Anti-TIGIT antibody formulations

Abstract

In particular, the present invention provides formulations comprising an anti-TIGIT antibody having the same CDR as those shown in Fig. 3 (i.e., the same CDR as those of CPA.9.086. H4 (S241P)), as described herein.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 346,167, filed on May 26, 2023, which is incorporated herein by reference in its entirety. Background Art

[0003] TIGIT is a co-inhibitory receptor that is highly expressed on effector and regulatory (Treg) CD4+ T cells, effector CD8+ T cells, and NK cells. TIGIT has been shown to attenuate immune responses by: (1) direct signaling, (2) induction of ligand signaling, and (3) competition with and interruption of signaling by the co-stimulatory receptor CD226 (also known as DNAM-1). TIGIT signaling has been most extensively studied in NK cells, where binding to its cognate ligand, the poliovirus receptor (PVR, also known as CD155), has been shown to directly inhibit NK cytotoxicity 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 vivo. In addition to its direct effects on T cells and NK cells, TIGIT can also induce PVR-mediated signaling in dendritic cells or tumor cells, leading to increased production of anti-inflammatory cytokines such as IL10. In T cells, TIGIT can also inhibit lymphocyte responses by interrupting homodimerization of the co-stimulatory receptor CD226 and competing with it for binding to PVR.

[0004] TIGIT is highly expressed on lymphocytes, including tumor-infiltrating lymphocytes (TILs) and Tregs that infiltrate different types of tumors. PVR is also widely expressed in tumors, suggesting that the TIGIT-PVR signaling axis may be a major immune escape mechanism for cancer. Notably, TIGIT expression is closely associated with the expression of another important co-inhibitory receptor, PD1. TIGIT and PD1 are co-expressed on TILs in many human and mouse tumors. Unlike TIGIT and CTLA4, PD1 inhibition of T cell responses does not involve competition with co-stimulatory receptors for ligand binding.

[0005] An object of the present invention is to provide a formulation comprising an anti-TIGIT antibody having Figure 3 CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)). Summary of the invention

[0006] In some aspects, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody, the stable liquid pharmaceutical formulation comprising:

[0007] (a) an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0008] 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

[0009] 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);

[0010] (b) 8 mM to 12 mM histidine;

[0011] (c) 25 mM to 35 mM L-arginine;

[0012] (d) 8 mM to 12 mM L-methionine;

[0013] (e) 7% (w / v) to 9% (w / v) sucrose; and

[0014] (f) 70 ppm to 80 ppm polysorbate 80,

[0015] Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0016] In some embodiments of paragraph

[0004] , the anti-TIGIT antibody comprises a CH1-hinge-CH2-CH3 sequence of IgG4, wherein the hinge region optionally comprises a mutation.

[0017] In some embodiments of paragraphs

[0004] to

[0005] , the anti-TIGIT antibody comprises a CH1-hinge-CH2-CH3 sequence of IgG4, wherein the hinge region optionally comprises a mutation.

[0018] In some embodiments of paragraphs

[0004] to

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

[0019] In some embodiments of paragraphs

[0004] to

[0007] , the anti-TIGIT antibody comprises the CL region of a human κ2 light chain.

[0020] In some embodiments of paragraphs

[0004] to

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

[0021] In some embodiments of paragraphs

[0004] to

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

[0022] In some embodiments of paragraphs

[0004] to

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

[0023] In some embodiments of paragraphs

[0004] to

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

[0024] In some embodiments of paragraphs

[0004] to

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

[0025] In some embodiments of paragraphs

[0004] to

[0013] , the pharmaceutical formulation comprises about 8% sucrose.

[0026] In some embodiments of paragraphs

[0004] to

[0014] , the pharmaceutical formulation comprises about 75 ppm polysorbate 80.

[0027] In some aspects, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody, the stable liquid pharmaceutical formulation comprising:

[0028] (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0029] i) a heavy chain variable domain comprising vhCDR1, vhCDR2 and vhCDR3 from the heavy chain of CPA.9.086.H4(S241P) (SEQ ID NO: 1); and

[0030] ii) a light chain variable domain comprising vlCDR1, vlCDR2 and vlCDR3 from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 6);

[0031] (b) about 10 mM histidine;

[0032] (c) about 30 mM L-arginine;

[0033] (d) about 10 mM L-methionine;

[0034] (e) about 8% (w / v) sucrose; and

[0035] (f) about 75 ppm polysorbate 80,

[0036] Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0037] In some aspects, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody, the stable liquid pharmaceutical formulation comprising:

[0038] (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0039] i) the heavy chain variable domain from the heavy chain of CPA.9.086.H4(S241P) (SEQ ID NO: 1); and

[0040] ii) the light chain variable domain from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 6);

[0041] (b) about 10 mM histidine;

[0042] (c) about 30 mM L-arginine;

[0043] (d) about 10 mM L-methionine;

[0044] (e) about 8% (w / v) sucrose; and

[0045] (f) about 75 ppm polysorbate 80,

[0046] Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0047] In some aspects, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody, the stable liquid pharmaceutical formulation comprising:

[0048] (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0049] i) the heavy chain from CPA.9.086.H4(S241P) (SEQ ID NO: 5); and

[0050] ii) the light chain from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 10);

[0051] (b) about 10 mM histidine;

[0052] (c) about 30 mM L-arginine;

[0053] (d) about 10 mM L-methionine;

[0054] (e) about 8% (w / v) sucrose; and

[0055] (f) about 75 ppm polysorbate 80,

[0056] Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0057] In some embodiments of paragraphs

[0017] to

[0018] , the pharmaceutical formulation 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.

[0058] In some embodiments of paragraphs

[0017] to

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

[0059] In some embodiments of paragraphs

[0004] to

[0020] , the pharmaceutical formulation 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.

[0060] In some embodiments of paragraphs

[0004] to

[0021] , the pharmaceutical formulation is administered at a dose 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.

[0061] 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.

[0062] In some embodiments of paragraphs

[0004] to

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

[0063] In some embodiments of paragraphs

[0004] to

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

[0064] In some embodiments of paragraphs

[0004] to

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

[0065] In some embodiments of paragraphs

[0004] to

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

[0066] In some embodiments of paragraphs

[0026] to

[0027] , 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 colorectal), 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 carcinoma, lung cancer. , melanoma, non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), glioma, renal cell carcinoma (RCC), renal cell tumor (RCC), lymphoma (non-Hodgkin's lymphoma (NHL) and Hodgkin's 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 carcinoma (Merkel cell carcinoma), Cells cancer), microsatellite instability-high (MSI-H) cancer, KRAS mutant tumors, 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 carcinoma (including adenoid cystic tumors), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, multiple myeloma, gastroesophageal junction cancer and / or myelodysplastic syndrome (MDS).

[0067] In some embodiments, the formulation is obtained by lyophilizing the stable liquid pharmaceutical formulation according to any one of paragraphs

[0004] to

[0028] .

[0068] In some embodiments, the stable lyophilized pharmaceutical formulation according to any one of paragraphs

[0004] to

[0029] is used for treating cancer.

[0069] In some embodiments of paragraph

[0030] , 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 colorectal), 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 carcinoma, lung cancer, melanoma, non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), glioma, renal cell carcinoma (RCC), renal cell tumor (RCC), lymphoma (non-Hodgkin's lymphoma (NHL) and Hodgkin's 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 Carcinoma (Merkel Cells cancer), microsatellite instability-high (MSI-H) cancer, KRAS mutant tumors, 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 carcinoma (including adenoid cystic neoplasms), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, multiple myeloma, gastroesophageal junction cancer and / or myelodysplastic syndrome (MDS). BRIEF DESCRIPTION OF THE DRAWINGS

[0070] Figure 1 The sequences of human and cynomolgus monkey (referred to as cyno) TIGIT ECD are depicted.

[0071] Figure 2 The sequences of human IgG4 and alternative versions of IgG4 are depicted.

[0072] Figure 3 The sequence of the anti-TIGIT antibody CPA.9.086 (S241P) is depicted. Unless otherwise indicated, CDRs use IMGT numbering (including antibodies in the sequence listing).

[0073] Figure 4 Depicted is the SEC-HPLC separation of CPA.9.086.H4(S241P) monomer (peak 1) and its aggregates (peak 2) in liquid stability samples.

[0074] Figure 5Depicted is a representative electropherogram of a liquid stability sample consisting of three regions: an acidic region (left), a main region (center), and a basic region (right).

[0075] Figure 6 provides photographs of formulation buffer (1) and CPA.9.086.H4 (S241P) (2) in a 100 mL bottle (A) and a 10 mL glass vial (B).

[0076] Figure 7 provides photographs of lyophilized CPA.9.086.H4 (S241P) in vials (A1 and A2) and reconstituted product vial (B2) compared to buffer solution (B1).

[0077] Figure 8 provides photographs of 6 month liquid stability samples (A) and reconstituted lyophilized stability samples (B) compared to buffer (1) at 5°C (2) and 25°C (3).

[0078] Figure 9 provides a comparison of formulation buffer (left) and freeze-thaw samples at -20°C and -70°C. Samples were frozen and thawed once (1X), three times (3X), and five times (5X).

[0079] FIG. 10 provides a comparison of formulation buffer (left) and samples shaken at room temperature (right) for 20 minutes (A), 6 hours (B), and 24 hours (C). DETAILED DESCRIPTION

[0080] I. introduce

[0081] The present invention relates to a stable formulation of the anti-TIGIT antibody CPA.9.086 (S241P) (e.g., having Figure 3 In some embodiments, the anti-TIGIT antibodies include antibodies having CDRs identical to those shown in the table above and the CDRs identical to those shown in the table above. In particular, the preparations include antibodies comprising heavy and light chains and 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 antibodies having CDRs identical to those shown in the table above. Figure 3 Those anti-TIGIT antibodies having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with heavy and light chains provided in.

