Anti-TIGIT antibody preparation

Abstract

The present invention provides a formulation comprising an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4 (S241P) described in this specification).

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 346,167, filed May 26, 2023, the entire disclosure of which is incorporated herein by reference.

Background Art

[0002] TIGIT is a co - inhibitory receptor highly expressed on effector and regulatory (Treg) CD4 + T cells, effector CD8 + T cells, and NK cells. TIGIT has been shown to attenuate the immune response by (1) direct signaling, (2) induction of ligand signaling, and (3) competition with the costimulatory receptor CD226 (also known as DNAM - 1) and thereby interfering with its signaling. TIGIT signaling has been most studied in NK cells, and binding to its cognate ligand, the poliovirus receptor (PVR, also known as CD155), has been shown to directly inhibit the cytotoxicity of NK cells via its cytoplasmic ITIM domain. Knockout of the TIGIT gene or antibody blockade of the TIGIT / PVR interaction has been shown to enhance NK cell killing in vitro and exacerbate autoimmune diseases in vitro. In addition to its direct effects on T cells and NK cells, TIGIT can induce PVR - mediated signaling in dendritic cells or tumor cells, which leads to an increase in the production of anti - inflammatory cytokines such as IL10. In T cells, TIGIT can also inhibit lymphocyte responses by interfering with the homodimerization of the costimulatory receptor CD226 and competing with it for binding to PVR.

[0003] TIGIT is highly expressed in lymphocytes, including tumor-infiltrating lymphocytes (TILs) and Tregs, which infiltrate various types of tumors. PVR is also widely expressed in tumors, suggesting that the TIGIT-PVR signaling axis may be a major immune evasion mechanism in cancer. Notably, TIGIT expression is closely correlated with the expression of another important co-inhibitory receptor, PD1. TIGIT and PD1 are co-expressed on TILs of many human and mouse tumors. Different from TIGIT and CTLA4, PD1 inhibition of T cell responses does not involve competition for ligand binding with co-stimulatory receptors.

[0004] An object of the present invention is to provide a formulation comprising an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)).

Summary of the Invention

[0005] In some aspects, the present invention provides (a) an anti-TIGIT antibody, wherein the anti-TIGIT antibody comprises i) a heavy chain variable domain comprising vhCDR1, vhCDR2, and vhCDR3 from the heavy chain (SEQ ID NO: 5) of CPA.9.086.H4(S241P), and ii) a light chain variable domain comprising vlCDR1, vlCDR2, and vlCDR3 from the light chain (SEQ ID NO: 10) of CPA.9.086.H4(S241P), (b) 8 mM to 12 mM of histidine, (c) 25 mM to 35 mM of L-arginine, (d) 8 mM to 12 mM of L-methionine, (e) 7% (w / v) to 9% (w / v) of sucrose, (f) 70 ppm to 80 ppm of polysorbate 80, and provides a stable liquid pharmaceutical formulation of the anti-TIGIT antibody, wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0006] ​In some embodiments of paragraph

[0004] , the anti-TIGIT antibody comprises the CH1-hinge-CH2-CH3 sequence of IgG4, and the hinge region optionally contains mutations.

[0007] In some embodiments of paragraphs

[0004] to

[0005] , the anti-TIGIT antibody comprises the CH1-hinge-CH2-CH3 sequence of IgG4, and the hinge region optionally contains mutations.

[0008] In some embodiments of paragraphs

[0004] to

[0006] , the heavy chain variable domain is derived from the heavy chain of CPA.9.086.H4 (S241P) (SEQ ID NO: 1), and the light chain variable domain is derived from the light chain of CPA.9.086.H4 (S241P) (SEQ ID NO: 6).

[0009] In some embodiments of paragraphs

[0004] to

[0007] , the anti-TIGIT antibody comprises the CL region of the human kappa 2 light chain.

[0010] In some embodiments of paragraphs

[0004] to

[0008] , the pharmaceutical formulation comprises from about 15 mg / mL to about 25 mg / mL of the anti-TIGIT antibody.

[0011] In some embodiments of paragraphs

[0004] to

[0009] , the pharmaceutical formulation comprises about 20 mg / mL of the anti-TIGIT antibody.

[0012] In some embodiments of paragraphs

[0004] to

[0010] , the pharmaceutical formulation comprises about 10 mM of histidine.

[0013] In some embodiments of paragraphs

[0004] to

[0011] , the pharmaceutical formulation comprises about 30 mM of L-arginine.

[0014] In some embodiments of paragraphs

[0004] to

[0012] , the pharmaceutical formulation comprises about 10 mM of L-methionine.

[0015] In some embodiments of paragraphs

[0004] to

[0013] , the pharmaceutical preparation contains about 8% sucrose.

[0016] In some embodiments of paragraphs

[0004] to

[0014] , the pharmaceutical preparation contains about 75 ppm of polysorbate 80.

[0017] In some aspects, the present invention (a) an anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody i) a heavy chain variable domain (SEQ ID NO: 1) containing vhCDR1, vhCDR2, and vhCDR3 from the heavy chain of CPA.9.086.H4(S241P), and ii) a light chain variable domain (SEQ ID NO: 6) containing vlCDR1, vlCDR2, and vlCDR3 from the light chain of CPA.9.086.H4(S241P), and (b) about 10 mM of histidine, and (c) about 30 mM of L-arginine, and (d) about 10 mM of L-methionine, and (e) about 8% (w / v) of sucrose, and (f) about 75 ppm of polysorbate 80, and provides a stable liquid pharmaceutical preparation of the anti-TIGIT antibody, wherein the pharmaceutical preparation has a pH of 5.4 + / - 0.2.

[0018] In some aspects, the present invention (a) an anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody i) a heavy chain variable domain (SEQ ID NO: 1) from the heavy chain of CPA.9.086.H4(S241P), and ii) a light chain variable domain (SEQ ID NO: 6) from the light chain of CPA.9.086.H4(S241P), and (b) about 10 mM of histidine, and (c) about 30 mM of L-arginine, and (d) about 10 mM of L-methionine, and (e) about 8% (w / v) of sucrose, and​ (f) containing about 75 ppm of polysorbate 80 and, The pharmaceutical preparation provides a stable liquid pharmaceutical preparation of an anti-TIGIT antibody having a pH of 5.4 + / - 0.2.

[0019] In some embodiments, the present invention is, (a) an anti-TIGIT antibody of about 20 mg / mL, wherein the anti-TIGIT antibody is, i) a heavy chain from CPA.9.086.H4(S241P) (SEQ ID NO: 5), and ii) a light chain from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 10), an anti-TIGIT antibody containing, (b) about 10 mM of histidine, and (c) about 30 mM of L-arginine, and (d) about 10 mM of L-methionine, and (e) about 8% (w / v) of sucrose, and (f) about 75 ppm of polysorbate 80, and containing, The pharmaceutical preparation provides a stable liquid pharmaceutical preparation of an anti-TIGIT antibody having a pH of 5.4 + / - 0.2.

[0020] In some embodiments of paragraphs

[0017] to

[0018] , the pharmaceutical preparation is stable at 5°C to 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, or 8 months.

[0021] In some embodiments of paragraphs

[0017] to

[0018] , the pharmaceutical preparation is stable at 5°C to 25°C for at least 6 months, at least 12 months, or at least 18 months.

[0022] In some embodiments of paragraphs

[0004] to

[0020] , the pharmaceutical preparation is administered at a dose of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 20 mg / kg, or about 1 mg / kg to about 10 mg / kg.

[0023] In some embodiments of paragraphs

[0004] to

[0021] , the pharmaceutical formulation is administered at a dosage of about 0.01 mg / kg, about 0.01 mg / kg, about 0.03 mg / kg, about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg, or about 30 mg / kg.

[0024] In some embodiments of paragraphs

[0004] to

[0022] , the anti-TIGIT antibody is administered once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, or once every six weeks.

[0025] In some embodiments of paragraphs

[0004] to

[0023] , the anti-TIGIT antibody is administered as a single dose.

[0026] In some embodiments of paragraphs

[0004] to

[0024] , the pharmaceutical formulation is formulated for intravenous (IV) infusion.

[0027] In some embodiments of paragraphs

[0004] to

[0025] , the pharmaceutical formulation is administered for the treatment of cancer.

[0028] In some embodiments of paragraphs

[0004] to

[0026] , the pharmaceutical formulation is for use in a method of treating cancer.

[0029] In some embodiments of paragraphs

[0026] to

[0027] , the cancer is prostate cancer, liver cancer (HCC), colorectal cancer (CRC), colorectal cancer MSS (MSS-CRC; including refractory MSS colorectal cancer), CRC (MSS unknown), ovarian cancer (including ovarian tumors), endometrial cancer (including endometrial tumors), breast cancer, pancreatic cancer, gastric cancer, cervical cancer, head and neck cancer, thyroid cancer, testicular cancer, urothelial cancer, lung cancer, melanoma, non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), glioma, renal cell cancer (RCC), renal cell carcinoma (RCC), lymphoma (non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HD)), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), diffuse large B-cell lymphoma, testicular germ cell tumor, mesothelioma, esophageal cancer, triple-negative breast cancer, Merkel cell cancer, high-frequency MSI cancer, KRAS mutant tumor, adult T-cell leukemia / lymphoma, pleural mesothelioma, anal SCC, small cell lung cancer, lung adenocarcinoma, neuroendocrine lung cancer (including neuroendocrine lung tumors), HNSCC, PD1-refractory or recurrent HNSCC, NSCLC, PD1-refractory or recurrent NSCLC, NSCLC, PD1-refractory or recurrent NSCLC, NSCLC large cell, NSCLC squamous, uterine SCC, malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, NSCLC, adenoid cystic carcinoma (including adenoid cystic carcinoma tumors), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, multiple myeloma, esophagogastric junction cancer, and / or myelodysplastic syndrome (MDS) selected from the group consisting of.

[0030] In some embodiments, the formulation is obtained by lyophilizing the stable liquid pharmaceutical formulation described in any one of paragraphs

[0004] to

[0028] .

[0031] In some embodiments, the use of the stable lyophilized pharmaceutical formulation described in any one of paragraphs

[0004] to

[0029] for the treatment of cancer.

