Methods of treating pancreatic cancer using anti-CTLA4 antibodies

Abstract

Methods of treating pancreatic cancer with antibodies that specifically bind to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) are provided.

Description

[Technical Field]

[0001] Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 383,724, filed November 15, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] Sequence Listing Reference This application contains a Sequence Listing that has been submitted electronically in ST.26 format, which is incorporated herein by reference in its entirety (the ST.26 copy, created on November 14, 2023, is named "205365_seqlist.xml" and is 10,360 bytes in size). [Background technology]

[0003] Although ranked 10th in incidence, pancreatic cancer is the third leading cause of cancer death in the United States. This high incidence-to-mortality ratio is due to the fact that patients are typically diagnosed at an advanced stage. Therefore, in addition to improving early detection of pancreatic cancer patients to reduce overall mortality, new treatments for advanced disease are urgently needed.

[0004] Currently, the standard initial treatment for patients with metastatic pancreatic cancer is systemic combination chemotherapy (e.g., 5-fluorouracil, oxaliplatin, irinotecan, nab-paclitaxel, and gemcitabine). However, these systemic therapies have demonstrated only modest efficacy, resulting in a median overall survival of less than one year in patients with metastatic pancreatic cancer. Furthermore, to date, immune checkpoint inhibitors have not shown significant success in pancreatic cancer, except for microsatellite instability-high (MSI-H) cancers, which account for only approximately 1% of pancreatic cancers.

[0005] Therefore, there remains a need for new and effective methods of treating metastatic pancreatic cancer. Summary of the Invention

[0006] The present disclosure is directed to methods of treating pancreatic cancer using an antibody that specifically binds human cytotoxic T-lymphocyte antigen 4 (CTLA-4), alone or in combination with nab-paclitaxel and / or gemcitabine. Also provided herein are specific methods of administering an antibody that specifically binds human CTLA-4 to result in a reduction in tumor burden in a subject. In one embodiment, the method comprises a therapeutically effective amount that safely and effectively treats metastatic pancreatic cancer.

[0007] In one aspect, provided herein is a method of treating pancreatic cancer in a subject in need of such treatment, comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of 25 mg to 250 mg.

[0008] In one aspect, provided herein is a method for enhancing T cell activation in a subject with pancreatic cancer, comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of 25 mg to 250 mg, the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8.

[0009] In certain embodiments, the antibody is administered at a dose of about 25 mg to 200 mg. In one embodiment, the antibody is administered at a dose of 25 mg to 150 mg. In one embodiment, the antibody is administered at a dose of 50 mg to 150 mg. In one embodiment, the antibody is administered at a dose of 50 mg to 200 mg. In one embodiment, the antibody is administered at a dose of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg.

[0010] In one embodiment, the antibody is administered intravenously. In one embodiment, the antibody is administered by intravenous infusion over about 30 minutes.

[0011] In one embodiment, the antibody is administered once a week. In one embodiment, the antibody is administered once every two weeks. In one embodiment, the antibody is administered once every three weeks. In one embodiment, the antibody is administered once every four weeks. In one embodiment, the antibody is administered once every five weeks. In one embodiment, the antibody is administered once every six weeks.

[0012] In one embodiment, the antibody is administered intravenously at a dose of 25 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 50 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 75 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 100 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 125 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 150 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 175 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 200 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 225 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 250 mg once every six weeks.

[0013] In one embodiment, the dose is a therapeutically effective amount.

[0014] In one embodiment, the pancreatic cancer is pancreatic ductal adenocarcinoma. In one embodiment, the pancreatic cancer is unresectable. In one embodiment, the pancreatic cancer is metastatic. In one embodiment, the pancreatic cancer is recurrent and / or refractory.

[0015] In one embodiment, the subject has received at least one prior chemotherapy. In one embodiment, the at least one prior chemotherapy is 5-fluorouracil, leucovorin, irinotecan, or oxaliplatin. In one embodiment, the subject has previously been treated with 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin. In one embodiment, the pancreatic cancer has recurred following standard of care treatment.

[0016] In one embodiment, the method further comprises administering nab-paclitaxel to the subject. In one embodiment, nab-paclitaxel is administered at a dose of 75 mg / m 2 , 100 mg / m 2 , or 125 mg / m 2 In one embodiment, nab-paclitaxel is administered once weekly. In one embodiment, nab-paclitaxel is administered on days 1, 8, and 15 of a 6-week cycle.

[0017] In one embodiment, the method further comprises administering gemcitabine to the subject. In one embodiment, gemcitabine is administered at 600 mg / m 2 , 800 mg / m 2 , or 1000 mg / m 2 In one embodiment, gemcitabine is administered once weekly. In one embodiment, gemcitabine is administered on days 1, 8, and 15 of a 6-week cycle.

[0018] In one embodiment, the antibody is administered on day 1 of a 6-week cycle, and nab-paclitaxel and gemcitabine are administered on days 1, 8, and 15 of the 6-week cycle. In one embodiment, the antibody is administered to the subject before nab-paclitaxel and gemcitabine. In one embodiment, nab-paclitaxel is administered before gemcitabine.

[0019] In one embodiment, the cancer is refractory to standard of care treatment. In one embodiment, the standard of care treatment is chemotherapy or radiation. In one embodiment, the standard of care treatment is 5-fluorouracil, leucovorin, irinotecan, and / or oxaliplatin.

[0020] In one embodiment, the method reduces tumor size in a subject. In one embodiment, the method increases T cell activation in a subject. In one embodiment, the method reduces CA19-9, CA125, or CEA levels in a subject.

[0021] In one embodiment, prior to administration of the antibody, the subject has measurable disease by baseline imaging per RECIST 1.1. In one embodiment, prior to administration of the antibody, the subject has an Eastern Cooperative Oncology Group performance status (PS) of 0 to 1. In one embodiment, prior to administration of the antibody, the subject has a predicted life expectancy of 12 weeks or greater.

[0022] In one embodiment, prior to administration of the antibody, the subject has: a) neutrophils > 1500 / μL; b) platelets > 100 x 10 3 Have adequate organ function as defined by one or more of the following: c) hemoglobin ≥ 9.0 g / dL, d) creatinine clearance ≥ 30 mL / min measured or calculated according to local institutional standards, e) aspartate aminotransferase (AST) / alanine aminotransferase (ALT) < 3.0 × upper limit of normal (ULN), f) direct bilirubin < 1.5 × ULN (except for patients with Gilbert's syndrome, who must have total bilirubin < 3.0 × ULN), and / or g) serum albumin ≥ 3.0 g / dL.

[0023] In one embodiment, the subject has no partial or complete bowel obstruction, signs / symptoms of bowel obstruction, or known radiological evidence of impending obstruction within the past three months.

[0024] In one embodiment, the subject has liver metastasis, i.e., the cancer has metastasized to the liver. In one embodiment, the subject has one or more liver lesions. In one embodiment, the method of the present invention reduces one or more liver lesions. For example, in one embodiment, administering an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) in combination with nab-paclitaxel and / or gemcitabine reduces liver lesions in the subject by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, or 45% or more.

[0025] Thus, provided herein is a method of treating a subject having cancer that has metastasized to the liver, comprising administering to the subject gemcitabine, nab-paclitaxel, and an antibody that specifically binds to CTLA-4.

[0026] In one embodiment, the subject has not received immune checkpoint inhibitor therapy prior to administration of the antibody. In one embodiment, the subject has not received multiple chemotherapy regimens prior to administration of the antibody. In one embodiment, the subject has no history of central nervous system (CNS) metastases. In one embodiment, the subject has no concurrent malignancy requiring treatment or no history of a malignancy that has been active within two years prior to administration of the antibody. In one embodiment, the subject has not received cytotoxic or targeted therapy within three weeks prior to administration of the antibody. In one embodiment, the subject has not received another monoclonal antibody therapy, antibody-drug conjugate therapy, or radioimmunoconjugate therapy within four weeks prior to administration of the antibody. In one embodiment, the subject has not received small molecule tyrosine kinase inhibitor therapy within two weeks prior to administration of the antibody.

[0027] In one embodiment, the subject does not have refractory ascites, defined as the need for therapeutic paracentesis two or more times within the past four weeks, four or more times within the past 90 days, or one or more times within the past two weeks prior to administration of the antibody. In one embodiment, the subject does not have clinically significant cardiovascular disease.

[0028] In one embodiment, the cancer has metastasized to the liver.

[0029] In one embodiment, the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively. In one embodiment, the antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO: 8. In one embodiment, the antibody comprises a human IgG1 heavy chain constant region comprising the S239D / A330L / I332E mutations numbered according to the EU numbering system. In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10.

[0030] In one embodiment, the antibody is botencilimab.

[0031] In one aspect, provided herein is an antibody that specifically binds human CTLA-4 for use in the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0032] In one aspect, provided herein is an antibody that specifically binds human CTLA-4 for use in the manufacture of a medicament for the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0033] In one aspect, provided herein is the use of an antibody that specifically binds human CTLA-4 for the treatment of pancreatic cancer, performed according to any one of the methods disclosed herein.

[0034] In one aspect, provided herein is an antibody that specifically binds human CTLA-4, gemcitabine, and nab-paclitaxel for use in the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0035] In one aspect, provided herein is an antibody that specifically binds human CTLA-4, gemcitabine, and nab-paclitaxel for use in the manufacture of a medicament for the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0036] In one aspect, provided herein is the use of an antibody that specifically binds human CTLA-4, gemcitabine, and nab-paclitaxel for the treatment of pancreatic cancer, performed according to any one of the methods disclosed herein.

[0037] In one aspect, provided herein are gemcitabine, nab-paclitaxel, and an antibody that specifically binds human CTLA-4 for use in the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0038] In one aspect, provided herein are gemcitabine, nab-paclitaxel, and an antibody that specifically binds human CTLA-4 for use in the manufacture of a medicament for the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0039] In one aspect, provided herein is the use of gemcitabine, nab-paclitaxel, and an antibody that specifically binds human CTLA-4 for the treatment of pancreatic cancer, performed according to any one of the methods disclosed herein.

[0040] In one aspect, provided herein is a method of treating a subject having cancer that has metastasized to the liver, the method comprising administering to the subject gemcitabine, nab-paclitaxel, and an antibody that specifically binds to CTLA-4.

[0041] In one embodiment, the subject has pancreatic cancer.

[0042] In one embodiment, the antibody comprises one or more mutations in the Fc region to increase binding to FcγRIIA and / or FcγRIIIA, hi one embodiment, the antibody comprises a human IgG1 Fc region comprising S239D / A330L / I332E mutations numbered according to the EU numbering system.

[0043] In one embodiment, an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, is administered at a dose of 25 mg to 250 mg.

[0044] In one embodiment, the antibody is administered at a dose of 25 mg to 200 mg. In one embodiment, the antibody is administered at a dose of about 100 mg to 200 mg. In one embodiment, the antibody is administered at a dose of about 150 mg to 200 mg. In one embodiment, the antibody is administered at a dose of about 150 mg.

[0045] In one embodiment, gemcitabine is 600 mg / m 2 , 800 mg / m 2 , or 1000 mg / m 2 is administered at a dose of

[0046] In one embodiment, nab-paclitaxel is 75 mg / m 2 , 100 mg / m 2 , or 125 mg / m 2 is administered at a dose of

[0047] In one embodiment, the antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8.

