.15:1.75, at least about 1:1.20:1.75, at least about 1:1.25:1.75, at least about 1:1.30:1.75, at least about 1:1.35:1.75, at least about 1:1.40:1.75, at least about 1:1.45:1.75, at least about 1:1.50:1.75, at least about 1: 1.55:1.75, at least about 1:1.60:1.75, at least about 1:1.65:1.75, at least about 1:1.70:1.75, at least about 1:1.75:1.75, at least about 1:1.80:1.75, at least about 1:1.85:1.75, at least about 1:1.90:1.75, at least about 1:1.95:1.75 or at least about 1:2:1.75.

[0294] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.80, at least about 1:0.30:1.80, at least about 1:0.35:1.80, at least about 1:0.40:1.80, at least about 1:0.45:1.80, at least about 1:0.50:1.80, at least about 1:0.55:1.80, or at least about 1:0.60:1.80. .80, at least about 1:0.60:1.80, at least about 1:0.65:1.80, at least about 1:0.70:1.80, at least about 1:0.75:1.80, at least about 1:0.80:1.80, at least about 1:0.85:1.80, at least about 1:0.90:1.80, at least about 1:0.95:1.80, at least about 1:1:1.80, at least about 1:1.05: 1.80, at least about 1:1.10:1.80, at least about 1:1.15:1.80, at least about 1:1.20:1.80, at least about 1:1.25:1.80, at least about 1:1.30:1.80, at least about 1:1.35:1.80, at least about 1:1.40:1.80, at least about 1:1.45:1.80, at least about 1:1.50:1.80, at least about 1: 1.55:1.80, at least about 1:1.60:1.80, at least about 1:1.65:1.80, at least about 1:1.70:1.80, at least about 1:1.75:1.80, at least about 1:1.80:1.80, at least about 1:1.85:1.80, at least about 1:1.90:1.80, at least about 1:1.95:1.80 or at least about 1:2:1.80.

[0295] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.85, at least about 1:0.30:1.85, at least about 1:0.35:1.85, at least about 1:0.40:1.85, at least about 1:0.45:1.85, at least about 1:0.50:1.85, at least about 1:0.55:1.85, or at least about 1:0.60:1.85. .85, at least about 1:0.60:1.85, at least about 1:0.65:1.85, at least about 1:0.70:1.85, at least about 1:0.75:1.85, at least about 1:0.80:1.85, at least about 1:0.85:1.85, at least about 1:0.90:1.85, at least about 1:0.95:1.85, at least about 1:1:1.85, at least about 1:1.05: 1.85, at least about 1:1.10:1.85, at least about 1:1.15:1.85, at least about 1:1.20:1.85, at least about 1:1.25:1.85, at least about 1:1.30:1.85, at least about 1:1.35:1.85, at least about 1:1.40:1.85, at least about 1:1.45:1.85, at least about 1:1.50:1.85, at least about 1: 1.55:1.85, at least about 1:1.60:1.85, at least about 1:1.65:1.85, at least about 1:1.70:1.85, at least about 1:1.75:1.85, at least about 1:1.80:1.85, at least about 1:1.85:1.85, at least about 1:1.90:1.85, at least about 1:1.95:1.85 or at least about 1:2:1.85.

[0296] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.90, at least about 1:0.30:1.90, at least about 1:0.35:1.90, at least about 1:0.40:1.90, at least about 1:0.45:1.90, at least about 1:0.50:1.90, at least about 1:0.55:1.90, or at least about 1:0.60:1.90. .90, at least about 1:0.60:1.90, at least about 1:0.65:1.90, at least about 1:0.70:1.90, at least about 1:0.75:1.90, at least about 1:0.80:1.90, at least about 1:0.85:1.90, at least about 1:0.90:1.90, at least about 1:0.95:1.90, at least about 1:1:1.90, at least about 1:1.05: 1.90, at least about 1:1.10:1.90, at least about 1:1.15:1.90, at least about 1:1.20:1.90, at least about 1:1.25:1.90, at least about 1:1.30:1.90, at least about 1:1.35:1.90, at least about 1:1.40:1.90, at least about 1:1.45:1.90, at least about 1:1.50:1.90, at least about 1: 1.55:1.90, at least about 1:1.60:1.90, at least about 1:1.65:1.90, at least about 1:1.70:1.90, at least about 1:1.75:1.90, at least about 1:1.80:1.90, at least about 1:1.85:1.90, at least about 1:1.90:1.90, at least about 1:1.95:1.90 or at least about 1:2:1.90.

[0297] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:1.95, at least about 1:0.30:1.95, at least about 1:0.35:1.95, at least about 1:0.40:1.95, at least about 1:0.45:1.95, at least about 1:0.50:1.95, at least about 1:0.55:1.95, or at least about 1:0.60:1.95. .95, at least about 1:0.60:1.95, at least about 1:0.65:1.95, at least about 1:0.70:1.95, at least about 1:0.75:1.95, at least about 1:0.80:1.95, at least about 1:0.85:1.95, at least about 1:0.90:1.95, at least about 1:0.95:1.95, at least about 1:1:1.95, at least about 1:1.05: 1.95, at least about 1:1.10:1.95, at least about 1:1.15:1.95, at least about 1:1.20:1.95, at least about 1:1.25:1.95, at least about 1:1.30:1.95, at least about 1:1.35:1.95, at least about 1:1.40:1.95, at least about 1:1.45:1.95, at least about 1:1.50:1.95, at least about 1: 1.55:1.95, at least about 1:1.60:1.95, at least about 1:1.65:1.95, at least about 1:1.70:1.95, at least about 1:1.75:1.95, at least about 1:1.80:1.95, at least about 1:1.85:1.95, at least about 1:1.90:1.95, at least about 1:1.95:1.95 or at least about 1:2:1.95.

[0298] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to PVRIG antagonist is at least about 1:0.25:2, at least about 1:0.30:2, at least about 1:0.35:2, at least about 1:0.40:2, at least about 1:0.45:2, at least about 1:0.50:2, at least about 1:0.55:2, at least about 1:0.60:2, at least about 1:0.65:2, at least about 1:0.70:2, at least about 1:0.75:2, at least about 1:0.80:2, at least about 1:0.85:2, at least about 1:0.90:2, at least about 1:0.95:2, at least about 1:1:2, or at least about 1:1. :1.05:2, at least about 1:1.10:2, at least about 1:1.15:2, at least about 1:1.20:2, at least about 1:1.25:2, at least about 1:1.30:2, at least about 1:1.35:2, at least about 1:1.40:2, at least about 1:1.45:2, at least about 1:1.50:2, at least about 1:1.55:2, at least about 1:1.60:2, at least about 1:1.65:2, at least about 1:1.70:2, at least about 1:1.75:2, at least about 1:1.80:2, at least about 1:1.85:2, at least about 1:1.90:2, at least about 1:1.95:2 or at least about 1:2:2.

[0299] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.25:0.25, at least about 1:0.30:0.30, at least about 1:0.35:0.35, at least about 1:0.40:0.40, at least about 1:0.45:0.45, at least about 1:0.50:0.50, at least about 1:0.55:0.50, at least about 1:0.55:0.50, at least about 1:0.60:0.60, at least about 1:0.65 ... 0.55, at least about 1:0.60:0.60, at least about 1:0.65:0.65, at least about 1:0.70:0.70, at least about 1:0.75:0.75, at least about 1:0.80:0.80, at least about 1:0.85:0.85, at least about 1:0.90:0.90, at least about 1:0.95:0.95, at least about 1:1:1, at least about 1:1.05: 1.05, at least about 1:1.10:1.10, at least about 1:1.15:1.15, at least about 1:1.20:1.20, at least about 1:1.25:1.25, at least about 1:1.30:1.30, at least about 1:1.35:1.35, at least about 1:1.40:1.40, at least about 1:1.45:1.45, at least about 1:1.50:1.50, at least about 1 :1.55:1.55, at least about 1:1.60:1.60, at least about 1:1.65:1.65, at least about 1:1.70:1.70, at least about 1:1.75:1.75, at least about 1:1.80:1.80, at least about 1:1.85:1.85, at least about 1:1.90:1.90, at least about 1:1.95:1.95 or at least about 1:2:2.