[0082] II. TIGIT proteins

[0083] The present invention provides an antibody that specifically binds to TIGIT protein and prevents activation by its ligand protein, PVR poliovirus receptor (also known as CD155) human plasma membrane glycoprotein, wherein the anti-TIGIT antibody is CPA.9.086 (S241P) or has a binding affinity to Figure 3 Anti-TIGIT antibodies that have CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086 (S241P)). TIGIT (or T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory 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 contains characteristic sequence elements 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 those that are specific for TIGIT ECD, such that the binding of TIGIT to PVR is blocked, such as Figure 3 Anti-TIGIT antibodies that have CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)).

[0084] Therefore, as used herein, the term "TIGIT" or "TIGIT protein" or "TIGIT polypeptide" may optionally include any such protein or variant, conjugate or fragment thereof, including but not limited to known or wild-type TIGIT, as described herein, as well as any naturally occurring splice variant, amino acid variant or isomer, in particular the ECD fragment of TIGIT.

[0085] III. Anti-TIGIT antibodies

[0086] Therefore, the present invention provides a Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) can be formulated according to the formulations described herein.

[0087] As discussed below, the term "antibody" is generally used. Antibodies that can be used in the present invention can take the various forms described herein, including traditional antibodies and antibody derivatives, fragments and mimetics as described below. In general, the term "antibody" includes any polypeptide including at least one antigen binding domain, as described more fully below. Antibodies can be polyclonal, monoclonal, xenogeneic, allogeneic, isogenic or modified forms thereof, as described herein, wherein monoclonal antibodies are particularly useful in many embodiments. In some embodiments, the antibodies of the present invention specifically or substantially specifically bind to TIGIT molecules. As used herein, the terms "monoclonal antibody" and "monoclonal antibody composition" refer to a population of antibody molecules containing only one species of antigen binding sites that can immunoreact with a specific epitope of an antigen, while the terms "polyclonal antibody" and "polyclonal antibody composition" refer to a population of antibody molecules containing multiple species of antigen binding sites that can interact with a specific antigen. A monoclonal antibody composition typically exhibits a single binding affinity to a specific antigen with which it immunoreacts.

[0088] The amino-terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids that are primarily responsible for antigen recognition, generally referred to in the art and herein as an "Fv domain" or "Fv region". In the variable region, each of the V domains of the heavy and light chains gathers three loops to form an antigen binding site. Each of these loops is called a complementary determining region (hereinafter referred to as a "CDR"), where the variation in the amino acid sequence is most significant. "Variable" refers to the fact that the sequence of certain segments of the variable region differs greatly between antibodies. The variability within the variable region is not evenly distributed. Instead, the V region consists of relatively invariant fragments of 15 to 30 amino acids, called framework regions (FRs), which are separated by shorter regions with extreme variability, called "hypervariable regions".

[0089] Each VH and VL is composed of three hypervariable regions ("complementarity determining regions", "CDRs") and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0090] The hypervariable regions generally encompass amino acid residues 24-34 (LCDR1; "L" for light chain), 50-56 (LCDR2), and 89-97 (LCDR3) in the light chain variable region, and about 31-35B (HCDR1; "H" for heavy chain), 50-65 (HCDR2), and 95-102 (HCDR3) in the heavy chain variable region, although the numbering sometimes varies slightly, as will be appreciated by those skilled in the art; Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5th ed. Public Health Service, National Institutes of Health, 1994. Health, Bethesda, Md. (1991) and / or those residues that form a hypervariable loop (e.g., residues 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3) in the light chain variable region and residues 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 invention are described below and are herein Figure 3 Shown in.

[0091] The carboxyl terminal portion of each chain defines the constant region that is primarily responsible for effector function. Kabat et al. collected a large number of primary sequences of heavy and light chain variable regions. Based on the degree of conservation of the sequence, they classified each primary sequence into CDR and framework and made a list thereof (see SEQUENCES OF IMMUNOLOGICAL INTEREST, 5th edition, NIH publication, No. 91-3242, EA Kabat et al., incorporated by reference in its entirety).

[0092] In the IgG subclass of immunoglobulin, there are several immunoglobulin domains in the heavy chain. "Immunoglobulin (Ig) domain" herein refers to an immunoglobulin region with a unique tertiary structure. The present invention is interested in the heavy chain domain, including a constant heavy (CH) domain and a hinge domain. In the context of IgG antibodies, each IgG isotype has three CH regions. Therefore, the "CH" domain in the IgG context is as follows: "CH1" refers to positions 118 to 220 according to the EU index in Kabat. "CH2" refers to positions 237 to 340 according to the EU index in Kabat, and "CH3" refers to positions 341 to 447 according to the EU index in Kabat.

[0093] Therefore, the present invention provides variable heavy domains, variable light domains, heavy constant domains, light constant domains and Fc domains as used herein. As used herein, "variable region" means the region of immunoglobulin, which comprises one or more Ig domains encoded by any one of Vκ or Vλ and / or VH genes constituting κ, λ and heavy chain immunoglobulin loci, respectively. Therefore, the variable heavy domain comprises vhFR1-vhCDR1-vhFR2-vhCDR2-vhFR3-vhCDR3-vhFR4, and the variable light domain comprises vlFR1-vlCDR1-vlFR2-vlCDR2-vlFR3-vlCDR3-vlFR4. "Heavy constant region" herein means the CH1-hinge-CH2-CH3 part of an antibody. As used herein, "Fc" or "Fc region" or "Fc domain" means a polypeptide comprising the constant region of an antibody (excluding the first constant region immunoglobulin domain and, in some cases, a portion of the hinge). Thus, 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 flexible hinge N-termini of these domains. For IgA and IgM, Fc may include the J chain. For 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). Although the boundaries of the Fc region may vary, the human IgG heavy chain Fc region is generally defined as including residues C226 or P230 at its carboxyl terminus, where numbering is according to the EU index in Kabat. In some embodiments, as described more fully below, amino acid modifications are made to the Fc region, for example, to alter binding to one or more FcγR receptors or to the FcRn receptor.

[0094] Therefore, as used herein, "Fc variant" or "variant Fc" means a protein comprising 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 parent Fc polypeptide. The identity of the WT amino acids may not be specified, in which case the above variant is referred to as 428L / 434S. It should be noted that the order in which the substitutions are provided is arbitrary, that is, for example, 428L / 434S is the same Fc variant as M428L / N434S, etc. For all positions involving antibodies discussed in the present invention, unless otherwise indicated, the amino acid position numbering is according to the EU index.

[0095] As used herein, "Fab" or "Fab region" means a polypeptide comprising the VH, CH1, VL and CL immunoglobulin domains. Fab can refer to this region alone, or to this region 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 comprising the VL and VH domains of a single antibody. As will be appreciated by those skilled in the art, these are typically composed of two chains.

[0096] Throughout this specification, when referring to residues in the variable domain (approximately residues 1 to 107 in the light chain variable region and residues 1 to 113 in the heavy chain variable region), the IMTG numbering system or the Kabat numbering system (e.g., Kabat et al., supra (1991)) is generally used. The EU numbering in Kabat is generally used for constant domains and / or Fc domains.

[0097] The definition of "antibody" includes the "antigen-binding portion" of an antibody (also used interchangeably with "antigen-binding fragment," "antibody fragment," and "antibody derivative"). That is, for the purposes of the present invention, Figure 3Anti-TIGIT antibodies having CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) have the minimum functional requirements for their binding to the TIGIT antigen. As will be appreciated by those skilled in the art, there are a large number of antigen fragments and derivatives that retain the ability to bind to an antigen and also have alternative structures, including but not limited to: (i) a Fab fragment comprising VL, VH, CL and CH1 domains; (ii) a Fd fragment comprising VH and CH1 domains; (iii) a F(ab')2 fragment, which is a bivalent fragment comprising two linked Fab fragments (vii) a single-chain Fv molecule (scFv), in which the VH domain and the VL domain are linked by a peptide linker that allows the 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. USA 85:5879-5883, the entire texts of which are incorporated by reference); (iv) a "diabody" or "tribody", which is a multivalent or multispecific fragment constructed by gene fusion (Tomlinson et al., 2000, Methods Enzymol. 326:461-479; WO 94 / 13804; Holliger et al., 1993, Proc. Natl. Acad. Sci. USA 90:6444-6448, the entire text of which is incorporated by reference); (v) "domain antibodies" or "dAbs" (sometimes referred to as "immunoglobulin single variable domains"), including single antibody variable domains V-HHdAbs from other species such as rodents (e.g., as disclosed in WO 00 / 29004), nurse sharks, and camelids; (vi) SMIPs (small molecule immunopharmaceuticals), camelid antibodies, nanobodies, and IgNARs. The present invention relates to antibodies having Figure 3 An anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is generally based on the IgG class, which has several subclasses, including but not limited to IgG4.

[0098] The amino terminal portion of each chain includes a variable region of about 100 to 110 or more amino acids that are primarily responsible for antigen recognition, commonly referred to in the art and herein as an "Fv domain" or "Fv region". In the variable region, each of the V domains of the heavy and light chains gathers three loops to form an antigen binding site. Each of these loops is called a complementary determining region (hereinafter referred to as a "CDR"), in which the amino acid sequence varies most significantly. "Variable" refers to the fact that the sequence of certain segments of the variable region differs greatly between antibodies. The variability within the variable region is not evenly distributed. Instead, the V region consists of relatively unchanging fragments of 15 to 30 amino acids, called framework regions (FRs), which are separated by shorter regions with extreme variability, called "hypervariable regions", each of which is 9 to 15 amino acids long or longer.