[0048] In one embodiment, the antibody comprises botencilimab. [Brief explanation of the drawings]

[0049] [Figure 1A] 1 is a graph showing tumor growth curves for mice treated with either isotype / vehicle control, botencilimab ms, or conventional anti-CTLA-4 antibodies. [Figure 1B] Graph showing tumor growth curves of mice treated with either isotype / solvent control, botencilimab ms alone (AGEN1181), nab-paclitaxel (Nab-p) + gemcitabine (Gem), or a combination of botencilimab ms (AGEN1181) and nab-paclitaxel (Nab-p) + gemcitabine (Gem). [Figure 1C] 1 is a graph showing the weight of mice during treatment. [Figure 2A] 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group. [Figure 2B] FIG. 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: the botencilimab ms monotherapy group. [Figure 2C] 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: nab-paclitaxel + gemcitabine group. [Figure 2D] 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: botencilimab ms and nab-paclitaxel+gemcitabine groups. [Figure 3A] 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group. [Figure 3B] FIG. 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: the botencilimab ms monotherapy group. [Figure 3C] FIG. 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: cisplatin plus gemcitabine group. [Figure 3D] 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: botencilimab ms and cisplatin + gemcitabine groups. [Figure 4A] 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group. [Figure 4B] 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: nab-paclitaxel + gemcitabine + cisplatin group. [Figure 4C] FIG. 1 is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: the botenlimab ms monotherapy group. [Figure 4D] This is one of a series of graphs showing tumor growth curves for individual mice in each treatment group: the anti-PD-1 antibody monotherapy group. [Figure 5] 1 shows the percent change from baseline in tumor markers (CA19-9 or CEA) over time in individual patients (n=5) with metastatic pancreatic cancer who progressed on FOLFIRINOX and received 150 mg botencilimab Q6W plus gemcitabine (1000 mg / m²) / nab-paclitaxel (125 mg / m²). * indicates the percent change in tumor marker in the fifth patient who showed clinical progression and was removed from the study. DETAILED DESCRIPTION OF THE INVENTION

[0050] The present disclosure is directed to methods of treating pancreatic cancer using an antibody that specifically binds human cytotoxic T-lymphocyte antigen 4 (CTLA-4), alone or in combination with nab-paclitaxel and / or gemcitabine. Also provided herein are specific methods of administering an antibody that specifically binds human CTLA-4 to result in a reduction in tumor burden in a subject. In one embodiment, the method comprises a therapeutically effective amount that safely and effectively treats metastatic pancreatic cancer.

[0051] definition As used herein, the terms "antibody" and "antibodies" include full-length antibodies, antigen-binding fragments of full-length antibodies, and molecules comprising antibody CDRs, VH regions, and / or VL regions. Examples of antibodies include, but are not limited to, monoclonal antibodies, recombinantly produced antibodies, monospecific antibodies, multispecific antibodies (including bispecific antibodies), human antibodies, humanized antibodies, chimeric antibodies, immunoglobulins, synthetic antibodies, tetrameric antibodies comprising two heavy chain molecules and two light chain molecules, antibody light chain monomers, antibody heavy chain monomers, antibody light chain dimers, antibody heavy chain dimers, antibody light chain-antibody heavy chain pairs, intrabodies, heteroconjugate antibodies, antibody drug conjugates, single domain antibodies, monovalent antibodies, single chain antibodies or single chain Fvs (scFvs), camelized antibodies, affibodies, Fab fragments, F(ab')2 fragments, disulfide-linked Fvs (sdFvs), anti-idiotypic (anti-Id) antibodies (including, for example, anti-anti-Id antibodies), and antigen-binding fragments of any of the above. In certain embodiments, the antibody described herein refers to a polyclonal antibody population. An antibody can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG2a or IgG2b) of immunoglobulin molecule. In certain embodiments, the antibodies described herein are IgG antibodies, or classes thereof (e.g., human IgG1 or IgG4) or subclasses thereof. In one embodiment, the antibody is a humanized monoclonal antibody. In one embodiment, the antibody is a human monoclonal antibody.

[0052] As used herein, the term "CDR" or "complementarity-determining region" refers to the noncontiguous antigen-binding sites found within the variable regions of both heavy and light chain polypeptides. These particular regions are described, for example, by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of Proteins of Immunological Interest. (1991), Chothia et al., J. Mol. Biol. 196:901-917 (1987), and MacCallum et al., J. Mol. Biol. 262:732-745 (1996), all of which are incorporated by reference in their entireties, where the definitions include overlapping or subsets of amino acid residues when compared against each other (see Table 1 below). In certain embodiments, the term "CDR" refers to the CDR defined by MacCallum et al., J. Mol. Biol. 262:732-745 (1996) and Martin A. "Protein Sequence and Structure Analysis of Antibody Variable Domains," in Antibody Engineering, Kontermann and Duebel, eds., Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In certain embodiments, the term "CDR" refers to the CDR defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., Sequences of Proteins of Immunological Interest. (1991). In certain embodiments, the heavy chain CDRs and light chain CDRs of an antibody are defined using different rules. In certain embodiments, the heavy chain and / or light chain CDRs are defined by performing a structural analysis of the antibody and identifying residues in the variable region(s) that are predicted to contact the epitope region of the target molecule (e.g., human CTLA-4).CDRH1, CDRH2, and CDRH3 represent the heavy chain CDRs, and CDRL1, CDRL2, and CDRL3 represent the light chain CDRs. [Table 1]

[0053] As used herein, the terms "variable region" and "variable domain" are used interchangeably and are common in the art. The variable region generally refers to the portion of an antibody that differs extensively in sequence among antibodies and is used to determine the binding and specificity of a particular antibody for its particular antigen; usually, a portion of either the light or heavy chain, typically approximately the amino-terminal 110 to 120 or 110 to 125 amino acids in mature heavy chains and approximately 90 to 115 amino acids in mature light chains. Sequence variability is concentrated in those regions called complementarity-determining regions (CDRs), while the more highly conserved regions within variable domains are called framework regions (FRs). While not wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of the light and heavy chains are primarily responsible for the interaction and specificity of the antibody with the antigen. In certain embodiments, the variable region is a human variable region. In certain embodiments, the variable region comprises rodent or murine CDRs and human framework regions (FRs). In one embodiment, the variable region is a primate (e.g., non-human primate) variable region, hi one embodiment, the variable region comprises rodent or murine CDRs and primate (e.g., non-human primate) framework regions (FRs).

[0054] As used herein, the terms "VH" and "VL" refer to antibody heavy and light chain variable regions, respectively, as described in Kabat et al., (1991) Sequences of Proteins of Immunological Interest (NIH Publication No. 91-3242, Bethesda), which is incorporated herein by reference in its entirety.

[0055] As used herein, the term "constant region" is a term that is common in the art. The constant region is the portion of an antibody, e.g., the carboxyl-terminal portion of the light and / or heavy chain, that is not directly involved in binding the antibody to an antigen, but that can exhibit various effector functions, such as interaction with Fc receptors (e.g., Fc gamma receptors).

[0056] As used herein, the term "heavy chain," when used in reference to an antibody, can refer to any of the different types, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), based on the amino acid sequence of the constant region, which give rise to antibodies of the IgA, IgD, IgE, IgG, and IgM classes, respectively, including subclasses of IgG, e.g., IgG1, IgG2, IgG3, and IgG4.

[0057] As used herein, the term "light chain," when used in reference to an antibody, can refer to any of the different types, e.g., kappa (κ) or lambda (λ), based on the amino acid sequence of the constant region. Light chain amino acid sequences are well known in the art. In one embodiment, the light chain is a human light chain.

[0058] As used herein, the terms "specifically bind," "specifically recognize," "immunospecifically bind," and "immunospecifically recognize" are analogous terms in the context of antibodies and refer to a molecule that binds to an antigen (e.g., an epitope or immune complex), as such binding is understood by one of skill in the art. For example, a molecule that specifically binds to an antigen may generally bind to other peptides or polypeptides with lower affinity, as determined by, for example, immunoassays, BIAcore®, KinExA 3000 instruments (Sapidyne Instruments, Boise, ID), or other assays known in the art. In one embodiment, a molecule that specifically binds to an antigen binds to the antigen with a K A that is at least 2 logs (e.g., 10-fold), 2.5 logs, 3 logs, 4 logs, or more, greater than the K A when the molecule nonspecifically binds to another antigen.

[0059] As used herein, the term "EU numbering system" refers to the EU numbering convention for antibody constant regions as described in Edelman, GM et al., Proc. Natl. Acad. USA, 63, 78-85 (1969), and Kabat et al., Sequences of Proteins of Immunological Interest, USDept. Health and Human Services, 5th edition, 1991, each of which is incorporated herein by reference in its entirety.

[0060] As used herein, the term "subject" includes any human or non-human animal. In one embodiment, the subject is a human.

[0061] As used herein, in the context of administering a therapy to a subject, the term "effective amount" refers to the amount of therapy that achieves a desired prophylactic or therapeutic effect.

[0062] As used herein, the terms "treat," "treating," and "treatment" refer to therapeutic or prophylactic measures as described herein. Methods of "treatment" employ administering an antibody to a subject with a disease or disorder, or a predisposition to having such a disease or disorder, to prevent, cure, delay, reduce the severity of, or ameliorate one or more symptoms of the disease or disorder, or a recurrent disease or disorder, or to prolong the subject's survival beyond that expected in the absence of such treatment.

[0063] As used herein, the term "standard of care" refers to the most common treatments prescribed for a particular type of cancer. In one embodiment, the standard of care for metastatic pancreatic cancer includes 5FU, leucovorin, irinotecan, and oxaliplatin (i.e., FOLFIRINOX).

[0064] As used herein, the term "targeted therapy" refers to a therapy that inhibits a specific protein. In one embodiment, the targeted therapy inhibits a protein (e.g., KRAS) known to be important for the growth and / or survival of pancreatic cancer cells.

[0065] As used herein, the term "cytotoxic therapy" refers to a therapy that inhibits or slows cell division. In one embodiment, the cytotoxic therapy kills cancer cells. In one embodiment, the cytotoxic therapy is fluorouracil, capecitabine, oxaliplatin, irinotecan, or trifluridine tipiracil.

[0066] As used herein, the term "tumor burden" refers to the number of cancer cells, the size of the tumor, or the amount of cancer in a subject's body.

[0067] As used herein, the term "about," when referring to a measurable value, such as a dosage, encompasses variations of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of a given value or range, as appropriate for practicing the methods disclosed herein.

[0068] Anti-CTLA-4 antibody Antibodies that specifically bind to human CTLA-4 (i.e., anti-CTLA-4 antibodies) useful in the methods and uses described herein include, but are not limited to, those listed below.

[0069] In one embodiment, the antibody comprises a heavy chain variable region (VH) comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7. In one embodiment, the antibody comprises a heavy chain variable region (VH) comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO:8.

[0070] In one embodiment, the antibody comprises the CDRH1, CDRH2, and CDRH3 amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively. In one embodiment, the antibody comprises the CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 amino acid sequences set forth in SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

[0071] In one embodiment, the antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 7. In one embodiment, the antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO:8.

[0072] In one embodiment, the antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8.

[0073] In one embodiment, the antibody comprises a heavy chain constant region selected from the group consisting of human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In one embodiment, the heavy chain constant region is IgG1. In one embodiment, the heavy chain constant region is IgG2. In one embodiment, the antibody comprises a light chain constant region selected from the group consisting of a human kappa light chain constant region and a human lambda light chain constant region.

[0074] In one embodiment, the antibody comprises an IgG1 heavy chain constant region. In one embodiment, the amino acid sequence of the IgG1 heavy chain constant region comprises S239D / I332E mutations numbered according to the EU numbering system. In one embodiment, the amino acid sequence of the IgG1 heavy chain constant region comprises S239D / A330L / I332E mutations numbered according to the EU numbering system. In one embodiment, the amino acid sequence of the IgG1 heavy chain constant region comprises L235V / F243L / R292P / Y300L / P396L mutations numbered according to the EU numbering system. In one embodiment, the IgG1 heavy chain constant region is an afucosylated IgG1.

[0075] In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9. In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9 and a light chain comprising an amino acid sequence that is at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 10.

[0076] In one embodiment, the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9 and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 10. In one embodiment, the amino acid sequence of the heavy chain consists of the amino acid sequence set forth in SEQ ID NO: 9 and the amino acid sequence of the light chain consists of the amino acid sequence set forth in SEQ ID NO: 10.