[0300] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.25:0.30, at least about 1:0.25:0.35, at least about 1:0.25:0.40, at least about 1:0.25:0.45, at least about 1:0.25:0.50, at least about 1:0.25:0.55, or at least about 1:0. 25:0.60, at least about 1:0.25:0.65, at least about 1:0.25:0.70, at least about 1:0.25:0.75, at least about 1:0.25:0.80, at least about 1:0.25:0.85, at least about 1:0.25:0.90, at least about 1:0.25:0.95, at least about 1:0.25:1, at least about 1:0.25:1.05, at least Also about 1:0.25:1.10, at least about 1:0.25:1.15, at least about 1:0.25:1.20, at least about 1:0.25:1.25, at least about 1:0.25:1.30, at least about 1:0.25:1.35, at least about 1:0.25:1.40, at least about 1:0.25:1.45, at least about 1:0.25:1.50, at least about 1:0.25: 1.55, at least about 1:0.25:1.60, at least about 1:0.25:1.65, at least about 1:0.25:1.70, at least about 1:0.25:1.75, at least about 1:0.25:1.80, at least about 1:0.25:1.85, at least about 1:0.25:1.90, at least about 1:0.25:1.95 or at least about 1:0.25:2.

[0301] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.30:0.25, at least about 1:0.30:0.30, at least about 1:0.30:0.35, at least about 1:0.30:0.40, at least about 1:0.30:0.45, at least about 1:0.30:0.50, or at least about 1:0.30:0. 55, at least about 1:0.30:0.60, at least about 1:0.30:0.65, at least about 1:0.30:0.70, at least about 1:0.30:0.75, at least about 1:0.30:0.80, at least about 1:0.30:0.85, at least about 1:0.30:0.90, at least about 1:0.30:0.95, at least about 1:0.30:1, at least about 1:0.30: 1.05, at least about 1:0.30:1.10, at least about 1:0.30:1.15, at least about 1:0.30:1.20, at least about 1:0.30:1.25, at least about 1:0.30:1.30, at least about 1:0.30:1.35, at least about 1:0.30:1.40, at least about 1:0.30:1.45, at least about 1:0.30:1.50, at least about 1: 0.30:1.55, at least about 1:0.30:1.60, at least about 1:0.30:1.65, at least about 1:0.30:1.70, at least about 1:0.30:1.75, at least about 1:0.30:1.80, at least about 1:0.30:1.85, at least about 1:0.30:1.90, at least about 1:0.30:1.95 or at least about 1:0.30:2.

[0302] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.35:0.25, at least about 1:0.35:0.30, at least about 1:0.35:0.35, at least about 1:0.35:0.40, at least about 1:0.35:0.45, at least about 1:0.35:0.50, or at least about 1:0.35:0. 55, at least about 1:0.35:0.60, at least about 1:0.35:0.65, at least about 1:0.35:0.70, at least about 1:0.35:0.75, at least about 1:0.35:0.80, at least about 1:0.35:0.85, at least about 1:0.35:0.90, at least about 1:0.35:0.95, at least about 1:0.35:1, at least about 1:0.35: 1.05, at least about 1:0.35:1.10, at least about 1:0.35:1.15, at least about 1:0.35:1.20, at least about 1:0.35:1.25, at least about 1:0.35:1.30, at least about 1:0.35:1.35, at least about 1:0.35:1.40, at least about 1:0.35:1.45, at least about 1:0.35:1.50, at least about 1: 0.35:1.55, at least about 1:0.35:1.60, at least about 1:0.35:1.65, at least about 1:0.35:1.70, at least about 1:0.35:1.75, at least about 1:0.35:1.80, at least about 1:0.35:1.85, at least about 1:0.35:1.90, at least about 1:0.35:1.95 or at least about 1:0.35:2.

[0303] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.40:0.25, at least about 1:0.40:0.30, at least about 1:0.40:0.35, at least about 1:0.40:0.40, at least about 1:0.40:0.45, at least about 1:0.40:0.50, or at least about 1:0.40:0. 55, at least about 1:0.40:0.60, at least about 1:0.40:0.65, at least about 1:0.40:0.70, at least about 1:0.40:0.75, at least about 1:0.40:0.80, at least about 1:0.40:0.85, at least about 1:0.40:0.90, at least about 1:0.40:0.95, at least about 1:0.40:1, at least about 1:0.40:0. 1.05, at least about 1:0.40:1.10, at least about 1:0.40:1.15, at least about 1:0.40:1.20, at least about 1:0.40:1.25, at least about 1:0.40:1.30, at least about 1:0.40:1.35, at least about 1:0.40:1.40, at least about 1:0.40:1.45, at least about 1:0.40:1.50, at least about 1:0.40:1.60, at least about 1:0.40:1.70, at least about 1:0.40:1.80, at least about 1:0.40:1.90, at least about 1:0.40:1.10, at least about 1:0.40:1.11 0.40:1.55, at least about 1:0.40:1.60, at least about 1:0.40:1.65, at least about 1:0.40:1.70, at least about 1:0.40:1.75, at least about 1:0.40:1.80, at least about 1:0.40:1.85, at least about 1:0.40:1.90, at least about 1:0.40:1.95 or at least about 1:0.40:2.

[0304] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.45:0.25, at least about 1:0.45:0.30, at least about 1:0.45:0.35, at least about 1:0.45:0.40, at least about 1:0.45:0.45, at least about 1:0.45:0.50, or at least about 1:0.45:0. 55, at least about 1:0.45:0.60, at least about 1:0.45:0.65, at least about 1:0.45:0.70, at least about 1:0.45:0.75, at least about 1:0.45:0.80, at least about 1:0.45:0.85, at least about 1:0.45:0.90, at least about 1:0.45:0.95, at least about 1:0.45:1, at least about 1:0.45: 1.05, at least about 1:0.45:1.10, at least about 1:0.45:1.15, at least about 1:0.45:1.20, at least about 1:0.45:1.25, at least about 1:0.45:1.30, at least about 1:0.45:1.35, at least about 1:0.45:1.40, at least about 1:0.45:1.45, at least about 1:0.45:1.50, at least about 1: 0.45:1.55, at least about 1:0.45:1.60, at least about 1:0.45:1.65, at least about 1:0.45:1.70, at least about 1:0.45:1.75, at least about 1:0.45:1.80, at least about 1:0.45:1.85, at least about 1:0.45:1.90, at least about 1:0.45:1.95 or at least about 1:0.45:2.

[0305] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.50:0.25, at least about 1:0.50:0.30, at least about 1:0.50:0.35, at least about 1:0.50:0.40, at least about 1:0.50:0.45, at least about 1:0.50:0.50, or at least about 1:0.50:0. 55, at least about 1:0.50:0.60, at least about 1:0.50:0.65, at least about 1:0.50:0.70, at least about 1:0.50:0.75, at least about 1:0.50:0.80, at least about 1:0.50:0.85, at least about 1:0.50:0.90, at least about 1:0.50:0.95, at least about 1:0.50:1, at least about 1:0.50:0. 1.05, at least about 1:0.50:1.10, at least about 1:0.50:1.15, at least about 1:0.50:1.20, at least about 1:0.50:1.25, at least about 1:0.50:1.30, at least about 1:0.50:1.35, at least about 1:0.50:1.40, at least about 1:0.50:1.45, at least about 1:0.50:1.50, at least about 1: It can be 0.50:1.55, at least about 1:0.50:1.60, at least about 1:0.50:1.65, at least about 1:0.50:1.70, at least about 1:0.50:1.75, at least about 1:0.50:1.80, at least about 1:0.50:1.85, at least about 1:0.50:1.90, at least about 1:0.50:1.95 or at least about 1:0.50:2.