[0099] Each VH and VL is composed of three hypervariable regions ("complementarity determining regions", "CDRs") and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0100] The hypervariable region generally encompasses amino acid residues about 24-34 (LCDR1; "L" for light chain), 50-56 (LCDR2), and 89-97 (LCDR3) in the light chain variable region, and about 31-35B (HCDR1; "H" for light chain), 50-65 (HCDR2), and 95-102 (HCDR3) in the heavy chain variable region; Kabat et al., SEQUENCES OF PROTEINS OF IMMUNOLOGICAL INTEREST, 5th ed. Public Health Service, National Institutes of Health, 1994. Health, Bethesda, Md. (1991) and / or those residues that form a hypervariable loop (e.g., residues 26-32 (LCDR1), 50-52 (LCDR2), and 91-96 (LCDR3) in the light chain variable region and residues 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 invention are described below.

[0101] As will be appreciated by those skilled in the art, the precise numbering and placement of CDRs may vary between different numbering systems. However, it should be understood that disclosure of variable heavy and / or variable light sequences includes disclosure of the associated (intrinsic) CDRs. Thus, the disclosure of each heavy chain variable region is the disclosure of vhCDRs (e.g., vhCDR1, vhCDR2, and vhCDR3), and the disclosure of each light chain variable region is the 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):

[0102] Kabat+Clothia IMGT Kabat AbM Chothia touch vhCDR1 26-35 27-38 31-35 26-35 26-32 30-35 vhCDR2 50-65 56-65 50-65 50-58 53-55 47-58 vhCDR3 95-102 105-117 95-102 95-102 96-101 93-101 vlCDR1 24-34 27-38 24-34 24-34 26-32 30-36 vlCDR2 50-56 56-65 50-56 50-56 50-52 46-55 vlCDR3 89-97 105-117 89-97 89-97 91-96 89-96

[0103] Throughout this specification, the IMGT and / or Kabat numbering systems (e.g., Kabat et al., supra (1991)) are generally used when referring to residues in the variable domain (approximately residues 1 to 107 in the light chain variable domain and residues 1 to 113 in the heavy chain variable domain) as well as the hinge and EU numbering systems in the Fc region.

[0104] The present invention provides an anti-TIGIT antibody having Figure 3 The "complete CDR set" in this case comprises three variable light CDRs and three variable heavy CDRs, e.g. Figure 3 The vlCDR1, vlCDR2, vlCDR3, vhCDR1, vhCDR2 and vhCDR3 provided in the above. These can be part of a larger variable light domain or variable heavy domain, respectively. In addition, when heavy and light chains are used, the variable heavy domain and variable light domain can be located on separate polypeptide chains, or in the case of scFv sequences, on a single polypeptide chain.

[0105] CDR helps to form an antigen binding site, or more specifically, to form an epitope binding site of an antibody. "Epitope" refers to a determining region that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope. An epitope is a molecular group such as an amino acid or a sugar side chain, and generally has specific structural properties and specific charge properties. A single antigen may have more than one epitope. An epitope may include amino acid residues that are directly involved in binding (also referred to as the immunodominant component of an epitope) and other amino acid residues that are not directly involved in binding, such as amino acid residues that are effectively blocked by a specific antigen binding peptide; in other words, the amino acid residues are located within the footprint of a specific antigen binding peptide. An epitope may be conformational or linear. A conformational epitope is produced by spatially juxtaposed amino acids from different fragments of a linear polypeptide chain. A linear epitope is an epitope produced by adjacent amino acid residues in a polypeptide chain. The difference between a conformational epitope and a non-conformational epitope may be that, in the presence of a denaturing solvent, the binding to the former rather than the latter is lost. An epitope generally includes at least 3, and more generally at least 5 or 8 to 10 amino acids of a unique spatial conformation. Antibodies that recognize the same epitope can be validated by simple immunoassays showing the ability of one antibody to block the binding of another antibody to the target antigen, ie, "binning."

[0106] Another type of heavy chain Ig domain is the hinge region. "Hinge" or "hinge region" or "antibody hinge region" or "immunoglobulin hinge region" herein means a flexible polypeptide comprising amino acids between the first constant domain and the second constant domain of an antibody. Structurally, the IgG CH1 domain ends at EU position 220, and the IgG CH2 domain starts at residue EU position 237. Therefore, for IgG, the antibody hinge is defined herein as including positions 221 to 236, wherein numbering is according to the EU index in Kabat.

[0107] The light chain generally comprises two domains: a variable light domain (containing the light chain CDRs and forming the Fv region together with the variable heavy domain) and a constant light chain region (commonly referred to as CL or CK). Generally speaking, either a constant λ domain or a constant κ domain can be used, with λ being commonly used in the present invention.

[0108] Generally speaking, Figure 3An anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) is recombinant. As used herein, "recombinant" refers broadly to a product, such as a cell or nucleic acid, protein or vector, indicating that the cell, nucleic acid, protein or vector has been modified by the introduction of a heterologous nucleic acid or protein or by the alteration of a native nucleic acid or protein, or that the cell is derived from a cell so modified. Thus, for example, a recombinant cell expresses genes that are not found within the cell in its native (non-recombinant) form, or expresses native genes that are otherwise abnormally expressed, under-expressed, or not expressed at all.

[0109] As used herein, the term "recombinant antibody" includes all antibodies prepared, expressed, produced or isolated by recombinant means, such as (a) antibodies isolated from animals (e.g., mice) that are transgenic or transchromosomal for human immunoglobulin genes or hybridomas prepared therefrom (described further below); (b) antibodies isolated from host cells transformed to express human antibodies, such as transfectomas; (c) antibodies isolated from recombinant combinatorial human antibody libraries; and (d) antibodies prepared, expressed, produced or isolated by any other means involving splicing of human immunoglobulin gene sequences into 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 undergo in vitro mutagenesis to non-CDR regions (or, when using animals with transgenic human Ig sequences, undergo in vivo somatic mutagenesis), and thus the V H Area and V L The amino acid sequence of the region is as follows: H Sequence and V L Sequences that are related to, but may not naturally exist in vivo in the human antibody germline repertoire.

[0110] A. Chimeric and humanized anti-TIGIT antibodies

[0111] In some embodiments, having Figure 3Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)) can be derived from mixtures from different species, such as chimeric antibodies and / or humanized antibodies. In general, both "chimeric antibodies" and "humanized antibodies" refer to antibodies that bind to regions from more than one species. For example, a "chimeric antibody" traditionally comprises a variable region from a mouse (or rat, in some cases) and a constant region from a human. A "humanized antibody" generally refers to a non-human antibody in which the variable domain framework region is replaced with a sequence found in a human antibody. Typically, in a humanized antibody, the entire antibody except the CDRs is encoded by a polynucleotide of human origin or is identical to this antibody except within its CDRs. CDRs (some or all of which are encoded by nucleic acids derived from a non-human organism) are transplanted into the β-sheet framework of a human antibody variable region to produce an antibody whose specificity is determined by the transplanted CDRs. The creation of such antibodies is described in, for example, WO 92 / 11018, Jones, 1986, Nature 321:522-525, Verhoeyen et al., 1988, Science 239:1534-1536, which are incorporated by reference in their entirety. It is often necessary to "back-mutate" selected acceptor framework residues to the corresponding donor residues to restore the affinity lost in the initial graft construct (US 5530101; US ​​5585089; US 5693761; US ​​5693762; US 6180370; US 5859205; US5821337; US 6054297; US 6407213, which are incorporated by reference in their entirety). Humanized antibodies will also optimally include at least a portion of an immunoglobulin constant region, and typically all, typically the constant region of a human immunoglobulin, and will therefore typically include a human Fc region. Humanized antibodies can also be generated using mice with a genetically engineered immune system. Roque et al., 2004, Biotechnol. Prog. 20: 639-654, incorporated 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), and references cited therein, incorporated by reference in their entirety).Humanization methods include, but are not limited to, those 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, which is incorporated by reference in its entirety. Humanization or other methods to reduce the immunogenicity of non-human antibody variable regions may include surface remodeling methods, such as described in Roguska et al., 1994, Proc. Natl. Acad. Sci. USA 91:969-973, which is incorporated by reference in its entirety.

[0112] Therefore, with Figure 3 The vhCDRs and vlCDRs from an anti-TIGIT antibody that have CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)) can be humanized (or "re-humanized" for those that have already been humanized).

[0113] In some embodiments, having Figure 3An anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) comprises a heavy chain variable region from a specific germline heavy chain immunoglobulin gene and / or a light chain variable region from a specific germline light chain immunoglobulin gene. For example, such an antibody may comprise or consist of a human antibody comprising a heavy chain or light chain variable region that is a "product of" or "derived from" a specific germline sequence. Human antibodies that are "products of" or "derived from" human germline immunoglobulin sequences can be identified by comparing the amino acid sequence of the human antibody with the amino acid sequence of a human germline immunoglobulin and selecting the human germline immunoglobulin sequence that is closest in sequence to the human antibody sequence (i.e., has the greatest percent identity). A human antibody that is "the product of" or "derived from" a particular human germline immunoglobulin sequence may contain amino acid differences compared to the germline sequence due to, for example, naturally occurring somatic mutations or intentionally introduced site-directed mutations. However, a humanized antibody is typically at least 90% identical in amino acid sequence to an amino acid sequence encoded by a human germline immunoglobulin gene, and contains amino acid residues that identify the antibody as derived from a human sequence when compared to germline immunoglobulin amino acid sequences of other species (e.g., mouse germline sequences). In some cases, a humanized antibody may be at least 95%, 96%, 97%, 98%, or 99%, or even at least 96%, 97%, 98%, or 99% identical in amino acid sequence to an amino acid sequence encoded by a germline immunoglobulin gene excluding the CDRs. That is, the framework region of the variable region (heavy or light) may be at least 96%, 97%, 98%, or 99% identical in amino acid sequence to the framework amino acids encoded by a human germline immunoglobulin gene, while the CDRs are identical to the human germline immunoglobulin genes. Figure 3 Those CDRs shown are identical (ie, CDRs identical to those of CPA.9.086.H4(S241P)).