[0077] In one embodiment, the antibody is botenlimab (also known as AGEN1181), the amino acid sequence of which is shown in Table 2 below. [Table 2]

[0078] Treatment methods The present disclosure demonstrates that antibodies that specifically bind to human CTLA-4 (e.g., botencilimab) are highly effective in treating pancreatic cancer. The present disclosure also demonstrates that antibodies that specifically bind to human CTLA-4 (e.g., botencilimab) are highly effective in treating metastatic pancreatic adenocarcinoma that has progressed on prior 5FU + leucovorin + irinotecan + oxaliplatin (FOLFIRINOX) therapy. Thus, the present disclosure is broadly directed to methods of treating pancreatic cancer using antibodies that specifically bind to human CTLA-4 as monotherapy or in combination with nab-paclitaxel and gemcitabine.

[0079] In one aspect, provided herein is a method for treating pancreatic cancer in a subject in need of such treatment, comprising administering to the subject an effective amount of an antibody that specifically binds to human CTLA-4, the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8.

[0080] In one aspect, provided herein is a method for enhancing T cell activation in a subject with pancreatic cancer, comprising administering to the subject an effective amount of an antibody that specifically binds to human CTLA-4, the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8.

[0081] In one aspect, provided herein is a method of treating pancreatic cancer in a subject in need of such treatment, comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of about 5 mg to about 250 mg.

[0082] In one aspect, provided herein is a method for enhancing T cell activation in a subject with pancreatic cancer, comprising administering to the subject an antibody that specifically binds to human CTLA-4, the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of about 5 mg to about 250 mg.

[0083] In one aspect, provided herein is a method of treating pancreatic cancer in a subject in need of such treatment, comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of 5 mg to 250 mg.

[0084] In one aspect, provided herein is a method for enhancing T cell activation in a subject with pancreatic cancer, comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of 5 mg to 250 mg, the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8.

[0085] In one embodiment, provided herein is a method of treating pancreatic cancer in a subject in need of such treatment, comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of about 5 mg to about 200 mg.

[0086] In one embodiment, provided herein is a method for enhancing T cell activation in a subject with pancreatic cancer, comprising administering to the subject an antibody that specifically binds to human CTLA-4, the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of about 5 mg to about 200 mg.

[0087] In one embodiment, provided herein is a method of treating pancreatic cancer in a subject in need of such treatment, comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of 5 mg to 200 mg.

[0088] In one embodiment, provided herein is a method for enhancing T cell activation in a subject with pancreatic cancer, comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of 5 mg to 200 mg, the antibody comprising a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8.

[0089] In one embodiment, the antibody is administered at a dose of about 25 mg to about 250 mg. In one embodiment, the antibody is administered at a dose of about 25 mg to about 200 mg. In one embodiment, the antibody is administered at a dose of about 25 mg to about 150 mg. In one embodiment, the antibody is administered at a dose of about 50 mg to about 150 mg. In one embodiment, the antibody is administered at a dose of about 75 mg to about 150 mg.

[0090] In one embodiment, the antibody is administered at a dose of 25 mg to 250 mg. In one embodiment, the antibody is administered at a dose of 25 mg to 200 mg. In one embodiment, the antibody is administered at a dose of 50 mg to 175 mg. In one embodiment, the antibody is administered at a dose of 25 mg to 150 mg. In one embodiment, the antibody is administered at a dose of 50 mg to 150 mg. In one embodiment, the antibody is administered at a dose of 75 mg to 150 mg.

[0091] In one embodiment, the antibody is administered at a dose of about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

[0092] In one embodiment, the antibody is administered at a dose of 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg.

[0093] In one embodiment, the antibody is administered intravenously. In one embodiment, the antibody is administered intratumorally.

[0094] In one embodiment, the antibody is administered by intravenous infusion over about 30 minutes. In one embodiment, the antibody is administered by intravenous infusion over about 45 minutes. In one embodiment, the antibody is administered by intravenous infusion over about 60 minutes. In one embodiment, the antibody is administered by intravenous infusion over about 90 minutes.

[0095] In one embodiment, the antibody is administered about once a week. In one embodiment, the antibody is administered about once every two weeks. In one embodiment, the antibody is administered about once every three weeks. In one embodiment, the antibody is administered about once every four weeks. In one embodiment, the antibody is administered about once every five weeks. In one embodiment, the antibody is administered about once every six weeks. In one embodiment, the antibody is administered about once every seven weeks. In one embodiment, the antibody is administered about once every eight weeks.

[0096] In one embodiment, the antibody is administered once a week. In one embodiment, the antibody is administered once every two weeks. In one embodiment, the antibody is administered once every three weeks. In one embodiment, the antibody is administered once every four weeks. In one embodiment, the antibody is administered once every five weeks. In one embodiment, the antibody is administered once every six weeks. In one embodiment, the antibody is administered once every seven weeks. In one embodiment, the antibody is administered once every eight weeks.

[0097] In one embodiment, the antibody is administered intravenously at a dose of about 25 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 50 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 75 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 100 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 125 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 150 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 175 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 200 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 225 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of about 250 mg once every six weeks.

[0098] In one embodiment, the antibody is administered intravenously at a dose of 25 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 50 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 75 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 100 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 125 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 150 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 175 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 200 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 225 mg once every six weeks. In one embodiment, the antibody is administered intravenously at a dose of 250 mg once every six weeks.

[0099] In one embodiment, the dose is a therapeutically effective amount.

[0100] In one embodiment, the pancreatic cancer is pancreatic ductal adenocarcinoma. In one embodiment, the pancreatic cancer is unresectable. In one embodiment, the pancreatic cancer is metastatic. In one embodiment, the pancreatic cancer is recurrent and / or refractory. In one embodiment, the pancreatic cancer has progressed after 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin therapy (i.e., FOLFIRINOX therapy).

[0101] In one embodiment, the subject has received at least one prior chemotherapy. In one embodiment, the at least one prior chemotherapy is 5-fluorouracil, leucovorin, irinotecan, or oxaliplatin. In one embodiment, the subject has previously received treatment with 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (i.e., FOLFIRINOX therapy). In one embodiment, the pancreatic cancer has recurred following standard treatment.

[0102] In one embodiment, the method further comprises administering nab-paclitaxel to the subject. In one embodiment, the nab-paclitaxel is administered at a dose of about 50 mg / m 2 to approximately 200 mg / m 2 In one embodiment, nab-paclitaxel is administered at a dose of about 75 mg / m 2 to approximately 125 mg / m 2 In one embodiment, nab-paclitaxel is administered at a dose of about 75 mg / m 2 , about 100mg / m 2 , or about 125 mg / m 2 In one embodiment, nab-paclitaxel is administered once weekly. In one embodiment, nab-paclitaxel is administered on days 1, 8, and 15 of a 6-week cycle.

[0103] In one embodiment, the method further comprises administering nab-paclitaxel to the subject. In one embodiment, the nab-paclitaxel is administered at a dose of 75 mg / m 2 to 200 mg / m 2 In one embodiment, nab-paclitaxel is administered at a dose of 75 mg / m 2 to 125 mg / m 2In one embodiment, nab-paclitaxel is administered at a dose of 75 mg / m 2 , 100 mg / m 2 , or 125 mg / m 2 In one embodiment, nab-paclitaxel is administered once weekly. In one embodiment, nab-paclitaxel is administered on days 1, 8, and 15 of a 6-week cycle.

[0104] In one embodiment, the method further comprises administering gemcitabine to the subject. In one embodiment, the gemcitabine is administered at a dose of about 500 mg / m 2 to approximately 1500 mg / m 2 In one embodiment, gemcitabine is administered at a dose of about 600 mg / m 2 to approximately 1000 mg / m 2 In one embodiment, gemcitabine is administered at a dose of about 600 mg / m 2 , about 800mg / m 2 , or about 1000 mg / m 2 In one embodiment, gemcitabine is administered once weekly. In one embodiment, gemcitabine is administered on days 1, 8, and 15 of a 6-week cycle.

[0105] In one embodiment, the method further comprises administering gemcitabine to the subject. In one embodiment, gemcitabine is administered at 500 mg / m 2 to 1500 mg / m 2 In one embodiment, gemcitabine is administered at a dose of 600 mg / m 2 to 1000 mg / m 2 In one embodiment, gemcitabine is administered at a dose of 600 mg / m 2 , 800 mg / m 2 , or 1000 mg / m 2 In one embodiment, gemcitabine is administered once weekly. In one embodiment, gemcitabine is administered on days 1, 8, and 15 of a 6-week cycle.

[0106] In one embodiment, the antibody is administered intravenously at a dose of 25 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 100 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 200 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 225 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2In one embodiment, the antibody is administered intravenously at a dose of 250 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 is administered at a dose of

[0107] In one embodiment, the antibody is administered intravenously at a dose of 25 mg and nab-paclitaxel is administered at 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2In one embodiment, the antibody is administered intravenously at a dose of 225 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 250 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 is administered at a dose of

[0108] In one embodiment, the antibody is administered intravenously at a dose of 25 mg and nab-paclitaxel is administered at 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2In one embodiment, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 225 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 250 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 600 mg / m 2 is administered at a dose of

[0109] In one embodiment, the antibody is administered intravenously at a dose of 25 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 100 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 200 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 225 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 250 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 is administered at a dose of

[0110] In one embodiment, the antibody is administered intravenously at a dose of 25 mg and nab-paclitaxel is administered at 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 225 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 250 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 is administered at a dose of

[0111] In one embodiment, the antibody is administered intravenously at a dose of 25 mg and nab-paclitaxel is administered at 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2In one embodiment, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 225 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 250 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 800 mg / m 2 is administered at a dose of

[0112] In one embodiment, the antibody is administered intravenously at a dose of 25 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2In one embodiment, the antibody is administered intravenously at a dose of 100 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 200 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 225 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 250 mg once every six weeks and nab-paclitaxel is administered at a dose of 75 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 is administered at a dose of

[0113] In one embodiment, the antibody is administered intravenously at a dose of 25 mg and nab-paclitaxel is administered at 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 225 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 250 mg and nab-paclitaxel is administered at a dose of 100 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 is administered at a dose of

[0114] In one embodiment, the antibody is administered intravenously at a dose of 25 mg and nab-paclitaxel is administered at 125 mg / m 2and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 75 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 125 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 150 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 175 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 225 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 In one embodiment, the antibody is administered intravenously at a dose of 250 mg and nab-paclitaxel is administered at a dose of 125 mg / m 2 and gemcitabine at a dose of 1000 mg / m 2 is administered at a dose of

[0115] In any of the embodiments of the methods disclosed herein, the antibody is administered on day 1 of a 6-week cycle, and nab-paclitaxel and gemcitabine are administered on days 1, 8, and 15 of the 6-week cycle. In one embodiment, the antibody is administered to the subject before nab-paclitaxel and gemcitabine. In one embodiment, nab-paclitaxel is administered before gemcitabine. In one embodiment, nab-paclitaxel is administered intravenously. In one embodiment, gemcitabine is administered intravenously.

[0116] In one embodiment, the method comprises two 6-week cycles. In one embodiment, the method comprises three 6-week cycles. In one embodiment, the method comprises four 6-week cycles. In one embodiment, the method comprises five 6-week cycles. In one embodiment, the method comprises five 6-week cycles. In one embodiment, the method comprises six 6-week cycles. In one embodiment, the method comprises seven 6-week cycles. In one embodiment, the method comprises eight 6-week cycles.

[0117] In one embodiment, the subject is a human subject. In one embodiment, the method does not include administration of cisplatin.

[0118] In one embodiment, the cancer is refractory to standard of care treatment. In one embodiment, the standard of care treatment is chemotherapy or radiation. In one embodiment, the standard of care treatment is 5-fluorouracil, leucovorin, irinotecan, and / or oxaliplatin.

