Methods of treating pancreatic cancer using anti-CTLA4 antibodies

Abstract

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

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application Serial No. 63 / 383,724, filed on November 15, 2022, the entire disclosure of which is hereby incorporated by reference herein.

[0003] References to sequence listings

[0004] This application contains a Sequence Listing, which has been submitted electronically in ST.26 format and is hereby incorporated by reference in its entirety (the ST.26 version created on November 14, 2023 is named "205365_seqlist.xml" and is 10,360 bytes in size). Background Art

[0005] Despite ranking tenth in incidence, pancreatic cancer is the third leading cause of cancer death in the United States. This high mortality-to-incidence ratio is due to patients often being diagnosed at advanced stages. Therefore, in addition to advancing early detection of pancreatic cancer patients to reduce overall mortality, new therapies for advanced disease are urgently needed.

[0006] Currently, the standard initial treatment for patients with metastatic pancreatic cancer is systemic combination chemotherapy (e.g., 5-fluorouracil, oxaliplatin, irinotecan, albumin-bound paclitaxel, gemcitabine). However, these systemic therapies have only shown modest efficacy and result in a median overall survival of less than one year for patients with metastatic pancreatic cancer. In addition, immune checkpoint inhibitors have not shown much success in pancreatic cancer to date, except for those with high microsatellite instability (MSI-H) pancreatic cancer (which only accounts for about 1% of pancreatic cancers).

[0007] Therefore, there remains a need for new and effective methods of treating metastatic pancreatic cancer. Summary of the Invention

[0008] The present disclosure is directed to methods for treating pancreatic cancer using an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), alone or in combination with nab-paclitaxel and / or gemcitabine. Also provided herein are specific methods for administering an antibody that specifically binds to human CTLA-4 that results in a reduction in tumor burden in a subject. In embodiments, the method comprises administering a therapeutically effective amount that safely and effectively treats metastatic pancreatic cancer.

[0009] In one aspect, provided herein is a method of treating pancreatic cancer in a subject in need thereof, the method comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) at a dose of 25 mg to 250 mg, 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.

[0010] In one aspect, provided herein is a method of enhancing activation of T cells in a subject having pancreatic cancer, the method comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of 25 mg to 250 mg, 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.

[0011] In certain embodiments, the antibody is administered at a dose of about 25 mg to 200 mg. In embodiments, the antibody is administered at a dose of 25 mg to 150 mg. In embodiments, the antibody is administered at a dose of 50 mg to 150 mg. In embodiments, the antibody is administered at a dose of 50 mg to 200 mg. In embodiments, 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.

[0012] In embodiments, the antibody is administered intravenously. In embodiments, the antibody is administered by intravenous infusion over about 30 minutes.

[0013] In embodiments, the antibody is administered once a week. In embodiments, the antibody is administered once every 2 weeks. In embodiments, the antibody is administered once every 3 weeks. In embodiments, the antibody is administered once every 4 weeks. In embodiments, the antibody is administered once every 5 weeks. In embodiments, the antibody is administered once every 6 weeks.

[0014] In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 25 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 50 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 75 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 100 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 125 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 150 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 175 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 200 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 225 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 250 mg.

[0015] In embodiments, the dose is a therapeutically effective amount.

[0016] In embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma. In embodiments, the pancreatic cancer is unresectable. In embodiments, the pancreatic cancer is metastatic. In embodiments, the pancreatic cancer is recurrent and / or refractory.

[0017] In embodiments, the subject has received at least one prior chemotherapy. In embodiments, the at least one prior chemotherapy is 5-fluorouracil, leucovorin, irinotecan, or oxaliplatin. In embodiments, the subject has previously been treated with 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin. In embodiments, the pancreatic cancer has recurred after standard of care treatment.

[0018] In an embodiment, the method further comprises administering nab-paclitaxel to the subject. In an embodiment, nab-paclitaxel is administered at a dose of 75 mg / m 2 , 100mg / m 2 or 125 mg / m 2 In an embodiment, nab-paclitaxel is administered once weekly. In an embodiment, nab-paclitaxel is administered on days 1, 8, and 15 of a 6-week cycle.

[0019] In an embodiment, the method further comprises administering gemcitabine to the subject. In an embodiment, gemcitabine is administered at 600 mg / m 2 , 800mg / m 2 or 1000 mg / m 2 In an embodiment, gemcitabine is administered once a week. In an embodiment, gemcitabine is administered on days 1, 8, and 15 of a 6-week cycle.

[0020] In embodiments, 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 a 6-week cycle. In embodiments, the antibody is administered to the subject prior to nab-paclitaxel and gemcitabine. In embodiments, nab-paclitaxel is administered prior to gemcitabine.

[0021] In embodiments, the cancer is refractory to standard of care therapy. In embodiments, the standard of care therapy is chemotherapy or radiation. In embodiments, the standard of care therapy is 5-fluorouracil, folinic acid, irinotecan, and / or oxaliplatin.

[0022] In an embodiment, the method reduces tumor size in a subject. In an embodiment, the method increases T cell activation in a subject. In an embodiment, the method reduces the level of CA 19-9, CA 125, or CEA in a subject.

[0023] In an embodiment, prior to the administration of the antibody, the subject has measurable disease on baseline imaging according to RECIST 1.1. In an embodiment, prior to the administration of the antibody, the subject has an Eastern Cooperative Oncology Group performance status (PS) of 0 to 1. In an embodiment, prior to the administration of the antibody, the subject's predicted life expectancy is ≥12 weeks.

[0024] In embodiments, prior to administration of the antibody, the subject has adequate organ function as defined by one or more of the following: a) neutrophils ≥ 1500 / μL; b) platelets ≥ 100×10 3 / μL; c) hemoglobin ≥9.0 g / dL; d) creatinine clearance ≥30 mL / minute, 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, in whom the total bilirubin level must be <3.0 × ULN); and / or g) serum albumin ≥3.0 g / dL.

[0025] In embodiments, the subject has no partial or complete intestinal obstruction, signs / symptoms of intestinal obstruction, or known radiographic evidence of impending obstruction within the last 3 months.

[0026] In embodiments, the subject has liver metastases, i.e., cancer has spread to the liver. In embodiments, the subject has one or more liver lesions. In embodiments, the methods of the present invention reduce one or more liver lesions. For example, in embodiments, administration of 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.

[0027] Thus, 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.

[0028] In an embodiment, the subject has not received immune checkpoint inhibitor treatment before the administration of the antibody. In an embodiment, the subject has not received more than one chemotherapy regimen before the administration of the antibody. In an embodiment, the subject has no history of central nervous system (CNS) metastasis. In an embodiment, the subject has no concurrent malignancy requiring treatment or a history of previous malignancy active within 2 years before the administration of the antibody. In an embodiment, the subject has not received cytotoxic therapy or targeted therapy within 3 weeks before the administration of the antibody. In an embodiment, the subject has not received other monoclonal antibody treatments, antibody-drug conjugate therapy, or radioimmunoconjugate therapy within 4 weeks before the administration of the antibody. In an embodiment, the subject has not received small molecule tyrosine kinase inhibitor treatment within 2 weeks before the administration of the antibody.