[0306] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.55:0.25, at least about 1:0.55:0.30, at least about 1:0.55:0.35, at least about 1:0.55:0.40, at least about 1:0.55:0.45, at least about 1:0.55:0.50, at least about 1:0.55:0.60, at least about 1:0.55:0.70, at least about 1:0.55:0.80, at least about 1:0.55:0.90, at least about 1:0.55:0.10, at least about 1:0.55:0.11, at least about 1:0.55:0.25, at least about 1:0.55:0.30, at least about 1:0.55:0.35, at least about 1:0.55:0.40, at least about 1:0.55:0.45, at least about 1:0.55:0.50, at least about 1:0.55:0.60, at least about 1:0.55:0.70, at least about 1:0.55:0.80, at least about 1:0.55:0.90, at least about 1:0.55:0.12 0.55, at least about 1:0.55:0.60, at least about 1:0.55:0.65, at least about 1:0.55:0.70, at least about 1:0.55:0.75, at least about 1:0.55:0.80, at least about 1:0.55:0.85, at least about 1:0.55:0.90, at least about 1:0.55:0.95, at least about 1:0.55:1, at least about 1:0.55:1. 55:1.05, at least about 1:0.55:1.10, at least about 1:0.55:1.15, at least about 1:0.55:1.20, at least about 1:0.55:1.25, at least about 1:0.55:1.30, at least about 1:0.55:1.35, at least about 1:0.55:1.40, at least about 1:0.55:1.45, at least about 1:0.55:1.50, at least or at least about 1:0.55:1.55, at least about 1:0.55:1.60, at least about 1:0.55:1.65, at least about 1:0.55:1.70, at least about 1:0.55:1.75, at least about 1:0.55:1.80, at least about 1:0.55:1.85, at least about 1:0.55:1.90, 1:0.55:1.95 or at least about 1:0.55:2.

[0307] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.60:0.25, at least about 1:0.60:0.30, at least about 1:0.60:0.35, at least about 1:0.60:0.40, at least about 1:0.60:0.45, at least about 1:0.60:0.50, or at least about 1:0.60:0. 55, at least about 1:0.60:0.60, at least about 1:0.60:0.65, at least about 1:0.60:0.70, at least about 1:0.60:0.75, at least about 1:0.60:0.80, at least about 1:0.60:0.85, at least about 1:0.60:0.90, at least about 1:0.60:0.95, at least about 1:0.60:1, at least about 1:0.60: 1.05, at least about 1:0.60:1.10, at least about 1:0.60:1.15, at least about 1:0.60:1.20, at least about 1:0.60:1.25, at least about 1:0.60:1.30, at least about 1:0.60:1.35, at least about 1:0.60:1.40, at least about 1:0.60:1.45, at least about 1:0.60:1.50, at least about 1:0.60:1.60 0.60:1.55, at least about 1:0.60:1.60, at least about 1:0.60:1.65, at least about 1:0.60:1.70, at least about 1:0.60:1.75, at least about 1:0.60:1.80, at least about 1:0.60:1.85, at least about 1:0.60:1.90, at least about 1:0.60:1.95 or at least about 1:0.60:2.

[0308] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.65:0.25, at least about 1:0.65:0.30, at least about 1:0.65:0.35, at least about 1:0.65:0.40, at least about 1:0.65:0.45, at least about 1:0.65:0.50, or at least about 1:0.65:0. 55, at least about 1:0.65:0.60, at least about 1:0.65:0.65, at least about 1:0.65:0.70, at least about 1:0.65:0.75, at least about 1:0.65:0.80, at least about 1:0.65:0.85, at least about 1:0.65:0.90, at least about 1:0.65:0.95, at least about 1:0.65:1, at least about 1:0.65: 1.05, at least about 1:0.65:1.10, at least about 1:0.65:1.15, at least about 1:0.65:1.20, at least about 1:0.65:1.25, at least about 1:0.65:1.30, at least about 1:0.65:1.35, at least about 1:0.65:1.40, at least about 1:0.65:1.45, at least about 1:0.65:1.50, at least about 1: 0.65:1.55, at least about 1:0.65:1.60, at least about 1:0.65:1.65, at least about 1:0.65:1.70, at least about 1:0.65:1.75, at least about 1:0.65:1.80, at least about 1:0.65:1.85, at least about 1:0.65:1.90, at least about 1:0.65:1.95 or at least about 1:0.65:2.

[0309] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.70:0.25, at least about 1:0.70:0.30, at least about 1:0.70:0.35, at least about 1:0.70:0.40, at least about 1:0.70:0.45, at least about 1:0.70:0.50, or at least about 1:0.70:0. 55, at least about 1:0.70:0.60, at least about 1:0.70:0.65, at least about 1:0.70:0.70, at least about 1:0.70:0.75, at least about 1:0.70:0.80, at least about 1:0.70:0.85, at least about 1:0.70:0.90, at least about 1:0.70:0.95, at least about 1:0.70:1, at least about 1:0.70: 1.05, at least about 1:0.70:1.10, at least about 1:0.70:1.15, at least about 1:0.70:1.20, at least about 1:0.70:1.25, at least about 1:0.70:1.30, at least about 1:0.70:1.35, at least about 1:0.70:1.40, at least about 1:0.70:1.45, at least about 1:0.70:1.50, at least about 1: 0.70:1.55, at least about 1:0.70:1.60, at least about 1:0.70:1.65, at least about 1:0.70:1.70, at least about 1:0.70:1.75, at least about 1:0.70:1.80, at least about 1:0.70:1.85, at least about 1:0.70:1.90, at least about 1:0.70:1.95 or at least about 1:0.70:2.

[0310] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.75:0.25, at least about 1:0.75:0.30, at least about 1:0.75:0.35, at least about 1:0.75:0.40, at least about 1:0.75:0.45, at least about 1:0.75:0.50, or at least about 1:0.75:0. 55, at least about 1:0.75:0.60, at least about 1:0.75:0.65, at least about 1:0.75:0.70, at least about 1:0.75:0.75, at least about 1:0.75:0.80, at least about 1:0.75:0.85, at least about 1:0.75:0.90, at least about 1:0.75:0.95, at least about 1:0.75:1, at least about 1:0.75: 1.05, at least about 1:0.75:1.10, at least about 1:0.75:1.15, at least about 1:0.75:1.20, at least about 1:0.75:1.25, at least about 1:0.75:1.30, at least about 1:0.75:1.35, at least about 1:0.75:1.40, at least about 1:0.75:1.45, at least about 1:0.75:1.50, at least about 1: It can be 0.75:1.55, at least about 1:0.75:1.60, at least about 1:0.75:1.65, at least about 1:0.75:1.70, at least about 1:0.75:1.75, at least about 1:0.75:1.80, at least about 1:0.75:1.85, at least about 1:0.75:1.90, at least about 1:0.75:1.95 or at least about 1:0.75:2.

[0311] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.80:0.25, at least about 1:0.80:0.30, at least about 1:0.80:0.35, at least about 1:0.80:0.40, at least about 1:0.80:0.45, at least about 1:0.80:0.50, at least about 1:0.80:0. 55, at least about 1:0.80:0.60, at least about 1:0.80:0.65, at least about 1:0.80:0.70, at least about 1:0.80:0.75, at least about 1:0.80:0.80, at least about 1:0.80:0.85, at least about 1:0.80:0.90, at least about 1:0.80:0.95, at least about 1:0.80:1, at least about 1:0.80: 1.05, at least about 1:0.80:1.10, at least about 1:0.80:1.15, at least about 1:0.80:1.20, at least about 1:0.80:1.25, at least about 1:0.80:1.30, at least about 1:0.80:1.35, at least about 1:0.80:1.40, at least about 1:0.80:1.45, at least about 1:0.80:1.50, at least about 1:0.80:1.60 0.80:1.55, at least about 1:0.80:1.60, at least about 1:0.80:1.65, at least about 1:0.80:1.70, at least about 1:0.80:1.75, at least about 1:0.80:1.80, at least about 1:0.80:1.85, at least about 1:0.80:1.90, at least about 1:0.80:1.95 or at least about 1:0.80:2.