[0119] In one embodiment, the method reduces tumor size in a subject. In one embodiment, the method increases T cell activation in a subject. In one embodiment, the method reduces CA19-9, CA125, or CEA levels in a subject.

[0120] In one embodiment, prior to administration of the antibody, the subject has measurable disease by baseline imaging per RECIST 1.1. In one embodiment, prior to administration of the antibody, the subject has an Eastern Cooperative Oncology Group performance status (PS) of 0 to 1. In one embodiment, prior to administration of the antibody, the subject has a predicted life expectancy of 12 weeks or greater.

[0121] In one embodiment, prior to administration of the antibody, the subject has: a) neutrophils > 1500 / μL; b) platelets > 100 x 10 3 Have adequate organ function as defined by one or more of the following: c) hemoglobin ≥ 9.0 g / dL, d) creatinine clearance ≥ 30 mL / min measured or calculated according to local institutional standards, e) aspartate aminotransferase (AST) / alanine aminotransferase (ALT) < 3.0 × upper limit of normal (ULN), f) direct bilirubin < 1.5 × ULN (except for patients with Gilbert's syndrome, who must have total bilirubin < 3.0 × ULN), and / or g) serum albumin ≥ 3.0 g / dL.

[0122] In one embodiment, the subject has no partial or complete bowel obstruction, signs / symptoms of bowel obstruction, or known radiological evidence of impending obstruction within the past three months.

[0123] In one embodiment, the subject has not received immune checkpoint inhibitor therapy prior to administration of the antibody. In one embodiment, the subject has not received multiple chemotherapy regimens prior to administration of the antibody. In one embodiment, the subject has no history of central nervous system (CNS) metastases. In one embodiment, the subject has no concurrent malignancy requiring treatment or no history of a malignancy that has been active within two years prior to administration of the antibody. In one embodiment, the subject has not received cytotoxic or targeted therapy within three weeks prior to administration of the antibody. In one embodiment, the subject has not received another monoclonal antibody therapy, antibody-drug conjugate therapy, or radioimmunoconjugate therapy within four weeks prior to administration of the antibody. In one embodiment, the subject has not received small molecule tyrosine kinase inhibitor therapy within two weeks prior to administration of the antibody.

[0124] In one embodiment, the subject does not have refractory ascites, defined as the need for therapeutic paracentesis two or more times within the past four weeks, four or more times within the past 90 days, or one or more times within the past two weeks prior to administration of the antibody. In one embodiment, the subject does not have clinically significant cardiovascular disease.

[0125] In one embodiment, the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) are assessed for subjects according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

[0126] In one embodiment, the method results in a complete response as defined by RECIST 1.1. In one embodiment, the method results in a partial response as defined by RECIST 1.1. In one embodiment, the method results in stable disease as defined by RECIST 1.1.

[0127] In one embodiment, the method results in about a 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% reduction in tumor burden in the subject. In one embodiment, the method results in no change in tumor burden in the subject. In one embodiment, the method results in about a 1% reduction in tumor burden in the subject. In one embodiment, the method results in about a 5% reduction in tumor burden in the subject. In one embodiment, the method results in about a 10% reduction in tumor burden in the subject. In one embodiment, the method results in about a 20% reduction in tumor burden in the subject. In one embodiment, the method results in about a 30% reduction in tumor burden in the subject. In one embodiment, the method results in about a 40% reduction in tumor burden in the subject. In one embodiment, the method results in about a 50% reduction in tumor burden in the subject. In one embodiment, the method results in about a 60% reduction in tumor burden in the subject. In one embodiment, the method results in about a 70% reduction in tumor burden in the subject. In one embodiment, the method results in about an 80% reduction in tumor burden in the subject. In one embodiment, the method results in about a 90% reduction in tumor burden in the subject. In one embodiment, the method results in about a 100% reduction in tumor burden in the subject.

[0128] In one embodiment, the method results in a decrease in tumor burden. In one embodiment, the method results in an increase in survival rate. In one embodiment, the method results in an increase in overall survival. In one embodiment, the method results in an increase in progression-free survival.

[0129] In one aspect, provided herein is an antibody that specifically binds human CTLA-4 for use in the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0130] In one aspect, provided herein is an antibody that specifically binds human CTLA-4 for use in the manufacture of a medicament for the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0131] In one aspect, provided herein is the use of an antibody that specifically binds human CTLA-4 for the treatment of pancreatic cancer, performed according to any one of the methods disclosed herein.

[0132] In one aspect, provided herein is an antibody that specifically binds human CTLA-4, gemcitabine, and nab-paclitaxel for use in the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0133] In one aspect, provided herein is an antibody that specifically binds human CTLA-4, gemcitabine, and nab-paclitaxel for use in the manufacture of a medicament for the treatment of pancreatic cancer according to any one of the methods disclosed herein.

[0134] In one aspect, provided herein is the use of an antibody that specifically binds human CTLA-4, gemcitabine, and nab-paclitaxel for the treatment of pancreatic cancer, performed according to any one of the methods disclosed herein. [Example]

[0135] Example 1 - Botencilimab (AGEN1181) in Combination with Nab-Paclitaxel and Gemcitabine in a Mouse Model of Pancreatic Cancer Botencilimab was tested for its ability to inhibit pancreatic cancer growth in a mouse model of pancreatic cancer.

[0136] Female C57BL / 6J mice (6-8 weeks old) were inoculated with KPC (KrasG12D, P53- / -Pdx1-Cre) tumor masses (approximately 100 mm) isolated from KPC tumor-bearing mice. 3 For transplantation, mice were anesthetized with isoflurane.

[0137] Mice were then randomized and treated with the designated antibodies, chemotherapy, or their combinations. Antibodies included isotype control, a mouse surrogate for conventional or first-generation anti-CTLA-4 (clone 9D9 mouse IgG2b), a mouse surrogate for botencilimab (botencilimab ms The chemotherapy drugs included gemcitabine, nab-paclitaxel (Abraxane), and cisplatin.

[0138] Antibodies (100 μg / dose) were administered intraperitoneally (ip) twice weekly for 3 weeks. Mice treated with doublet chemotherapy received gemcitabine (70 mg / kg) i.p. and Abraxane (25 mg / kg) i.v. or gemcitabine (70 mg / kg) i.p. and cisplatin (4 mg / kg) i.p. on days 1 and 4. Mice treated with triplet chemotherapy received gemcitabine (70 mg / kg) i.p., Abraxane (25 mg / kg) i.v., and cisplatin (4 mg / kg) i.p. on days 1 and 4.

[0139] The results shown in Figure 1A demonstrate that the Fc-engineered antibody botencilimab has greater antitumor activity in a mouse model of pancreatic cancer compared with a conventional anti-CTLA-4 antibody with a wild-type Fc. The results shown in Figure 1B demonstrate that tumor growth in mice treated with botencilimab in combination with nab-paclitaxel and gemcitabine was significantly slower than that in mice treated with botencilimab. ms The results demonstrate that the progression of nab-paclitaxel was significantly slower than that of mice treated with either nab-paclitaxel alone (P < 0.0001) or nab-paclitaxel plus gemcitabine (P = 0.0059). Furthermore, the results shown in Figure 1C demonstrate that there was no significant difference in body weight change between treatment groups, suggesting that there was no significant toxicity associated with these treatments.

[0140] The results shown in Figures 2 and 3 indicate that the combination of botencilimab with doublet chemotherapy exhibits increased antitumor activity compared to doublet chemotherapy alone. For the analysis of the combination of botencilimab with the nab-paclitaxel + gemcitabine doublet, the individual tumor growth curves are shown in Figure 2A (isotype control) and Figure 2B (botencilimab). ms 2C (monotherapy), Figure 2C (nab-paclitaxel + gemcitabine), and Figure 2D (botencilimab and nab-paclitaxel + gemcitabine). The results of these individual treatment groups demonstrate that the majority of mice treated with the combination of botencilimab and nab-paclitaxel + gemcitabine showed tumor shrinkage and even achieved complete remission (3 out of 10 mice). For the analysis of the combination of botencilimab and the cisplatin + gemcitabine doublet, the individual tumor growth curves are shown in Figure 3A (isotype control), Figure 3B (botencilimab ms monotherapy), Figure 3C (cisplatin plus gemcitabine), and Figure 3D (botencilimab and cisplatin plus gemcitabine).

[0141] Furthermore, the results shown in Figure 4 demonstrate that botencilimab has greater antitumor activity in mice compared to anti-PD-1 antibodies. Individual tumor growth curves are shown in Figure 4A (isotype control), Figure 4B (triplet chemotherapy, Abraxane + cisplatin + gemcitabine), and Figure 4C (botencilimab ms 4D (anti-PD-1 antibody monotherapy), and Fig. 4D (anti-PD-1 antibody monotherapy).

[0142] These results demonstrate that botencilimab has promising preclinical activity in combination with nab-paclitaxel and gemcitabine in the KPC syngenic mouse model of difficult-to-treat pancreatic ductal adenocarcinoma, superior to chemotherapy alone.

[0143] Example 2 - Phase 2 Study of Botencilimab (AGEN1181) in Combination with Nab-Paclitaxel and Gemcitabine for the Treatment of Metastatic Pancreatic Cancer This phase 2 study further evaluated the safety and efficacy of botencilimab in patients with metastatic pancreatic cancer who had progressed on previous 5FU plus leucovorin plus irinotecan plus oxaliplatin (FOLFIRINOX).

[0144] A. Study Design Overall Design This was a prospective, multicenter, randomized, open-label, phase 2 clinical trial of botencilimab in combination with nab-paclitaxel and gemcitabine. The trial was conducted in two parts: Part 1 was a safety lead-in to establish the safety of the proposed combination of botencilimab and nab-paclitaxel and gemcitabine and to determine the botencilimab dose in Part 2. Part 2 was a randomized, open-label evaluation of botencilimab (at the dose level determined in Part 1) in combination with nab-paclitaxel and gemcitabine, and nab-paclitaxel and gemcitabine alone.

[0145] This study enrolled patients with metastatic pancreatic ductal adenocarcinoma who had previously progressed on a FOLFIRINOX regimen for advanced metastatic disease. Investigators assessed and documented disease progression on any version of FOLFIRINOX for metastatic disease in patient source documents as part of the screening process. Baseline study procedures included computed tomography (CT) of the chest, abdomen, and pelvis (preferred), or magnetic resonance imaging (MRI) only if CT was contraindicated, routine laboratory testing, and tumor markers.

[0146] research treatment Part 1 - Safety Lead-in: The safety of the proposed combination was established based on a modified 3 + 3 dose escalation rule in 18 patients.

[0147] Three patients were enrolled and received botencilimab (dose level 1: 50 mg Q6W) plus gemcitabine (1000 mg / m 2 ) / nab-paclitaxel (125 mg / m 2) (Table 4). Based on the initial safety signals observed in these first three dose-limiting toxicity (DLT)-evaluable patients treated at dose level 1, the botencilimab dose was escalated, expanded, or decreased as follows: If none of the first three DLT-evaluable patients receiving -50 mg experienced a DLT within the DLT assessment interval, three additional patients were enrolled at escalated dose level 2, botencilimab 150 mg. If one of the first three DLT-evaluable patients receiving -50 mg experienced a DLT within the DLT assessment interval, three additional patients were enrolled at this dose level, botencilimab 50 mg. -Dose De-escalation: If two or more of the first three or six DLT-evaluable patients receiving 50 mg experienced a DLT within the DLT assessment interval, three additional patients were enrolled at reduced dose level -1, botencilimab 25 mg. If two or more of the first three or six DLT-evaluable patients receiving -25 mg experienced a DLT within the DLT assessment interval, the study did not proceed to Part 2. If only 1 of 6 DLT-evaluable patients experienced a DLT for a particular dose level within the DLT assessment interval, that dose level was considered tolerable in Part 2.

[0148] "DLT-evaluable" refers to any patient who received at least one dose of botencilimab and at least one cycle of gemcitabine / nab-paclitaxel or who experienced a DLT and was toxicity-evaluable.