[0114] B. TIGIT antibodies

[0115] The present invention provides an anti-TIGIT antibody having Figure 3 CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)). (For convenience, "anti-TIGIT antibody" and "TIGIT antibody" are used interchangeably). Figure 3Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) specifically bind to human TIGIT, and preferably the ECD of human TIGIT. The present invention also provides anti-TIGIT antigen binding domains, including full-length antibodies, which contain CDRs identical to those of CPA.9.086(S241P) and bind to TIGIT.

[0116] For example, by having 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 about 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 larger K D The antibodies show specific binding to TIGIT or TIGIT epitopes, wherein K D Refers to the equilibrium dissociation constant for a specific antibody-antigen interaction. Typically, an antibody that specifically binds to an antigen will have a K of 20, 50, 100, 500, 1000, 5,000, 10,000, or more times that of a control molecule of the TIGIT antigen or epitope. D .

[0117] However, for optimal binding to TIGIT expressed on the surface of NK and T cells, Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) preferably have a KD of less than 50 nM, and most preferably less than 1 nM (of which less than 0.1 nM and less than 1 pM can be used in the methods of the invention).

[0118] Furthermore, for example, it is possible to Figure 3An anti-TIGIT antibody that has CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) exhibits specific binding to a specific antigen or epitope, and the anti-TIGIT antibody has a Ka (associated rate constant) of at least 20 times, 50 times, 100 times, 500 times, 1000 times, 5,000 times, 10,000 times or more of the TIGIT antigen or epitope relative to a control epitope, wherein ka refers to the association rate constant for a specific antibody-antigen interaction.

[0119] In some embodiments, having Figure 3 The anti-TIGIT antibodies having CDRs identical to those shown in the table (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) have a K of 100 nM or less, 50 nM or less, 10 nM or less, or 1 nM or less (i.e., higher binding affinity) or 1 pM or less. D Binds to human TIGIT, where K D Determined by known methods, such as surface plasmon resonance (SPR, such as Biacore assay), ELISA, KINEXA and most commonly SPR (at 25°C or 37°C).

[0120] With Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) are labeled as follows. Antibodies have reference numbers, such as "CPA.9.086". This represents the combination of a variable heavy chain and a variable light chain, such as Figure 3As depicted, for example, it is to be understood that these antibodies include 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 (e.g., variable domains and constant domains) of the molecule, and "CPA.9.086.LC" refers to the entire light chain (e.g., variable domains and constant domains) of the same molecule. In general, human kappa light chains are used for the constant domains of each phage (or humanized hybridoma) antibody herein, although in some embodiments lambda light constant domains are used. "CPA.9.086.H4" would be a CPA.9.086 variable domain linked to a human IgG4. It should be noted that in some cases, a human IgG may have additional mutations, as described below, and this may be annotated. For example, in many embodiments, there may be an S241P mutation in a human IgG4, and this may be annotated, for example, as "CPA.9.086.H4 (S241P)". A human IgG4 sequence with this S241P hinge variant is as follows Figure 3 The present invention further provides variable heavy domains and light domains and full-length heavy chains and light chains, such as Figure 3 provided in.

[0121] In some embodiments, the present invention provides a scFv that binds to TIGIT, comprising a variable heavy domain and a variable light domain connected by a scFv linker as described above, and comprising Figure 3 The CDRs identical to those shown (i.e., the CDRs identical to those of CPA.9.086.H4(S241P) of the present invention). The VL and VH domains can be in any orientation, e.g., "VH-linker-VL" or "VL-linker" or "VH" from N-terminus to C-terminus. They are named by their component parts; e.g., "scFv-CPA.9.086VH-linker-VL" or "scFv-CPA.9.086.VL-linker-VH". Thus, "scFv-CPA.9.086" can be in any orientation.

[0122] In many embodiments, having Figure 3Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) are human (derived from bacteriophage) and block binding of TIGIT and PVR, and exemplary antibodies and their components are summarized as follows (eg Figure 3 Provided):

[0123] 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);

[0124] 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.

[0125] In addition, with Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)) include variants of the above-mentioned variable heavy and light chains. In this case, when an Fc variant is used, the variable heavy chain can be 80%, 90%, 95%, 98% or 99% identical to the "VH" sequence herein, and / or contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid changes or more. When an Fc variant is used, the variable light chain provided can be 80%, 90%, 95%, 98% or 99% identical to the "VL" sequence herein (and in particular CPA.9.086), and / or contain 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 amino acid changes or more. In these embodiments, the invention includes these variants as long as the antibody still binds TIGIT and contains CDRs that are identical to those of CPA.9.086(S241P).

[0126] Similarly, when an Fc variant is used, a Figure 3The invention also provides heavy and light chains of anti-TIGIT antibodies that have CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)), which 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 amino acid changes or more. In these embodiments, the invention includes these variants as long as the antibody still binds to TIGIT and contains CDRs identical to those of CPA.9.086 (S241P). S

[0127] In addition, with Figure 3 The framework regions of the variable heavy and variable light chains of an anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) herein) can be humanized as known in the art (with occasional variants in the CDRs as needed), and thus can be generated. Figure 3 In addition, the humanized variable heavy and light domains can then be fused to human constant regions, such as those from IgG4 (including IgG4(S241P)).

[0128] In particular, as known in the art, mouse VH and VL chains can be humanized as known in the art, for example, using the IgBLAST program of the NCBI website, as outlined in Ye et al. Nucleic Acids Res. 41: W34-W40 (2013), the entire contents of which are incorporated herein by reference regarding humanization methods. IgBLAST obtains mouse VH and / or VL sequences and compares them with a known human germline sequence library.

[0129] Therefore, with Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) comprises an amino acid sequence selected from the group consisting of: (a) a sequence listed herein; (b) an amino acid sequence having 90% or greater, 95% or greater, 98% or greater, or 99% or greater sequence identity to the sequence specified in (a) and having Figure 3 (c) a polypeptide having an amino acid sequence encoded by a polynucleotide having a nucleic acid sequence encoding the amino acids listed herein. In particular, the CPA.9.086 antibody may have a sequence selected from (a), (b) or (c).

[0130] In addition, the definition includes Figure 3 Anti-TIGIT antibodies that have CDRs identical to those shown in the table (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) are antibodies that share identity with the TIGIT antibodies listed herein but retain the same Figure 3 That is, in certain embodiments, the anti-TIGIT antibodies according to the present invention comprise heavy and light chain variable regions that respectively comprise amino acid sequences identical to all or part of the anti-TIGIT amino acid sequence, wherein the antibody retains the desired functional properties of the parent anti-TIGIT antibody and comprises the same CDRs as those of the parent anti-TIGIT antibody. Figure 3 The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % homology = # of identical positions / total # of positions x 100), which takes into account the number of gaps that need to be introduced for optimal alignment of the two sequences and the length of each gap. 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.

[0131] 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)), which has been 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 Needleman and Wunsch (J. Mol. Biol. 48: 444-453 (1970)) algorithm, which has been incorporated into the GAP program in the GCG software package (commercially available), using a Blossum 62 matrix or a PAM250 matrix and a gap weight of 16, 14, 12, 10, 8, 6 or 4 and a length weight of 1, 2, 3, 4, 5 or 6.

[0132] Additionally or alternatively, the protein sequences of the invention can be further used as "query sequences" to search public databases, e.g., to identify related sequences. Such searches can be performed using the XBLAST program (version 2.0) of Altschul et al. (1990) J Mol. Biol. 215: 403-10. BLAST protein searches can be performed with the XBLAST program, score = 50, word length = 3, to obtain amino acid sequences homologous to antibody molecules according to at least some embodiments of the invention. In order to obtain gapped alignments for comparison purposes, gapped BLAST can be utilized, as described in Altschul et al., (1997) Nucleic Acids Res. 25 (17): 3389-3402. When utilizing BLAST programs and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0133] Generally speaking, it is used to compare Figure 3 The percent identity between anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is at least 75%, at least 80%, at least 90%, with percent identities of at least about 95%, 96%, 97%, 98% or 99% being preferred. The percent identity can be along the entire amino acid sequence, such as the entire heavy or light chain, or along a portion of these chains, as long as the CDRs are identical to those of the antibody. Figure 3 For example, included within the definition of anti-TIGIT antibodies of the invention are those that share identity along the entire variable region (e.g., where the identity along the variable region is 95% or 98% identical), or along the entire constant region, or along only the Fc domain, as long as the CDRs are identical to those of Figure 3 In particular, the present invention provides TIGIT antibodies that have at least 75%, at least 80%, at least 90%, preferably at least about 95%, 96%, 97%, 98% or 99% percent identity to the CPA.9.086 antibody, and as long as the CDRs are identical to those of the CPA.9.086.H4(S241P) antibody, the present invention provides TIGIT antibodies that have at least 75%, at least 80%, at least 90%, preferably at least about 95%, 96%, 97%, 98% or 99% percent identity to the CPA.9.086 antibody. Figure 3 Those CDRs shown are identical (ie, CDRs identical to those of CPA.9.086.H4(S241P)).

[0134] Also included are sequences wherein the TIGIT antibody comprises a Figure 3Those CDRs that are identical to those shown (i.e., CDRs that are identical to those of CPA.9.086.H4(S241P)), but their identity along the variable region may be lower, such as 95% or 98% percent identity. Specifically, the present invention provides TIGIT antibodies having CDRs that are identical to those of CPA.9.086 but having framework regions that are 95% or 98% identical to those of CPA.9.086.