[0029] In embodiments, the subject does not have refractory ascites prior to administration of the antibody, the refractory ascites being defined as requiring 2 or more therapeutic paracentesis procedures in the last 4 weeks, or ≥ 4 in the last 90 days or ≥ 1 in the last 2 weeks. In embodiments, the subject does not have clinically significant cardiovascular disease.

[0030] In embodiments, the cancer has metastasized to the liver.

[0031] In embodiments, the antibodies comprise 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 embodiments, the antibodies comprise 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 embodiments, the antibodies comprise a human IgG1 heavy chain constant region comprising the S239D / A330L / I332E mutations numbered according to the EU numbering system. In embodiments, the antibodies comprise 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.

[0032] In embodiments, the antibody is botencilimab.

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

[0034] In one aspect, provided herein is an antibody that specifically binds to human CTLA-4 for use in the manufacture of a medicament for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0035] In one aspect, provided herein is the use of an antibody that specifically binds to human CTLA-4 for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

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

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

[0038] In one aspect, provided herein is the use of an antibody that specifically binds to human CTLA-4, gemcitabine, and nab-paclitaxel for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

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

[0040] In one aspect, provided herein are gemcitabine, nab-paclitaxel, and an antibody that specifically binds to human CTLA-4 for use in the manufacture of a medicament for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0041] In one aspect, provided herein is the use of gemcitabine, nab-paclitaxel, and an antibody that specifically binds to human CTLA-4 for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0042] 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.

[0043] In embodiments, the subject has pancreatic cancer.

[0044] In embodiments, the antibody comprises one or more mutations in the Fc region to increase binding to FcγRIIA and / or FcγRIIIA.In embodiments, the antibody comprises a human IgG1 Fc region comprising the S239D / A330L / I332E mutations numbered according to the EU numbering system.

[0045] In embodiments, an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) is administered at a dose of 25 mg to 250 mg, 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.

[0046] In an embodiment, the antibody is administered at a dose of 25 mg to 200 mg. In an embodiment, the antibody is administered at a dose of about 100 to 200 mg. In an embodiment, the antibody is administered at a dose of about 150 to 200 mg. In an embodiment, the antibody is administered at a dose of about 150 mg.

[0047] In the embodiment, gemcitabine was administered at 600 mg / m 2 , 800mg / m 2 or 1000 mg / m 2 Dosage administration.

[0048] In the examples, nab-paclitaxel was administered at 75 mg / m 2 , 100mg / m 2 or 125 mg / m2 Dosage administration.

[0049] In an 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.

[0050] In embodiments, the antibody comprises botencilimab. BRIEF DESCRIPTION OF THE DRAWINGS

[0051] Figure 1A Figure 2 shows the effect of isotype / vehicle control, botencilimab, and ms Figure 3 is a graph of tumor growth curves of mice treated with either anti-CTLA-4 or conventional anti-CTLA-4 antibodies. Figure 1B Figures show the effect of isotype / vehicle control, botencilimab alone, and ms (AGEN1181), albumin-bound paclitaxel (Nab-p) + gemcitabine (Gem), or botencilimab ms Figure 2 is a graph of tumor growth curves of mice treated with a combination of nab-paclitaxel (AGEN1181) and nab-paclitaxel (Nab-p) + gemcitabine (Gem). Figure 1C is a graph showing the body weight of mice during treatment.

[0052] Figure 2A A to D are a series of graphs showing tumor growth curves for individual mice in each treatment group. Figure 2A is the isotype control treatment group, Figure 2B Botencilimab ms Monotherapy group, Figure 2C is the albumin-bound paclitaxel + gemcitabine group, and Figure 2D Botencilimab ms and nab-paclitaxel + gemcitabine group.

[0053] Figure 3A A to D are a series of graphs showing tumor growth curves for individual mice in each treatment group. Figure 3A is the isotype control treatment group, Figure 3B Botencilimab ms Monotherapy group, Figure 3C is the cisplatin + gemcitabine group, and Figure 3D Botencilimab ms and cisplatin + gemcitabine group.

[0054] Figure 4A A to D are a series of graphs showing tumor growth curves for individual mice in each treatment group. Figure 4A is the isotype control treatment group, Figure 4B It is the albumin-bound paclitaxel + gemcitabine + cisplatin group, Figure 4C Botencilimab ms monotherapy group, and Figure 4D It is the anti-PD-1 antibody monotherapy group.

[0055] Figure 5 The results show that the patients receiving 150mg botencilimab Q6W plus gemcitabine (1000mg / m 2 ) / albumin-bound paclitaxel (125 mg / m 2 Figure 2 shows a graph of the percent change from baseline in tumor markers (CA 19-9 or CEA) over time in individual patients (n=5) with metastatic pancreatic cancer who progressed on FOLFIRINOX. *Indicates the percent change in tumor markers in the fifth patient, who showed clinical progression and was removed from the study. DETAILED DESCRIPTION

[0056] The present disclosure is directed to methods for treating pancreatic cancer using an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4), alone or in combination with nab-paclitaxel and / or gemcitabine. Also provided herein are specific methods for administering an antibody that specifically binds to human CTLA-4 that results in a reduction in tumor burden in a subject. In embodiments, the method comprises administering a therapeutically effective amount that safely and effectively treats metastatic pancreatic cancer.

[0057] definition

[0058] As used herein, the term "antibody" or "antibodies" includes 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 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, heterologous conjugate antibodies, antibody-drug conjugates, single domain antibodies, monovalent antibodies, single chain antibodies or single chain Fv (scFv), camelized antibodies, affibodies, Fab fragments, F(ab')2 fragments, disulfide-linked Fv (sdFv), 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 antibodies described herein refer to polyclonal antibody colonies. Antibodies can be any type of immunoglobulin molecule (e.g., IgG, IgE, IgM, IgD, IgA, or IgY), any classification (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, or IgA2), or any subclass (e.g., IgG2a or IgG2b). In certain embodiments, the antibodies described herein are IgG antibodies or their classification (e.g., human IgG1 or IgG4) or subclasses. In an embodiment, the antibody is a humanized monoclonal antibody. In an embodiment, the antibody is a human monoclonal antibody.

[0059] As used herein, the term "CDR" or "complementarity determining region" refers to the non-contiguous antigen binding sites found within the variable regions of heavy and light chain polypeptides. For example, 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 herein by reference in their entirety, wherein the definitions include overlapping or subsets of amino acid residues when compared to each other (see Table 1 below). In certain embodiments, the term "CDR" is a CDR as 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, ed. Kontermann and Dübel, Chapter 31, pp. 422-439, Springer-Verlag, Berlin (2001). In certain embodiments, the term "CDR" is a CDR as defined by Kabat et al., J. Biol. Chem. 252, 6609-6616 (1977) and Kabat et al., in Sequences of Proteins of Immunological Interest. (1991). In certain embodiments, different conventions are used to define the heavy chain CDR and light chain CDR of an antibody. In certain embodiments, the heavy chain CDRs and / or light chain CDRs are defined by performing structural analysis of the antibody and identifying residues in the variable region that are predicted to contact the epitope region of the target molecule (e.g., human CTLA-4). CDRH1, CDRH2, and CDRH3 represent heavy chain CDRs, and CDRL1, CDRL2, and CDRL3 represent light chain CDRs.