[0312] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.85:0.25, at least about 1:0.85:0.30, at least about 1:0.85:0.35, at least about 1:0.85:0.40, at least about 1:0.85:0.45, at least about 1:0.85:0.50, or at least about 1:0.85:0. 55, at least about 1:0.85:0.60, at least about 1:0.85:0.65, at least about 1:0.85:0.70, at least about 1:0.85:0.75, at least about 1:0.85:0.80, at least about 1:0.85:0.85, at least about 1:0.85:0.90, at least about 1:0.85:0.95, at least about 1:0.85:1, at least about 1:0.85: 1.05, at least about 1:0.85:1.10, at least about 1:0.85:1.15, at least about 1:0.85:1.20, at least about 1:0.85:1.25, at least about 1:0.85:1.30, at least about 1:0.85:1.35, at least about 1:0.85:1.40, at least about 1:0.85:1.45, at least about 1:0.85:1.50, at least about 1: 0.85:1.55, at least about 1:0.85:1.60, at least about 1:0.85:1.65, at least about 1:0.85:1.70, at least about 1:0.85:1.75, at least about 1:0.85:1.80, at least about 1:0.85:1.85, at least about 1:0.85:1.90, at least about 1:0.85:1.95 or at least about 1:0.85:2.

[0313] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.90:0.25, at least about 1:0.90:0.30, at least about 1:0.90:0.35, at least about 1:0.90:0.40, at least about 1:0.90:0.45, at least about 1:0.90:0.50, or at least about 1:0.90:0. 55, at least about 1:0.90:0.60, at least about 1:0.90:0.65, at least about 1:0.90:0.70, at least about 1:0.90:0.75, at least about 1:0.90:0.80, at least about 1:0.90:0.85, at least about 1:0.90:0.90, at least about 1:0.90:0.95, at least about 1:0.90:1, at least about 1:0.90: 1.05, at least about 1:0.90:1.10, at least about 1:0.90:1.15, at least about 1:0.90:1.20, at least about 1:0.90:1.25, at least about 1:0.90:1.30, at least about 1:0.90:1.35, at least about 1:0.90:1.40, at least about 1:0.90:1.45, at least about 1:0.90:1.50, at least about 1: 0.90:1.55, at least about 1:0.90:1.60, at least about 1:0.90:1.65, at least about 1:0.90:1.70, at least about 1:0.90:1.75, at least about 1:0.90:1.80, at least about 1:0.90:1.85, at least about 1:0.90:1.90, at least about 1:0.90:1.95 or at least about 1:0.90:2.

[0314] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.95:0.25, at least about 1:0.95:0.30, at least about 1:0.95:0.35, at least about 1:0.95:0.40, at least about 1:0.95:0.45, at least about 1:0.95:0.50, or at least about 1:0.95:0. 55, at least about 1:0.95:0.60, at least about 1:0.95:0.65, at least about 1:0.95:0.70, at least about 1:0.95:0.75, at least about 1:0.95:0.80, at least about 1:0.95:0.85, at least about 1:0.95:0.90, at least about 1:0.95:0.95, at least about 1:0.95:1, at least about 1:0.95: 1.05, at least about 1:0.95:1.10, at least about 1:0.95:1.15, at least about 1:0.95:1.20, at least about 1:0.95:1.25, at least about 1:0.95:1.30, at least about 1:0.95:1.35, at least about 1:0.95:1.40, at least about 1:0.95:1.45, at least about 1:0.95:1.50, at least about 1: It can be 0.95:1.55, at least about 1:0.95:1.60, at least about 1:0.95:1.65, at least about 1:0.95:1.70, at least about 1:0.95:1.75, at least about 1:0.95:1.80, at least about 1:0.95:1.85, at least about 1:0.95:1.90, at least about 1:0.95:1.95 or at least about 1:0.95:2.

[0315] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1:0.25, at least about 1:1:0.30, at least about 1:1:0.35, at least about 1:1:0.40, at least about 1:1:0.45, at least about 1:1:0.50, at least about 1:1:0.55, at least about 1:1:0.60, at least about 1:1:0.65, at least about 1:1:0.70, at least about 1:1:0.75, at least about 1:1:0.80, at least about 1:1:0.85, at least about 1:1:0.90, at least about 1:1:0.95, at least about 1: ... 1:1:1.05, at least about 1:1:1.10, at least about 1:1:1.15, at least about 1:1:1.20, at least about 1:1:1.25, at least about 1:1:1.30, at least about 1:1:1.35, at least about 1:1:1.40, at least about 1:1:1.45, at least about 1:1:1.50, at least about 1:1:1.55, at least about 1:1:1.60, at least about 1:1:1.65, at least about 1:1:1.70, at least about 1:1:1.75, at least about 1:1:1.80, at least about 1:1:1.85, at least about 1:1:1.90, at least about 1:1:1.95 or at least about 1:1:2.

[0316] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.05:0.25, at least about 1:1.05:0.30, at least about 1:1.05:0.35, at least about 1:1.05:0.40, at least about 1:1.05:0.45, at least about 1:1.05:0.50, or at least about 1:1.05:0. 55, at least about 1:1.05:0.60, at least about 1:1.05:0.65, at least about 1:1.05:0.70, at least about 1:1.05:0.75, at least about 1:1.05:0.80, at least about 1:1.05:0.85, at least about 1:1.05:0.90, at least about 1:1.05:0.95, at least about 1:1.05:1, at least about 1:1.05: 1.05, at least about 1:1.05:1.10, at least about 1:1.05:1.15, at least about 1:1.05:1.20, at least about 1:1.05:1.25, at least about 1:1.05:1.30, at least about 1:1.05:1.35, at least about 1:1.05:1.40, at least about 1:1.05:1.45, at least about 1:1.05:1.50, at least about 1: 1.05:1.55, at least about 1:1.05:1.60, at least about 1:1.05:1.65, at least about 1:1.05:1.70, at least about 1:1.05:1.75, at least about 1:1.05:1.80, at least about 1:1.05:1.85, at least about 1:1.05:1.90, at least about 1:1.05:1.95 or at least about 1:1.05:2.

[0317] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.10:0.25, at least about 1:1.10:0.30, at least about 1:1.10:0.35, at least about 1:1.10:0.40, at least about 1:1.10:0.45, at least about 1:1.10:0.50, or at least about 1:1.10:0. 55, at least about 1:1.10:0.60, at least about 1:1.10:0.65, at least about 1:1.10:0.70, at least about 1:1.10:0.75, at least about 1:1.10:0.80, at least about 1:1.10:0.85, at least about 1:1.10:0.90, at least about 1:1.10:0.95, at least about 1:1.10:1, at least about 1:1.10: 1.05, at least about 1:1.10:1.10, at least about 1:1.10:1.15, at least about 1:1.10:1.20, at least about 1:1.10:1.25, at least about 1:1.10:1.30, at least about 1:1.10:1.35, at least about 1:1.10:1.40, at least about 1:1.10:1.45, at least about 1:1.10:1.50, at least about 1: 1.10:1.55, at least about 1:1.10:1.60, at least about 1:1.10:1.65, at least about 1:1.10:1.70, at least about 1:1.10:1.75, at least about 1:1.10:1.80, at least about 1:1.10:1.85, at least about 1:1.10:1.90, at least about 1:1.10:1.95 or at least about 1:1.10:2.