[0135] IV. Preparation of anti-TIGIT antibodies

[0136] With Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)) can be formulated into a pharmaceutical composition comprising a carrier suitable for the desired delivery method. Suitable carriers include any material that retains the anti-tumor function of the therapeutic composition when combined with the therapeutic composition and that generally does not react with the patient's immune system. Examples include, but are not limited to, any of a variety of standard pharmaceutical carriers, such as sterile phosphate-buffered saline solutions, bacteriostatic water, and the like (see generally Remington's Pharmaceutical Sciences 16th edition, A. Osal., ed., 1980).

[0137] As used herein, the term "active" refers to Figure 3 One or more functional activities of an anti-TIGIT antibody and / or antigen-binding portion thereof having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), as long as they comprise CDRs identical to those of CPA.9.086(S241P). Functional activities include, but are not limited to, biological activity and / or binding affinity.

[0138] As used herein, the term "stability" is used in the context of a structure, for example, relating to a Figure 3 The structural integrity of an anti-TIGIT antibody and / or antigen-binding portion thereof having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), or used in a functional context, such as involving having Figure 3 The ability of an anti-TIGIT antibody and / or antigen-binding portion thereof to retain its function and / or activity over time with CDRs identical to those shown in the table (i.e., CDRs identical to those of CPA.9.086.H4(S241P)). Figure 3Anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) can be included in a formulation according to the methods and compositions described herein, and the stability of the protein refers to its stability in the formulation. Figure 3 The stability of anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) comprising the composition) is determined by measuring the binding activity of the composition, including, for example, using the assays described in the present application and the figures provided herein, as well as other applicable assays known in the art.

[0139] As used herein, Figure 3 A "shelf-stable" aqueous anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) comprising the composition) refers to a solution formulated to increase the stability of the protein in solution, for example, by at least 10% over a given storage time.

[0140] As used herein, "shelf life" refers to the period of time during which a formulation maintains a predetermined stability level at a predetermined temperature. In particular embodiments, the predetermined temperature refers to frozen (e.g., -80°C, -25°C, 0°C), refrigerated (e.g., 0°C to 10°C), or room temperature (e.g., 18°C ​​to 32°C) storage.

[0141] As used herein, the term "stabilization time" refers to the length of time that a formulation is considered stable. For example, the stability time of a formulation can refer to the length of time that protein aggregation and / or degradation levels in the formulation remain below a certain threshold value (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 that the formulation maintains a certain threshold value (e.g., 100%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, etc.) of the amount of activity (including, for example, binding activity) present in the formulation at the beginning of the storage period for biological activity.

[0142] A. Stable liquid formulation

[0143] In some embodiments, the present disclosure provides Figure 3The following examples are based in part on the discovery that compositions comprising at least one amino acid, salt, and / or nonionic surfactant provide stable aqueous formulations of anti-TIGIT antibodies having CDRs identical to those shown in the Table (i.e., CDRs identical to those of CPA.9.086.H4(S241P)). Figure 3 In some embodiments, the formulation does not contain sugars and / or sugar alcohols.

[0144] In one embodiment, having Figure 3 Storage-stable anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P) provided herein) will be stable for a period of time at a temperature between 5°C and 25°C. In some embodiments, having Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) comprising the composition) will be stable at refrigerated temperatures 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, having Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P) comprising 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 longer. In some embodiments, having Figure 3 9.086.H4(S241P) of 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, having the same Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) comprising the composition) will be stable for an extended period of time when stored at temperatures between 5°C and 25°C. In some embodiments, having Figure 3Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) comprising the composition) will be stable for an extended period of time when stored at temperatures between 10°C and 25°C. In some embodiments, having Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) comprising the composition) will be stable for an extended period of time when stored at temperatures between 15°C and 25°C. In some embodiments, having Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P) comprising the composition) will be stable for an extended period of time when stored at a temperature between 15°C and 20°C. In some embodiments, having Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of the CPA.9.086.H4(S241P) composition) will be stable for an extended period of time when stored at temperatures between 20°C and 25°C. In some embodiments, having Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (ie, CDRs identical to those of the CPA.9.086.H4(S241P) composition) will be stable for an extended period of time when stored at a temperature of about 25°C.

[0145] In one embodiment, having Figure 3 A stored anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of the CPA.9.086.H4(S241P) composition) is considered storage stable as long as the composition retains at least 40% of the antibody binding activity at the beginning of the storage period (e.g., time = 0). In another embodiment, the stored composition is considered stable as long as the composition retains at least 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more of the antibody binding activity at the beginning of the storage period (e.g., time = 0). In one embodiment, the antibody binding activity is measured using any assay known in the art.

[0146] In one embodiment, having Figure 3 The stored anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of the CPA.9.086.H4(S241P) composition) are considered stable as long as they have Figure 3The percentage of anti-TIGIT antibodies that have CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) in an aggregated state remains no more than 50%. Figure 3 The stored anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of the CPA.9.086.H4(S241P) composition) are considered stable as long as they have Figure 3 The percentage of anti-TIGIT antibodies present in an aggregated state that have CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) remains no more than 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.

[0147] In some embodiments, having Figure 3 A stored anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of the CPA.9.086.H4(S241P) composition) is considered stable as long as the composition retains at least 40% of the initial binding activity (e.g., at time = 0) after being subjected to mechanical stress. Figure 3 A stored anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of the CPA.9.086.H4(S241P) composition) is considered stable as long as the composition retains 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or more of the initial binding activity after being subjected to a mechanical stress (e.g., at time = 0). In some embodiments, the mechanical stress is agitation (e.g., shaking).

[0148] In some embodiments, the shelf life is determined by the percentage of activity remaining after storage for any of the above time periods at any of the above temperatures. In some embodiments, the shelf life means that the formulation retains 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% of the antibody activity as measured by any of the assays described herein or known in the art compared to the activity before storage for any of the above time amounts at any of the above temperatures.

[0149] In some embodiments, having Figure 3 The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 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. Figure 3 The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 10 mg / mL to 25 mg / mL. Figure 3 The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 10 mg / mL to 15 mg / mL. Figure 3 The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 10 mg / mL to 20 mg / mL. Figure 3 The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 10 mg / mL to 25 mg / mL. Figure 3 The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 15 mg / mL to 20 mg / mL. Figure 3 The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 15 mg / mL to 25 mg / mL. Figure 3 The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 15 mg / mL. Figure 3The concentration of an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is 20 mg / mL. Figure 3 The concentration of anti-TIGIT antibodies with CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)) was 25 mg / mL.

[0150] B. Amino Acids - Histidine and Arginine

[0151] In some embodiments, the present invention provides Figure 3 A stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising 8mM to 12mM histidine, 8mM to 10mM histidine, 10mM to 612mM histidine, or about 10mM histidine. In some embodiments, the pharmaceutical formulation comprises 8mM to 12mM histidine. In some embodiments, the pharmaceutical formulation comprises 8mM to 10mM histidine. In some embodiments, the pharmaceutical formulation comprises 10mM to 12mM histidine. In some embodiments, the pharmaceutical formulation comprises about 10mM histidine.

[0152] In some embodiments, the present invention provides Figure 3 9.086.H4(S241P)) comprising 25 mM to 35 mM L-arginine, 25 mM to 30 mM L-arginine, 30 mM to 35 mM L-arginine, about 20 mM L-arginine, about 25 mM L-arginine, about 30 mM L-arginine, or about 35 mM L-arginine. In some embodiments, the invention provides an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 9.086.H4(S241P)) (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising 25 mM to 35 mM L-arginine. In some embodiments, the invention provides a stable liquid pharmaceutical formulation having Figure 3 9.086.H4(S241P)) (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising 25 mM to 30 mM L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation having Figure 3 9.086.H4(S241P)) (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising 30 mM to 35 mM L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation having Figure 3 9.086.H4(S241P)) and an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising about 20 mM L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation having Figure 3 9.086.H4(S241P))) and an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising about 25 mM L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation having Figure 3 9.086.H4(S241P))) and an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising about 30 mM L-arginine. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation having Figure 3 A stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising about 35 mM L-arginine.

[0153] C. sucrose

[0154] In some embodiments, the present invention provides Figure 3 A stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation not comprising a sugar alcohol.

[0155] In some embodiments, the present invention provides Figure 3 9% sucrose. Figure 39.0% sucrose. Figure 3 9.086.H4(S241P)) (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising about 7.5%, 7.6%, 7.7%, 7.8%, 7.9%, 8.0%, 8.1%, 8.2%, 8.3% or 8.4% sucrose. In some embodiments, the invention provides a stable liquid pharmaceutical formulation having Figure 3 9.086.H4(S241P)) (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising about 7.9%, 8.0%, 8.1% or 8.2% sucrose. In some embodiments, the present invention provides a stable liquid pharmaceutical formulation having Figure 3 A stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation comprising about 8.0% sucrose.

[0156] D. Polysorbate 80

[0157] In some embodiments, the present invention provides Figure 3 A stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), which comprises a non-ionic surfactant polysorbate 80 (also known as polyoxyethylene (20) sorbitan monooleate) in the range of 70 ppm to 80 ppm.

[0158] In some embodiments, the present invention provides Figure 3A stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), wherein the stable liquid pharmaceutical formulation comprises about 70 ppm, about 75 ppm, or about 80 ppm of the non-ionic surfactant polysorbate 80 (also known as polyoxyethylene (20) sorbitan monooleate).

[0159] E. pH

[0160] In some embodiments, the present invention provides Figure 3 A stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)), the stable liquid pharmaceutical formulation being buffered at a physiologically acceptable buffer having a 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 5.2 to 5.5. In some embodiments, the pH is 5.3 to 5.5. In some embodiments, the pH is 5.4 to 5.5. In some embodiments, the pH is 5.3 to 5.6. In some embodiments, the pH is 5.4 to 5.6. In some embodiments, the pH is 5.5 to 5.6. In some embodiments, the pH is 5.4+ / -0.2.