[0060] Table 1: CDR Definition

[0061]

[0062] As used herein, the terms "variable region" and "variable domain" are used interchangeably and are common in the art. A variable region generally refers to a part of an antibody, generally a part of a light chain or a heavy chain, typically about 110 to 120 amino acids or 110 to 125 amino acids at the amino terminus in a mature heavy chain, and about 90 to 115 amino acids in a mature light chain, which are very different in sequence between antibodies and are used to determine the binding and specificity of a particular antibody to its specific antigen. The variability of the sequence is concentrated in those regions referred to as complementary determining regions (CDRs), while the more highly conserved regions in the variable region are referred to as framework regions (FRs). Without wishing to be bound by any particular mechanism or theory, it is believed that the CDRs of 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 mouse CDRs and human framework regions (FRs). In an embodiment, the variable region is a primate (e.g., non-human primate) variable region. In embodiments, the variable regions comprise rodent or murine CDRs and primate (eg, non-human primate) framework regions (FRs).

[0063] As used herein, the terms "VH" and "VL" refer to the 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.

[0064] As used herein, the term "constant region" is common in the art. The constant region is the portion of an antibody, e.g., the carboxyl terminal portion of a light chain and / or a heavy chain, that is not directly involved in binding the antibody to an antigen, but which may exhibit various effector functions, such as interaction with an Fc receptor (e.g., an Fcγ receptor).

[0065] As used herein, the term "heavy chain" when referring to an antibody can refer to any of the different types based on the amino acid sequence of the constant region, e.g., alpha (α), delta (δ), epsilon (ε), gamma (γ), and mu (μ), which give rise to the IgA, IgD, IgE, IgG, and IgM classes of antibodies, respectively, including the subclasses of IgG, e.g., IgG1, IgG2, IgG3, and IgG4.

[0066] As used herein, the term "light chain" when used to refer to an antibody can refer to any of the different types based on the amino acid sequence of the constant region, for example, kappa (κ) or lambda (λ). Light chain amino acid sequences are well known in the art. In an embodiment, the light chain is a human light chain.

[0067] 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 molecules that bind to an antigen (e.g., an epitope or immune complex), such binding being understood by one skilled in the art. For example, a molecule that specifically binds to an antigen may bind to other peptides or polypeptides, typically with lower affinity, as determined by, for example, immunoassays, As determined by a KinExA 3000 instrument (Sapidyne Instruments, Boise, ID) or other assays known in the art, in embodiments, a molecule that specifically binds to an antigen binds to the antigen with a KA that is at least 2 logs (e.g., a factor of 10), 2.5 logs, 3 logs, 4 logs, or greater than the KA when the molecule nonspecifically binds to another antigen.

[0068] As used herein, the term "EU numbering system" refers to the EU numbering convention for the constant regions of antibodies as described in Edelman G.M. et al., Proc. Natl. Acad. USA, 63, 78-85 (1969) and Kabat et al., Sequences of Proteins of Immunological Interest, U. Sept. Health and Human Services, 5th ed., 1991, each of which is incorporated herein by reference in its entirety.

[0069] As used herein, the term "subject" includes any human or non-human animal. In one embodiment, the subject is a human.

[0070] As used herein, the term "effective amount" in the context of administering a therapy to a subject refers to that amount of the therapy that achieves the desired prophylactic or therapeutic effect.

[0071] As used herein, the terms "treat," "treating," and "treatment" refer to therapeutic or prophylactic measures as described herein. The methods of "treatment" employ the administration of an antibody to a subject having a disease or disorder or susceptible to such a disease or disorder to prevent, cure, delay, lessen the severity of the disease or disorder or a recurring disease or disorder, or to ameliorate one or more symptoms thereof, or to prolong the subject's survival beyond that which would be expected in the absence of such treatment.

[0072] As used herein, the term "standard of care" refers to the most common treatment available for a particular type of cancer. In an embodiment, the standard of care for metastatic pancreatic cancer includes 5FU, folinic acid, irinotecan, and oxaliplatin (ie, FOLFIRINOX).

[0073] As used herein, the term "targeted therapy" refers to a therapy that inhibits a specific protein. In an embodiment, the targeted therapy inhibits a protein known to be important for the growth and / or survival of pancreatic cancer cells (eg, KRAS).

[0074] As used herein, the term "cytotoxic therapy" refers to a therapy that blocks or slows cell division. In embodiments, the cytotoxic therapy kills cancer cells. In embodiments, the cytotoxic therapy is fluorouracil, capecitabine, oxaliplatin, irinotecan, or trifluridine.

[0075] As used herein, the term "tumor burden" refers to the number of cancer cells, the size of a tumor, or the amount of cancer in a subject.

[0076] As used herein, when referring to a measurable value, such as a dosage, the term "about" encompasses variations of ±20%, ±15%, ±10%, ±5%, ±1%, or ±0.1% of a given value or range, as long as it is suitable for performing the methods disclosed herein.

[0077] Anti-CTLA-4 antibodies

[0078] Antibodies that specifically bind to human CTLA-4 (ie, anti-CTLA-4 antibodies) useful in the methods and uses described herein include, but are not limited to, those listed below.

[0079] In embodiments, 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 embodiments, 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.

[0080] In embodiments, the antibodies comprise the CDRH1, CDRH2, and CDRH3 amino acid sequences set forth in SEQ ID NOs: 1, 2, and 3, respectively. In embodiments, the antibodies comprise 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.

[0081] In embodiments, the antibody comprises a VH comprising the amino acid sequence set forth in SEQ ID NO: 7. In embodiments, 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 at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% identical to the amino acid sequence set forth in SEQ ID NO: 8.

[0082] In an 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.

[0083] In embodiments, the antibody comprises a heavy chain constant region selected from the group consisting of human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. In embodiments, the heavy chain constant region is IgG1. In embodiments, the heavy chain constant region is IgG2. In embodiments, 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.

[0084] In embodiments, the antibody comprises an IgG1 heavy chain constant region. In embodiments, the amino acid sequence of the IgG1 heavy chain constant region comprises S239D / I332E mutations numbered according to the EU numbering system. In embodiments, the amino acid sequence of the IgG1 heavy chain constant region comprises S239D / A330L / I332E mutations numbered according to the EU numbering system. In embodiments, 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 embodiments, the IgG1 heavy chain constant region is afucosylated IgG1.

[0085] In embodiments, the antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO: 9. In embodiments, 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 at least 90%, 95%, 96%, 97%, 98%, 99% or 100% identical to the amino acid sequence set forth in SEQ ID NO: 10.

[0086] In embodiments, 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 embodiments, 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.

[0087] In an embodiment, the antibody is botencilimab (also known as AGEN1181), the amino acid sequence of which is provided in Table 2 below.