[0318] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.15:0.25, at least about 1:1.15:0.30, at least about 1:1.15:0.35, at least about 1:1.15:0.40, at least about 1:1.15:0.45, at least about 1:1.15:0.50, or at least about 1:1.15:0. 55, at least about 1:1.15:0.60, at least about 1:1.15:0.65, at least about 1:1.15:0.70, at least about 1:1.15:0.75, at least about 1:1.15:0.80, at least about 1:1.15:0.85, at least about 1:1.15:0.90, at least about 1:1.15:0.95, at least about 1:1.15:1, at least about 1:1.15: 1.05, at least about 1:1.15:1.10, at least about 1:1.15:1.15, at least about 1:1.15:1.20, at least about 1:1.15:1.25, at least about 1:1.15:1.30, at least about 1:1.15:1.35, at least about 1:1.15:1.40, at least about 1:1.15:1.45, at least about 1:1.15:1.50, at least about 1: 1.15:1.55, at least about 1:1.15:1.60, at least about 1:1.15:1.65, at least about 1:1.15:1.70, at least about 1:1.15:1.75, at least about 1:1.15:1.80, at least about 1:1.15:1.85, at least about 1:1.15:1.90, at least about 1:1.15:1.95 or at least about 1:1.15:2.

[0319] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.20:0.25, at least about 1:1.20:0.30, at least about 1:1.20:0.35, at least about 1:1.20:0.40, at least about 1:1.20:0.45, at least about 1:1.20:0.50, or at least about 1:1.20:0. 55, at least about 1:1.20:0.60, at least about 1:1.20:0.65, at least about 1:1.20:0.70, at least about 1:1.20:0.75, at least about 1:1.20:0.80, at least about 1:1.20:0.85, at least about 1:1.20:0.90, at least about 1:1.20:0.95, at least about 1:1.20:1, at least about 1:1.20: 1.05, at least about 1:1.20:1.10, at least about 1:1.20:1.15, at least about 1:1.20:1.20, at least about 1:1.20:1.25, at least about 1:1.20:1.30, at least about 1:1.20:1.35, at least about 1:1.20:1.40, at least about 1:1.20:1.45, at least about 1:1.20:1.50, at least about 1: 1.20:1.55, at least about 1:1.20:1.60, at least about 1:1.20:1.65, at least about 1:1.20:1.70, at least about 1:1.20:1.75, at least about 1:1.20:1.80, at least about 1:1.20:1.85, at least about 1:1.20:1.90, at least about 1:1.20:1.95 or at least about 1:1.20:2.

[0320] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.25:0.25, at least about 1:1.25:0.30, at least about 1:1.25:0.35, at least about 1:1.25:0.40, at least about 1:1.25:0.45, at least about 1:1.25:0.50, or at least about 1:1.25:0. 55, at least about 1:1.25:0.60, at least about 1:1.25:0.65, at least about 1:1.25:0.70, at least about 1:1.25:0.75, at least about 1:1.25:0.80, at least about 1:1.25:0.85, at least about 1:1.25:0.90, at least about 1:1.25:0.95, at least about 1:1.25:1, at least about 1:1.25: 1.05, at least about 1:1.25:1.10, at least about 1:1.25:1.15, at least about 1:1.25:1.20, at least about 1:1.25:1.25, at least about 1:1.25:1.30, at least about 1:1.25:1.35, at least about 1:1.25:1.40, at least about 1:1.25:1.45, at least about 1:1.25:1.50, at least about 1: 1.25:1.55, at least about 1:1.25:1.60, at least about 1:1.25:1.65, at least about 1:1.25:1.70, at least about 1:1.25:1.75, at least about 1:1.25:1.80, at least about 1:1.25:1.85, at least about 1:1.25:1.90, at least about 1:1.25:1.95 or at least about 1:1.25:2.

[0321] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.30:0.25, at least about 1:1.30:0.30, at least about 1:1.30:0.35, at least about 1:1.30:0.40, at least about 1:1.30:0.45, at least about 1:1.30:0.50, or at least about 1:1.30:0. 55, at least about 1:1.30:0.60, at least about 1:1.30:0.65, at least about 1:1.30:0.70, at least about 1:1.30:0.75, at least about 1:1.30:0.80, at least about 1:1.30:0.85, at least about 1:1.30:0.90, at least about 1:1.30:0.95, at least about 1:1.30:1, at least about 1:1.30: 1.05, at least about 1:1.30:1.10, at least about 1:1.30:1.15, at least about 1:1.30:1.20, at least about 1:1.30:1.25, at least about 1:1.30:1.30, at least about 1:1.30:1.35, at least about 1:1.30:1.40, at least about 1:1.30:1.45, at least about 1:1.30:1.50, at least about 1: 1.30:1.55, at least about 1:1.30:1.60, at least about 1:1.30:1.65, at least about 1:1.30:1.70, at least about 1:1.30:1.75, at least about 1:1.30:1.80, at least about 1:1.30:1.85, at least about 1:1.30:1.90, at least about 1:1.30:1.95 or at least about 1:1.30:2.

[0322] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.35:0.25, at least about 1:1.35:0.30, at least about 1:1.35:0.35, at least about 1:1.35:0.40, at least about 1:1.35:0.45, at least about 1:1.35:0.50, or at least about 1:1. 35:0.55, at least about 1:1.35:0.65, at least about 1:1.35:0.70, at least about 1:1.35:0.75, at least about 1:1.35:0.80, at least about 1:1.35:0.85, at least about 1:1.35:0.90, at least about 1:1.35:0.95, at least about 1:1.35:1, at least about 1:1.35:1.05, at least Also about 1:1.35:1.10, at least about 1:1.35:1.15, at least about 1:1.35:1.20, at least about 1:1.35:1.25, at least about 1:1.35:1.30, at least about 1:1.35:1.35, at least about 1:1.35:1.40, at least about 1:1.35:1.45, at least about 1:1.35:1.50, at least about 1:1.35: 1.55, at least about 1:1.35:1.60, at least about 1:1.35:1.65, at least about 1:1.35:1.70, at least about 1:1.35:1.75, at least about 1:1.35:1.80, at least about 1:1.35:1.85, at least about 1:1.35:1.90, at least about 1:1.35:1.95 or at least about 1:1.35:2.

[0323] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.40:0.25, at least about 1:1.40:0.30, at least about 1:1.40:0.35, at least about 1:1.40:0.40, at least about 1:1.40:0.45, at least about 1:1.40:0.50, or at least about 1:1.40:0. 55, at least about 1:1.40:0.60, at least about 1:1.40:0.65, at least about 1:1.40:0.70, at least about 1:1.40:0.75, at least about 1:1.40:0.80, at least about 1:1.40:0.85, at least about 1:1.40:0.90, at least about 1:1.40:0.95, at least about 1:1.40:1, at least about 1:1.40:0. 1.05, at least about 1:1.40:1.10, at least about 1:1.40:1.15, at least about 1:1.40:1.20, at least about 1:1.40:1.25, at least about 1:1.40:1.30, at least about 1:1.40:1.35, at least about 1:1.40:1.40, at least about 1:1.40:1.45, at least about 1:1.40:1.50, at least about 1: 1.40:1.55, at least about 1:1.40:1.60, at least about 1:1.40:1.65, at least about 1:1.40:1.70, at least about 1:1.40:1.75, at least about 1:1.40:1.80, at least about 1:1.40:1.85, at least about 1:1.40:1.90, at least about 1:1.40:1.95 or at least about 1:1.40:2.

[0324] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.45:0.25, at least about 1:1.45:0.30, at least about 1:1.45:0.35, at least about 1:1.45:0.40, at least about 1:1.45:0.45, at least about 1:1.45:0.50, or at least about 1:1.45:0. 55, at least about 1:1.45:0.60, at least about 1:1.45:0.65, at least about 1:1.45:0.70, at least about 1:1.45:0.75, at least about 1:1.45:0.80, at least about 1:1.45:0.85, at least about 1:1.45:0.90, at least about 1:1.45:0.95, at least about 1:1.45:1, at least about 1:1.45: 1.05, at least about 1:1.45:1.10, at least about 1:1.45:1.15, at least about 1:1.45:1.20, at least about 1:1.45:1.25, at least about 1:1.45:1.30, at least about 1:1.45:1.35, at least about 1:1.45:1.40, at least about 1:1.45:1.45, at least about 1:1.45:1.50, at least about 1: 1.45:1.55, at least about 1:1.45:1.60, at least about 1:1.45:1.65, at least about 1:1.45:1.70, at least about 1:1.45:1.75, at least about 1:1.45:1.80, at least about 1:1.45:1.85, at least about 1:1.45:1.90, at least about 1:1.45:1.95 or at least about 1:1.45:2.