[0161] F. Stability determination

[0162] As discussed herein, including Figure 3 Stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)) show improved stability compared to a control formulation. In one embodiment, the improved stability includes retaining a higher percentage of binding activity and / or no reduction in binding activity compared to a control formulation in various stability assays. Such assays can be used to determine whether a formulation is a highly stable formulation. In some embodiments, a highly stable formulation has at least 5%, 10%, 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more activity than a control formulation when evaluated by any of the stability assays discussed herein or known in the art.

[0163] In some embodiments, comprising Figure 3Liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)) are tested under stress conditions, such as storage at high temperature, agitation, freeze / thaw cycles, or a combination of some of them. After such stress, the formulation is assayed using any of the methods described herein or known in the art to determine stability under these conditions.

[0164] In some embodiments, A280 measured by SoloVPE can be used to examine Figure 3 In some embodiments, the SoloVPE assay can be used to examine the presence of stable liquid pharmaceutical formulations of anti-TIGIT antibodies containing CDRs identical to those shown in Figure 3 The concentration of a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)). A280: Amino acids containing aromatic side chains exhibit strong UV absorption at a wavelength of 280 nm. Once the absorption coefficient of a given protein is determined, the concentration of the protein in solution can be calculated based on its absorbance. This method is designed to determine the protein concentration by measuring its absorbance at 280 nm using a SoloVPE instrument (without dilution) (https: / / www.ctechnologiesinc.com / products / solovpe).

[0165] In some embodiments, binding assays can be performed to examine the presence of Figure 3 Activity of stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)).

[0166] LabChip Analysis

[0167] In some embodiments, LabChip analysis is used to examine the presence of Figure 3 Purity, including, for example, IgG purity and HC+LC percentage, of a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown in Figure 394%, greater than 95%, greater than 96%, greater than 97%, or greater than 98% IgG purity. Figure 3 The stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) exhibit an IgG purity percentage of about 95% to 98%. Figure 3 The stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) exhibit an IgG purity percentage of about 96% to 97%. In some embodiments, the formulations contain CDRs identical to those of Figure 3 Stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) exhibit HC+LC percentages of about 96% to 100%. In some embodiments, the formulations contain CDRs identical to those of Figure 3 Stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) exhibit HC+LC percentages of about 97% to 100%. In some embodiments, the formulations contain CDRs identical to those of Figure 3 Stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)) exhibit HC+LC percentages ranging from about 98% to 100%.

[0168] In some embodiments, capillary isoelectric focusing (cIEF) can be used to analyze the presence of other substances (including, for example, weakly acidic substances) Figure 3 Stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)).

[0169] Antibodies can form subvisible particles in response to stress conditions such as heat, freeze / thaw cycles, and agitation. In some embodiments, microfluidics imaging (MFI) analysis can be used to analyze particles formed in response to stress conditions to determine whether the particles contain antibodies with Figure 3In some embodiments, the invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) provide formulations that are able to stabilize these stress conditions and prevent particle formation. MFI can be used to evaluate particle counts of different size ranges (<2μm, <5μm, <10μm, and <25μm) in different formulations under stress conditions. Typically, MFI data can be evaluated to select an appropriate formulation based on the lowest amount of particles / mL generated for all sizes of particles in all time points, conditions, and formulations.

[0170] In some embodiments, size exclusion chromatography (SEC) can be used to analyze the Figure 3 Stable liquid pharmaceutical formulations of anti-TIGIT antibodies having CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)).

[0171] G. Selected Formulation Examples

[0172] In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody, comprising:

[0173] (a) an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0174] i) a heavy chain variable domain comprising a heavy chain variable domain from CPA.9.086.H4(S241P);

[0175] chain (SEQ ID NO: 5); and

[0176] ii) 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);

[0177] (b) 8 mM to 12 mM histidine;

[0178] (c) 25 mM to 35 mM L-arginine;

[0179] (d) 8 mM to 12 mM L-methionine;

[0180] (e) 7% (w / v) to 9% (w / v) sucrose; and

[0181] (f) 70 ppm to 80 ppm polysorbate 80,

[0182] Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0183] In some embodiments, the present invention provides a stable liquid pharmaceutical formulation of an anti-TIGIT antibody, comprising:

[0184] (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0185] 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

[0186] 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);

[0187] (b) about 10 mM histidine;

[0188] (c) about 30 mM L-arginine;

[0189] (d) about 10 mM L-methionine;

[0190] (e) about 8% (w / v) sucrose; and

[0191] (f) about 75 ppm polysorbate 80,

[0192] Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0193] In some embodiments, the present invention provides a stable liquid pharmaceutical formulation comprising:

[0194] (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0195] i) the heavy chain variable domain from the heavy chain of CPA.9.086.H4(S241P) (SEQ ID NO: 1); and

[0196] ii) the light chain variable domain from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 6);

[0197] (b) about 10 mM histidine;

[0198] (c) about 30 mM L-arginine;

[0199] (d) about 10 mM L-methionine;

[0200] (e) about 8% (w / v) sucrose; and

[0201] (f) about 75 ppm polysorbate 80,

[0202] Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0203] In some embodiments, the present invention provides a stable liquid pharmaceutical formulation comprising:

[0204] (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0205] i) the heavy chain from CPA.9.086.H4(S241P) (SEQ ID NO: 5); and

[0206] ii) the light chain from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 10);

[0207] (b) about 10 mM histidine;

[0208] (c) about 30 mM L-arginine;

[0209] (d) about 10 mM L-methionine;

[0210] (e) about 8% (w / v) sucrose; and

[0211] (f) about 75 ppm polysorbate 80,

[0212] Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.2.

[0213] V. Administration of anti-TIGIT antibodies

[0214] Contains Figure 3Administration of a pharmaceutical composition (preferably in the form of a sterile aqueous solution) of an anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)) can be accomplished in a variety of ways. As is known in the art, protein therapeutics are typically delivered by IV infusion. The antibodies of the present invention can also be delivered using such methods. For example, intravenous administration can be performed by intravenous infusion with 0.9% sodium chloride as the infusion vehicle. Such techniques are disclosed in Remington's Pharmaceutical Sciences 16th edition, Osol, A. ed., 1980.

[0215] In some embodiments, the dosage and frequency of administration are selected to be effective in therapy or prevention. As known in the art, the adjustment of protein degradation, systemic delivery and local delivery and new protease synthesis rate and age, body weight, general health, sex, diet, administration time, drug interactions and disease severity may be necessary, and can be determined by routine experiments by those skilled in the art. In order to treat patients, the Fc variants of the present invention can be administered in a therapeutically effective dose. "Therapeutic effective dose" herein means the dosage that produces the effect to be achieved by its administration.

[0216] VI. dose

[0217] In some embodiments, having Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of the CPA.9.086.H4(S241P) formulation of the invention) can be formulated for administration, including as a unit dose formulation. Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of the CPA.9.086.H4(S241P) formulation) were administered at 0.01 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.02 mg / kg with Figure 3In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.03 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.04 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.05 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.06 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.07 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.08 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.09 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.1 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.2 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.3 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.5 mg / kg with Figure 3In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 0.8 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 1 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 2 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 3 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 4 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 5 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 6 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 7 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 8 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 9 mg / kg with Figure 3 In some embodiments, the dosage of an anti-TIGIT antibody having CDRs identical to those shown in Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) were administered at 10 mg / kg with Figure 3Dosage administration of anti-TIGIT antibodies having CDRs identical to those shown (ie, CDRs identical to those of the CPA.9.086.H4(S241P) formulation of the invention).

[0218] In some embodiments, having Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 0.01 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 9.086.H4(S241P)) is administered at a dose of about 10 mg / kg every 3 weeks. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 0.1 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 1 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 2 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 3 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 4 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 5 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 5 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 7 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 8 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose of about 9 mg / kg to about 10 mg / kg of the anti-TIGIT antibody. Figure 3 An anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose 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 anti-TIGIT antibody.

[0219] A. Selected dose

[0220] In some embodiments, the present invention provides Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are administered at a dose 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, Figure 3The anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are administered every 1, 2, 3, or 4 weeks. Figure 3 In some embodiments, an anti-TIGIT antibody having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered every 3 weeks. Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are configured for unit dose administration. Figure 3 The anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are formulated for administration at unit doses 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 every 1, 2, 3, or 4 weeks. Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are formulated for administration at unit doses of approximately 0.01 mg / kg, 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, 1 mg / kg, 3 mg / kg, and 10 mg / kg every 3 weeks.

[0221] In some embodiments, having Figure 3 An anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at a dose 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 dose 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.

[0222] In some embodiments, having Figure 3Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are 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. Figure 3 In some embodiments, CPA.9.086.H4(S241P) is administered at a dose 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 every 1, 2, 3, or 4 weeks.

[0223] In some embodiments, having Figure 3 An anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) is administered at about 10 mg / kg every 3 weeks. In some embodiments, CPA.9.086.H4(S241P) is administered at about 10 mg / kg every 3 weeks. In some embodiments, CPA.9.086.H4(S241P) is administered at about 3 mg / kg every 3 weeks.