[0088] Table 2: Amino acid sequence of Botencilimab

[0089]

[0090] Treatment

[0091] 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 broadly relates to methods for treating pancreatic cancer using antibodies that specifically bind to human CTLA-4 as monotherapy or in combination with nab-paclitaxel and gemcitabine.

[0092] In one aspect, provided herein is a method of treating pancreatic cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of 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.

[0093] In one aspect, provided herein is a method of enhancing activation of T cells in a subject having pancreatic cancer, the method comprising administering to the subject an effective amount of 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.

[0094] In one aspect, provided herein is a method of treating pancreatic cancer in a subject in need thereof, the method comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) at a dose of about 5 mg to about 250 mg, 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.

[0095] In one aspect, provided herein is a method of enhancing activation of T cells in a subject having pancreatic cancer, the method comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of about 5 mg to about 250 mg, 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.

[0096] In one aspect, provided herein is a method of treating pancreatic cancer in a subject in need thereof, the method comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) at a dose of 5 mg to 250 mg, 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.

[0097] In one aspect, provided herein is a method of enhancing activation of T cells in a subject having pancreatic cancer, the method comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of 5 mg to 250 mg, 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.

[0098] In an embodiment, provided herein is a method of treating pancreatic cancer in a subject in need thereof, the method comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) at a dose of about 5 mg to about 200 mg, 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.

[0099] In an embodiment, provided herein is a method of enhancing activation of T cells in a subject having pancreatic cancer, the method comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of about 5 mg to about 200 mg, 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.

[0100] In an embodiment, provided herein is a method of treating pancreatic cancer in a subject in need thereof, the method comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) at a dose of 5 mg to 200 mg, 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.

[0101] In an embodiment, provided herein is a method of enhancing activation of T cells in a subject having pancreatic cancer, the method comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of 5 mg to 200 mg, 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.

[0102] In an embodiment, the antibody is administered at a dose of about 25 mg to about 250 mg. In an embodiment, the antibody is administered at a dose of about 25 mg to about 200 mg. In an embodiment, the antibody is administered at a dose of about 25 mg to about 150 mg. In an embodiment, the antibody is administered at a dose of about 50 mg to about 150 mg. In an embodiment, the antibody is administered at a dose of about 75 mg to about 150 mg.

[0103] In an embodiment, the antibody is administered at a dose of 25 mg to 250 mg. In an embodiment, the antibody is administered at a dose of 25 mg to 200 mg. In an embodiment, the antibody is administered at a dose of 50 mg to 175 mg. In an embodiment, the antibody is administered at a dose of 25 mg to 150 mg. In an embodiment, the antibody is administered at a dose of 50 mg to 150 mg. In an embodiment, the antibody is administered at a dose of 75 mg to 150 mg.

[0104] In embodiments, 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.

[0105] In embodiments, 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.

[0106] In embodiments, the antibody is administered intravenously. In embodiments, the antibody is administered intratumorally.

[0107] In an embodiment, the antibody is administered by intravenous infusion over about 30 minutes. In an embodiment, the antibody is administered by intravenous infusion over about 45 minutes. In an embodiment, the antibody is administered by intravenous infusion over about 60 minutes. In an embodiment, the antibody is administered by intravenous infusion over about 90 minutes.

[0108] In embodiments, the antibody is administered about once a week. In embodiments, the antibody is administered about once every 2 weeks. In embodiments, the antibody is administered about once every 3 weeks. In embodiments, the antibody is administered about once every 4 weeks. In embodiments, the antibody is administered about once every 5 weeks. In embodiments, the antibody is administered about once every 6 weeks. In embodiments, the antibody is administered about once every 7 weeks. In embodiments, the antibody is administered about once every 8 weeks.

[0109] In embodiments, the antibody is administered once a week. In embodiments, the antibody is administered once every 2 weeks. In embodiments, the antibody is administered once every 3 weeks. In embodiments, the antibody is administered once every 4 weeks. In embodiments, the antibody is administered once every 5 weeks. In embodiments, the antibody is administered once every 6 weeks. In embodiments, the antibody is administered once every 7 weeks. In embodiments, the antibody is administered once every 8 weeks.

[0110] In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 25 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 50 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 75 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 100 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 125 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 150 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 175 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 200 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 225 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of about 250 mg.

[0111] In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 25 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 50 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 75 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 100 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 125 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 150 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 175 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 200 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 225 mg. In an embodiment, the antibody is administered intravenously once every 6 weeks at a dose of 250 mg.

[0112] In embodiments, the dose is a therapeutically effective amount.

[0113] In embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma. In embodiments, the pancreatic cancer is unresectable. In embodiments, the pancreatic cancer is metastatic. In embodiments, the pancreatic cancer is recurrent and / or refractory. In embodiments, the pancreatic cancer has progressed following treatment with 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin (i.e., FOLFIRINOX treatment).

[0114] In an embodiment, the subject has received at least one previous chemotherapy. In an embodiment, at least one previous chemotherapy is 5-fluorouracil, folinic acid, irinotecan or oxaliplatin. In an embodiment, the subject has previously been treated with 5-fluorouracil, folinic acid, irinotecan and oxaliplatin (i.e., FOLFIRINOX treatment). In an embodiment, the pancreatic cancer relapsed after standard of care treatment.

[0115] In embodiments, the method further comprises administering nab-paclitaxel to the subject. In embodiments, nab-paclitaxel is administered at a dose of about 50 mg / m 2 to about 200 mg / m 2 In an embodiment, nab-paclitaxel is administered at a dose of about 75 mg / m 2 Up to 125 mg / m 2 In an 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 an embodiment, nab-paclitaxel is administered once weekly. In an embodiment, nab-paclitaxel is administered on days 1, 8, and 15 of a 6-week cycle.

[0116] In an embodiment, the method further comprises administering nab-paclitaxel to the subject. In an embodiment, nab-paclitaxel is administered at a dose of 75 mg / m 2 Up to 200 mg / m 2 In the embodiment, albumin-bound paclitaxel is administered at a dose of 75 mg / m 2 Up to 125 mg / m 2 In the embodiment, albumin-bound paclitaxel is administered at a dose of 75 mg / m 2 , 100mg / m 2 or 125 mg / m 2 In an embodiment, nab-paclitaxel is administered once weekly. In an embodiment, nab-paclitaxel is administered on days 1, 8, and 15 of a 6-week cycle.

[0117] In an embodiment, the method further comprises administering gemcitabine to the subject. In an embodiment, gemcitabine is administered at about 500 mg / m2 About 1500 mg / m 2 In an embodiment, gemcitabine is administered at a dose of about 600 mg / m 2 to about 1000 mg / m 2 In an embodiment, gemcitabine is administered at a dose of about 600 mg / m 2 , about 800mg / m 2 or about 1000 mg / m 2 In an embodiment, gemcitabine is administered once a week. In an embodiment, gemcitabine is administered on days 1, 8, and 15 of a 6-week cycle.