[0325] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.50:0.25, at least about 1:1.50:0.30, at least about 1:1.50:0.35, at least about 1:1.50:0.40, at least about 1:1.50:0.45, at least about 1:1.50:0.50, or at least about 1:1.50:0. 55, at least about 1:1.50:0.60, at least about 1:1.50:0.65, at least about 1:1.50:0.70, at least about 1:1.50:0.75, at least about 1:1.50:0.80, at least about 1:1.50:0.85, at least about 1:1.50:0.90, at least about 1:1.50:0.95, at least about 1:1.50:1, at least about 1:1.50:0. 1.05, at least about 1:1.50:1.10, at least about 1:1.50:1.15, at least about 1:1.50:1.20, at least about 1:1.50:1.25, at least about 1:1.50:1.30, at least about 1:1.50:1.35, at least about 1:1.50:1.40, at least about 1:1.50:1.45, at least about 1:1.50:1.50, at least about 1: 1.50:1.55, at least about 1:1.50:1.60, at least about 1:1.50:1.65, at least about 1:1.50:1.70, at least about 1:1.50:1.75, at least about 1:1.50:1.80, at least about 1:1.50:1.85, at least about 1:1.50:1.90, at least about 1:1.50:1.95 or at least about 1:1.50:2.

[0326] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.55:0.25, at least about 1:1.55:0.30, at least about 1:1.55:0.35, at least about 1:1.55:0.40, at least about 1:1.55:0.45, at least about 1:1.55:0.50, or at least about 1:1.55:0. 55, at least about 1:1.55:0.60, at least about 1:1.55:0.65, at least about 1:1.55:0.70, at least about 1:1.55:0.75, at least about 1:1.55:0.80, at least about 1:1.55:0.85, at least about 1:1.55:0.90, at least about 1:1.55:0.95, at least about 1:1.55:1, at least about 1:1.55: 1.05, at least about 1:1.55:1.10, at least about 1:1.55:1.15, at least about 1:1.55:1.20, at least about 1:1.55:1.25, at least about 1:1.55:1.30, at least about 1:1.55:1.35, at least about 1:1.55:1.40, at least about 1:1.55:1.45, at least about 1:1.55:1.50, at least about 1: 1.55:1.55, at least about 1:1.55:1.60, at least about 1:1.55:1.65, at least about 1:1.55:1.70, at least about 1:1.55:1.75, at least about 1:1.55:1.80, at least about 1:1.55:1.85, at least about 1:1.55:1.90, at least about 1:1.55:1.95 or at least about 1:1.55:2.

[0327] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.60:0.25, at least about 1:1.60:0.30, at least about 1:1.60:0.35, at least about 1:1.60:0.40, at least about 1:1.60:0.45, at least about 1:1.60:0.50, or at least about 1:1.60:0. 55, at least about 1:1.60:0.60, at least about 1:1.60:0.65, at least about 1:1.60:0.70, at least about 1:1.60:0.75, at least about 1:1.60:0.80, at least about 1:1.60:0.85, at least about 1:1.60:0.90, at least about 1:1.60:0.95, at least about 1:1.60:1, at least about 1:1.60:0. 1.05, at least about 1:1.60:1.10, at least about 1:1.60:1.15, at least about 1:1.60:1.20, at least about 1:1.60:1.25, at least about 1:1.60:1.30, at least about 1:1.60:1.35, at least about 1:1.60:1.40, at least about 1:1.60:1.45, at least about 1:1.60:1.50, at least about 1: 1.60:1.55, at least about 1:1.60:1.60, at least about 1:1.60:1.65, at least about 1:1.60:1.70, at least about 1:1.60:1.75, at least about 1:1.60:1.80, at least about 1:1.60:1.85, at least about 1:1.60:1.90, at least about 1:1.60:1.95 or at least about 1:1.60:2.

[0328] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.65:0.25, at least about 1:1.65:0.30, at least about 1:1.65:0.35, at least about 1:1.65:0.40, at least about 1:1.65:0.45, at least about 1:1.65:0.50, or at least about 1:1.65:0. 55, at least about 1:1.65:0.60, at least about 1:1.65:0.65, at least about 1:1.65:0.70, at least about 1:1.65:0.75, at least about 1:1.65:0.80, at least about 1:1.65:0.85, at least about 1:1.65:0.90, at least about 1:1.65:0.95, at least about 1:1.65:1, at least about 1:1.65: 1.05, at least about 1:1.65:1.10, at least about 1:1.65:1.15, at least about 1:1.65:1.20, at least about 1:1.65:1.25, at least about 1:1.65:1.30, at least about 1:1.65:1.35, at least about 1:1.65:1.40, at least about 1:1.65:1.45, at least about 1:1.65:1.50, at least about 1: 1.65:1.55, at least about 1:1.65:1.60, at least about 1:1.65:1.65, at least about 1:1.65:1.70, at least about 1:1.65:1.75, at least about 1:1.65:1.80, at least about 1:1.65:1.85, at least about 1:1.65:1.90, at least about 1:1.65:1.95 or at least about 1:1.65:2.

[0329] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.70:0.25, at least about 1:1.70:0.30, at least about 1:1.70:0.35, at least about 1:1.70:0.40, at least about 1:1.70:0.45, at least about 1:1.70:0.50, or at least about 1:1.70:0. 55, at least about 1:1.70:0.60, at least about 1:1.70:0.65, at least about 1:1.70:0.70, at least about 1:1.70:0.75, at least about 1:1.70:0.80, at least about 1:1.70:0.85, at least about 1:1.70:0.90, at least about 1:1.70:0.95, at least about 1:1.70:1, at least about 1:1.70:0. 1.05, at least about 1:1.70:1.10, at least about 1:1.70:1.15, at least about 1:1.70:1.20, at least about 1:1.70:1.25, at least about 1:1.70:1.30, at least about 1:1.70:1.35, at least about 1:1.70:1.40, at least about 1:1.70:1.45, at least about 1:1.70:1.50, at least about 1: 1.70:1.55, at least about 1:1.70:1.60, at least about 1:1.70:1.65, at least about 1:1.70:1.70, at least about 1:1.70:1.75, at least about 1:1.70:1.80, at least about 1:1.70:1.85, at least about 1:1.70:1.90, at least about 1:1.70:1.95 or at least about 1:1.70:2.

[0330] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.75:0.25, at least about 1:1.75:0.30, at least about 1:1.75:0.35, at least about 1:1.75:0.40, at least about 1:1.75:0.45, at least about 1:1.75:0.50, or at least about 1:1.75:0. 55, at least about 1:1.75:0.60, at least about 1:1.75:0.65, at least about 1:1.75:0.70, at least about 1:1.75:0.75, at least about 1:1.75:0.80, at least about 1:1.75:0.85, at least about 1:1.75:0.90, at least about 1:1.75:0.95, at least about 1:1.75:1, at least about 1:1.75: 1.05, at least about 1:1.75:1.10, at least about 1:1.75:1.15, at least about 1:1.75:1.20, at least about 1:1.75:1.25, at least about 1:1.75:1.30, at least about 1:1.75:1.35, at least about 1:1.75:1.40, at least about 1:1.75:1.45, at least about 1:1.75:1.50, at least about 1: 1.75:1.55, at least about 1:1.75:1.60, at least about 1:1.75:1.65, at least about 1:1.75:1.70, at least about 1:1.75:1.75, at least about 1:1.75:1.80, at least about 1:1.75:1.85, at least about 1:1.75:1.90, at least about 1:1.75:1.95 or at least about 1:1.75:2.