[0224] VII. How to use anti-TIGIT antibodies

[0225] A. Therapeutic Uses

[0226] With Figure 3Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P) of the present invention) can be used to treat patients, such as human subjects, who typically suffer from conditions associated with TIGIT. The term "treatment" as used herein refers to therapeutic treatment and prophylactic or preventive measures, which in this example relate to the treatment of cancer; however, as described below, antibodies and pharmaceutical compositions are also provided for the treatment of infectious diseases, sepsis and / or autoimmune conditions, and / or for the inhibition of undesirable immune activation following gene therapy. Patients in need of treatment include patients who already have cancer and patients in need of cancer prevention. Therefore, the mammals to be treated herein may have been diagnosed with cancer or may be susceptible to cancer or be susceptible to cancer. As used herein, the term "treatment" refers to preventing, delaying the onset, curing, reversing, attenuating, alleviating, minimizing, inhibiting, terminating the harmful effects of the above-mentioned cancerous diseases, disorders or conditions, or stabilizing discernible symptoms. It also includes cancer treatment as described above. "Control" means reducing the severity of the disease, reducing the frequency of disease attacks, shortening the duration of such attacks, reducing the severity of such attacks, slowing / reducing cancer cell growth or proliferation, slowing the progression of at least one symptom. At least one symptom, improving at least one measurable physical parameter, etc. For example, immunostimulatory anti-TIGIT immune molecules should promote T cell or NK or cytokine immunity against target cells (e.g., cancer, infected cells, or pathogen cells), and thereby treat cancer or infectious diseases by depleting cells involved in the disease condition. In contrast, immunosuppressive anti-TIGIT immune molecules should reduce T cell or NK activity and / or the secretion of proinflammatory cytokines, which are involved in the pathology of some immune diseases (such as autoimmune disorders, inflammatory or allergic disorders), thereby treating or ameliorating the pathology and tissue destruction that the disease may be associated with such disorders (e.g., joint destruction associated with rheumatoid arthritis disorders).

[0227] With Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are provided at a therapeutically effective dose. Figure 3A "therapeutically effective dose" of an anti-TIGIT antibody having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4 (S241P)) preferably results in a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, an increase in lifespan, remission of the disease, or prevention or reduction of damage or disability caused by disease affliction. For example, for the treatment of TIGIT-positive tumors, a "therapeutically effective dose" 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%, and still more preferably at least about 80% relative to untreated subjects. The ability of a compound to inhibit tumor growth can be evaluated in an animal model system that predicts human tumor efficacy. Alternatively, this property of the composition can be evaluated by examining the ability of the compound to inhibit such inhibition in vitro by an assay known to practitioners in the art. A therapeutically effective amount of a therapeutic compound can reduce the size of a subject's tumor, or otherwise improve symptoms.

[0228] One of ordinary skill in the art would be able to determine a therapeutically effective amount based on factors such as the subject's size, the severity of the subject's symptoms, and the particular composition or route of administration selected.

[0229] 1. Cancer treatment

[0230] "Cancer therapy" herein refers to any method of preventing or treating cancer or ameliorating one or more symptoms of cancer. Typically, such therapy will involve administering a drug that has a therapeutic effect on the treatment of cancer, either alone or in combination with chemotherapy or radiation therapy or other biological agents. Figure 3 Immunostimulatory anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) and for enhancing their activity, i.e., in individuals in which expression of TIGIT inhibits anti-tumor responses and the efficacy or biological efficacy of chemotherapy or radiotherapy.

[0231] With Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P) of the present invention) are particularly useful in the treatment of cancer. In general, the antibodies of the present invention are immunomodulatory because they do not directly attack cancer cells, but anti-TIGIT antibodies have CDRs identical to those of Figure 3CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are used to stimulate the immune system (generally by inhibiting the activity of TIGIT). Therefore, unlike tumor-targeted therapies that aim to inhibit molecular pathways critical to tumor growth and progression and / or deplete tumor cells, cancer immunotherapy aims to stimulate the patient's own immune system to eliminate cancer cells, thereby providing lasting tumor destruction. Cancer immunotherapy can use a variety of approaches, including therapeutic cancer vaccines that induce tumor-specific T cell responses, and immunostimulatory antibodies that abrogate immunosuppressive pathways (i.e., inhibitory receptor antagonists = immune checkpoints).

[0232] Clinical responses to targeted or conventional anticancer therapies are often short-lived as cancer cells develop resistance and tumor relapse occurs. However, clinical applications of cancer immunotherapy over the past few years have shown that this type of therapy can have durable clinical responses, showing a dramatic impact on long-term survival. However, although the responses are long-lasting, only a minority of patients respond (in contrast to conventional or targeted therapies, where a large number of patients respond, but the responses are short-lived).

[0233] By the time a tumor is discovered clinically, it has already evaded the immune defense system by acquiring immune resistance and immunosuppressive properties through various mechanisms and a large number of immune cells and creating an immunosuppressive tumor microenvironment.

[0234] Therefore, with Figure 3 Anti-TIGIT antibodies that have CDRs identical to those shown in Table 1 (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) are useful in treating cancer. Due to the nature of the mechanism of action of immuno-oncology, TIGIT does not necessarily need to be overexpressed or associated with a specific cancer type; that is, the goal is to have antibodies with Figure 3 Anti-TIGIT antibodies with CDRs identical to those shown (ie, CDRs identical to those of CPA.9.086.H4(S241P)) inhibit T cell and NK cell activation, allowing the immune system to pursue the cancer.

[0235] As used herein, "cancer" refers broadly to any neoplastic disease (whether invasive or metastatic) characterized by abnormal and uncontrolled cell division that leads to malignant growth or tumors (e.g., unregulated cell growth). As used herein, the term "cancer" or "cancerous" should be understood to include any neoplastic disease (whether invasive, non-invasive or metastatic) characterized by abnormal and uncontrolled cell division that leads to malignant growth or tumors, non-limiting examples of which are described herein. This includes any physiological condition that is typically characterized by unregulated cell growth in mammals.

[0236] In some embodiments, having Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) can be used to treat solid tumors (including, for example, lung cancer, liver cancer, breast cancer, brain cancer, digestive tract cancer, etc.) and blood cancers (including, for example, leukemias and preleukemic diseases, lymphomas, plasma cell diseases) tumors, lymphomas, blastomas, sarcomas, and leukemias or lymphoid malignancies. In some embodiments, the cancer is early-stage. In some embodiments, the cancer is advanced (including metastatic). In some embodiments, cancers suitable for treatment by the present invention include cancers that express or do not express TIGIT, and also include non-metastatic or non-invasive as well as invasive or metastatic cancers, including cancers in which TIGIT suppresses anti-tumor responses and anti-invasive immune responses through immune, stromal, or diseased cells. In some embodiments, having the same Figure 3 Anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) can be used to treat vascularized tumors. Figure 3 Cancers treated with anti-TIGIT antibodies having CDRs identical to those shown in (i.e., CDRs identical to those of CPA.9.086.H4 (S241P) of the present invention) include tumors, lymphomas, sarcomas, and / or leukemias. In some embodiments, the use of Figure 3Cancers treated with anti-TIGIT antibodies that have CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) include melanoma, non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), mesothelioma, squamous cell carcinoma, lung cancer (including small cell lung cancer, non-small cell lung cancer, soft tissue sarcoma, Kaposi's sarcoma, lung adenocarcinoma, lung squamous carcinoma, peritoneal cancer, esophageal cancer, hepatocellular carcinoma, liver cancer (including HCC), gastric cancer, abdominal cancer (including gastrointestinal cancer), pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, urothelial carcinoma, bladder cancer, liver cancer, glioma, brain cancer (and edema, such as edema associated with brain tumors), breast cancer (including, for example, triple-negative breast cancer), adenocarcinoma), testicular cancer, testicular germ cell tumor, colon cancer, colorectal cancer (CRC), MSS colorectal cancer (MSS-CRC; including refractory MSS colorectal; MSS = microsatellite stable status), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, CRC (MSS unknown), rectal cancer, endometrial cancer (including endometrial tumors), uterine cancer, salivary gland cancer, kidney cancer, renal cell carcinoma (RCC), renal cell tumor (RCC), prostate cancer, vulvar cancer, thyroid cancer, liver cancer, carcinoid, head and neck cancer, B-cell lymphoma (including non-Hodgkin's lymphoma, and low-grade malignant / follicular non-Hodgkin's lymphoma (NHL), small lymphocytic (SL) N HL, intermediate / follicular NHL, intermediate-grade diffuse NHL, diffuse large B-cell lymphoma, high-grade immunoblastic NHL, high-grade lymphocytic NHL, high-grade small non-Hodgkin's lymphoma - cleaved cell non-Hodgkin's lymphoma, massive non-Hodgkin's lymphoma, mantle cell lymphoma, AIDS-related lymphoma and Waldenstrom's 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 myeloid leukemia, multiple myeloma, post-transplant lymphoproliferative disorder (PTLD), abnormal blood vessel proliferation associated with plaque tumors, , Meigs syndrome, Merkel cell carcinoma, MSI-high cancer, KRAS mutant tumors, adult T-cell leukemia / lymphoma, adenoid cystic carcinoma (including adenoid cystic tumors), malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, ovarian cancer (including ovarian tumors), pleural mesothelioma, neuroendocrine lung cancer (including pleural mesothelioma, neuroendocrine lung tumors), NSCLC large cell adenocarcinoma, non-small cell lung cancer (NSCLC), NSCLC squamous cell carcinoma, cervical squamous cell carcinoma (cervical SCC), anal squamous cell carcinoma (anal SCC), neuroendocrine lung cancer, cancer of unknown primary, gallbladder cancer, malignant melanoma, pleural mesothelioma, multiple myeloma, gastroesophageal junction cancer, and / or myelodysplastic syndrome (MDS).

[0237] In some embodiments, using Figure 3 The cancers treated by anti-TIGIT antibodies having the same CDRs as those shown (i.e., the same CDRs as those of CPA.9.086.H4(S241P)) include cancers selected from the group consisting of prostate cancer, liver cancer (HCC), colorectal cancer (CRC), colorectal cancer MSS (MSS-CRC; including refractory MSS colorectal), 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 carcinoma, lung cancer, melanoma, non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), glioma, renal cell carcinoma (RCC), renal cell tumor (RCC), lymphoma (non-Hodgkin's lymphoma (NHL) and Hodgkin's 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 carcinoma, microsatellite instability-high (MSI-H) cancer, KRAS mutant tumors, 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 carcinoma, cervical SCC, malignant melanoma, pancreatic cancer, pancreatic adenocarcinoma, NSCLC, adenoid cystic carcinoma (including adenoid cystic tumors), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, PD1 refractory or relapsed, multiple myeloma, gastroesophageal junction cancer, and / or myelodysplastic syndrome (MDS).