[0118] In an embodiment, the method further comprises administering gemcitabine to the subject. In an embodiment, gemcitabine is administered at 500 mg / m 2 Up to 1500 mg / m 2 In the embodiment, gemcitabine is administered at a dose of 600 mg / m 2 Up to 1000 mg / m 2 In the embodiment, gemcitabine is administered at a dose of 600 mg / m 2 , 800mg / m 2 or 1000 mg / m 2 In an embodiment, gemcitabine is administered once a week. In an embodiment, gemcitabine is administered on days 1, 8, and 15 of a 6-week cycle.

[0119] In the examples, the antibody was administered intravenously at a dose of 25 mg every 6 weeks and nab-paclitaxel was administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 In the embodiment, the antibody is administered intravenously at a dose of 50 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 75 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 100 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 125 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 150 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 175 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 200 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 225 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 250 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 600 mg / m 2 Dosage administration.

[0120] In the examples, the antibody was administered intravenously at a dose of 25 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 75 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 125 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2In the examples, the antibody was administered intravenously at a dose of 150 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 175 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 225 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 250 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 600 mg / m 2 Dosage administration.

[0121] In the examples, the antibody was administered intravenously at a dose of 25 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 50 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 75 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 100 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 125 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 150 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 175 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 200 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 225 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 250 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 600 mg / m 2 Dosage administration.

[0122] In the examples, the antibody was administered intravenously at a dose of 25 mg every 6 weeks and nab-paclitaxel was administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 In the embodiment, the antibody is administered intravenously at a dose of 50 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 75 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 100 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 125 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 150 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2In the examples, the antibody is administered intravenously at a dose of 175 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 200 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 225 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 250 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 800 mg / m 2 Dosage administration.

[0123] In the examples, the antibody was administered intravenously at a dose of 25 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 75 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 125 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 150 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2In the examples, the antibody was administered intravenously at a dose of 175 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 225 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 250 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 800 mg / m 2 Dosage administration.

[0124] In the examples, the antibody was administered intravenously at a dose of 25 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 50 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 75 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 125 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 100 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 150 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 175 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 200 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 225 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 250 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 800 mg / m 2 Dosage administration.

[0125] In the examples, the antibody was administered intravenously at a dose of 25 mg every 6 weeks and nab-paclitaxel was administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 In the embodiment, the antibody is administered intravenously at a dose of 50 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 75 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 100 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 125 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 150 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 175 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m2 In the examples, the antibody is administered intravenously at a dose of 200 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 225 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 250 mg every 6 weeks and nab-paclitaxel is administered intravenously at a dose of 75 mg / m 2 and gemcitabine at 1000 mg / m 2 Dosage administration.

[0126] In the examples, the antibody was administered intravenously at a dose of 25 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 50 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 75 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody is administered intravenously at a dose of 100 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 125 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 150 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 175 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2In the examples, the antibody is administered intravenously at a dose of 200 mg and nab-paclitaxel is administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 225 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 250 mg and nab-paclitaxel was administered intravenously at a dose of 100 mg / m 2 and gemcitabine at 1000 mg / m 2 Dosage administration.

[0127] In the examples, the antibody was administered intravenously at a dose of 25 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 50 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 75 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 100 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 125 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 150 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 175 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 200 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 225 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 In the examples, the antibody was administered intravenously at a dose of 250 mg and nab-paclitaxel was administered intravenously at a dose of 125 mg / m 2 and gemcitabine at 1000 mg / m 2 Dosage administration.

[0128] In embodiments of any 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 a 6-week cycle. In embodiments, the antibody is administered to the subject prior to nab-paclitaxel and gemcitabine. In embodiments, nab-paclitaxel is administered prior to gemcitabine. In embodiments, nab-paclitaxel is administered intravenously. In embodiments, gemcitabine is administered intravenously.

[0129] In an embodiment, the method comprises two 6-week cycles. In an embodiment, the method comprises three 6-week cycles. In an embodiment, the method comprises four 6-week cycles. In an embodiment, the method comprises five 6-week cycles. In an embodiment, the method comprises five 6-week cycles. In an embodiment, the method comprises six 6-week cycles. In an embodiment, the method comprises seven 6-week cycles. In an embodiment, the method comprises eight 6-week cycles.

[0130] In embodiments, the subject is a human subject.In embodiments, the method does not comprise administering cisplatin.

[0131] In embodiments, the cancer is refractory to standard of care therapy. In embodiments, the standard of care therapy is chemotherapy or radiation. In embodiments, the standard of care therapy is 5-fluorouracil, folinic acid, irinotecan, and / or oxaliplatin.

[0132] In an embodiment, the method reduces tumor size in a subject. In an embodiment, the method increases T cell activation in a subject. In an embodiment, the method reduces the level of CA 19-9, CA 125, or CEA in a subject.

[0133] In an embodiment, prior to the administration of the antibody, the subject has measurable disease on baseline imaging according to RECIST 1.1. In an embodiment, prior to the administration of the antibody, the subject has an Eastern Cooperative Oncology Group performance status (PS) of 0 to 1. In an embodiment, prior to the administration of the antibody, the subject's predicted life expectancy is ≥12 weeks.

[0134] In embodiments, prior to administration of the antibody, the subject has adequate organ function as defined by one or more of the following: a) neutrophils ≥ 1500 / μL; b) platelets ≥ 100×10 3 / μL; c) hemoglobin ≥9.0 g / dL; d) creatinine clearance ≥30 mL / minute, 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, in whom the total bilirubin level must be <3.0 × ULN); and / or g) serum albumin ≥3.0 g / dL.

[0135] In embodiments, the subject has no partial or complete intestinal obstruction, signs / symptoms of intestinal obstruction, or known radiographic evidence of impending obstruction within the last 3 months.

[0136] In an embodiment, the subject has not received immune checkpoint inhibitor treatment before the administration of the antibody. In an embodiment, the subject has not received more than one chemotherapy regimen before the administration of the antibody. In an embodiment, the subject has no history of central nervous system (CNS) metastasis. In an embodiment, the subject has no concurrent malignancy requiring treatment or a history of previous malignancy active within 2 years before the administration of the antibody. In an embodiment, the subject has not received cytotoxic therapy or targeted therapy within 3 weeks before the administration of the antibody. In an embodiment, the subject has not received other monoclonal antibody treatments, antibody-drug conjugate therapy, or radioimmunoconjugate therapy within 4 weeks before the administration of the antibody. In an embodiment, the subject has not received small molecule tyrosine kinase inhibitor treatment within 2 weeks before the administration of the antibody.

[0137] In embodiments, the subject does not have refractory ascites prior to administration of the antibody, the refractory ascites being defined as requiring 2 or more therapeutic paracentesis procedures in the last 4 weeks, or ≥ 4 in the last 90 days or ≥ 1 in the last 2 weeks. In embodiments, the subject does not have clinically significant cardiovascular disease.

[0138] In the examples, the objective response rate (ORR), duration of response (DOR), disease control rate (DCR), and progression-free survival (PFS) of the subjects were assessed according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

[0139] In embodiments, the method results in a complete response as defined by RECIST 1.1. In embodiments, the method results in a partial response as defined by RECIST 1.1. In embodiments, the method results in stable disease as defined by RECIST 1.1.