[0149] The DLT interval was from the first dose of study treatment on cycle 1, day 1, to the end of cycle 1 (day 41).

[0150] Dose-limiting toxicity (DLT) was defined by the occurrence of the following AEs considered related (including possibly related) to botencilimab during the DLT interval, from cycle 1 / day 1 to the end of cycle 1 (day 41), as defined by CTCAE version 5.0:

[0151] DLT was defined as the occurrence of a grade ≥3 AE (as defined by CTCAE v5.0) related (likely or possibly) to botencilimab during the DLT interval (C1 / D1 to the end of cycle 1 [day 41]), with the exception of any grade of fatigue, any grade of alopecia, any grade of cytopenia, any grade of nausea / vomiting, any grade ≥3 immune-mediated adverse event (irAE) that resolved to grade ≤2 within 3 days with appropriate management, any grade of endocrinopathies adequately controlled with hormone replacement, and any laboratory abnormality that did not require intervention and was deemed clinically insignificant by the investigator.

[0152] Part 2 - Randomization Phase: After completion of Part 1, a total of 60 patients were recruited to meet 48 evaluable patients, with 30 randomized to each group as detailed below. 1. Arm A (combination): Botencilimab according to the SoC (dose determined in Part 1 Q6W x 3 doses) + gemcitabine (1000 mg / m 2 ) / nab-paclitaxel (125 mg / m 2 )(Table 4) 2. Group B (standard of care): gemcitabine (1000 mg / m) according to the SoC 2 ) / nab-paclitaxel (125 mg / m 2 ) (Table 4) were included.

[0153] The botencilimab dose level selected in part 2 was based in part on all available safety data from part 1. In addition, all available clinical safety data, as well as pharmacokinetic, pharmacodynamic, and efficacy data from other applicable botencilimab studies, were considered part of the dose selection decision-making for part 2.

[0154] During the treatment period, patients underwent routine clinical examinations to monitor the administration of study treatment and safety, health status, and changes in disease status. CA19-9 (or CA125, or CEA if CA19-9 was not expressed) was collected at the start of each cycle (day 1) and on day 1 of each chemotherapy cycle.

[0155] Patients in group A received up to three doses of botencilimab (3 cycles). Patients in groups A and B received gemcitabine (1000 mg / m) according to the SoC (Table 4). 2 ) / nab-paclitaxel (125 mg / m 2 ) continued until unacceptable toxicity, disease progression, death, or the patient discontinued study treatment for any reason.

[0156] Antitumor response was determined through imaging assessments performed within 21 days prior to randomization (first dose of study drug for patients in Part 1). Tumor assessments during the study were performed every 8 weeks (+ / - 7 days) from randomization for the first 24 weeks, and every 12 weeks (+ / - 7 days) thereafter. Disease response was assessed periodically by an independent, blinded central reviewer blinded to treatment assignment. Confirmation of progressive disease (PD) was documented by imaging 4 to 6 weeks (but not later) after progression was diagnosed and reviewed by a central radiologist before discontinuation of study treatment.

[0157] Safety was assessed by monitoring AEs, SAEs, treatment discontinuation due to AEs, physical examination, vital signs, hematology, and chemistry tests.

[0158] Patients who discontinued study treatment for reasons other than progressive disease (PD) continued to undergo imaging assessments according to the SoA with visits at Q6W and then at Weeks 8, 16, 24, and Q12W until initiation of additional antineoplastic therapy or disease progression.

[0159] For survival follow-up, patients who started additional antineoplastic therapy or discontinued study imaging for other reasons were followed up for survival status by telephone Q12W until the end of the study. [Table 3] [Table 4]

[0160] The doses of nab-paclitaxel and gemcitabine were reduced in individual patients according to the schedule in Table 4. In general, doses reduced due to toxicity were not escalated to the starting level. In some cases, growth factors were used to treat hematologic toxicity and did not result in dose reductions.

[0161] A treatment delay of up to 4 weeks from chemotherapy was permitted to allow for resolution of toxicity or other concurrent illnesses that prevented the patient from receiving chemotherapy. If a dose change was necessary at the beginning of a cycle or within a cycle due to hematologic toxicity, the doses of nab-paclitaxel and gemcitabine were adjusted. If a patient experienced a grade 4 hematologic AE related to chemotherapy as determined by the investigator during cycle 1, the dose was reduced to dose level -1 for cycle 2 according to Table 4.

[0162] If a patient experienced a treatment delay within a treatment cycle due to hematologic toxicity, the dose held during that cycle was not replenished. Dose modifications due to hematologic toxicity (represented by blood counts and toxicity below) within a treatment cycle were adjusted. If a patient's neutropenia did not resolve within 28 days despite G-CSF treatment not being interrupted, study treatment was discontinued. Patients with fever (regardless of neutrophil count) had chemotherapy treatment discontinued. A complete sepsis workup was performed while continuing broad-spectrum antibiotics. If cultures were positive, antibiotics were modified depending on the sensitivity profile of the isolated organism. Patients with persistent fever after 3 weeks, despite not interrupting antibiotic treatment, discontinued study treatment. Patients with febrile neutropenia received G-CSF in addition to antibiotic treatment to hasten the resolution of febrile neutropenia (in accordance with current institutional guidelines). In all cases, blood counts returned to baseline levels before resuming chemotherapy treatment.

[0163] Doses were reduced for nonhematologic toxicities that occurred despite appropriate background medical therapy. If toxicity affected only neuropathy, only nab-paclitaxel was reduced. Nab-paclitaxel treatment was withheld for patients who experienced peripheral neuropathy of grade ≥ 3. Gemcitabine administration was continued during this period. Nab-paclitaxel treatment was resumed at the next lower dose level according to Table 4 in subsequent cycles after peripheral neuropathy improved to grade ≤ 1. The time to improvement to grade ≤ 1 was the adverse event duration used for reporting adverse events. Patients who experienced peripheral neuropathy requiring a delay of 28 days or more from the scheduled nab-paclitaxel administration discontinued nab-paclitaxel.

[0164] For patients who developed grade 2 or 3 skin toxicity, the doses of nab-paclitaxel and gemcitabine were reduced to the next lower dose level according to Table 4. If patients continued to experience these reactions despite dose reduction, treatment was discontinued. For patients who developed grade 4 skin toxicity, study treatment was discontinued.

[0165] If grade 2 mucositis or diarrhea occurred, nab-paclitaxel and gemcitabine were withheld until recovery to grade 1 or less, and then re-administered at the next lower dose level according to Table 4. Study treatment was discontinued for patients who developed grade 3 mucositis or diarrhea.

[0166] Asymptomatic or clinically mild pulmonary embolism was treated with low-molecular-weight heparin without interruption of treatment. Moderate to severe pulmonary embolism required permanent discontinuation of chemotherapy. Pulmonary toxicity has been reported with both gemcitabine and paclitaxel. Combination chemotherapy with gemcitabine and paclitaxel has shown a higher incidence of pneumonia (4%) compared with either drug alone. Early detection and treatment were necessary because it can be life-threatening or fatal.

[0167] During study participation, patients were closely monitored for signs and symptoms of pneumonia (i.e., persistent dry cough and transient or recurrent episodes of dyspnea accompanied by fever), and if observed, immediate clinical evaluation and timely implementation of appropriate management were initiated (emphasizing the need for corticosteroids if an infectious process was ruled out, and appropriate ventilation and oxygenation, if necessary). If asymptomatic grade 1 pneumonia was observed only on scans, patients received continued gemcitabine and nab-paclitaxel if they were clinically benefiting from the study and after thorough discussion with the medical monitor. If grade 1 interstitial pneumonia was diagnosed, study treatment was permanently discontinued.

[0168] If grade 1 interstitial pneumonia was diagnosed, study drug administration was interrupted and the patient was permanently discontinued from further study drug treatment. After excluding infectious etiologies, intravenous high-dose corticosteroid therapy and treatment of secondary pathogens were initiated without delay. Patients with an additional immunological component required immunomodulation with azathioprine or cyclophosphamide. Appropriate ventilation and oxygen support were used as needed.

[0169] Granulocyte colony-stimulating factor (G-CSF) was given according to institutional guidelines. In the absence of institutional guidelines, G-CSF was given according to the ASCO Clinical Practice Guideline Recommendations for the Use of Leukocyte Growth Factors: Guideline Summary Appendix C.

[0170] Adverse events (AEs) associated with botencilimab exposure may have had an immunological etiology. In some cases, these immune-mediated AEs (irAEs) occurred shortly after the first dose of treatment or several months after the last dose and simultaneously affected multiple body systems. Early recognition of irAEs and initiation of appropriate immunosuppressive therapy was important to reduce complications and improve patient outcomes. Based on existing clinical trial data, most irAEs were reversible and managed with discontinuation of botencilimab, administration of corticosteroids and / or infliximab, and / or other supportive care.

[0171] Administration of test drug Each treatment cycle was defined as 6 weeks, with botencilimab administered on day 1 of each cycle (Arm A) and gemcitabine / nab-paclitaxel administered on days 1, 8, and 15 of each 6-week cycle. Patients received three doses of botencilimab and continued to receive gemcitabine / nab-paclitaxel until disease progression, unacceptable toxicity, or the patient's desire to discontinue study treatment for any reason.

[0172] The drug administration order was botencilimab, nab-paclitaxel, and then gemcitabine. Nab-paclitaxel was administered before gemcitabine because it may be taken up by the process of macropinocytosis. Gemcitabine was given next because albumin-bound paclitaxel may reduce cytidine deaminase, which enhances gemcitabine activity (leading to less degradation of gemcitabine by the enzyme).

[0173] Supportive medications included palonosetron (Aloxi®) 0.25 mg IV, fosaprepitant (Emend®) 150 mg IV, and dexamethasone 12 mg IV, or an equivalent antiemetic regimen administered within 30 minutes before chemotherapy. Patients continued oral antiemetic prophylaxis at home for 2 days after chemotherapy. The type of oral antiemetic prophylaxis used varied based on institutional procedures, but efforts were made to minimize corticosteroid dose and duration; i.e., dexamethasone was not used on days 2 and 3 unless necessary, and alternatives included ondansetron if palonosetron was not given, or olanzapine.

[0174] Botencilimab was administered via IV infusion over 30 (±5) minutes. Patients were observed for infusion-related reactions for 30 minutes after the end of the infusion. Vital signs were measured before the start of each infusion and at the end of each infusion in all cycles. After the end of the infusion, the IV line was immediately flushed with saline according to institutional guidelines.

[0175] Gemcitabine / nab-paclitaxel was administered according to Table 4 and according to the prescribing information for gemcitabine and nab-paclitaxel.

[0176] Number of patients There were 18 patients in Part 1. Part 2 enrolled approximately 60 eligible patients (30 patients randomized to each group).

[0177] Patients who did not meet the criteria to be considered DLT-evaluable were replaced in Part 1. Patients who received at least one dose of study treatment were not replaced in Part 2 of the study.

[0178] Patients who met enrollment eligibility but were later determined to be ineligible at C1 / D1 did not receive study treatment and were replaced.

[0179] Treatment after disease progression For patients with progressive disease (PD) who continued study treatment per protocol, confirmatory imaging was performed at weeks 4–6. If the confirmatory scan confirmed PD by a ≥10% increase in the total measurable lesion(s), overt progression of the nonmeasurable lesion(s), or the appearance of new lesions, patients were discontinued from treatment.

[0180] Patients who tolerate the drug and are deemed by the investigator to have clinical benefit may continue treatment beyond initial RECIST 1.1-defined PD if they meet the following clinical stability criteria, with sponsor approval: Absence of clinical symptoms and signs indicative of PD (including deterioration of laboratory values). - No decline in ECOG status (Appendix A) due to primary malignancy - The patient tolerates the study medication and continued treatment will not interfere with or delay treatment that may prevent serious complications of the disease.