[0032] In some embodiments of paragraph

[0030] , the cancer is prostate cancer, liver cancer (HCC), colorectal cancer (CRC), colorectal cancer MSS (MSS-CRC; including refractory MSS colorectal cancer), CRC (MSS unknown), ovarian cancer (including ovarian tumors), endometrial cancer (including endometrial tumors), breast cancer, pancreatic cancer, gastric cancer, cervical cancer, head and neck cancer, thyroid cancer, testicular cancer, urothelial cancer, lung cancer, melanoma, non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), glioma, renal cell cancer (RCC), renal cell carcinoma tumor (RCC), lymphoma (non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HD)), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), diffuse large B-cell lymphoma, testicular germ cell tumor, mesothelioma, esophageal cancer, triple-negative breast cancer, Merkel cell cancer, high-frequency MSI cancer, KRAS variant tumor, adult T-cell leukemia / lymphoma, pleural mesothelioma, anal SCC, small cell lung cancer, lung adenocarcinoma, neuroendocrine lung cancer (including neuroendocrine lung cancer tumors), HNSCC, PD1-refractory or recurrent HNSCC, NSCLC, PD1-refractory or recurrent NSCLC, NSCLC, PD1-refractory or recurrent NSCLC, NSCLC large cell, NSCLC squamous, uterine SCC, malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, NSCLC, adenoid cystic carcinoma (including adenoid cystic carcinoma tumors), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, multiple myeloma, esophagogastric junction cancer, and / or myelodysplastic syndrome (MDS) selected from the group consisting of.

Brief Description of the Drawings

[0033]

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DETAILED DESCRIPTION OF THE INVENTION

[0034] I. Introduction The present invention is directed to stable formulations of the anti-TIGIT antibody CPA.9.086 (S241P) (e.g., an anti-TIGIT antibody having the same CDRs as those shown in Figure 3), and provides these formulations. In particular, these formulations include antibodies comprising a heavy chain and a light chain, and the vhCDR1, vhCDR2, vhCDR3, vlCDR1, vlCDR2, and vlCDR3 sequences from the anti-TIGIT antibody CPA.9.086 (S241P). In some embodiments, the anti-TIGIT antibodies include those having the same CDRs as those shown in Figure 3, and anti-TIGIT antibodies comprising the heavy and light chains provided in Figure 3.

[0035] II. TIGIT Protein The present invention provides an antibody that specifically binds to the TIGIT protein and prevents activation by its ligand protein, PVR, poliovirus receptor (also known as CD155), a human plasma membrane glycoprotein, and the anti-TIGIT antibody is CPA.9.086 (S241P), or an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086 (S241P)). TIGIT, or a T cell immunoreceptor having Ig and ITIM domains, is a coinhibitory receptor protein, also known as WUCAM, Vstm3, or Vsig9. TIGIT has an immunoglobulin variable domain, a transmembrane domain, and an immunoreceptor tyrosine-based inhibitory motif (ITIM), and includes a signature sequence element of the PVR protein family. The extracellular domain (ECD) sequences of TIGIT and PVR are shown in Figure 1. Antibodies formulated according to the present invention include antibodies specific for the TIGIT ECD, such as an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4 (S241P)), such that binding of TIGIT and PVR is blocked.

[0036] Accordingly, as used herein, the term "TIGIT" or "TIGIT protein" or "TIGIT polypeptide" includes, without limitation, any such protein, or variants, conjugates, or fragments thereof, including the known or wild-type TIGIT described herein, as well as any naturally occurring splice variants, amino acid variants or isoforms, and may optionally include, in particular, ECD fragments of TIGIT.

[0037] III. Anti-TIGIT Antibodies Accordingly, the present invention provides an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., having the same CDRs as those of CPA.9.086.H4(S241P) which can be formulated according to the formulations described herein).

[0038] As discussed below, the term "antibody" is used generally. Antibodies found for use in the present invention can take several forms described herein, including conventional antibodies, as well as antibody derivatives, fragments, and mimics as described below. Generally, the term "antibody" includes any polypeptide containing at least one antigen-binding domain, as more fully described below. Antibodies can be polyclonal, monoclonal, heterologous, homologous, syngeneic, or modified forms thereof as described herein, with monoclonal antibodies finding particular use in many embodiments. In some embodiments, the antibodies of the present invention bind specifically or substantially specifically to the TIGIT molecule. The terms "monoclonal antibody" and "monoclonal antibody composition" as used herein refer to a population of antibody molecules that contain only one type of antigen-binding site capable of immunoreacting with a particular epitope of an antigen, while the terms "polyclonal antibody" and "polyclonal antibody composition" refer to a population of antibody molecules that contain multiple types of antigen-binding sites capable of interacting with a particular antigen. Monoclonal antibody compositions typically exhibit a single binding affinity for the particular antigen to which they immunoreact.

[0039] The amino-terminal portion of each chain contains a variable region of about 100 to 110 or more amino acids that are generally referred to in the art and herein as the "Fv domain" or "Fv region" and that are mainly involved in antigen recognition. In the variable region, three loops are concentrated for each of the V domains of the heavy and light chains to form an antigen-binding site. Each of the loops is referred to as a complementarity-determining region (hereinafter referred to as "CDR"), where the variation in the amino acid sequence is most prominent. "Variable" refers to the fact that a particular segment of the variable region varies greatly in sequence between antibodies. The variability within the variable region is not uniformly distributed. Instead, the V region consists of relatively invariant stretches of 15 to 30 amino acids called framework regions (FRs) that are separated by shorter regions of extremely high variability called "hypervariable regions".

[0040] Each VH and VL is composed of three hypervariable regions ("complementarity-determining regions", "CDRs") and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0041] Hypervariable regions generally include approximately amino acid residues 24-34 (LCDR1, where "L" represents the light chain), 50-56 (LCDR2), and 89-97 (LCDR3) in the light chain variable region, and approximately 31-35B (HCDR1, where "H" represents the heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) in the heavy chain variable region (however, in some cases, the numbering may shift slightly as understood by those skilled in the art; Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991)), and / or residues that form hypervariable loops (e.g., residues 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3) in the light chain variable region, and 26-32 (HCDR1), 53-55 (HCDR2), and 96-101 (HCDR3) in the heavy chain variable region; Chothia and Lesk (1987) J. Mol. Biol. 196:901-917). The specific CDRs of the present invention are described below and shown in FIG. 3.

[0042] The carboxy-terminal portion of each chain defines a constant region that is mainly involved in effector functions. Kabat et al. collected a large number of primary sequences of the variable regions of the heavy and light chains. Based on the degree of sequence conservation, Kabat et al. classified the individual primary sequences into CDRs and frameworks and created a list thereof (see SEQUENCES OF IMMUNOLOGICAL INTEREST, 5th edition, NIH publication, No. 91-3242, E.A. Kabat et al. (incorporated by reference in its entirety)).

[0043] The IgG subclasses of immunoglobulins have several immunoglobulin domains in the heavy chain. The "immunoglobulin (Ig) domain" as used herein means a region of an immunoglobulin having a distinct three-dimensional structure. The heavy chain domains including the constant heavy (CH) domains and the hinge domain are of interest in the present invention. In the context of IgG antibodies, each IgG isotype has three CH regions. Thus, the "CH" domains in the context of IgG are as follows: "CH1" refers to positions 118 to 220 according to the EU index as in Kabat. "CH2" refers to positions 237 to 340 according to the EU index as in Kabat, and "CH3" refers to positions 341 to 447 according to the EU index as in Kabat.

[0044] Accordingly, the present invention provides a variable heavy domain, a variable light domain, a heavy constant domain, a light constant domain, and an Fc domain as used herein and described in detail herein. As used herein, the “variable region” means one or more Ig domains substantially encoded by either Vκ or Vλ, and / or the regions of immunoglobulins, each containing the VH gene that constitutes the kappa, lambda, and heavy chain immunoglobulin loci. Accordingly, the variable heavy domain contains vhFR1-vhCDR1-vhFR2-vhCDR2-vhFR3-vhCDR3-vhFR4, and the variable light domain contains vlFR1-vlCDR1-vlFR2-vlCDR2-vlFR3-vlCDR3-vlFR4. As used herein, the “heavy chain constant region” means the CH1-hinge-CH2-CH3 portion of an antibody. As used herein, “Fc” or “Fc region” or “Fc domain” means a polypeptide that includes the constant region of an antibody excluding the first constant region immunoglobulin domain, and optionally a portion of the hinge. Accordingly, Fc refers to the last two constant region immunoglobulin domains of IgA, IgD, and IgG, the last three constant region immunoglobulin domains of IgE and IgM, and the mobile hinge N-terminus for these domains. In the case of IgA and IgM, Fc may include the J chain. In the case of IgG, the Fc domain includes the immunoglobulin domains Cγ2 and Cγ3 (Cγ2 and Cγ3), and the lower hinge region between Cγ1 (Cγ1) and Cγ2 (Cγ2). The boundaries of the Fc region may vary, but the human IgG heavy chain Fc region is typically defined as including residue C226 or P230 at its carboxy terminus, where the numbering follows the EU index similar to Kabat. In some embodiments, amino acid modifications are made to the Fc region, for example, to alter its binding to one or more FcγR receptors or FcRn receptors, as described in more detail below.

[0045] Accordingly, as used herein, "Fc variant" or "variant Fc" means a protein that contains amino acid modifications in the Fc domain. The Fc variants of the present invention are defined according to the amino acid modifications that constitute them. Similarly, M428L / N434S defines an Fc variant having substitutions M428L and N434S relative to the parental Fc polypeptide. The identity of the WT amino acids need not be specified, in which case the aforementioned variant is referred to as 428L / 434S. It should be noted that the order in which the substitutions are provided is arbitrary, i.e., for example, 428L / 434S is the same Fc variant as M428L / N434S, etc. For all positions considered in the context of the present invention related to antibodies, unless otherwise specified, the numbering of amino acid positions follows the EU index.

[0046] As used herein, "Fab" or "Fab region" means a polypeptide containing the VH, CH1, VL, and CL immunoglobulin domains. Fab may refer to this region alone, or in the context of a full-length antibody, an antibody fragment, or a Fab fusion protein. As used herein, "Fv" or "Fv fragment" or "Fv region" means a polypeptide containing the VL and VH domains of a single antibody. As will be understood by those skilled in the art, they are generally composed of two chains.

[0047] Throughout this specification, either the IMTG numbering system or the Kabat numbering system is generally used when referring to residues within the variable domain (approximately residues 1-107 of the light chain variable region and residues 1-113 of the heavy chain variable region) (e.g., Kabat et al. (1991), supra). The EU numbering as seen in Kabat is generally used for the constant domain and / or the Fc domain.