[0140] In embodiments, the method results in a reduction of tumor burden in a subject by about 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. In embodiments, the method results in no change in tumor burden in a subject. In embodiments, the method results in a reduction of tumor burden in a subject by about 1%. In embodiments, the method results in a reduction of tumor burden in a subject by about 5%. In embodiments, the method results in a reduction of tumor burden in a subject by about 10%. In embodiments, the method results in a reduction of tumor burden in a subject by about 20%. In embodiments, the method results in a reduction of tumor burden in a subject by about 30%. In embodiments, the method results in a reduction of tumor burden in a subject by about 40%. In embodiments, the method results in a reduction of tumor burden in a subject by about 50%. In embodiments, the method results in a reduction of tumor burden in a subject by about 60%. In embodiments, the method results in a reduction of tumor burden in a subject by about 70%. In embodiments, the method results in a reduction of tumor burden in a subject by about 80%. In embodiments, the method results in a reduction of tumor burden in a subject by about 90%. In embodiments, the method results in a reduction of tumor burden in a subject by about 100%.

[0141] In embodiments, the method results in a decrease in tumor burden. In embodiments, the method results in an increase in survival. In embodiments, the method results in an increase in overall survival. In embodiments, the method results in an increase in progression-free survival.

[0142] In one aspect, provided herein is an antibody that specifically binds to human CTLA-4 for use in treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0143] In one aspect, provided herein is an antibody that specifically binds to human CTLA-4 for use in the manufacture of a medicament for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0144] In one aspect, provided herein is the use of an antibody that specifically binds to human CTLA-4 for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0145] In one aspect, provided herein is an antibody that specifically binds to human CTLA-4, gemcitabine, and nab-paclitaxel for use in treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0146] In one aspect, provided herein is an antibody that specifically binds to human CTLA-4, gemcitabine, and nab-paclitaxel for use in the manufacture of a medicament for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0147] In one aspect, provided herein is the use of an antibody that specifically binds to human CTLA-4, gemcitabine, and nab-paclitaxel for treating pancreatic cancer, wherein the treatment is performed according to any of the methods disclosed herein.

[0148] Examples

[0149] Example 1 - Combination of Botencilimab (AGEN1181) with Nab-paclitaxel and Gemcitabine in a Mouse Model of Pancreatic Cancer

[0150] Botencilimab was tested for its ability to inhibit pancreatic cancer growth in a mouse model of pancreatic cancer.

[0151] Female C57BL / 6J mice (6 to 8 weeks old) were implanted with KPC (KrasG12D, P53- / -Pdx1-Cre) tumor masses (approximately 100 mm) isolated from KPC tumor-bearing mice. 3 ). Mice were anesthetized with isoflurane for implantation.

[0152] Mice were then randomized and treated with the indicated antibodies, chemotherapy, or a combination thereof. Antibodies included: isotype control, conventional or first generation anti-CTLA-4 mouse surrogate (clone 9D9 mouse IgG2b), a mouse surrogate for botencilimab ( ms ; clone 9D9 mouse IgG2b.SDALIE) or anti-PD-1 (clone RMP1-14). Chemotherapeutic agents include gemcitabine, albumin-bound paclitaxel (Abraxane) and cisplatin.

[0153] Antibodies (100 μg / dose) were administered intraperitoneally (ip) twice a week for three weeks. Mice treated with double chemotherapy received gemcitabine (70 mg / kg) ip and abraxane (25 mg / kg) ip on day 1 and day 4, or gemcitabine (70 mg / kg) ip and cisplatin (4 mg / kg) ip. Mice treated with triple chemotherapy received gemcitabine (70 mg / kg) ip, abraxane (25 mg / kg) ip and cisplatin (4 mg / kg) ip on day 1 and day 4.

[0154] Figure 1A The results presented in demonstrate that botencilimab, an Fc-engineered antibody, has greater anti-tumor activity in a mouse model of pancreatic cancer compared to a conventional anti-CTLA-4 antibody with a wild-type Fc. Figure 1B The results shown in Figure 2 show that tumor growth in mice treated with the combination of botencilimab and nab-paclitaxel + gemcitabine was significantly slower than that in mice treated with botencilimab alone. ms (p value < 0.0001) or nab-paclitaxel + gemcitabine (p value = 0.0059) treated mice. Figure 1C The results shown in indicate that there were no significant differences in body weight changes between treatment groups, suggesting that there was no significant toxicity associated with these treatments.

[0155] The results of Figures 2 and 3 indicate that the combination of Botencilimab and doublet chemotherapy showed increased anti-tumor activity compared to doublet chemotherapy alone. For the analysis of Botencilimab combined with albumin-bound paclitaxel + gemcitabine doublet, individual tumor growth curves are shown in Figure 2A (isotype control), Figure 2B (Botencilimab ms monotherapy), Figure 2C (nab-paclitaxel + gemcitabine) and Figure 2D (Botencilimab and nab-paclitaxel + gemcitabine). These individual treatment group results showed that most mice treated with the combination of botencilimab and nab-paclitaxel + gemcitabine had reduced tumor size or even complete remission (3 out of 10 mice). For the analysis of the botencilimab combined with cisplatin + gemcitabine doublet, individual tumor growth curves are shown in Figure 3A (isotype control), Figure 3B (Botencilimab ms monotherapy), Figure 3C (cisplatin + gemcitabine) and Figure 3D (botencilimab and cisplatin + gemcitabine).

[0156] In addition, the results shown in Figure 4 indicate that Botencilimab has greater anti-tumor activity in mice compared to anti-PD-1 antibodies. Figure 4A (isotype control), Figure 4B (Triple chemotherapy, Abraxane + cisplatin + gemcitabine), Figure 4C (Botencilimab ms monotherapy) and Figure 4D (anti-PD-1 antibody monotherapy).

[0157] These results demonstrate promising preclinical activity of botencilimab in combination with nab-paclitaxel and gemcitabine, superior to chemotherapy alone, in the KPC syngeneic mouse model of refractory pancreatic ductal adenocarcinoma. Example 2 - Phase 2 Study of Botencilimab (AGEN1181) in Combination with Nab-paclitaxel and Gemcitabine for the Treatment of Metastatic Pancreatic Cancer

[0158] This phase 2 study further evaluated the safety and efficacy of botencilimab in patients with metastatic pancreatic cancer who had progressed on prior treatment with 5FU, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX).

[0159] A. Research Design

[0160] Overall design

[0161] 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 of the clinical trial was a safety run-in to determine the safety of the proposed combination of botencilimab with nab-paclitaxel and gemcitabine and to determine the botencilimab dose for Part 2. Part 2 was a randomized, open-label assessment of botencilimab (at the dose level determined in Part 1) in combination with nab-paclitaxel and gemcitabine, and nab-paclitaxel and gemcitabine alone.