[0181] Treatment duration Part 1: Patients receive gemcitabine (1000 mg / m) according to the SoC (Table 4) 2 ) / nab-paclitaxel (125 mg / m 2 Patients received up to three doses (three cycles) of botencilimab at the prescribed dose in combination with cefotaxime (C1000). After three doses of botencilimab, patients continued to receive gemcitabine / nab-paclitaxel according to the Study of Clinical Chemotherapy (SCC) until disease progression, unacceptable toxicity, or the patient wished to discontinue study treatment for any reason.

[0182] Part 2: Patients in group A (combination) received gemcitabine (1000 mg / m 2 ) / nab-paclitaxel (125 mg / m 2 Patients received up to three doses (three cycles) of botencilimab in combination with EGFR-1000 (SEQ ID NO: 1) at the dose determined in Part 1. After receiving three doses of botencilimab, patients continued to receive gemcitabine / nab-paclitaxel according to the Study of Clinical Chemotherapy (SOC) until disease progression, unacceptable toxicity, or the patient wished to discontinue study treatment for any reason.

[0183] Patients in group B (SoC) received gemcitabine (1000 mg / m ) according to the SoC (Table 4) until disease progression, unacceptable toxicity, or the patient's desire to discontinue study treatment for any reason. 2 ) / nab-paclitaxel (125 mg / m 2 After discontinuation of treatment, patients were followed for safety at 30 (±7) and 90 (±7) days and underwent long-term follow-up every 3 months for 12 months after the last dose.

[0184] Despite discontinuation of study treatment (e.g., due to toxicity), patients continued to receive scheduled imaging evaluations and concurrent outpatient care if they remained eligible to continue in the study.

[0185] If the study was not terminated for the reasons specified in Section 9.4, the entire study was terminated approximately 12 months after the last randomized patient completed the last dose of botencilimab, withdrew from the study, or was lost to follow-up (i.e., the patient could not be contacted by the investigator).

[0186] Prohibited drugs and treatments Medications or vaccinations specifically prohibited by the exclusion criteria were not permitted during the study. Clinical indications for any specifically prohibited medications or vaccinations during the study required discontinuation of study therapy or vaccination. The final decision regarding any supportive care or vaccinations rested with the investigator and / or the patient's physician. However, the decision for a patient to continue study treatment required mutual agreement between the investigator, sponsor, and patient.

[0187] Listed below are specific limitations of the combination therapy that were instituted during the course of the study: -Antineoplastic systemic chemotherapy or biological therapy other than SoC. - Immuno-oncology therapy not specified in this protocol. - Investigational medication other than the assigned study treatment. Systemic glucocorticoids (>10 mg prednisone equivalent for >1 week) for any purpose other than treating immune-related adverse events. Note: Prophylactic corticosteroid use to avoid allergic reactions (e.g., IV contrast or blood transfusion) is permitted, as is the use of inhaled or nasal or local corticosteroid injections. -The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised when administering nab-paclitaxel concomitantly with drugs known to inhibit or induce either CYP2C8 or CYP3A4.

[0188] Patients treated with any prohibited substances (with the exceptions noted above) for clinical management were excluded from the study. All treatments deemed necessary by the investigator for the patient's welfare were administered at the investigator's discretion in accordance with local standards of care. All concomitant medications were recorded on the electronic case report form (eCRF), including all prescription, over-the-counter, herbal supplements, and IV medications and fluids. Documentation of medication dose, frequency, route, and date was recorded on the eCRF if changes occurred during the study period.

[0189] Surgery and radiation therapy If patients required surgery for management of progressive malignancy, they were discontinued from study treatment. In cases of surgery for bowel obstruction, patients continued on study treatment unless PD was confirmed. Palliative radiation therapy for non-target lesions was permitted based on specific clinical scenarios and in consultation with the sponsor.

[0190] Permanent discontinuation of study drug treatment Botencilimab was permanently discontinued for any of the following reasons: - If an immune-related adverse event occurs that meets the criteria for discontinuation. - The patient is determined by the investigator to derive clinical benefit from the treatment, is clinically stable, and has confirmed PD, unless approved by the sponsor. No radiological progression per RECIST 1.1 Clinical progression as indicated by one or more signs and / or symptoms consistent with clinically significant disease progression, including worsening laboratory values, appearance of new lesion(s) / worsening of the most common clinical lesion. - Missed administration of two or more consecutive doses of study therapy due to noncompliance, unless specifically approved by the sponsor.

[0191] Tumor flare events, defined as localized pain, inflammation, or rash confined to the site of a known or suspected tumor, did not require treatment discontinuation.

[0192] Definition of research completion If the study was not terminated for the above reasons, the entire study ended 24 months after the last patient completed the 90-day safety follow-up visit; if the last patient withdrew from the study or was lost to follow-up (i.e., the patient could not be contacted by the investigator) before the 90-day safety follow-up visit, the study ended approximately 24 months from the date of that event.

[0193] B. Study Population Inclusion criteria To participate in this study, patients must meet all of the following inclusion criteria: 1. Voluntarily agree to participate by signing, dating, and giving written informed consent prior to any study-specific procedures. 2. Be 18 years of age or older. 3. A histologically confirmed diagnosis of pancreatic ductal adenocarcinoma. 4. Must have had disease progression on any version of FOLFIRINOX for metastatic disease. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Life expectancy is at least 3 months. 7. Measurable disease on baseline imaging by RECIST 1.1 criteria. 8. Pre-existing peripheral neuropathy of less than grade 2 according to NCI CTCAE, version 5.0. 9. Acceptable coagulation status as indicated by an INR ≤ 1.5 times the institutional upper limit of normal (ULN), except that patients receiving anticoagulation therapy may be included at the investigator's discretion. 10. Adequate organ function defined as the following laboratory values ​​within 7 days prior to the first dose of study drug, unless otherwise specified below: a. Neutrophils >1500 / μL (stable off any growth factors within 4 weeks prior to first dose of study drug). b. Platelets>100×10 3 / μL (transfusions to achieve this level within 2 weeks prior to the first dose of study drug will not be permitted). c. Hemoglobin >9.0 g / dL (transfusions to achieve this level are not permitted within 2 weeks prior to the first dose of study drug). d. Creatinine clearance ≥ 30 mL / min (measured or calculated according to institutional standards). e. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) < 3.0 × ULN. f. Direct bilirubin <1.5 × ULN (except for patients with Gilbert's syndrome, who must have a total bilirubin value <3.0 × ULN). g. Serum albumin ≥ 3.0 g / dL (must be confirmed within 3 days prior to the first administration of the study drug). 11. Female patients of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test at screening (within 72 hours after the first dose of study drug). WOCBP must agree to use highly effective contraception from the screening visit until 6 months after the last dose of study drug(s). Individuals of childbearing potential are defined as: a. Are over 50 years old and have not had a period for over a year. b. Amenorrhea for ≥2 years without hysterectomy and bilateral oophorectomy, and follicle-stimulating hormone levels in the postmenopausal range at the time of pre-study (screening) evaluation. c. After hysterectomy, bilateral oophorectomy, or tubal ligation. 12. Male patients with female partner(s) of childbearing potential must agree to use highly effective contraception for the duration of the study, from screening through 90 days after the last dose of study drug(s). Men with pregnant partners must agree to use condoms, but no additional contraception is required for the pregnant partner. 13. Willing and able to comply with the requirements of the Protocol.

[0194] Exclusion criteria Participants were excluded from the study if they met any of the following criteria: 1. Received two or more prior regimens for metastatic disease (i.e., FOLFIRINOX). 2. History of central nervous system (CNS) metastasis. 3. Concurrent malignancy requiring treatment (present at screening) or a history of active malignancy within 2 years prior to first dose of study drug (i.e., patients with a history of malignancy were eligible if treatment was completed at least 2 years prior to first dose of study drug and the patient was disease-free). Patients with a history of previous early-stage basal / squamous cell carcinoma, carcinoma in situ, or carcinoma in situ who had received definitive treatment at any time were also eligible. 4. Uncontrolled intercurrent illness, including but not limited to, cerebrovascular accident / stroke or myocardial infarction within 6 months of enrollment, clinically significant (i.e., active) cardiovascular disease, including unstable angina, congestive heart failure (New York Heart Association class ≥ III), or severe uncontrolled cardiac arrhythmia requiring medical therapy. 5. Active, uncontrolled infection requiring systemic intravenous anti-infective treatment within 2 weeks prior to the first dose of study drug. 6. Major surgery performed within 4 weeks prior to signing the informed consent form (ICF). 7. Prior treatment with immune checkpoint inhibitors. 8. Refractory ascites requiring therapeutic paracentesis more than twice within the past 4 weeks, more than four times within the past 90 days, or more than one time within the past 2 weeks prior to signing the ICF, or requiring diuretics within the past 2 weeks prior to signing the ICF. 9. Known radiological evidence of partial or complete bowel obstruction, signs / symptoms of bowel obstruction, or impending obstruction within 3 months prior to signing the ICF. 10. Clinically significant gastrointestinal (GI) disorders, including: a. GI perforation or non-healing ulcer within 6 months prior to ICF signing. Patient must have documented evidence of a completely healed site of previous perforation or ulcer (e.g., upper endoscopy, colonoscopy). b. Clinically significant GI bleeding within 3 months prior to ICF signing. c. History of active Crohn's disease or ulcerative colitis. 11. Treatment with any of the following classes of medications within the specified window prior to the first dose of study drug: a. Cytotoxic drugs within 3 weeks. b. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or investigational drugs for up to 4 weeks or 5 half-lives, whichever is shorter. c. Small molecule / tyrosine kinase inhibitors within 14 days. 12. History of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection within 10 days for mild or asymptomatic infection or within 20 days for severe / critical disease prior to first dose of study drug. 13. SARS-CoV-2 vaccination less than 7 days prior to first dose of study drug. 14. Known allergy or hypersensitivity to any study drug or any study drug excipients. 15. Symptomatic interstitial lung disease (ILD), history of ILD, or any pulmonary disease that may preclude the detection and management of new immune-related pulmonary toxicity. 16. History of allogeneic organ transplantation. 17. Mental illness or substance abuse disorder that would prevent cooperation with the requirements of this study. 18. Patients with a disease requiring systemic treatment with corticosteroids (prednisone equivalent >10 mg daily) within 14 days or other immunosuppressants within 30 days prior to the first dose of study drug. Inhaled or topical steroids and adrenal replacement steroid doses (prednisone equivalent ≤10 mg daily) are tolerated in the absence of active autoimmune disease. 19. Active autoimmune disease or a history of autoimmune disease requiring systemic treatment (i.e., involving use of disease-modifying or immunosuppressive medications) within 2 years prior to first dose of study drug. 20. Pregnant or breastfeeding patients. 21. Uncontrolled HIV infection. Patients must be on stable highly active antiretroviral therapy (HAART) with an undetectable viral load and normal CD4 count for at least 6 months prior to ICF signing. HIV serology testing at screening is not required. 22. Individuals with known hepatitis B (HBV) surface antigen positivity or any other HBV test positivity indicating acute or chronic infection. Patients who are receiving or have received anti-HBV therapy and have undetectable HBV DNA for at least 6 months prior to ICF signing. HBV serology testing at screening is not required. 23. Known active hepatitis C (HCV) with a positive serological test and confirmed by polymerase chain reaction (PCR). Patients receiving or having received antiretroviral therapy are eligible if they have been virally free by PCR for at least 6 months prior to ICF signing. HCV serology at screening is not required. 24. Dependence on total parenteral nutrition. 25. Patients with concomitant diarrhea > Grade 1 at the time of randomization despite optimal treatment with SoC pancreatic enzymes. 26. Known active or latent tuberculosis (testing not required at screening). 27. Any condition that, in the judgment of the principal investigator, may prevent the patient from participating in the study or evaluation of study results. 28. Unwillingness or inability to comply with the procedures required by this Protocol.