[0331] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.80:0.25, at least about 1:1.80:0.30, at least about 1:1.80:0.35, at least about 1:1.80:0.40, at least about 1:1.80:0.45, at least about 1:1.80:0.50, or at least about 1:1.80:0. 55, at least about 1:1.80:0.60, at least about 1:1.80:0.65, at least about 1:1.80:0.70, at least about 1:1.80:0.75, at least about 1:1.80:0.80, at least about 1:1.80:0.85, at least about 1:1.80:0.90, at least about 1:1.80:0.95, at least about 1:1.80:1, at least about 1:1.80:0. 1.05, at least about 1:1.80:1.10, at least about 1:1.80:1.15, at least about 1:1.80:1.20, at least about 1:1.80:1.25, at least about 1:1.80:1.30, at least about 1:1.80:1.35, at least about 1:1.80:1.40, at least about 1:1.80:1.45, at least about 1:1.80:1.50, at least about 1: 1.80:1.55, at least about 1:1.80:1.60, at least about 1:1.80:1.65, at least about 1:1.80:1.70, at least about 1:1.80:1.75, at least about 1:1.80:1.80, at least about 1:1.80:1.85, at least about 1:1.80:1.90, at least about 1:1.80:1.95 or at least about 1:1.80:2.

[0332] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.85:0.25, at least about 1:1.85:0.30, at least about 1:1.85:0.35, at least about 1:1.85:0.40, at least about 1:1.85:0.45, at least about 1:1.85:0.50, or at least about 1:1.85:0. 55, at least about 1:1.85:0.60, at least about 1:1.85:0.65, at least about 1:1.85:0.70, at least about 1:1.85:0.75, at least about 1:1.85:0.80, at least about 1:1.85:0.85, at least about 1:1.85:0.90, at least about 1:1.85:0.95, at least about 1:1.85:1, at least about 1:1.85: 1.05, at least about 1:1.85:1.10, at least about 1:1.85:1.15, at least about 1:1.85:1.20, at least about 1:1.85:1.25, at least about 1:1.85:1.30, at least about 1:1.85:1.35, at least about 1:1.85:1.40, at least about 1:1.85:1.45, at least about 1:1.85:1.50, at least about 1: 1.85:1.55, at least about 1:1.85:1.60, at least about 1:1.85:1.65, at least about 1:1.85:1.70, at least about 1:1.85:1.75, at least about 1:1.85:1.80, at least about 1:1.85:1.85, at least about 1:1.85:1.90, at least about 1:1.85:1.95 or at least about 1:1.85:2.

[0333] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.90:0.25, at least about 1:1.90:0.30, at least about 1:1.90:0.35, at least about 1:1.90:0.40, at least about 1:1.90:0.45, at least about 1:1.90:0.50, or at least about 1:1.90:0. 55, at least about 1:1.90:0.60, at least about 1:1.90:0.65, at least about 1:1.90:0.70, at least about 1:1.90:0.75, at least about 1:1.90:0.80, at least about 1:1.90:0.85, at least about 1:1.90:0.90, at least about 1:1.90:0.95, at least about 1:1.90:1, at least about 1:1.90: 1.05, at least about 1:1.90:1.10, at least about 1:1.90:1.15, at least about 1:1.90:1.20, at least about 1:1.90:1.25, at least about 1:1.90:1.30, at least about 1:1.90:1.35, at least about 1:1.90:1.40, at least about 1:1.90:1.45, at least about 1:1.90:1.50, at least about 1: 1.90:1.55, at least about 1:1.90:1.60, at least about 1:1.90:1.65, at least about 1:1.90:1.70, at least about 1:1.90:1.75, at least about 1:1.90:1.80, at least about 1:1.90:1.85, at least about 1:1.90:1.90, at least about 1:1.90:1.95 or at least about 1:1.90:2.

[0334] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:1.95:0.25, at least about 1:1.95:0.30, at least about 1:1.95:0.35, at least about 1:1.95:0.40, at least about 1:1.95:0.45, at least about 1:1.95:0.50, at least about 1:1.95:0.60, at least about 1:1.95:0.70, at least about 1:1.95:0.80, at least about 1:1.95:0.90, at least about 1:1.95:0.10, at least about 1:1.95:0.11, at least about 1:1.95:0.25, at least about 1:1.95:0.30, at least about 1:1.95:0.35, at least about 1:1.95:0.40, at least about 1:1.95:0.45, at least about 1:1.95:0.50, at least about 1:1.95:0.60, at least about 1:1.95:0.70, at least about 1:1.95:0.80, at least about 1:1.95:0.90 0.95:0.55, at least about 1:1.95:0.60, at least about 1:1.95:0.65, at least about 1:1.95:0.70, at least about 1:1.95:0.75, at least about 1:1.95:0.80, at least about 1:1.95:0.85, at least about 1:1.95:0.90, at least about 1:1.95:0.95, at least about 1:1.95:1, at least at least about 1:1.95:1.05, at least about 1:1.95:1.10, at least about 1:1.95:1.15, at least about 1:1.95:1.20, at least about 1:1.95:1.25, at least about 1:1.95:1.30, at least about 1:1.95:1.35, at least about 1:1.95:1.40, at least about 1:1.95:1.45, at least about 1:1. 95:1.50, at least about 1:1.95:1.55, at least about 1:1.95:1.60, at least about 1:1.95:1.65, at least about 1:1.95:1.70, at least about 1:1.95:1.75, at least about 1:1.95:1.80, at least about 1:1.95:1.85, at least about 1:1.95:1.90, at least about 1:1.95:1.95, or at least about 1:1.95:2.

[0335] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:2:0.25, at least about 1:2:0.30, at least about 1:2:0.35, at least about 1:2:0.40, at least about 1:2:0.45, at least about 1:2:0.50, at least about 1:2:0.55, at least about 1:2:0.60, at least about 1:2:0.65, at least about 1:2:0.70, at least about 1:2:0.75, at least about 1:2:0.80, at least about 1:2:0.85, at least about 1:2:0.90, at least about 1:2:0.95, at least about 1:2:1, at least about 1:2:1. 1:2:1.05, at least about 1:2:1.10, at least about 1:2:1.15, at least about 1:2:1.20, at least about 1:2:1.25, at least about 1:2:1.30, at least about 1:2:1.35, at least about 1:2:1.40, at least about 1:2:1.45, at least about 1:2:1.50, at least about 1:2:1.55, at least about 1:2:1.60, at least about 1:2:1.65, at least about 1:2:1.70, at least about 1:2:1.75, at least about 1:2:1.80, at least about 1:2:1.85, at least about 1:2:1.90, at least about 1:2:1.95 or at least about 1:2:2.

[0336] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.25:0.25, at least about 1:0.30:0.25, at least about 1:0.35:0.25, at least about 1:0.40:0.25, at least about 1:0.45:0.25, at least about 1:0.50:0.25, or at least about 1:0.55:0. 25, at least about 1:0.60:0.25, at least about 1:0.65:0.25, at least about 1:0.70:0.25, at least about 1:0.75:0.25, at least about 1:0.80:0.25, at least about 1:0.85:0.25, at least about 1:0.90:0.25, at least about 1:0.95:0.25, at least about 1:1:0.25, at least about 1:1.05: 0.25, at least about 1:1.10:0.25, at least about 1:1.15:0.25, at least about 1:1.20:0.25, at least about 1:1.25:0.25, at least about 1:1.30:0.25, at least about 1:1.35:0.25, at least about 1:1.40:0.25, at least about 1:1.45:0.25, at least about 1:1.50:0.25, at least about 1: 1.55:0.25, at least about 1:1.60:0.25, at least about 1:1.65:0.25, at least about 1:1.70:0.25, at least about 1:1.75:0.25, at least about 1:1.80:0.25, at least about 1:1.85:0.25, at least about 1:1.90:0.25, at least about 1:1.95:0.25 or at least about 1:2:0.25.