[0048] The "antigen-binding portion" of an antibody (which may also be used interchangeably with "antigen-binding fragment", "antibody fragment", and "antibody derivative") is included within the definition of "antibody". That is, for the purposes of the present invention, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) of the present invention) has the minimal functional requirements for binding to the TIGIT antigen. As will be understood by those skilled in the art, despite retaining the ability to bind to an antigen, (i) a Fab fragment consisting of the VL, VH, CL, and CH1 domains, (ii) an Fd fragment consisting of the VH and CH1 domains, (iii) an F(ab’)2 fragment (a bivalent fragment containing two linked Fab fragments), (vii) a single-chain Fv molecule (scFv) (wherein the VH domain and the VL domain are linked by a peptide linker, thereby enabling these two domains to associate to form an antigen-binding site) (Bird et al., 1988, Science 242:423-426, Huston et al., 1988, Proc. Natl. Acad. Sci. U.S.A. 85:5879-5883 (incorporated herein by reference in its entirety)), (iv) a "diabody" or "tribody" (a multivalent or multispecific fragment constructed by gene fusion) (Tomlinson et.al., 2000, Methods Enzymol. 326:461-479, WO94 / 13804, Holliger et al., 1993, Proc. Natl. Acad. Sci. U.S.A. 90:6444-6448 (incorporated herein by reference in its entirety)), (v) a "domain antibody" or "dAb" (which may be referred to as an "immunoglobulin single variable domain" and includes single antibody variable domains from other species such as rodents (e.g., as disclosed in WO00 / 29004), tenrecs, and camelid V-HH dAbs), (vi) SMIP (small molecule immunopharmaceutical), camelibody, nanobody, and IgNAR, and there are numerous antigen fragments and derivatives with alternative structures, including but not limited to these.The present invention is directed to anti-TIGIT antibodies having CDRs identical to those shown in Figure 3 (i.e., CDRs identical to those of CPA.9.086.H4(S241P) generally based on the IgG class having several subclasses including, but not limited to, IgG4).

[0049] The amino-terminal portion of each chain contains a variable region of about 100 to 110 or more amino acids that is mainly involved in antigen recognition and is generally referred to in the art and herein as the "Fv domain" or "Fv region". In the variable region, three loops are concentrated for each of the V domains of the heavy and light chains to form an antigen-binding site. Each of the loops is referred to as a complementarity-determining region (hereinafter referred to as "CDR"), where the variation in the amino acid sequence is most prominent. "Variable" refers to the fact that certain segments of the variable region vary greatly in sequence between antibodies. The variability within the variable region is not uniformly distributed. Instead, the V region consists of relatively invariant stretches called framework regions (FRs) of 15 to 30 amino acids separated by shorter regions of extremely high variability called "hypervariable regions" each 9 to 15 amino acids or more in length.

[0050] Each VH and VL is composed of three hypervariable regions ("complementarity-determining regions", "CDRs") and four FRs arranged in the following order from the amino terminus to the carboxy terminus: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0051] Hypervariable regions generally include approximately amino acid residues 24-34 (LCDR1, where "L" represents the light chain), 50-56 (LCDR2), and 89-97 (LCDR3) in the light chain variable region, and approximately residues 31-35B (HCDR1, where "H" represents the heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) in the heavy chain variable region from Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) and / or residues that form hypervariable loops (e.g., residues 26-32 (LCDR1), 50-52 (LCDR2) and 91-96 (LCDR3) in the light chain variable region and 26-32 (HCDR1), 53-55 (HCDR2) and 96-101 (HCDR3) in the heavy chain variable region; Chothia and Lesk (1987) J. Mol. Biol. 196:901-917). Specific CDRs of the present invention are described below.

[0052] As will be appreciated by those skilled in the art, the exact numbering and placement of CDRs can vary between different numbering systems. However, it should be understood that the disclosure of a variable heavy and / or variable light sequence includes the disclosure of the relevant (native) CDRs. Thus, the disclosure of each variable heavy region is a disclosure of vhCDRs (e.g., vhCDR1, vhCDR2, and vhCDR3), and the disclosure of each variable light region is a disclosure of vlCDRs (e.g., vlCDR1, vlCDR2, and vlCDR3). A useful comparison of CDR numbering is as follows; see Lafranc et al., Dev. Comp. Immunol. 27(1):55-77 (2003). [Table 1]

[0053] Throughout this specification, the IMGT and / or Kabat numbering systems are generally used when referring to residues within the variable domains (approximately residues 1-107 of the light chain variable region and residues 1-113 of the heavy chain variable region) and the hinge, and the EU numbering system is for the Fc region (e.g., Kabat et al., (1991) supra).

[0054] The present invention provides an anti-TIGIT antibody having CDRs that are identical to those shown in Figure 3 (i.e., identical to those of CPA.9.086.H4(S241P)). In this case, a "complete CDR set" includes three variable light chain and three variable heavy chain CDRs, e.g., vlCDR1, vlCDR2, vlCDR3, vhCDR1, vhCDR2, and vhCDR3, as provided in Figure 3. These can each be part of a larger variable light or variable heavy domain. Additionally, the variable heavy and variable light domains can be on separate polypeptide chains when heavy and light chains are used, or on a single polypeptide chain in the case of an scFv sequence.

[0055] CDR contributes to the formation of antigen binding, or more specifically, to the formation of the epitope-binding site of an antibody. An "epitope" refers to a determinant that interacts with the specific antigen-binding site within the variable region of an antibody molecule known as a paratope. An epitope is a grouping of molecules such as amino acids or sugar side chains and typically has specific structural characteristics as well as specific charge characteristics. A single antigen may have two or more epitopes. An epitope can include amino acid residues that are directly involved in binding (also referred to as the immunodominant components of the epitope) and other amino acid residues that are not directly involved in binding, for example, amino acid residues that are effectively blocked by a specific antigen-binding peptide, in other words, amino acid residues within the footprint of a specific antigen-binding peptide. An epitope can be either conformational or linear. A conformational epitope is created by the spatial juxtaposition of amino acids from different segments of a linear polypeptide chain. A linear epitope is created by adjacent amino acid residues within a polypeptide chain. Conformational epitopes and non-conformational epitopes can be distinguished in that in the presence of a denaturing solvent, binding to the former is lost, but binding to the latter is not. An epitope typically contains at least 3, more commonly at least 5, or 8 - 10 amino acids within its unique three-dimensional structure. Antibodies that recognize the same epitope can be verified in a simple immunoassay that shows the ability of one antibody to block the binding of another antibody to the target antigen, for example, "binning".

[0056] Another type of Ig domain of the heavy chain is the hinge region. As used herein, "hinge" or "hinge region" or "antibody hinge region" or "immunoglobulin hinge region" means a flexible polypeptide containing the amino acids between the first and second constant domains of an antibody. Structurally, the IgG CH1 domain ends at EU position 220, and the IgG CH2 domain begins at residue EU position 237. Thus, in the case of IgG, the antibody hinge is defined herein to include positions 221 - 236, and the numbering follows the EU index as in Kabat.

[0057] Light chains generally contain two domains: a variable light chain domain (including the light chain CDRs and forming an Fv region together with the variable heavy domain), and a constant light chain region (often referred to as CL or Cκ). Generally, either the constant lambda or constant kappa domain can be used, and lambda is generally useful in the present invention.

[0058] Generally, anti-TIGIT antibodies having CDRs generally the same as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) of the present invention) are recombinant. As used herein, "recombinant" broadly refers to a product, for example, a cell, or a nucleic acid, protein, or vector, where the cell, nucleic acid, protein, or vector has been modified by the introduction of a heterologous nucleic acid or protein or the modification of a native nucleic acid or protein, or the cell is derived from a cell so modified. Thus, for example, a recombinant cell expresses a gene not found in its native (non-recombinant) form, or alternatively expresses a native gene that is abnormally expressed, under-expressed, or not expressed at all.

[0059] As used herein, the term "recombinant antibody" includes all antibodies prepared, expressed, produced, or isolated by recombinant means, e.g., antibodies isolated from (a) an animal (e.g., a mouse) transgenic or chromosomally integrated for human immunoglobulin genes, or a hybridoma prepared therefrom (described further below), (b) a host cell transformed to express human antibodies, e.g., an antibody isolated from a transfectoma, (c) an antibody isolated from a recombinant combinatorial human antibody library, and (d) an antibody prepared, expressed, produced, or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework regions and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis of non-CDR regions (or in vivo somatic mutagenesis if transgenic animals for human Ig sequences are used), and thus, the amino acid sequences of the V H region and V L region are derived from and related to human germline V H sequences and V L sequences, while being sequences that may not naturally occur in the human antibody germline repertoire in vivo.

[0060] A. Chimeric and Humanized Anti-TIGIT Antibodies In some embodiments, anti-TIGIT antibodies having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) can be derived from mixtures from different species (e.g., chimeric antibodies and / or humanized antibodies). Generally, both “chimeric antibodies” and “humanized antibodies” refer to antibodies that combine regions from two or more species. For example, “chimeric antibodies” have traditionally included variable region(s) from mouse (or in some cases rat) and constant region(s) from human. “Humanized antibodies” generally refer to non-human antibodies having variable domain framework regions swapped with sequences found in human antibodies. Generally, in a humanized antibody, the entire antibody except for the CDRs is encoded by a human-derived polynucleotide or is identical to such an antibody except within its CDRs. CDRs that are partially or entirely encoded by nucleic acids of non-human origin are grafted into the beta-sheet framework of the human antibody variable region to produce an antibody whose specificity is determined by the grafted CDRs. The production of such antibodies is described, for example, in WO92 / 11018, Jones, 1986, Nature 321:522-525, Verhoeyen et al., 1988, Science 239:1534-1536, all of which are incorporated herein by reference in their entirety. “Backmutations” of selected acceptor framework residues to the corresponding donor residues are often required to restore the affinity lost in the initial graft construct (US5530101, US5585089, US5693761, US5693762, US6180370, US5859205, US5821337, US6054297, US6407213 (all of which are incorporated herein by reference in their entirety)). Humanized antibodies also preferably include at least a portion, usually all, of an immunoglobulin constant region, typically that of a human immunoglobulin, and thus will typically include a human Fc region. Humanized antibodies can also be generated using mice having a genetically engineered immune system. Roque et al., 2004, Biotechnol. Prog. 20:639-654, which is incorporated herein by reference in its entirety.A variety of techniques and methods for humanizing and reshaping non-human antibodies are well known in the art (see Tsurushita & Vasquez, 2004, Humanization of Monoclonal Antibodies, Molecular Biology of B Cells, 533-545, Elsevier Science (USA) (incorporated by reference in its entirety) and the references cited therein). Humanization methods include, but are not limited to, the methods described in Jones et al., 1986, Nature 321:522-525; Riechmann et al., 1988, Nature 332:323-329; Verhoeyen et al., 1988, Science, 239:1534-1536; Queen et al., 1989, Proc Natl Acad Sci, USA 86:10029-33; He et al., 1998, J. Immunol. 160:1029-1035; Carter et al., 1992, Proc Natl Acad Sci USA 89:4285-9; Presta et al., 1997, Cancer Res. 57(20):4593-9; Gorman et al., 1991, Proc. Natl. Acad. Sci. USA 88:4181-4185; O’Connor et al., 1998, Protein Eng 11:321-8 (each incorporated by reference in its entirety). Other methods for humanizing, or reducing the immunogenicity of the variable regions of non-human antibodies, may include, for example, surface resurfacing methods such as those described in Roguska et al., 1994, Proc. Natl. Acad. Sci. USA 91:969-973, which is incorporated by reference in its entirety).

[0061] Accordingly, the vhCDR and vlCDR from an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) can be humanized (or “re-humanized” with respect to an already humanized one).