[0162] The study enrolled patients with metastatic pancreatic ductal adenocarcinoma who had progressed on a previous FOLFIRINOX regimen for their advanced metastatic disease. As part of the screening process, investigators assessed and documented disease progression on any version of FOLFIRINOX for metastatic disease in the patient's source files. 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 tests, and tumor markers.

[0163] Study Treatment

[0164] Part 1 - Safety Run-in: Establish the safety of the proposed combination in 18 patients according to a modified 3+3 dose-escalation rule.

[0165] Three patients were enrolled and treated with fixed doses of botencilimab (dose level 1: 50 mg Q6W) + gemcitabine (1000 mg / m 2 ) / albumin-bound paclitaxel (125 mg / m 2 Based on initial safety signals noted in the first three dose-limiting toxicity (DLT)-evaluable patients treated at dose level 1, botencilimab dose escalation, expansion, or reduction was as follows:

[0166] - If none of the first 3 DLT-evaluable patients at 50 mg experience a DLT within the DLT assessment interval, enroll an additional 3 patients at escalating dose level 2: botencilimab 150 mg.

[0167] - If 1 of the first 3 DLT-evaluable patients at 50 mg experiences a DLT during the DLT evaluation interval,

[0168] Three additional patients were enrolled at this dose level 1: botencilimab 50 mg.

[0169] -Dose reduction: If >1 of the first 3 or 6 DLT-evaluable patients at 50 mg experiences a DLT within the DLT assessment interval, enroll an additional 3 patients at a reduced dose level of -1: botencilimab 25 mg.

[0170] - If >1 of the first 3 or 6 DLT-evaluable patients at 25 mg experienced a DLT within the DLT assessment interval, the study did not proceed to Part 2.

[0171] - If no more than 1 of 6 DLT-evaluable patients experiences a DLT within the DLT assessment interval for a specific dose level, that dose level is considered tolerable for Part 2.

[0172] “DLT-evaluable” was defined as any patient who received at least one dose of botencilimab and at least one cycle of gemcitabine / nab-paclitaxel, or any patient who experienced a DLT-evaluable toxicity.

[0173] The DLT interval was the time from the first administration of study treatment on Cycle 1 Day 1 to the end of Cycle 1 (Day 41).

[0174] Dose-limiting toxicity (DLT) was defined as the occurrence of any of the following AEs considered related (including possibly related) to botencilimab as defined in CTCAE version 5.0 during the DLT interval (Cycle 1 / Day 1 to the end of Cycle 1 (Day 41)).

[0175] A DLT was defined as a grade ≥3 AE (as defined by CTCAE v5.0) occurring (possibly or probably) related to botencilimab during the DLT interval (C1 / D1 to the end of cycle 1 [day 41]), excluding the following: fatigue of any grade, alopecia of any grade, cytopenias of any grade, nausea / vomiting of any grade, grade 3≥ immune-related adverse events (irAEs) that resolved to grade ≤2 with appropriate management within 3 days, endocrinopathies of any grade that were adequately controlled with hormone replacement, and any laboratory abnormality that did not require intervention and was considered clinically insignificant by the investigator.

[0176] Part 2 - Randomization Phase: After completion of Part 1, as detailed below, a total of 60 patients will be randomized, 30 to each group, to meet the 48 evaluable patients. The two groups will include:

[0177] 1. Group A (combination): Botencilimab (dose determined in Part 1 Q6W × 3 doses) + gemcitabine (1000 mg / m 2 ) / albumin-bound paclitaxel (125 mg / m 2 )

[0178] 2. Group B (standard care): According to SoC (Table 4), gemcitabine (1000 mg / m 2 ) / albumin-bound paclitaxel (125 mg / m 2 ).

[0179] The dose level of botencilimab selected for Part 2 was based in part on all available safety data obtained from Part 1. In addition, all available clinical safety data, as well as pharmacokinetic, pharmacodynamic, and efficacy data obtained from other applicable studies of botencilimab, were considered as part of the Part 2 dose selection decision.

[0180] During treatment, patients undergo routine clinic visits to administer study treatment and monitor safety, health, and disease status changes. CA 19-9 (or CA125 or CEA, if not an expresser of CA 19-9) is collected at the beginning of each cycle (Day 1) and on Day 1 of each chemotherapy cycle.

[0181] Patients in Group A received up to 3 doses of botencilimab (3 cycles). Patients in Groups A and B continued with gemcitabine (1000 mg / m 2 ) / albumin-bound paclitaxel (125 mg / m 2 ) until intolerable toxicity, disease progression, death, or the patient discontinued study treatment for any reason.

[0182] Antitumor efficacy was determined via imaging assessments performed within 21 days prior to randomization (first dose of study drug for patients in Part 1). Tumor assessments in the study were performed every 8 weeks (+ / - 7 days) for the first 24 weeks from randomization and every 12 weeks (+ / - 7 days) thereafter. Disease response was assessed regularly by independent blinded central review, blinded to treatment assignment. Confirmation of progressive disease (PD) was confirmed by imaging 4 to 6 weeks (but not later) after diagnosis and review of progression by a central radiologist before discontinuation of study treatment.

[0183] Safety was assessed via monitoring of AEs, SAEs, treatment discontinuation due to AEs, physical examinations, vital signs, hematology, and chemistry laboratories.

[0184] Patients who discontinued study treatment for reasons other than progressive disease (PD) continued to have imaging assessed according to the SoA, visit Q6W and thereafter at 8, 16, 24, and Q12W until initiation of additional antitumor therapy or disease progression.

[0185] For survival follow-up, patients who initiated additional anti-tumor therapy or discontinued imaging on study for other reasons were followed for survival status Q12W via telephone calls until the end of the study.

[0186] Table 3: Study Treatments

[0187]

[0188] Table 4: Standard of Care Dose Reductions

[0189] Dosage levels Albumin-bound paclitaxel Gemcitabine Level 0 (baseline) <![CDATA[125mg / m 2 ]]> <![CDATA[1000mg / m 2 ]]> Level 1 <![CDATA[100mg / m 2 ]]> <![CDATA[800mg / m 2 ]]> Level 2 <![CDATA[75mg / m 2 ]]> <![CDATA[600mg / m 2 ]]> If additional dose reduction is necessary stop stop

[0190] Dose reductions of nab-paclitaxel and gemcitabine were performed in individual patients according to the schedule in Table 4. Generally, dose reductions for toxicity were not escalated to the starting level. In some cases, growth factors were used to treat hematologic toxicity and did not constitute a dose reduction.

[0191] Chemotherapy was delayed for up to 4 weeks to allow for recovery of toxicities or other intercurrent illnesses that prevented the patient from receiving chemotherapy. If dose modification was required at the start of the cycle or within the cycle due to hematologic toxicity, the dose of nab-paclitaxel and gemcitabine was adjusted. During Cycle 1, if a patient experienced a Grade 4 hematologic AE determined by the investigator to be related to chemotherapy, the dose was reduced to dose level -1 for Cycle 2 according to Table 4.