[0238] In some embodiments, using Figure 3 Cancers treated with anti-TIGIT antibodies having CDRs identical to those shown (i.e., CDRs identical to those of CPA.9.086.H4(S241P)) include advanced cancers, ovarian cancer, lung cancer, non-small cell lung cancer (NSCLC), PD1-refractory or recurrent NSCLC, colon cancer, colorectal cancer (CRC), MSS-CRC, plasma cell neoplasms, head and neck squamous cell carcinoma (HNSCC), PD1-refractory or recurrent HNSCC, and breast cancer.

[0239] Examples

[0240] Example 1: Stable pharmaceutical preparation CPA.9.086.H4 (S241P)

[0241] This example describes the characteristics and preparation of a stable pharmaceutical formulation comprising:

[0242] (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising:

[0243] i) the heavy chain from CPA.9.086.H4(S241P) (SEQ ID NO: 5); and

[0244] ii) the light chain from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 10);

[0245] (b) about 10 mM histidine;

[0246] (c) about 30 mM L-arginine;

[0247] (d) about 10 mM L-methionine;

[0248] (e) about 8% (w / v) sucrose; and

[0249] (f) about 75 ppm polysorbate 80,

[0250] Therein a pharmaceutical formulation was prepared having a pH of 5.4 + / - 0.2.

[0251] Formulation checks of CPA.9.086.H4(S241P) in phosphate buffer at pH 7.0 demonstrated antibody solubility >20 mg / mL. Therefore, formulations of CPA.9.086.H4(S241P) with a target antibody concentration of 20 mg / mL were investigated.

[0252] This formulation provides an antibody concentration of 20 mg / mL and has a target pH of 5.4 and is prepared for further packaging.For administration to a patient, CPA.9.086.H4 (S241P) will be diluted with 0.9% sodium chloride and placed in an appropriate administration container.

[0253] The stability of CPA.9.086.H4 (S241P) was observed at pH 5.4 (range: 5.4 ± 0.2) 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. While L-histidine was used as a buffer component, L-arginine, L-methionine, sucrose, and polysorbate 80 were used to stabilize the protein and prevent self-association and aggregation. In addition, L-methionine acted as an antioxidant, and polysorbate 80 was used as a surfactant.

[0254] The formulation components are provided in Table 1. The quantities listed per vial are based on an actual target fill volume of 5.3 mL, equivalent to a target fill weight of 5.5 g / vial. The nominal amount of CPA.9.086.H4 (S241P) per vial is 100 mg.

[0255] Table 1: CPA.9.086.H4 (S241P) formulation components

[0256]

[0257] *Quantities based on a nominal fill volume of 5.0 mL

[0258] **Quantities based on actual target fill volume of 5.3 mL / vial (= target fill weight of 5.5 g / vial)

[0259] Temperature stability is determined by the following factors:

[0260] Liquid stability samples at 5°C and 25°C for 0.5, 1, 2 and 6 months

[0261] Freeze-dried samples can be kept for 1, 3 and 6 months at 5°C and 25°C

[0262] The data obtained indicated that CPA.9.086.H4(S241P) in liquid and lyophilized formulations were stable for at least 6 months at 5° C. At 25° C., CPA.9.086.H4(S241P) showed higher stability in lyophilized formulations.

[0263] The stability of the samples was also determined based on freeze / thaw, shake, aggregation, fragmentation and other standard analyses and was determined to be stable. The stable formulation also maintained the biological function of CPA.9.086.H4 (S241P).

[0264] in conclusion

[0265] CPA.9.086.H4(S241P) was stable in terms of physical appearance, aggregate formation, and other properties in liquid and lyophilized formulations for at least 6 months at 5°C. Other results further demonstrated that CPA.9.086.H4(S241P) was stable in terms of physical appearance, aggregates, fragment formation, and alkaline / acidic substances during repeated freeze / thaw, shaking, mixing, and filtration.

[0266] The above examples are provided to fully disclose and describe to those of ordinary skill in the art how to make and use embodiments of the compositions, systems and methods of the present invention and are not intended to limit the scope of what the inventors regard as their invention. Modifications of the above modes for carrying out the present 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 mentioned in this specification are indicative of the skill level of those skilled in the art to which the present invention pertains.

[0267] All headings and section names are used for clarity and reference purposes only and should not be considered limiting in any way. For example, those skilled in the art will appreciate the usefulness of combining aspects from different headings and sections when appropriate, in accordance with the spirit and scope of the invention as described herein.

[0268] All references cited herein are incorporated by reference in their entirety and 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.

[0269] Many modifications and variations can be made to the present disclosure without departing from the spirit and scope of the present disclosure, as will be apparent to those skilled in the art. The specific embodiments and examples described herein are provided by way of example only, and the application is limited only by the terms of the appended claims and the full scope of equivalents to which the claims are entitled.

Claims

1. A stable liquid pharmaceutical preparation of an anti-TIGIT antibody, comprising: (a) an anti-TIGIT antibody, the anti-TIGIT antibody comprising: 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); (b) 8 mM to 12 mM histidine; (c) 25 mM to 35 mM L-arginine; (d) 8 mM to 12 mM L-methionine; (e) 7% (w / v) to 9% (w / v) sucrose; and (f) 70 ppm to 80 ppm polysorbate 80, Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.

2.

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

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

4. The stable liquid drug according to any one of claims 1 to 3, wherein the heavy chain variable domain is from the heavy chain of CPA.9.086.H4(S241P) (SEQ ID NO: 1) and the light chain variable domain is 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 human κ2 light chain.

6. The stable liquid drug formulation of any one of claims 1 to 5, wherein the drug formulation comprises about 15 mg / mL to about 25 mg / mL of 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 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 histidine.

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

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

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

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

13. A stable liquid pharmaceutical formulation of an anti-TIGIT antibody, comprising: (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising: 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); (b) about 10 mM histidine; (c) about 30 mM L-arginine; (d) about 10 mM L-methionine; (e) about 8% (w / v) sucrose; and (f) about 75 ppm polysorbate 80, Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.

2.

14. A stable liquid pharmaceutical formulation of an anti-TIGIT antibody, comprising: (a) about 20 mg / mL of an anti-TIGIT antibody, the anti-TIGIT antibody comprising: i) the heavy chain variable domain from the heavy chain of CPA.9.086.H4(S241P) (SEQ ID NO: 5); and ii) the light chain variable domain from the light chain of CPA.9.086.H4(S241P) (SEQ ID NO: 10); (b) about 10 mM histidine; (c) about 30 mM L-arginine; (d) about 10 mM L-methionine; (e) about 8% (w / v) sucrose; and (f) about 75 ppm polysorbate 80, Wherein the pharmaceutical formulation has a pH of 5.4 + / - 0.

2.

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

2.

16. The stable liquid pharmaceutical formulation of any one of claims 1 to 15, wherein the pharmaceutical formulation 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.

17. The stable liquid pharmaceutical formulation according to any one of claims 1 to 16, wherein the pharmaceutical formulation is stable at 5°C to 25°C for at least 6 months, at least 12 months or at least 18 months.

18. The stable liquid pharmaceutical formulation of any one of claims 1 to 17, wherein the pharmaceutical formulation 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.

19. The stable liquid pharmaceutical formulation of any one of claims 1 to 18, wherein the pharmaceutical formulation is administered at a dose 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.

20. The stable liquid pharmaceutical formulation of any one of claims 1 to 19, wherein 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.

21. The stable liquid pharmaceutical formulation of any one of claims 1 to 20, wherein the anti-TIGIT antibody is administered in a single dose.

22. The stable liquid pharmaceutical formulation according to any one of claims 1 to 21, wherein the pharmaceutical formulation is formulated for intravenous (IV) infusion.

23. The stable liquid pharmaceutical formulation according to any one of claims 1 to 22, wherein the pharmaceutical formulation is administered for the treatment of cancer.

24. The stable liquid pharmaceutical formulation according to any one of claims 1 to 23, for use in a method of treating cancer.

25. The stable liquid pharmaceutical formulation of 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 colorectal), 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 carcinoma, lung cancer, melanoma, non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), glioma, renal cell carcinoma (RCC), renal cell tumor (RCC), lymphoma (non-Hodgkin's lymphoma (NHL) and Hodgkin's 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 carcinoma (Merkel cell carcinoma), Cells cancer), microsatellite instability-high (MSI-H) cancer, KRAS mutant tumors, 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 carcinoma (including adenoid cystic tumors), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, multiple myeloma, gastroesophageal junction cancer, and myelodysplastic syndrome (MDS).

26. A stable lyophilized pharmaceutical formulation, wherein the formulation is obtained by lyophilizing the stable liquid pharmaceutical formulation according to any one of claims 1 to 25.

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

28. The method of 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 colorectal), 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 carcinoma, lung cancer, melanoma, non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), glioma, renal cell carcinoma (RCC), renal cell tumor (RCC), lymphoma (non-Hodgkin's lymphoma (NHL) and Hodgkin's 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 Carcinoma (Merkel Cells cancer), microsatellite instability-high (MSI-H) cancer, KRAS mutant tumors, 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 carcinoma (including adenoid cystic neoplasms), primary peritoneal cancer, microsatellite stable primary peritoneal cancer, platinum-resistant microsatellite stable primary peritoneal cancer, multiple myeloma, gastroesophageal junction cancer, and myelodysplastic syndrome (MDS).

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