[0337] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.25:0.30, at least about 1:0.30:0.30, at least about 1:0.35:0.30, at least about 1:0.40:0.30, at least about 1:0.45:0.30, at least about 1:0.50:0.30, or at least about 1:0.55:0. 30, at least about 1:0.60:0.30, at least about 1:0.65:0.30, at least about 1:0.70:0.30, at least about 1:0.75:0.30, at least about 1:0.80:0.30, at least about 1:0.85:0.30, at least about 1:0.90:0.30, at least about 1:0.95:0.30, at least about 1:1:0.30, at least about 1:1.05:0.30 0.30, at least about 1:1.10:0.30, at least about 1:1.15:0.30, at least about 1:1.20:0.30, at least about 1:1.25:0.30, at least about 1:1.30:0.30, at least about 1:1.35:0.30, at least about 1:1.40:0.30, at least about 1:1.45:0.30, at least about 1:1.50:0.30, at least about 1: 1.55:0.30, at least about 1:1.60:0.30, at least about 1:1.65:0.30, at least about 1:1.70:0.30, at least about 1:1.75:0.30, at least about 1:1.80:0.30, at least about 1:1.85:0.30, at least about 1:1.90:0.30, at least about 1:1.95:0.30 or at least about 1:2:0.30.

[0338] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.25:0.35, at least about 1:0.30:0.35, at least about 1:0.35:0.35, at least about 1:0.40:0.35, at least about 1:0.45:0.35, at least about 1:0.50:0.35, or at least about 1:0.55:0. 35, at least about 1:0.60:0.35, at least about 1:0.65:0.35, at least about 1:0.70:0.35, at least about 1:0.75:0.35, at least about 1:0.80:0.35, at least about 1:0.85:0.35, at least about 1:0.90:0.35, at least about 1:0.95:0.35, at least about 1:1:0.35, at least about 1:1.05: 0.35, at least about 1:1.10:0.35, at least about 1:1.15:0.35, at least about 1:1.20:0.35, at least about 1:1.25:0.35, at least about 1:1.30:0.35, at least about 1:1.35:0.35, at least about 1:1.40:0.35, at least about 1:1.45:0.35, at least about 1:1.50:0.35, at least about 1: 1.55:0.35, at least about 1:1.60:0.35, at least about 1:1.65:0.35, at least about 1:1.70:0.35, at least about 1:1.75:0.35, at least about 1:1.80:0.35, at least about 1:1.85:0.35, at least about 1:1.90:0.35, at least about 1:1.95:0.35 or at least about 1:2:0.35.

[0339] In further embodiments, the ratio of PD-1 antagonist to TIGIT antagonist to CD96 antagonist is at least about 1:0.25:0.40, at least about 1:0.30:0.40, at least about 1:0.35:0.40, at least about 1:0.40:0.40, at least about 1:0.45:0.40, at least about 1:0.50:0.40, or at least about 1:0.55:0. 40, at least ab...

Claims

1. A combination pharmaceutical comprising a CD96 binding protein, a PD-1 antagonist and a TIGIT antagonist for treating cancer in a human, wherein the CD96 binding protein comprises a CDRH1 of SEQ ID NO: 115; a CDRH2 of SEQ ID NO: 145; a CDRH3 of SEQ ID NO: 147; a CDRL1 of SEQ ID NO: 97; a CDRL2 of SEQ ID NO: 99; and a CDRL3 of SEQ ID NO:

101.

2. The pharmaceutical combination of claim 1, wherein the CD96 binding protein comprises a VH region of SEQ ID NO:86 and a VL region of SEQ ID NO:

85.

3. The pharmaceutical combination according to claim 1 or 2, wherein the CD96 binding protein is an antibody.

4. The pharmaceutical combination of claim 3 , wherein the CD96 antibody further comprises a human wild-type IgG1 Fc domain.

5. The pharmaceutical combination according to claim 4, wherein the CD96 antibody comprises a heavy chain of SEQ ID NO: 165 and a light chain of SEQ ID NO:

166.

6. The pharmaceutical combination according to any one of claims 1 to 5, wherein the TIGIT antagonist is an anti-TIGIT antibody.

7. The pharmaceutical combination of claim 6, wherein the anti-TIGIT antibody comprises a VH region of SEQ ID NO:362 and a VL region of SEQ ID NO:

363.

8. The pharmaceutical combination according to claim 7, wherein the anti-TIGIT antibody is EOS884488.

9. The pharmaceutical combination according to any one of claims 1 to 8, wherein the PD-1 antagonist is an anti-PD-1 antibody.

10. The pharmaceutical combination of claim 9, wherein the anti-PD-1 antibody comprises the heavy chain sequence of SEQ ID NO: 160 and the light chain sequence of SEQ ID NO:

161.

11. The combination pharmaceutical of claim 10, wherein the anti-PD-1 antibody is dostallimab.

12. The pharmaceutical combination of any one of claims 1 to 11, wherein the PD-1 antagonist and the TIGIT antagonist are administered to the human in a ratio of about 1.0:0.80 to about 1.0:1.2 (PD-1 antagonist:TIGIT antagonist).

13. The pharmaceutical combination of any one of claims 1 to 12, wherein the CD96 binding protein, the PD-1 antagonist and the TIGIT antagonist are administered to the human simultaneously or sequentially in any order.

14. The pharmaceutical combination according to any one of claims 1 to 12, wherein a pharmaceutical composition comprising the CD96 binding protein, the PD-1 antagonist and the TIGIT antagonist is administered to the human.

15. The combination pharmaceutical of any one of claims 1 to 14, wherein the cancer is a solid tumor.

16. The pharmaceutical combination according to any one of claims 1 to 14, wherein the cancer is selected from the group consisting of ovarian cancer, lung cancer, gastric cancer, bladder cancer, colorectal cancer, liver cancer, kidney cancer and head and neck squamous cell carcinoma.

17. The pharmaceutical combination according to claim 16, wherein the cancer is lung cancer.

18. The pharmaceutical combination according to claim 17, wherein the lung cancer is non-small cell lung cancer (NSCLC).

19. A pharmaceutical composition comprising a CD96 binding protein for treating cancer in a human, wherein the pharmaceutical composition is administered in combination with a PD-1 antagonist and a TIGIT antagonist, and the CD96 binding protein comprises a CDRH1 of SEQ ID NO: 115; a CDRH2 of SEQ ID NO: 145; a CDRH3 of SEQ ID NO: 147; a CDRL1 of SEQ ID NO: 97; a CDRL2 of SEQ ID NO: 99; and a CDRL3 of SEQ ID NO:

101.

20. The pharmaceutical composition of claim 19, wherein the pharmaceutical composition, the PD-1 antagonist and the TIGIT antagonist are administered to the human simultaneously or sequentially in any order.

21. A pharmaceutical composition comprising a PD-1 antagonist for treating cancer in a human, wherein the pharmaceutical composition is administered in combination with a CD96 binding protein and a TIGIT antagonist, wherein the CD96 binding protein comprises a CDRH1 of SEQ ID NO: 115; a CDRH2 of SEQ ID NO: 145; a CDRH3 of SEQ ID NO: 147; a CDRL1 of SEQ ID NO: 97; a CDRL2 of SEQ ID NO: 99; and a CDRL3 of SEQ ID NO:

101.

22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition, CD96 binding protein and TIGIT antagonist are administered to the human simultaneously or sequentially in any order.

23. A pharmaceutical composition comprising a TIGIT antagonist for treating cancer in a human, wherein the pharmaceutical composition is administered in combination with a CD96 binding protein and a PD-1 antagonist, wherein the CD96 binding protein comprises a CDRH1 of SEQ ID NO: 115; a CDRH2 of SEQ ID NO: 145; a CDRH3 of SEQ ID NO: 147; a CDRL1 of SEQ ID NO: 97; a CDRL2 of SEQ ID NO: 99; and a CDRL3 of SEQ ID NO:

101.

24. The pharmaceutical composition of claim 23, wherein the pharmaceutical composition, the CD96 binding protein and the PD-1 antagonist are administered to the human simultaneously or sequentially in any order.

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