[0062] In certain embodiments, an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) comprises a heavy chain variable region derived from a specific germline heavy chain immunoglobulin gene and / or a light chain variable region derived from a specific germline light chain immunoglobulin gene. For example, such an antibody can include, or alternatively consist of, a human antibody that includes a heavy or light chain variable region that is a "product" of a specific germline sequence or "derived therefrom". A human antibody that is a "product" of a human germline immunoglobulin sequence or "derived therefrom" can be identified as such by comparing the amino acid sequence of the human antibody to the amino acid sequence of a human germline immunoglobulin and selecting the human germline immunoglobulin that has the sequence closest to that of the human antibody (i.e., the highest percent identity). A human antibody that is a "product" of a specific human germline immunoglobulin sequence or "derived therefrom" can include amino acid differences compared to the germline sequence, for example, due to naturally occurring somatic mutations or the intentional introduction of site-specific mutations. However, a humanized antibody is typically at least 90% identical in amino acid sequence to the amino acid sequence encoded by a human germline immunoglobulin gene and includes amino acid residues that identify the antibody as being derived from a human sequence when compared to the germline amino acid sequences of other species (e.g., mouse germline sequences). In certain cases, a humanized antibody can be at least 95, 96, 97, 98, or 99%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the amino acid sequence encoded by a germline immunoglobulin gene, excluding the CDRs. That is, the framework region of the variable region (either heavy or light chain) can be at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the framework amino acids encoded by a single human germline immunoglobulin gene, while the CDRs can be the same as those shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)).

[0063] B.TIGIT antibody The present invention provides an anti-TIGIT antibody having CDRs identical to those shown in FIG. 3 (i.e., CDRs identical to those of CPA.9.086.H4(S241P)). (For convenience, "anti-TIGIT antibody" and "TIGIT antibody" are used interchangeably). An anti-TIGIT antibody having CDRs identical to those shown in FIG. 3 (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) specifically binds to human TIGIT, preferably the ECD of human TIGIT. The present invention further provides an anti-TIGIT antigen-binding domain (including full-length antibodies) that is identical to that of CPA.9.086(S241P) and contains CDRs that bind to TIGIT.

[0064] Specific binding to TIGIT or an epitope of TIGIT is at least about 10 -4 M, at least about 10 -5 M, at least about 10 -6 M, at least about 10 -7 M, at least about 10 -8 M, at least about 10 -9 M, alternatively at least 10 -10 M, at least about 10 -11 M, at least about 10 -12 M, at least about 10 -13 M, at least about 10 -14 M, at least about 10 -15 M or greater K D can be shown by an antibody having, where K D refers to the equilibrium dissociation constant of a particular antibody-antigen interaction. Typically, an antibody that specifically binds to an antigen will have a K D that is 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5,000-fold, 10,000-fold or greater than that for a control molecule compared to the TIGIT antigen or epitope.

[0065] However, for optimal binding to TIGIT expressed on the surface of NK cells and T cells, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) preferably has a KD of less than 50 nM, most preferably less than 1 nM, and less than 0.1 nM and less than 1 pM are useful in the methods of the invention.

[0066] Also, specific binding to a particular antigen or epitope can be shown, for example, by an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and having a Ka (referring to the association rate constant) for the TIGIT antigen or epitope that is at least 20-fold, 50-fold, 100-fold, 500-fold, 1000-fold, 5,000-fold, 10,000-fold or more compared to a control.

[0067] In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 of the invention (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) binds to human TIGIT with a K D and the K D is determined at 25°C or 37°C by known methods, such as surface plasmon resonance (SPR, e.g., Biacore assay), ELISA, KINEXA, most typically SPR.

[0068] An anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) described herein) is labeled as follows. The antibody has a reference number, for example, "CPA.9.086". This represents a combination of a variable heavy chain and a variable light chain, for example, as depicted in Figure 3, based on the understanding that these antibodies contain two heavy chains and two light chains. "CPA.9.086.VH" refers to the variable heavy portion of CPA.9.086, while "CPA.9.086.VL" is the variable light chain. "CPA.9.086.vhCDR1", "CPA.9.086.vhCDR2", "CPA.9.086.vhCDR3", "CPA.9.086.vlCDR1", "CPA.9.086.vlCDR2", and "CPA.9.086.vlCDR3" refer to the indicated CDRs. "CPA.9.086.HC" refers to the entire heavy chain of this molecule (e.g., variable and constant domains), and "CPA.9.086.LC" refers to the entire light chain of the same molecule (e.g., variable and constant domains). Generally, the human kappa light chain is used for the constant domain of each phage (or humanized hybridoma) antibody herein, but in some embodiments, the lambda light chain constant domain is used. "CPA.9.086.H4" is the CPA.9.086 variable domain linked to human IgG4. In some cases, the human IgG may have additional mutations, such ones are described below, and it should be noted that these can be annotated. For example, in many embodiments, the S241P mutation may be present in human IgG4, which can be annotated, for example, as "CPA.9.086.H4(S241P)". The human IgG4 sequence with this S241P hinge variant is shown in Figure 3. The present invention further provides a variable heavy domain and light domain, as well as full-length heavy and light chains, as provided in Figure 3.

[0069] In some embodiments, the invention provides an scFv that binds to TIGIT, which comprises a variable heavy domain and a variable light domain linked by the scFv linker outlined above, and that comprises the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). The VL and VH domains can be in either orientation, e.g., "VH-linker-VL" or "VL-linker-VH" or "VH" from the N-terminus to the C-terminus. These are named by their component parts, e.g., "scFv-CPA.9.086.VH-linker-VL" or "scFv-CPA.9.086.VL-linker-VH". Thus, "scFv-CPA.9.086" can be in either orientation.

[0070] In many embodiments, anti-TIGIT antibodies having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) of the present invention) are human (derived from phage), block the binding of TIGIT to PVR, and are exemplary antibodies whose components are outlined (provided in Figure 3): CPA.9.086, CPA.9.086.VH, CPA.9.086.VL, CPA.9.086.HC, CPA.9.086.LC, CPA.9.086.H1, CPA.9.086.H2, CPA.9.086.H3; CPA.9.086.H4; CPA.9.086.H4(S241P); CPA.9.086.vhCDR1, CPA.9.086.vhCDR2, CPA.9.086.vhCDR3, CPA.9.086.vlCDR1, CPA.9.086.vlCDR2, CPA.9.086.vlCDR3, and scFv-CPA.9.086.

[0071] In addition, anti-TIGIT antibodies having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) include the variants of the variable heavy and light chains described above. In this case, the variable heavy chain can be 80%, 90%, 95%, 98%, or 99% identical to the "VH" sequence herein and / or can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid changes when using an Fc variant. A variable light chain is provided that can be 80%, 90%, 95%, 98%, or 99% identical to the "VL" sequence herein (and in particular CPA.9.086) and / or can contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid changes when using an Fc variant. In these embodiments, the invention includes these variants as long as the antibody still binds to TIGIT and contains the same CDR as that of CPA.9.086(S241P).

[0072] Similarly, heavy and light chains of anti-TIGIT antibodies having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) that are 80%, 90%, 95%, 98%, or 99% identical to the full-length "HC" and "LC" sequences and / or contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acid changes when using an Fc variant are provided. In these embodiments, the invention includes these variants as long as the antibody still binds to TIGIT and contains the same CDR as that of CPA.9.086(S241P). S

[0073] In addition, the framework regions of the variable heavy and variable light chains of anti-TIGIT antibodies having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) herein) can be humanized as known in the art (occasionally generating variants in the CDRs as needed), and thus, humanized variants of the VH and VL chains of FIG. 3 can be generated. Further, the humanized variable heavy and light domains can then be fused to a human constant region, for example, a constant region from IgG4 (including IgG4(S241P)).

[0074] In particular, as is known in the art, mouse VH and VL chains can be humanized using the IgBLAST program on the NCBI website, as outlined, for example, in Ye et al. Nucleic Acids Res. 41:W34-W40 (2013), which is hereby incorporated by reference in its entirety for the humanization method. IgBLAST takes the mouse VH and / or VL sequences and compares them to a library of known human germline sequences.

[0075] Accordingly, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) of the present invention) comprises an amino acid sequence selected from the group consisting of: (a) the sequences recited herein; (b) an amino acid sequence having at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with a sequence specified in (a) and having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)); (c) a polypeptide having an amino acid sequence encoded by a polynucleotide having a nucleic acid sequence encoding the amino acids recited herein. In particular, the CPA.9.086 antibody can have a sequence selected from (a), (b), or (c).

[0076] In addition, the definition of an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) includes antibodies that share identity with the TIGIT antibodies listed herein but maintain the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). That is, in certain embodiments, the anti-TIGIT antibodies according to the present invention each comprise heavy and light chain variable regions that include amino acid sequences that are identical to all or a portion of the anti-TIGIT amino acid sequence, and this antibody retains the desired functional properties of the parental anti-TIGIT antibody and includes the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). The percent identity between two sequences is a function of the number of identical positions that those sequences share, taking into account the number of gaps that need to be introduced to optimally align the two sequences and the length of each gap (i.e., % homology = number of identical positions / total number of positions × 100). The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the following non-limiting examples.

[0077] The percent identity between two amino acid sequences can be determined using the algorithm of E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17 (1988)), incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the algorithm of Needleman and Wunsch (J. Mol. Biol. 48:444-453 (1970)), incorporated into the GAP program in the GCG software package (commercially available), using either a Blossum 62 matrix or a PAM250 matrix, and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6.

[0078] In addition or alternatively, the protein sequences of the invention can further be used as "query sequences" to perform a search against public databases, for example, to identify related sequences. Such a search can be performed using the XBLAST program (version 2.0) of Altschul, et al. (1990) J Mol. Biol. 215:403-10. A BLAST protein search can be performed with the XBLAST program, score = 50, word length = 3, to obtain amino acid sequences that are homologous to antibody molecules according to at least some embodiments of the invention. Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402 to obtain a gapped alignment for comparison purposes. When utilizing the BLAST and Gapped BLAST programs, the default parameters of each program (e.g., XBLAST and NBLAST) can be used.

[0079] Generally, the percentage identity for comparison between anti-TIGIT antibodies having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is at least 75%, at least 80%, at least 90%, and preferably at least about 95, 96, 97, 98, or 99% percent identity. The percentage identity can be across the entire amino acid sequence, for example, across the entire heavy or light chain or a portion of the chain, as long as it is the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). For example, the definition of the anti-TIGIT antibody of the present invention includes those that share identity across the entire variable region (e.g., when the identity is 95 or 98% identical across the variable region), or across the entire constant region, or only across the Fc domain, as long as it is the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). In particular, the present invention provides a TIGIT antibody having at least 75%, at least 80%, at least 90% identity, preferably at least about 95, 96, 97, 98, or 99% percent identity with the CPA.9.086 antibody, as long as it is the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)).

[0080] For example, TIGIT antibodies include those having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)), but may have a lower identity across the variable region (e.g., 95 or 98% percent identity). In particular, the present invention provides a TIGIT antibody having the same CDR as CPA.9.086, but the framework region is 95 or 98% identical to CPA.9.086.