[0195] C. Study Assessments and Procedures All screening assessments were completed and reviewed to ensure potential patients met all eligibility criteria. The investigator maintained a screening log to record details of all screened patients and to confirm eligibility or record the reason for screening failure, if applicable.

[0196] Procedures performed as part of the patient's routine clinical management (e.g., blood count) and obtained before signing of the informed consent form (ICF) were utilized for screening or baseline purposes if the procedure met protocol-specified criteria and was performed within the time frame of other baseline assessments.

[0197] Repeat or unscheduled samples and images were taken for safety reasons or technical problems with the samples.

[0198] screening The investigator, or a qualified designee, obtained written informed consent from each potential patient before participation in this clinical study. After the patient signed the ICF, they were assigned a unique, sequential patient number. Once assigned, a number cannot be reassigned if the original patient proves ineligible or withdraws consent.

[0199] Patients who met all inclusion criteria and none of the exclusion criteria were enrolled in the study. Patients who did not meet the inclusion and exclusion criteria were considered to have failed screening, and their demographic information and reasons for failure were recorded.

[0200] During the screening period, attention was paid to washout periods for prior treatment and prohibited medications.

[0201] Treatment and evaluation period Patients continued to undergo all evaluations while actively receiving treatment.

[0202] Visit the hospital when treatment is discontinued A discontinuation visit (within 7 days of the last dose) occurred when study treatment was discontinued for any reason. If the discontinuation visit occurred approximately 30 days after the last dose of study treatment, at the time of the mandatory 30-day safety follow-up visit, the procedure was not repeated.

[0203] 30-day safety follow-up visit A mandatory 30-day safety follow-up visit was conducted for all patients 30 days (± 7 days) after the last dose of study treatment or before initiating new antineoplastic therapy, whichever occurred first. Patients with AEs > grade 1 were further followed until the AE resolved from grade 0 to 1 or until new antineoplastic therapy was initiated, whichever occurred first. Patients with ongoing TRAEs at the safety visit were followed until the TRAE resolved, stabilized, or was deemed clinically insignificant by the investigator.

[0204] All patients who discontinue treatment for any reason will also undergo a 90-day safety follow-up visit (±7 days).

[0205] Efficacy follow-up (treatment discontinued, study ongoing) Patients who discontinued study treatment for reasons other than PD continued to have scheduled visits and imaging evaluations.

[0206] Survival follow-up Patients who did not continue with study visits and imaging (e.g., after initiating subsequent antitumor therapy) were contacted by telephone Q12W (±14 days) to assess survival status until the end of the entire study. For patients lost to follow-up, survival data were obtained from official records.

[0207] Anti-cancer therapy after research The investigator, or a qualified designee, reviewed all new anticancer therapies initiated after the last dose of study drug. If a patient initiated a new anticancer therapy within 4 weeks of the last dose of study drug, a 30-day safety follow-up visit occurred before the first dose of the new therapy. Once the new anticancer therapy was initiated, patients were transitioned to survival follow-up.

[0208] Efficacy evaluation Response assessment was performed according to RECIST 1.1 (Eisenhauer 2009). For all patients, tumor response assessment was performed by radiological imaging assessment of C / A / P (and other sites as required for the specific tumor type or clinical history) by CT (preferred) or MRI (if CT was contraindicated) evaluation. In general, lesions detected at baseline were followed up at subsequent tumor assessment visits using the same imaging method, preferably the same imaging device.

[0209] Following the first objective response (PR or CR by RECIST 1.1), a confirmatory set of imaging studies was obtained 4 to 6 weeks later. Confirmed PD was demonstrated by imaging 4 to 6 weeks later (but not later) after progression was diagnosed and reviewed by a central radiologist before discontinuation of study treatment.

[0210] Tumor response to treatment was assigned based on assessment of target, non-target, and new lesion response according to RECIST 1.1 (all measurements were recorded in metric units). To assess objective response, baseline tumor burden was estimated and used for comparison with subsequent measurements. At baseline, tumor lesions were classified as target and non-target lesions. These assessment results were recorded as specifically as possible so that pre- and post-treatment results provided the best opportunity to accurately assess tumor response.

[0211] If patients discontinued treatment but remained on study, scans were performed according to their respective assessment schedules. Additional imaging was performed if clinically indicated according to the investigator's discretion.

[0212] Tumor Imaging Initial tumor imaging was performed during the screening period to establish a baseline disease burden. Scans performed as part of routine clinical management were acceptable as screening scans if they were of sufficient quality up to 21 days before the first dose.

[0213] Investigators performed scans in addition to scheduled study scans if clinically indicated per the investigator's discretion. Timing of imaging during the study followed calendar days and was not adjusted for delayed treatment administration or clinic visits. For consistency, the same imaging technique was used for patients throughout the study.

[0214] Brain imaging MRI, with or without contrast, was the preferred brain imaging modality, but CT was acceptable if MRI was clinically contraindicated. Patients with a history of CNS metastases underwent brain imaging on the same schedule as chest / abdominal / pelvic imaging.

[0215] During the study, brain CT / MRI scans were performed if clinically indicated due to the onset of new symptoms.

[0216] Safety evaluation The safety profile of the study treatment was assessed through recording, reporting, and analysis of baseline medical conditions, AEs, physical examination findings including vital signs, and clinical laboratory tests. A comprehensive assessment of any overt toxicity experienced by the patient was conducted from the time the patient signed the informed consent and throughout the course of the study. Study site personnel were responsible for reporting any AEs, whether observed by the investigator or reported by the patient.

[0217] Primary efficacy analysis PFS was defined as the time from randomization to progression or death assessed by an IRC according to RECIST 1.1, whichever occurred first. Patients without an event (death or PD) at the analysis cutoff date were censored at the date of their last tumor assessment or the start of new anticancer therapy. Median PFS and its 95% CI, if estimated, were constructed using the generalized Brookmeyer and Crowley method (Brookmeyer 1982). Cumulative probabilities of PFS at 3-month intervals were calculated using the Kaplan-Meier method for each treatment group and presented with two-sided 95% CIs using the Greenwood formula. PFS censoring rules followed the FDA Industry Guidance for Clinical Trial Endpoints for Anticancer Drug and Biologics Approval (U.S. Food and Drug Administration, 2007). Data for patients without disease progression or death at the time of analysis were censored at the time of their last adequate tumor assessment. Data for patients lost to follow-up before documented disease progression were censored at the date of their last adequate tumor assessment at which the patient was found to be progression-free. Data for patients who started receiving new anticancer therapy were censored at the date of the last relevant tumor assessment before the introduction of the new therapy.

[0218] In the final analysis, PFS distributions between arms A and B were compared descriptively using the log-rank test. Between-arm hazard ratios and their two-sided 95% CIs were estimated from Cox regression models. Details of PFS analysis and censoring were provided in the SAP.

[0219] The primary and final analysis of the study was performed after approximately 46 PFS events were observed by IRC review or 12 months after the last patient was randomized, whichever occurred first. Additional analyses including updated efficacy and safety data were conducted after the end of the study.

[0220] Secondary efficacy analysis Objective response rate (ORR) ORR was defined as the proportion of patients who achieved best overall response (BOR) among objective responses (CR or PR). BOR was defined as the best response recorded from randomization until data cutoff, disease progression, or initiation of new anticancer treatment. Patients without post-baseline response assessments were considered non-responders for BOR. Confirmed ORRs assessed by the IRC according to RECIST 1.1 were summarized in the same manner as described in the CRR.

[0221] Duration of response (DOR) DOR was defined as the time from first objective response to first documented progression assessed by an IRC according to RECIST 1.1 or death, whichever occurred first. DOR was summarized using the Kaplan-Meier method for responders only. All censoring rules for PFS analysis also applied to DOR. Cumulative probabilities of DOR at 3-month intervals were calculated and presented with two-sided 95% CIs.

[0222] Overall survival (OS) OS, defined as the time to death from any cause, was analyzed in the intention-to-treat analysis set, and patients were censored at the date of their last known survival or the data cutoff date, whichever came first. Median OS and cumulative OS probability estimated at 6-month intervals were calculated for each treatment group using Kaplan-Meier estimation and presented with two-sided 95% CI. The final analysis included a descriptive comparison of OS between the two groups, as well as PFS.

[0223] Complete response (CR) Complete response was assessed according to RECIST v1.1 criteria by an IRC and defined as a decline in CA19-9 (or CA125, or CEA if CA19-9 was not expressed) to the normal range (from at least >2×ULN) at the time of CR assessment by the IRC.

[0224] The complete response rate (CRR) and corresponding Clopper-Pearson 95% CI for each group were summarized. Additionally, the difference in ORR between groups was calculated with 95% CI constructed using the Miettinen-Nurminen method.

[0225] CA19-9 changes Changes in CA19-9 were assessed from the start of study treatment until the date of progressive disease, death, or last tumor evaluation or initiation of new anticancer therapy. CA19-9 normalization was defined as a decrease in CA19-9 values ​​to the normal range (from at least >2×ULN). For patients who did not express CA19-9, CA125 or CEA was assessed.

[0226] Safety analysis All safety endpoints were analyzed in the safety analysis set using actual treatment assignment.

[0227] Degree of exposure The extent of exposure to each study drug was summarized descriptively as the number of doses received (number and percentage of patients), duration of exposure (days), cumulative total dose per patient (mg), dose intensity, and relative dose intensity. The number (percentage) of patients requiring dose interruptions, dose delays, and discontinuations due to AEs was summarized for each study drug. The frequency of dose adjustments and discontinuations described above was summarized by category.

[0228] Patient data listings were provided with all administration records and summary statistics calculated.

[0229] Adverse events (AEs) All AEs were coded using MedDRA v25.0 or higher and graded using NCI CTCAE v5.0. AEs with a worsening in severity from the date of onset or baseline (pretreatment) at or after the first dose of study drug and up to 90 days after discontinuation of study treatment (i.e., last dose of randomized treatment) or until initiation of first anticancer therapy (including radiation therapy, excluding palliative radiation therapy) after discontinuation of study treatment (whichever occurred first) were considered treatment-emergent adverse events (TEAEs) and included in summary tables. All AEs, whether treatment-emergent or not, were included in the listings.

[0230] The incidence of TEAEs was reported as the number (proportion) of patients with TEAEs by systemic, organ, class, and preferred term. The number (proportion) of patients with TEAEs was also summarized by relationship to study drug. TRAEs included AEs that the investigator considered to be related to study drug or for which causality assessment was lacking.

[0231] SAEs, deaths, TEAEs of severity ≥ grade 3, irAEs, TRAEs, and TEAEs that led to treatment discontinuation, dose interruption, or dose delay were summarized. D. Objectives and Endpoints [Table 5]

[0232] The primary and final analysis of the study was performed after approximately 46 PFS events were observed by IRC review or 12 months after the last patient was randomized, whichever occurred first. Additional analyses including updated efficacy and safety data were conducted after the end of the study.

[0233] E. Initial Results Initial analysis included 150 mg botencilimab Q6W plus gemcitabine (1000 mg / m 2 ) / nab-paclitaxel (125 mg / m 2This study was conducted on evaluable patients with metastatic pancreatic cancer who had progressed on FOLFIRINOX and were receiving FOLFIRINOX. All patients had liver metastases. Sustained tumor marker reductions were observed in 80% (n=5) of the evaluable patients (Figure 5). As shown in Figure 5, four of the patients demonstrated a reduction in tumor marker (CA19-9 or CEA) change from baseline. The fifth patient experienced clinical progression and was removed from the study. Two patients demonstrated a partial response at 16 weeks, both of which continued to respond, with target lesion reductions of -47% and -37%. The other two patients demonstrated stable disease with tumor shrinkages of -20% and -13% at 8 weeks. Further analysis of the study results is ongoing.

[0234] Incorporation by Reference All patent and non-patent literature references cited above are incorporated herein by reference in their entirety.