[0081] IV. Formulation of Anti-TIGIT Antibodies An anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) can be formulated into a pharmaceutical composition containing a carrier suitable for the desired delivery method. Suitable carriers include any substance that, when combined with the therapeutic composition, retains the anti-tumor function of the therapeutic composition and is generally non-reactive with the patient's immune system. Examples include, but are not limited to, any of several standard pharmaceutical carriers such as sterile phosphate buffered saline, bacteriostatic water, etc. (generally, see Remington’s Pharmaceutical Sciences 16 th Edition, A. Osal., Ed., 1980).

[0082] As used herein, the term "active" refers to the functional activity(ies) of an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and / or having its antigen-binding portion, as long as it contains the same CDR as that of CPA.9.086.H4(S241P). Functional activity includes, but is not limited to, biological activity and / or binding affinity.

[0083] As used herein, the term "stability" is used in the structural context in relation to the structural integrity of an anti-TIGIT antibody having the same CDR as shown in, for example, FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and / or its antigen-binding portion, or in the functional context in relation to, for example, the ability of the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and / or its antigen-binding portion to retain its function and / or activity over time. As will be appreciated, an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) may be included in a formulation according to the methods and compositions described herein, and the stability of the protein refers to its stability in that formulation. In some embodiments, the stability of an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) is determined by measuring the binding activity of the composition, including, for example, using the assays described in the applications and figures provided herein, as well as other applicable assays known in the art.

[0084] As used herein, a "storage-stable" aqueous anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) refers to a solution formulated to enhance the stability of the protein in solution (e.g., by at least 10%) over a given storage time.

[0085] As used herein, "shelf life" refers to the period during which a formulation maintains a predetermined level of stability at a predetermined temperature. In certain embodiments, the predetermined temperature refers to storage at freezing (e.g., -80°C, -25°C, 0°C), refrigeration (e.g., 0° - 10°C), or room temperature (e.g., 18°C - 32°C).

[0086] As used herein, the term "stability time" refers to the length of time during which the formulation is considered stable. For example, the stability time of a formulation can refer to the length of time during which the level of protein aggregation and / or degradation in the formulation remains below a certain threshold (e.g., 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, etc.) and / or the length of time during which the formulation maintains a biological activity that exceeds a certain threshold (e.g., 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, etc.) of the amount of activity (e.g., including binding activity) present in the formulation at the start of the storage period.

[0087] A. Stabilized liquid formulation In some embodiments, the present disclosure provides a stabilized aqueous formulation of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). The following embodiments are based in part on the discovery that a liquid anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is stabilized by including at least one amino acid, salt, and / or nonionic surfactant as compared to a composition lacking at least one amino acid, salt, and / or nonionic surfactant. In some embodiments, the formulation does not contain sugars and / or sugar alcohols.

[0088] In one embodiment, a storage-stable anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) provided herein) will be stabilized at a temperature of 5°C to 25°C for a certain period. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) will be stable at refrigeration temperature for at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 21 days, 28 days or more. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) will be stable for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks or more. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) will be stable for at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months or more. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) is stable for a long period when stored at a temperature of 5°C to 25°C. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) is stable for a long period when stored at a temperature of 10°C to 25°C. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) is stable for a long period when stored at a temperature of 15°C to 25°C.In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P) including the composition) is stable for a long period when stored at a temperature of 15°C to 20°C. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) composition) is stable for a long period when stored at a temperature of 20°C to 25°C. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) composition) is stable for a long period when stored at a temperature of about 25°C.

[0089] In one embodiment, a stored anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) composition) is considered storage-stable as long as it maintains at least 40% of the antibody binding activity present at the start of the storage period (e.g., time = 0) of the composition. In another embodiment, the stored composition is considered stable as long as it maintains at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more of the antibody binding activity present at the start of the storage period (e.g., time = 0) of the composition. In one embodiment, the antibody binding activity is measured using any assay known in the art.

[0090] In one embodiment, a stored anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) composition) is considered stable as long as the percentage of the anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) present in an aggregated state remains 50% or less. In some embodiments, a stored anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) composition) is considered stable as long as the percentage of the anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) present in an aggregated state remains 45%, 40%, 35%, 30%, 25%, 24%, 23%, 22%, 21%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or less.

[0091] In some embodiments, a stored anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) composition) is considered stable as long as it maintains at least 40% of its initial binding activity (e.g., at time = 0) after the composition has been subjected to mechanical stress. In another embodiment, a stored anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) composition) is considered stable as long as it maintains 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more of its initial binding activity (e.g., at time = 0) after the composition has been exposed to mechanical stress. In some embodiments, the mechanical stress is agitation (e.g., shaking).

[0092] In some embodiments, the shelf life is determined by the activity rate remaining after storage for any of the above periods at any of the above temperatures. In some embodiments, the shelf life, when measured by any of the assays described herein or known in the art, is at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 100% antibody activity compared to the activity before the formulation is stored for any of the above amounts of time at any of the above temperatures.

[0093] In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 10 mg / mL to 25 mg / mL, 10 mg / mL to 15 mg / mL, 10 mg / mL to 20 mg / mL, 15 mg / mL to 20 mg / mL, 15 mg / mL to 25 mg / mL, or 20 mg / mL to 25 mg / mL. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 10 mg / mL to 25 mg / mL. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 10 mg / mL to 15 mg / mL. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 10 mg / mL to 20 mg / mL. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 10 mg / mL to 25 mg / mL. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 15 mg / mL to 20 mg / mL. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 15 mg / mL to 25 mg / mL. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 15 mg / mL. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 20 mg / mL.In some embodiments, the anti-TIGIT antibody having the same CDR as that shown in Figure 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) has a concentration of 25 mg / mL.

[0094] B. Amino acids - Histidine and Arginine In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDR as that shown in Figure 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and containing 8 mM to 12 mM histidine, 8 mM to 10 mM histidine, 10 mM to 12 mM histidine, or about 10 mM histidine. In some embodiments, the pharmaceutical formulation contains 8 mM to 12 mM histidine. In some embodiments, the pharmaceutical formulation contains 8 mM to 10 mM histidine. In some embodiments, the pharmaceutical formulation contains 10 mM to 12 mM histidine. In some embodiments, the pharmaceutical formulation contains about 10 mM histidine.

[0095] In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and containing 25 mM to 35 mM of L-arginine, 25 mM to 30 mM of L-arginine, 30 mM to 35 mM of L-arginine, about 20 mM of L-arginine, about 25 mM of L-arginine, about 30 mM of L-arginine, or about 35 mM of L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and containing 25 mM to 35 mM of L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and containing 25 mM to 30 mM of L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and containing 30 mM to 35 mM of L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and containing about 20 mM of L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and containing about 25 mM of L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and containing about 30 mM of L-arginine.In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and containing about 35 mM of L-arginine.

[0096] C. Sucrose In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) and free of sugar alcohols.

[0097] In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and containing sucrose in an amount of about 7.0% - 9.0%, 7.5% - 8.5%, 7.5% - 9.0%, 8.0% - 8.5%, 8.0% - 9%, or 8.5% - 9%. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and containing sucrose in an amount of about 7.0%, 7.1%, 7.2%, 7.3%, 7.4%, 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, 8.4%, 8.5%, 8.6%, 8.7%, 8.8%, 8.9%, 9.0%. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and containing sucrose in an amount of about 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3%, or 8.4%. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and containing sucrose in an amount of about 7.9%, 8.0%, 8.1%, or 8.2%. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) and containing sucrose in an amount of about 8.0%.

[0098] D. Polysorbate 80 In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) as shown in FIG. 3 and containing a nonionic surfactant polysorbate 80 (also known as polyoxyethylene (20) sorbitan monooleate) in the range of 70 ppm to 80 ppm.

[0099] In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) as shown in FIG. 3 and containing about 70 ppm, about 75 ppm, or about 80 ppm of a nonionic surfactant polysorbate 80 (also known as polyoxyethylene (20) sorbitan monooleate).

[0100] E. pH In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) as shown in FIG. 3 and buffered at a physiologically acceptable pH of about 5.2 to about 5.6. In some embodiments, the pH is about 5.2, 5.3, 5.4, 5.5, or 5.6. In some embodiments, the pH is from 5.2 to 5.5. In some embodiments, the pH is from 5.3 to 5.5. In some embodiments, the pH is from 5.4 to 5.5. In some embodiments, the pH is from 5.3 to 5.6. In some embodiments, the pH is from 5.4 to 5.6. In some embodiments, the pH is from 5.5 to 5.6. In some embodiments, the pH is 5.4 + / - 0.2.

[0101] F. Stability assay As discussed herein, a stable liquid pharmaceutical formulation comprising an anti-TIGIT antibody having the same CDR as that shown in Figure 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) exhibits improved stability compared to a control formulation. In one embodiment, the improved stability includes retention of a higher percentage of binding activity and / or no decrease in binding activity compared to the control formulation in various stability assays. Such assays can be used to determine whether the formulation is a highly stabilized formulation. In some embodiments, a highly stabilized formulation has an activity that is at least 5%, 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more greater than that of the control formulation when evaluated by any of the stability assays discussed herein or known in the art.

[0102] In some embodiments, a liquid pharmaceutical formulation comprising an anti-TIGIT antibody having the same CDR as that shown in Figure 3 (i.e., the same CDR as that of its CPA.9.086.H4(S241P)) is tested under stress factor conditions such as storage at high temperature, agitation, freeze / thaw cycles, or some combination thereof. After such stress factors, the formulation is assayed using any of the methods described herein or known in the art to determine its stability under these conditions.

[0103] In some embodiments, the appearance of a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) can be examined using A280 by the SoloVPE assay. In some embodiments, the concentration of a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) can be examined using the SoloVPE assay. A280: Amino acids containing aromatic side chains exhibit strong ultraviolet absorption at a wavelength of 280 nm. Once the extinction coefficient of a given protein is established, the concentration of the protein in solution can be calculated from its absorbance. This method is designed to determine protein concentration by measuring the absorbance at 280 nm using a SoloVPE instrument without dilution (https: / / www.ctechnologiesinc.com / products / solovpe).

[0104] In some embodiments, a binding assay can be performed to examine the activity of a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)).

[0105] LabChip analysis In some embodiments, LabChip analysis is used to examine the purity (e.g., including IgG purity) and HC+LC percentage of a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). In some embodiments, a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) exhibits an IgG purity percentage of more than 94%, more than 95%, more than 96%, more than 97%, or more than 98%. In some embodiments, a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) exhibits an IgG purity percentage of about 95% - 98%. In some embodiments, a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) exhibits an IgG purity percentage of about 96% - 97%. In some embodiments, a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) exhibits an HC+LC percentage of about 96% - 100%. In some embodiments, a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) exhibits an HC+LC percentage of about 97% - 100%. In some embodiments, a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) exhibits an HC+LC percentage of about 98% - 100%.

[0106] In some embodiments, capillary isoelectric focusing (cIEF) can be used to analyze a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) for the presence of additional species, such as trace acidic species.

[0107] Antibodies can form invisible particles in response to stress conditions such as heat, freeze / thaw cycles, and agitation. In some embodiments, microflow imaging (MFI) analysis can be used to analyze a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) for particle formation in response to stress conditions. In some embodiments, a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) provides a formulation that can be stabilized against these stress conditions and protected from particle formation. MFI can be used to evaluate the number of particles in different size ranges (<2 μm, <5 μm, <10 μm, and <25 μm) in different formulations under stress conditions. Typically, MFI data can be evaluated to select an appropriate formulation based on the production of the minimum amount of particles / mL for all particle sizes across all time points, conditions, and formulations.

[0108] In some embodiments, size exclusion chromatography (SEC) can be used to analyze a stable liquid pharmaceutical formulation containing an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)).

[0109] G. Embodiments of the Selected Formulation In some embodiments, the present invention provides (a) an anti-TIGIT antibody, wherein the anti-TIGIT antibody (i) A heavy chain variable domain comprising vhCDR1, vhCDR2, and vhCDR3 from the heavy chain of CPA.9.086.H4(S241P) (SEQ ID NO: 5), and (ii) A light chain variable domain comprising vlCDR1, vlCDR2, and vlCDR3 from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 10), an anti-TIGIT antibody, and (b) 8 mM to 12 mM of histidine, and (c) 25 mM to 35 mM of L-arginine, and (d) 8 mM to 12 mM of L-methionine, and (e) 7% (w / v) to 9% (w / v) of sucrose, and (f) 70 ppm to 80 ppm of polysorbate 80, and a stable liquid pharmaceutical formulation of an anti-TIGIT antibody is provided, wherein the pharmaceutical formulation has a pH of 5.4 ± 0.2. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody, comprising:

[0110] In some embodiments, the present invention provides (a) An anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody comprises (i) A heavy chain variable domain comprising vhCDR1, vhCDR2, and vhCDR3 from the heavy chain of CPA.9.086.H4(S241P) (SEQ ID NO: 5), and (ii) A light chain variable domain comprising vlCDR1, vlCDR2, and vlCDR3 from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 10), and (b) About 10 mM of histidine, and (c) About 30 mM of L-arginine, and (d) About 10 mM of L-methionine, and (e) About 8% (w / v) of sucrose, and (f) About 75 ppm of polysorbate 80, and a stable liquid pharmaceutical formulation of an anti-TIGIT antibody is provided, wherein the pharmaceutical formulation has a pH of 5.4 ± 0.2. In some embodiments, the present invention provides

[0111] In some embodiments, the present invention provides (a) An anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody comprises i) the heavy chain variable domain (SEQ ID NO: 1) from the heavy chain of CPA.9.086.H4(S241P), and ii) the light chain variable domain (SEQ ID NO: 6) from the light chain of CPA.9.086.H4(S241P), and an anti-TIGIT antibody, (b) About 10 mM histidine, and (c) About 30 mM L-arginine, and (d) About 10 mM L-methionine, and (e) About 8% (w / v) sucrose, and (f) About 75 ppm polysorbate 80, and provides a stable liquid pharmaceutical formulation, wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2. A stable liquid pharmaceutical formulation is provided.

[0112] In some embodiments, the present invention provides (a) An anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody comprises i) the heavy chain (SEQ ID NO: 5) from CPA.9.086.H4(S241P), and ii) the light chain (SEQ ID NO: 10) from the light chain of CPA.9.086.H4(S241P), and an anti-TIGIT antibody, (b) About 10 mM histidine, and (c) About 30 mM L-arginine, and (d) About 10 mM L-methionine, and (e) About 8% (w / v) sucrose, and (f) About 75 ppm polysorbate 80, and provides a stable liquid pharmaceutical formulation, wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2. A stable liquid pharmaceutical formulation is provided.

[0113] V. Administration of Anti-TIGIT Antibody Administration of a pharmaceutical preparation comprising an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)), preferably in the form of a sterile aqueous solution, can be carried out in various ways. As is known in the art, protein therapeutics are often delivered by IV infusion. The antibodies of the present invention can also be delivered using such methods. For example, administration may be by intravenous infusion using 0.9% sodium chloride as an infusion vehicle. Such techniques are disclosed in Remington’s Pharmaceutical Sciences 16th edition, Osol, A. Ed., 1980.

[0114] The dosage and dosing frequency are selected to be therapeutically or prophylactically effective in some embodiments. As is known in the art, proteolysis, systemic versus local delivery, and the rate of new protease synthesis, as well as adjustments to age, weight, general health, sex, diet, administration time, drug interactions, and the severity of the condition may be required, which will be confirmable by routine experimentation by those skilled in the art. To treat a patient, a therapeutically effective amount of the Fc variant of the present invention can be administered. As used herein, "therapeutically effective amount" means an amount that produces the effect for which it is administered.

[0115] VI. Dosage In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) formulation of the present invention) can be formulated for administration as a unit dosage formulation. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of the CPA.9.086.H4(S241P) formulation) is administered at a dosage of 0.01 mg / kg of the anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of 0.02 mg / kg of the anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of 0.03 mg / kg of the anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of 0.04 mg / kg of the anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of 0.05 mg / kg of the anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)).In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.06 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.07 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.08 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.09 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.1 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.2 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)).In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.3 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.5 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 0.8 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 1 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 2 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 3 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)).In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 4 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 5 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 6 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 7 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 8 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)). In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 9 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)).In some embodiments, an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is administered at a dose of 10 mg / kg of an anti-TIGIT antibody having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)).

[0116] In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 0.01 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 10 mg / kg every three weeks. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 0.1 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 1 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 2 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 3 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 4 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 5 mg / kg to about 10 mg / kg of the anti-TIGIT antibody.In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 5 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 7 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 8 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 9 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg of the anti-TIGIT antibody.

[0117] A. Selected Dosage In some embodiments, the present invention provides that an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at dosages of about 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg. In some embodiments, an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered once every three weeks. In some embodiments, an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is formulated for administration in a unit dosage. In some embodiments, an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is formulated for administration in a unit dosage of about 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg once a week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, an anti-TIGIT antibody having the same CDR as shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is formulated for administration in a unit dosage of about 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, 10 mg / kg once every three weeks.

[0118] In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at a dosage of about 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg of the anti-TIGIT antibody. In some embodiments, CPA.9.086.H4(S241P) is administered at a dosage of about 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg of the anti-TIGIT antibody.

[0119] In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at about 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg of the anti-TIGIT antibody every week, every two weeks, every three weeks, or every four weeks. In some embodiments, CPA.9.086.H4(S241P) is administered at about 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, or 10 mg / kg every week, every two weeks, every three weeks, or every four weeks.

[0120] In some embodiments, an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is administered at about 10 mg / kg every three weeks. In some embodiments, CPA.9.086.H4(S241P) is administered at about 10 mg / kg every three weeks. In some embodiments, CPA.9.086.H4(S241P) is administered at about 3 mg / kg every three weeks.

[0121] VII. Method of Using Anti-TIGIT Antibody A. Therapeutic Use An anti-TIGIT antibody having a CDR identical to that shown in FIG. 3 (i.e., identical to that of CPA.9.086.H4(S241P)) is generally useful for the treatment of patients (e.g., human subjects) having a condition associated with TIGIT. As used herein, the term "treatment" refers to both therapeutic treatment and prophylactic or preventive measures related to the treatment of cancer in this example, but as described below, the use of antibodies and pharmaceutical compositions also provides treatment methods for infectious diseases, sepsis, and / or autoimmune conditions, and / or inhibition of unwanted immune activation following gene therapy. Those in need of treatment include those already having cancer and those in whom cancer should be prevented. Thus, the mammal to be treated herein may be diagnosed as having cancer, or may be prone to or sensitive to cancer. As used herein, the term "treating" refers to preventing a harmful effect, delaying its onset, curing, reversing, attenuating, reducing, minimizing, suppressing, stopping, or stabilizing recognizable symptoms of the above-mentioned cancerous disease, disorder, or condition. This also includes managing cancer as described above. "Managing" means reducing the severity of the disease, reducing the frequency of disease attacks, reducing the duration of such attacks, reducing the severity of such attacks, delaying / reducing cancer cell growth or proliferation, delaying the progression of at least one symptom, alleviating at least one measurable physical parameter, etc. For example, an immune-stimulating anti-TIGIT immune molecule should promote T cell or NK or cytokine immunity against target cells, such as cancer, infection, or pathogenic cells, thereby treating cancer or an infectious disease by depleting the cells involved in the disease state. Conversely, an immune-inhibitory anti-TIGIT immune molecule reduces T cell or NK activity and / or the secretion of inflammatory cytokines involved in the disease pathology of some immune diseases such as autoimmunity, inflammation, or allergic conditions, thereby treating or alleviating the disease pathology and tissue destruction (e.g., joint destruction associated with rheumatoid arthritis conditions) that may be associated with such conditions.

[0122] An anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) is provided in a therapeutically effective dosage. The "therapeutically effective dosage" of an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) according to at least some embodiments of the present invention preferably results in a decrease in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, an increase in survival duration, disease remission, or the prevention or reduction of functional or physical impairments resulting from the pain of the disease. For example, for the treatment of TIGIT-positive tumors, the "therapeutically effective dosage" preferably inhibits cell growth or tumor growth by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, still more preferably at least about 80%, compared to untreated subjects. The ability of a compound to inhibit tumor growth can be evaluated in an animal model system that predicts efficacy in human tumors. Alternatively, this property of the composition can be evaluated by examining the ability of the compound to inhibit, by assays known to those of skill in the art, such in vitro inhibition. A therapeutically effective amount of a therapeutic compound can reduce tumor size or otherwise alleviate symptoms in a subject.

[0123] One of ordinary skill in the art will be able to determine a therapeutically effective amount based on factors such as the size of the subject, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0124] 1. Cancer treatment As used herein, "cancer therapy" refers to any method of preventing or treating cancer, or alleviating one or more of the symptoms of cancer. Typically, such therapy involves administering, alone or in combination with chemotherapy, radiation therapy, or other biologics, an immune-stimulatory anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) of the present invention) to enhance its activity, i.e., in an individual in whom TIGIT expression inhibits the anti-tumor response and the efficacy of chemotherapy or radiation therapy or the efficacy of a biologic.

[0125] An anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) of the present invention) is particularly useful for the treatment of cancer. Generally, the antibodies of the present invention are immunomodulatory in that, rather than directly attacking cancerous cells, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) of the present invention) generally stimulates the immune system by inhibiting the action of TIGIT. Thus, unlike tumor-targeted therapies aimed at inhibiting molecular pathways essential for tumor growth and development and / or depleting tumor cells, cancer immunotherapy aims to stimulate the patient's own immune system to eliminate cancer cells and provide long-lasting tumor destruction. Various approaches can be used in cancer immunotherapy, including therapeutic cancer vaccines for inducing tumor-specific T cell responses and immune-stimulatory antibodies for removing immunosuppressive pathways (i.e., antagonists of inhibitory receptors = immune checkpoint).