Claims

1. A method for treating pancreatic cancer in a subject in need of such treatment, comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), wherein the antibody comprises a heavy chain variable region (VH) comprising CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of 25 mg to 250 mg.

2. A method for enhancing T cell activation in a subject with pancreatic cancer, comprising administering to the subject an antibody that specifically binds to human CTLA-4, wherein the antibody comprises a heavy chain variable region (VH) comprising the CDRH1, CDRH2, and CDRH3 amino acid sequences of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising the CDRL1, CDRL2, and CDRL3 amino acid sequences of the VL amino acid sequence set forth in SEQ ID NO: 8, at a dose of 25 mg to 250 mg.

3. 3. The method of claim 1 or 2, wherein the antibody is administered at a dose of 25 mg to 200 mg.

4. 3. The method of claim 1 or 2, wherein the antibody is administered at a dose of 50 mg to 200 mg.

5. 3. The method of claim 1 or 2, wherein the antibody is administered at a dose of 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, or 250 mg.

6. 6. The method of any one of claims 1 to 5, wherein the antibody is administered intravenously.

7. 7. The method of any one of claims 1 to 6, wherein the antibody is administered by intravenous infusion over a period of about 30 minutes.

8. 8. The method of any one of claims 1 to 7, wherein the antibody is administered once a week.

9. 8. The method of any one of claims 1 to 7, wherein the antibody is administered once every two weeks.

10. 8. The method of any one of claims 1 to 7, wherein the antibody is administered once every three weeks.

11. 8. The method of any one of claims 1 to 7, wherein the antibody is administered once every four weeks.

12. 8. The method of any one of claims 1 to 7, wherein the antibody is administered once every five weeks.

13. 8. The method of any one of claims 1 to 7, wherein the antibody is administered once every six weeks.

14. 8. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously at a dose of 25 mg once every six weeks.

15. 8. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously at a dose of 50 mg once every six weeks.

16. 8. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously at a dose of 75 mg once every six weeks.

17. 8. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously at a dose of 100 mg once every six weeks.

18. 8. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously at a dose of 150 mg once every six weeks.

19. 19. The method of any one of claims 1 to 18, wherein the dose is a therapeutically effective amount.

20. 20. The method of any one of claims 1 to 19, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

21. 21. The method of any one of claims 1 to 20, wherein the pancreatic cancer is unresectable.

22. 22. The method of any one of claims 1 to 21, wherein the pancreatic cancer is metastatic.

23. 23. The method of any one of claims 1 to 22, wherein the pancreatic cancer is recurrent and / or refractory.

24. 24. The method of any one of claims 1 to 23, wherein the subject has received at least one prior chemotherapy.

25. 25. The method of claim 24, wherein the at least one prior chemotherapy is 5-fluorouracil, leucovorin, irinotecan, or oxaliplatin.

26. 10. The method of any one of the preceding claims, wherein the subject has previously received treatment with 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin.

27. 10. The method of any one of the preceding claims, wherein the pancreatic cancer has progressed after standard of care treatment.

28. 10. The method of any one of the preceding claims, wherein the method further comprises administering to the subject nab-paclitaxel.

29. Nab-paclitaxel 75 mg / m ２ , 100 mg / m ２ , or 125 mg / m ２ 29. The method of claim 28, wherein the dose is

30. 30. The method of claim 28 or 29, wherein nab-paclitaxel is administered once weekly.

31. 30. The method of claim 28 or 29, wherein nab-paclitaxel is administered on days 1, 8, and 15 of a 6-week cycle.

32. 10. The method of any one of the preceding claims, wherein the method further comprises administering gemcitabine to the subject.

33. Gemcitabine 600 mg / m ２ , 800 mg / m ２ , or 1000 mg / m ２ 33. The method of claim 32, wherein the dose is

34. 34. The method of claim 32 or 33, wherein gemcitabine is administered once weekly.

35. 34. The method of claim 32 or 33, wherein gemcitabine is administered on days 1, 8, and 15 of a 6-week cycle.

36. 36. The method of any one of claims 32 to 35, wherein the antibody is administered on day 1 of a six-week cycle, and nab-paclitaxel and gemcitabine are administered on days 1, 8, and 15 of said six-week cycle.

37. 37. The method of any one of claims 32 to 36, wherein the antibody is administered to the subject prior to nab-paclitaxel and gemcitabine.

38. 38. The method of any one of claims 32 to 37, wherein nab-paclitaxel is administered before gemcitabine.

39. 10. The method of any one of the preceding claims, wherein the cancer is refractory to standard therapeutic treatment.

40. 40. The method of claim 39, wherein the standard of care treatment is chemotherapy or radiation.

41. 41. The method of claim 39 or 40, wherein the standard of care treatment is 5-fluorouracil, leucovorin, irinotecan, and / or oxaliplatin.

42. 10. The method of any one of the preceding claims, wherein said method reduces tumor size in said subject.

43. 10. The method of any one of the preceding claims, wherein said method increases T cell activation in said subject.

44. 10. The method of any one of the preceding claims, wherein said method reduces the level of CA19-9, CA125, or CEA in said subject.

45. 10. The method of any one of the preceding claims, wherein prior to administration of the antibody, the subject has measurable disease on baseline imaging by RECIST 1.

1.

46. 10. The method of any one of the preceding claims, wherein the subject has an Eastern Cooperative Oncology Group performance status (PS) of 0-1 prior to administration of the antibody.

47. 10. The method of any one of the preceding claims, wherein prior to administration of the antibody, the subject has a predicted life expectancy of 12 weeks or more.

48. Prior to administration of the antibody, the subject: a) Neutrophils ≧1500 / μL, b) Platelet count ≥ 100 × 10⁻⁶ ３ / μL, c) hemoglobin ≥ 9.0 g / dL; d) Creatinine clearance ≥ 30 mL / min, as measured or calculated according to local institutional standards; e) aspartate aminotransferase (AST) / alanine aminotransferase (ALT) < 3.0 × upper limit of normal (ULN); f) direct bilirubin <1.5 x ULN (except for patients with Gilbert's syndrome, who should have a total bilirubin level <3.0 x ULN), and / or 10. The method of any one of the preceding claims, wherein the patient has adequate organ function as defined by one or more of the following: g) serum albumin > 3.0 g / dL.

49. 10. The method of any one of the preceding claims, wherein the subject has no partial or complete bowel obstruction, signs / symptoms of bowel obstruction, or known radiological evidence of impending obstruction within the past three months.

50. 10. The method of any one of the preceding claims, wherein the subject has not received immune checkpoint inhibitor therapy prior to administration of the antibody.

51. 10. The method of any one of the preceding claims, wherein the subject has not received multiple chemotherapy regimens prior to administration of the antibody.

52. 10. The method of any one of the preceding claims, wherein the subject has no prior history of central nervous system (CNS) metastases.

53. 10. The method of any one of the preceding claims, wherein the subject does not have an concurrent malignancy requiring treatment or has no history of a previous malignancy that was active within two years prior to administration of the antibody.

54. 10. The method of any one of the preceding claims, wherein the subject has not received a cytotoxic or targeted therapy within three weeks prior to administration of the antibody.

55. 10. The method of any one of the preceding claims, wherein the subject has not received another monoclonal antibody therapy, antibody drug conjugate therapy, or radioimmunoconjugate therapy within four weeks prior to administration of the antibody.

56. 10. The method of any one of the preceding claims, wherein the subject has not received small molecule tyrosine kinase inhibitor therapy within two weeks prior to administration of the antibody.

57. 10. The method of any one of the preceding claims, wherein the subject does not suffer from refractory ascites, defined as the need for therapeutic paracentesis two or more times within the last four weeks, or four or more times within the last 90 days, or one or more times within the last two weeks prior to administration of the antibody.

58. 10. The method of any one of the preceding claims, wherein the subject does not suffer from clinically significant cardiovascular disease.

59. 10. The method of any one of the preceding claims, wherein the cancer has metastasized to the liver.

60. 10. The method of any one of the preceding claims, wherein the antibody comprises the CDRH1 amino acid sequence, CDRH2 amino acid sequence, CDRH3 amino acid sequence, CDRL1 amino acid sequence, CDRL2 amino acid sequence, and CDRL3 amino acid sequence set forth in SEQ ID NOs: 1, 2, 3, 4, 5, and 6, respectively.

61. 10. The method of any one of the preceding claims, wherein the antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:

8.

62. 10. The method of any one of the preceding claims, wherein the antibody comprises a human IgG1 heavy chain constant region comprising the S239D / A330L / I332E mutations numbered according to the EU numbering system.

63. 10. The method of any one of the preceding claims, wherein the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:9 and a light chain comprising the amino acid sequence set forth in SEQ ID NO:

10.

64. 10. The method of any one of the preceding claims, wherein the antibody is botencilimab.

65. An antibody that specifically binds to human CTLA-4 for use in the treatment of pancreatic cancer according to the method of any one of the preceding claims.

66. 10. An antibody that specifically binds to human CTLA-4 for use in the manufacture of a medicament for the treatment of pancreatic cancer performed according to the method of any one of the preceding claims.

67. 10. Use of an antibody that specifically binds to human CTLA-4 for the treatment of pancreatic cancer according to the method of any one of the preceding claims.

68. Gemcitabine, nab-paclitaxel and an antibody that specifically binds to human CTLA-4 for use in the treatment of pancreatic cancer according to the method of any one of the preceding claims.

69. 10. Gemcitabine, nab-paclitaxel and an antibody that specifically binds to human CTLA-4 for use in the manufacture of a medicament for the treatment of pancreatic cancer performed according to the method of any one of the preceding claims.

70. 10. The use of gemcitabine, nab-paclitaxel, and an antibody that specifically binds to human CTLA-4 for the treatment of pancreatic cancer according to the method of any one of the preceding claims.

71. A method of treating a subject having cancer that has metastasized to the liver, comprising administering to the subject gemcitabine, nab-paclitaxel, and an antibody that specifically binds to human CTLA-4.

72. 72. The method of claim 71, wherein the subject has pancreatic cancer.

73. The method of claim 71 or claim 72, wherein the antibody comprises one or more mutations in the Fc region to enhance binding to FcγRIIA and / or FcγRIIIA.

74. 74. The method of any one of claims 71 to 73, wherein the antibody comprises a human IgGl Fc region comprising S239D / A330L / I332E mutations numbered according to the EU numbering system.

75. 75. The method of any one of claims 71 to 74, wherein the antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), comprising a heavy chain variable region (VH) comprising the CDRH1 amino acid sequence, CDRH2 amino acid sequence, and CDRH3 amino acid sequence of the VH amino acid sequence set forth in SEQ ID NO: 7, and a light chain variable region (VL) comprising the CDRL1 amino acid sequence, CDRL2 amino acid sequence, and CDRL3 amino acid sequence of the VL amino acid sequence set forth in SEQ ID NO: 8, is administered at a dose of 25 mg to 250 mg.

76. 76. The method of any one of claims 71 to 75, wherein the antibody is administered at a dose of 25 mg to 200 mg.

77. 77. The method of any one of claims 71 to 76, wherein the antibody is administered at a dose of about 100 mg to 200 mg.

78. 78. The method of any one of claims 71 to 77, wherein the antibody is administered at a dose of about 150 mg to 200 mg.

79. 79. The method of any one of claims 71-78, wherein the antibody is administered at a dose of about 150 mg.

80. Gemcitabine 600 mg / m ２ , 800 mg / m ２ , or 1000 mg / m ２ 80. The method of any one of claims 71 to 79, wherein the dose is

81. 81. The method of any one of claims 71 to 80, wherein nab-paclitaxel is administered at a dose of 75 mg / m2, 100 mg / m2, or 125 mg / m2.

82. 82. The method of any one of claims 71 to 81, wherein the antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:

8.

83. 83. The method of any one of claims 71 to 82, wherein the antibody comprises botencilimab.

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