[0126] Clinical responses to targeted chemotherapy or conventional cancer therapies tend to be transient because cancer cells develop resistance and tumor recurrence occurs. However, the clinical use of cancer immunotherapies over the past several years has shown that this type of therapy can have durable clinical responses and dramatic effects on long-term survival rates. However, the responses, while long-term, are seen in only a minority of patients (relative to conventional or targeted chemotherapies where many patients respond but the response is transient).

[0127] By the time a tumor is clinically detected, the tumor has already evaded the immune defense system by acquiring immune resistance and immunosuppressive properties, and by creating an immunosuppressive tumor microenvironment through various mechanisms and various immune cells.

[0128] Accordingly, an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) is useful in the treatment of cancer. Due to the nature of the immuno-oncology mechanism of action, TIGIT does not necessarily need to be overexpressed or correlated with a particular cancer type, which means that the goal is to relieve the suppression of T cell and NK cell activation in an anti-TIGIT antibody having the same CDRs as those shown in Figure 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) so that the immune system can target the cancer.

[0129] As used herein, "cancer" broadly refers to any neoplastic disease (whether invasive or metastatic) characterized by abnormal and uncontrolled cell division that causes malignant growth or tumors (e.g., uncontrolled cell growth). The terms "cancer" or "cancerous" as used herein should be understood to encompass any neoplastic disease (whether invasive, non-invasive, or metastatic) characterized by abnormal and uncontrolled cell division that causes malignant growth or tumors, and non-limiting examples of these are described herein. This also includes any physiological state in mammals that is typically characterized by uncontrolled cell growth.

[0130] In some embodiments, anti-TIGIT antibodies having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) can be used for the treatment of solid tumors (e.g., including cancers of the lung, liver, breast, brain, GI tract) and blood cancers (e.g., leukemia and pre-leukemic disorders, lymphoma, plasma cell disorders) cancers, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. In some embodiments, the cancer is in the early stage. In some embodiments, the cancer is progressive (including metastasis). In some embodiments, cancers suitable for the treatment of the present invention include cancers that express or do not express TIGIT, and further include non-metastatic or non-invasive cancers and invasive or metastatic cancers, including cancers in which TIGIT expression by immune, stromal, or diseased cells suppresses the anti-tumor response and anti-invasive immune response. In some embodiments, anti-TIGIT antibodies having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P) of the present invention) can be used for the treatment of vascularized tumors. In some embodiments, cancers for treatment using anti-TIGIT antibodies having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) include cancers, lymphomas, sarcomas, and / or leukemias. In some embodiments, cancers for treatment using anti-TIGIT antibodies having the same CDRs as those shown in FIG. 3 (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) include melanoma, non-melanoma skin cancer (squamous and basal cell cancer), mesothelioma, squamous cell cancer, lung cancer (small cell lung cancer, non-small cell lung cancer, soft tissue sarcoma, Kaposi's sarcoma, lung adenocarcinoma, lung squamous cell cancer, peritoneal cancer, esophageal cancer, hepatocellular carcinoma, liver cancer (including HCC), gastric cancer, stomach cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, urothelial cancer, bladder cancer, hepatocytoma, glioma, brain cancer (and edema such as those associated with brain tumors), breast cancer (e.g., including triple-negative breast cancer), testicular cancer, testicular germ cell tumor, colon cancer, colorectal cancer (CRC), colorectal cancer MSS (MSS-CRC;Including refractory MSS colorectal (MSS = microsatellite stable state), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, CRC (MSS unknown), rectal cancer, endometrial cancer (including endometrial carcinoma), uterine carcinoma, salivary gland carcinoma, kidney cancer, renal cell carcinoma (RCC), renal cell carcinoma tumor (RCC), prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, carcinoid tumor, head and neck cancer, B-cell lymphoma (including non-Hodgkin lymphoma, and low-grade / follicular non-Hodgkin lymphoma (NHL), small lymphocytic (SL) NHL, intermediate / follicular NHL, intermediate diffuse NHL, diffuse large B-cell lymphoma, high-grade immunoblastic NHL, high-grade lymphoblastic NHL, high-grade small non-cleaved cell NHL, large lesion NHL, mantle cell lymphoma, AIDS-related lymphoma, and Waldenström macroglobulinemia), Hodgkin lymphoma (HD), chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), T-cell acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), hairy cell leukemia, chronic myelogenous leukemia, multiple myeloma, post-transplant lymphoproliferative disorder (PTLD), abnormal vascular proliferation associated with nevus syndrome, Meigs syndrome, Merkel cell carcinoma, MSI-high cancer, KRAS mutant tumor, adult T-cell leukemia / lymphoma, adenoid cystic carcinoma (including adenoid cystic carcinoma tumor), malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, ovarian cancer (including ovarian carcinoma), pleural mesothelioma, neuroendocrine lung cancer (including pleural mesothelioma, neuroendocrine lung cancer tumor), NSCLC large cell adenocarcinoma, non-small cell lung cancer tumor (NSCLC), NSCLC squamous cell, cervical squamous cell carcinoma tumor (cervical SCC), anal squamous cell carcinoma tumor (anal SCC), neuroendocrine lung cancer tumor, cancer of unknown primary, gallbladder cancer, malignant melanoma, pleural mesothelioma, multiple myeloma, esophagogastric junction cancer, and / or myelodysplastic syndrome (MDS).;

[0131] In some embodiments, cancers for treatment using an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) include prostate cancer, liver cancer (HCC), colorectal cancer (CRC), colorectal cancer MSS (MSS-CRC; including refractory MSS colon), CRC (MSS unknown), ovarian cancer (including ovarian tumors), endometrial cancer (including endometrial tumors), breast cancer, pancreatic cancer, gastric cancer, cervical cancer, head and neck cancer, thyroid cancer, testicular cancer, urothelial cancer, lung cancer, melanoma, non-melanoma skin cancer (squamous and basal cell carcinomas), glioma, renal cell cancer (RCC), renal cell carcinoma (RCC), lymphoma (non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HD)), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), diffuse large B-cell lymphoma, testicular germ cell tumor, mesothelioma, esophageal cancer, triple-negative breast cancer, Merkel cell cancer, MSI-high cancer, KRAS mutant tumor, adult T-cell leukemia / lymphoma, pleural mesothelioma, anal SCC, small cell lung cancer, lung adenocarcinoma, neuroendocrine lung cancer (including neuroendocrine lung tumors), HNSCC, NSCLC, NSCLC large cell, NSCLC squamous cell, cervical SCC, malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, NSCLC, adenoid cystic cancer (including adenoid cystic carcinomas), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, PD1 refractory or recurrent, multiple myeloma, gastroesophageal junction cancer, and / or myelodysplastic syndrome (MDS) are included.

[0132] In some embodiments, cancers for treatment using an anti-TIGIT antibody having the same CDR as that shown in FIG. 3 (i.e., the same CDR as that of CPA.9.086.H4(S241P)) include advanced cancer, ovarian cancer, lung cancer, non-small cell lung carcinoma (NSCLC), PD1 refractory or recurrent NSCLC, colon cancer, colorectal cancer (CRC), MSS-CRC, plasma cell tumor, head and neck squamous cell carcinoma (HNSCC), PD1 refractory or recurrent HNSCC, and breast cancer.

Example

[0133] Example 1: Stable pharmaceutical formulation CPA.9.086.H4 (S241P) This example describes (a) An anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody comprises (i) a heavy chain from CPA.9.086.H4 (S241P) (SEQ ID NO: 5), and (ii) a light chain from the light chain of CPA.9.086.H4 (S241P) (SEQ ID NO: 10), and an anti-TIGIT antibody, (b) about 10 mM histidine, and (c) about 30 mM L-arginine, and (d) about 10 mM L-methionine, and (e) about 8% (w / v) sucrose, and (f) about 75 ppm polysorbate 80, and describes the characteristics and preparation of a stable pharmaceutical formulation, wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2. Examination of the formulation of CPA.9.086.H4 (S241P) in phosphate buffer at pH 7.0 demonstrated that the solubility of the antibody was > 20 mg / mL. Therefore, a formulation of CPA.9.086.H4 (S241P) with a target antibody concentration of 20 mg / mL was studied.

[0134]

[0135] The formulation was provided at an antibody concentration of 20 mg / mL and a target pH of 5.4 and prepared for further packaging. For administration to patients, CPA.9.086.H4 (S241P) is diluted with 0.9% sodium chloride and placed in a suitable administration container.

[0136] ​In a formulation containing 30 mM L-arginine, 10 mM L-histidine, 10 mM L-methionine, 8% (w / v) sucrose, and 75 ppm polysorbate 80 at pH 5.4 (range: 5.4 ± 0.2), the stability of CPA.9.086.H4(S241P) was observed. L-histidine was used as a buffer component. On the other hand, L-arginine, L-methionine, sucrose, and polysorbate 80 were used to stabilize the protein and prevent self-association and aggregation. In addition, L-methionine functions as an antioxidant and polysorbate 80 functions as a surfactant.

[0137] Table 1 provides the formulation components. The amounts per listed vial are based on an actual target fill volume of 5.3 mL, which corresponds to a target fill weight of 5.5 g / vial. The official weight of CPA.9.086.H4(S241P) per vial is 100 mg. [Table 2]

[0138] The temperature stability was determined based on the following. ● Liquid stability samples at 5 °C and 25 °C for 0.5, 1, 2, and 6 months ● Lyophilized stability samples at 5 °C and 25 °C for 1, 3, and 6 months

[0139] The data obtained showed that CPA.9.086.H4(S241P) was stable at 5 °C in both liquid and lyophilized formulations during storage for at least 6 months. At 25 °C, CPA.9.086.H4(S241P) showed higher stability in the lyophilized formulation.

[0140] Also, based on freeze / thaw, agitation, aggregation, fragmentation, and other standard assays, the samples were determined to be stable. The stable formulation also maintained the biological function of CPA.9.086.H4(S241P).

[0141] Conclusion CPA.9.086.H4(S241P) was stable in both liquid and lyophilized formulations with respect to physical appearance, aggregate formation, and other properties for at least six months at 5°C. Additional results further showed that CPA.9.086.H4(S241P) was stable with respect to physical appearance, aggregates, fragments, and formation of basic / acidic species under repeated freeze / thaw, shaking, mixing, and filtration processes.

[0142] The above examples are provided to give those skilled in the art a complete disclosure and description of how to make and use embodiments of the compositions, systems, and methods of the invention, and are not intended to limit the scope of what the inventors regard as their invention. Modifications of the above-described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the following claims. All patents and publications referred to herein are indicative of the state of the art to which the invention pertains.

[0143] All headings and section designations are used for purposes of clarification and reference only and should not be considered limiting in any way. For example, those skilled in the art will recognize the utility of combining various aspects from different headings and sections as necessary in accordance with the spirit and scope of the invention described herein.

[0144] All references cited herein are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.

[0145] As will be apparent to those skilled in the art, many modifications and variations of this application can be made without departing from the spirit and scope of the application. The specific embodiments and examples described herein are provided by way of example only and should be limited only by the terms of the appended claims together with the full scope of equivalents to which the claims are entitled.

Claims

1. A stable liquid pharmaceutical formulation of an anti-TIGIT antibody, comprising: (a) an anti-TIGIT antibody, wherein the anti-TIGIT antibody comprises: (i) a heavy chain variable domain comprising vhCDR1, vhCDR2, and vhCDR3 from the heavy chain of CPA.9.086.H4 (S241P) (SEQ ID NO: 5), and (ii) a light chain variable domain comprising vlCDR1, vlCDR2, and vlCDR3 from the light chain of CPA.9.086.H4 (S241P) (SEQ ID NO: 10), and (b) 8 mM to 12 mM of histidine, (c) 25 mM to 35 mM of L-arginine, (d) 8 mM to 12 mM of L-methionine, (e) 7% (w / v) to 9% (w / v) of sucrose, and (f) 70 ppm to 80 ppm of polysorbate 80, and the pharmaceutical formulation has a pH of 5.4 ± 0.2, a stable liquid pharmaceutical formulation.

2. The stable liquid pharmaceutical formulation according to claim 1, wherein the anti-TIGIT antibody comprises the CH1-hinge-CH2-CH3 sequence of IgG4, and the hinge region optionally comprises a mutation.

3. The stable liquid pharmaceutical formulation according to claim 1, wherein the anti-TIGIT antibody comprises the CH1-hinge-CH2-CH3 sequence of IgG4, and the hinge region optionally comprises a mutation.

4. The stable liquid pharmaceutical formulation according to any one of claims 1 to 3, wherein the heavy chain variable domain is derived from the heavy chain of CPA.9.086.H4 (S241P) (SEQ ID NO: 1), and the light chain variable domain is derived from the light chain of CPA.9.086.H4 (S241P) (SEQ ID NO: 6).

5. The stable liquid pharmaceutical formulation according to any one of claims 1 to 4, wherein the anti-TIGIT antibody comprises the CL region of the human kappa 2 light chain.

6. The stable liquid pharmaceutical formulation according to any one of claims 1 to 5, wherein the pharmaceutical formulation comprises about 15 mg / mL to about 25 mg / mL of the anti-TIGIT antibody.

7. The stable liquid pharmaceutical formulation according to any one of claims 1 to 6, wherein the pharmaceutical formulation comprises about 20 mg / mL of the anti-TIGIT antibody.

8. The stable liquid pharmaceutical formulation according to any one of claims 1 to 7, wherein the pharmaceutical formulation comprises about 10 mM of histidine.

9. The stable liquid pharmaceutical formulation according to any one of claims 1 to 8, wherein the pharmaceutical formulation comprises about 30 mM of L-arginine.

10. The stable liquid pharmaceutical preparation according to any one of claims 1 to 9, wherein the pharmaceutical preparation contains about 10 mM of L-methionine.

11. The stable liquid pharmaceutical preparation according to any one of claims 1 to 10, wherein the pharmaceutical preparation contains about 8% of sucrose.

12. The stable liquid pharmaceutical preparation according to any one of claims 1 to 11, wherein the pharmaceutical preparation contains about 75 ppm of polysorbate 80.

13. A stable liquid pharmaceutical preparation of an anti-TIGIT antibody, (a) an anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody i) contains a heavy chain variable domain including vhCDR1, vhCDR2, and vhCDR3 from the heavy chain (SEQ ID NO: 5) of CPA.9.086.H4 (S241P), and ii) a light chain variable domain including vlCDR1, vlCDR2, and vlCDR3 from the light chain (SEQ ID NO: 10) of CPA.9.086.H4 (S241P), an anti-TIGIT antibody, (b) about 10 mM of histidine, (c) about 30 mM of L-arginine, (d) about 10 mM of L-methionine, (e) about 8% (w / v) of sucrose, (f) about 75 ppm of polysorbate 80, and the pharmaceutical preparation has a pH of 5.4 ± 0.2, a stable liquid pharmaceutical preparation.

14. A stable liquid pharmaceutical preparation of an anti-TIGIT antibody, (a) an anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody i) contains a heavy chain variable domain from the heavy chain (SEQ ID NO: 5) of CPA.9.086.H4 (S241P), and ii) a light chain variable domain from the light chain (SEQ ID NO: 10) of CPA.9.086.H4 (S241P), an anti-TIGIT antibody, (b) about 10 mM of histidine, (c) about 30 mM of L-arginine, (d) about 10 mM of L-methionine, (e) about 8% (w / v) of sucrose, (f) about 75 ppm of polysorbate 80, and the pharmaceutical preparation has a pH of 5.4 ± 0.2, a stable liquid pharmaceutical preparation.

15. A stable liquid pharmaceutical preparation of an anti-TIGIT antibody, (a) an anti-TIGIT antibody at about 20 mg / mL, wherein the anti-TIGIT antibody i) contains the heavy chain (SEQ ID NO: 5) from CPA.9.086.H4 (S241P), and ii) the light chain (SEQ ID NO: 10) from the light chain of CPA.9.086.H4 (S241P), an anti-TIGIT antibody, (b) about 10 mM of histidine, (c) about 30 mM of L-arginine, and (d) about 10 mM of L-methionine, and (e) about 8% (w / v) of sucrose, and (f) about 75 ppm of polysorbate 80, and comprising the pharmaceutical preparation is a stable liquid pharmaceutical preparation having a pH of 5.4 ± 0.

2. **Claim 16** The stable liquid pharmaceutical preparation according to any one of claims 1 to 15, wherein the pharmaceutical preparation is stable at 5°C to 25°C for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, or 8 months. **Claim 17** The stable liquid pharmaceutical preparation according to any one of claims 1 to 16, wherein the pharmaceutical preparation is stable at 5°C to 25°C for at least 6 months, at least 12 months, or at least 18 months. **Claim 18** The stable liquid pharmaceutical preparation according to any one of claims 1 to 17, wherein the pharmaceutical preparation is administered at a dosage of about 0.01 mg / kg to about 100 mg / kg, about 0.05 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 20 mg / kg, or about 1 mg / kg to about 10 mg / kg. **Claim 19** The stable liquid pharmaceutical preparation according to any one of claims 1 to 18, wherein the pharmaceutical preparation is administered at a dosage of about 0.01 mg / kg, about 0.01 mg / kg, about 0.03 mg / kg, about 0.1 mg / kg, about 0.3 mg / kg, about 1 mg / kg, about 3 mg / kg, about 10 mg / kg, about 15 mg / kg, or about 20 mg / kg, or about 30 mg / kg. **Claim 20** The stable liquid pharmaceutical preparation according to any one of claims 1 to 19, wherein the anti-TIGIT antibody is administered once every week, once every two weeks, once every three weeks, or once every four weeks, once every five weeks, or once every six weeks. **Claim 21** The stable liquid pharmaceutical preparation according to any one of claims 1 to 20, wherein the anti-TIGIT antibody is administered as a single dose. **Claim 22** The stable liquid pharmaceutical preparation according to any one of claims 1 to 21, wherein the pharmaceutical preparation is formulated for intravenous (IV) infusion. **Claim 23** The stable liquid pharmaceutical preparation according to any one of claims 1 to 22, wherein the pharmaceutical preparation is administered for the treatment of cancer. **Claim 24** The stable liquid pharmaceutical preparation according to any one of claims 1 to 23, for use in a method of treating cancer. **Claim 25** The stable liquid pharmaceutical preparation according to claim 23 or 24, wherein the cancer is selected from the group consisting of prostate cancer, liver cancer (HCC), colorectal cancer (CRC), colorectal cancer MSS (MSS-CRC; including refractory MSS colon), CRC (MSS unknown), ovarian cancer (including ovarian tumors), endometrial cancer (including endometrial tumors), breast cancer, pancreatic cancer, gastric cancer, cervical cancer, head and neck cancer, thyroid cancer, testicular cancer, urothelial cancer, lung cancer, melanoma, non-melanoma skin cancer (squamous and basal cell tumors), glioma, renal cell cancer (RCC), renal cell carcinoma (RCC), lymphoma (non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HD)), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), diffuse large B-cell lymphoma, testicular germ cell tumor, mesothelioma, esophageal cancer, triple-negative breast cancer, Merkel cell cancer, MSI-high cancer, KRAS variant tumor, adult T-cell leukemia / lymphoma, pleural mesothelioma, anal SCC, small cell lung cancer, lung adenocarcinoma, neuroendocrine lung cancer (including neuroendocrine lung tumors), HN SCC, PD1-refractory or recurrent HN SCC, NSCLC, PD1-refractory or recurrent NSCLC, NSCLC large cell, NSCLC squamous epithelial cell, cervical SCC, malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, NSCLC, adenoid cystic cancer (including adenoid cystic tumors), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, multiple myeloma, esophagogastric junction cancer, and myelodysplastic syndrome (MDS).

26. A stable lyophilized pharmaceutical preparation obtained by lyophilizing the stable liquid pharmaceutical preparation according to any one of claims 1 to 25.

27. Use of the stable lyophilized pharmaceutical preparation according to any one of claims 1 to 26 for the treatment of cancer.

28. The cancer according to claim 27, wherein the cancer is selected from the group consisting of prostate cancer, liver cancer (HCC), colorectal cancer (CRC), colorectal cancer MSS (MSS-CRC; including refractory MSS colon), CRC (MSS unknown), ovarian cancer (including ovarian tumors), endometrial cancer (including endometrial tumors), breast cancer, pancreatic cancer, gastric cancer, cervical cancer, head and neck cancer, thyroid cancer, testicular cancer, urothelial cancer, lung cancer, melanoma, non-melanoma skin cancer (squamous and basal cell tumors), glioma, renal cell cancer (RCC), renal cell carcinoma (RCC), lymphoma (non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HD)), acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL), diffuse large B-cell lymphoma, testicular germ cell tumor, mesothelioma, esophageal cancer, triple-negative breast cancer, Merkel cell cancer, MSI-high cancer, KRAS variant tumor, adult T-cell leukemia / lymphoma, pleural mesothelioma, anal SCC, small cell lung cancer, lung adenocarcinoma, neuroendocrine lung cancer (including neuroendocrine lung tumors), HNSCC, PD1-refractory or recurrent HNSCC, NSCLC, PD1-refractory or recurrent NSCLC, NSCLC large cell, NSCLC squamous cell, cervical SCC, malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, NSCLC, adenoid cystic cancer (including adenoid cystic tumors), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, multiple myeloma, esophagogastric junction cancer, and myelodysplastic syndrome (MDS).

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