[0192] If a patient's treatment is delayed within a treatment cycle due to hematological toxicity, the doses held during a cycle are not replenished. Adjust the dose modification caused by hematological toxicity (represented by the blood counts and toxicity below) within the treatment cycle. If a patient does not experience the resolution of neutropenia within 28 days, despite uninterrupted G-CSF treatment, the study treatment is still stopped. Patients with fever (regardless of neutrophil count) interrupt chemotherapy treatment. A comprehensive sepsis diagnostic examination is performed while continuing with broad-spectrum antibiotics. If the culture is positive, the antibiotics are changed according to the sensitivity profile of the isolated organism. Despite uninterrupted antibiotic treatment, patients with persistent fever after 3 weeks stop study treatment. In addition to antibiotic treatment, patients with febrile neutropenia also received G-CSF to speed up the resolution of their febrile neutropenia (following current institutional guidelines). In all cases, blood counts returned to baseline levels before resuming chemotherapy treatment.

[0193] For non-hematologic toxicities that occur despite adequate background medication, reduce the dose. If toxicity affects only neuropathy, reduce only nab-paclitaxel. In patients who experience Grade 3 or higher peripheral neuropathy, withhold nab-paclitaxel therapy. During this period, gemcitabine administration should continue. After peripheral neuropathy improves to Grade 1 or lower, resume nab-paclitaxel therapy in the subsequent cycle at the next lower dose level according to Table 4. The time to resolution to Grade 1 or lower is the adverse event duration used for adverse event reporting. Patients who experience peripheral neuropathy requiring a delay of 28 days or more in the scheduled nab-paclitaxel dose should have nab-paclitaxel discontinued.

[0194] Patients who developed Grade 2 or 3 skin toxicity had their nab-paclitaxel and gemcitabine doses reduced to the next lower dose level according to Table 4. If patients continued to experience these reactions despite the dose reduction, treatment was discontinued. Patients who developed Grade 4 skin toxicity had study treatment discontinued.

[0195] If Grade 2 mucositis or diarrhea occurred, withhold nab-paclitaxel and gemcitabine until resolved to ≤ Grade 1, then reconstitute at the next lower dose level according to Table 4. Patients who developed Grade 3 mucositis or diarrhea had study treatment discontinued.

[0196] Asymptomatic or clinically mild pulmonary embolism is treated with low molecular weight heparin without interruption of treatment. Moderate to severe pulmonary embolism requires permanent discontinuation of chemotherapy. Pulmonary toxicity has been reported with both gemcitabine and paclitaxel. Combination chemotherapy with gemcitabine and paclitaxel has been shown to have a higher incidence of pneumonitis (4%) compared to either agent alone. Early detection and treatment are necessary as it can be life-threatening or even fatal.

[0197] During study participation, patients were carefully monitored for signs and symptoms of pneumonitis (i.e., transient or recurrent episodes of dyspnea accompanied by unhelpful persistent cough or fever), and if observed, prompt clinical evaluation and prompt initiation of appropriate management (emphasis on the need for corticosteroids if infectious processes have been excluded, and appropriate ventilation and oxygen support when needed). If only asymptomatic Grade 1 pneumonitis was detected on scan, patients continued on gemcitabine and nab-paclitaxel, provided they received clinical benefit from the study and after a thorough discussion with the medical monitor. Administration of study treatment was permanently discontinued upon diagnosis of > Grade 1 interstitial pneumonitis.

[0198] Study drug administration was interrupted following the diagnosis of Grade 1 interstitial pneumonia, and the patient permanently discontinued further study drug treatment. After excluding infectious etiologies, high-dose intravenous corticosteroid therapy and secondary pathogen coverage were immediately initiated. Patients with additional immunologic components required immunomodulation with azathioprine or cyclophosphamide. Appropriate ventilation and oxygen support were used as needed.

[0199] Granulocyte colony-stimulating factor (G-CSF) was given according to institutional guidelines. If institutional guidelines were not available, white blood cell growth factors were recommended according to the American Society of Clinical Oncology practice guidelines: G-CSF is given in Appendix C of the Guidelines Summary.

[0200] Adverse events (AEs) associated with botencilimab exposure may have an immunologic etiology. In some cases, these immune-related AEs (irAEs) occur shortly after the first dose of treatment or several months after the last dose and affect more than one body system simultaneously. Early identification of irAEs and initiation of appropriate immunosuppressive therapy are critical to reducing complications and improving patient outcomes. Based on available clinical trial data, most irAEs are reversible and managed with interruption of botencilimab, administration of corticosteroids and / or infliximab, and / or other supportive care.

[0201] Study drug administration

[0202] Individual treatment cycles were defined as 6 weeks, with botencilimab administered on day 1 of each cycle (Group A) and gemcitabine / nab-paclitaxel administered on days 1, 8, and 15. Patients received 3 doses of botencilimab and continued on gemcitabine / nab-paclitaxel until disease progression, unacceptable toxicity, or patient discontinuation of study treatment for any reason.

[0203] The order of drug administration was botencilimab, nab-paclitaxel, and then gemcitabine. Nab-paclitaxel was given before gemcitabine because it may be absorbed by the process of macropinocytosis. Gemcitabine was given next because albumin-bound paclitaxel may decrease cytidine deaminase and thus enhance gemcitabine activity (less degradation of gemcitabine by the enzyme).

[0204] Supportive medications include: Palonosetron 0.25 mg IV, fosaprepitant Patients were treated with 150 mg IV of salbutamol and 12 mg IV of dexamethasone, or an equivalent antiemetic regimen, within 30 minutes prior to chemotherapy. Patients continued oral antiemetic prophylaxis at home for 2 days following chemotherapy. The type of antiemetic prophylaxis used varied by institutional protocol, but efforts were made to minimize the dose and duration of corticosteroids, i.e., dexamethasone was not used on days 2 and 3 unless needed; alternatives included ondansetron (if palonosetron was not given) or olanzapine.

[0205] Botencilimab was administered via IV infusion over 30 (±5) minutes. Patients were observed for 30 minutes after the end of the infusion for infusion-related reactions. For all cycles, vital signs were measured before and at the end of each infusion. The IV line was flushed with normal saline immediately after the infusion, according to institutional guidelines.

[0206] Gemcitabine / nab-paclitaxel was administered according to Table 4 and according to the gemcitabine and nab-paclitaxel prescribing information.

[0207] Number of patients

[0208] There were 18 patients in part 1. In part 2, approximately 60 eligible patients were enrolled (30 patients randomized to each group).

[0209] Patients who did not meet the criteria to be considered evaluable for a DLT were replaced in Part 1. For Part 2 of the study, patients who received at least one dose of study treatment were not replaced.

[0210] Patients who were eligible for inclusion but were later determined to be ineligible on C1 / D1 did not receive study treatment and were replaced.

[0211] Treatment after disease progression

[0212] For patients with progressive disease (PD) who remained on study treatment per protocol, confirmatory imaging was performed at weeks 4 to 6. If PD was confirmed as a 10% or greater increase in the sum of measurable lesions, unequivocal progression of non-measurable lesions, or the appearance of new lesions on the confirmatory scan, the patient discontinued treatment.

[0213] Patients who tolerated the drug and were considered by the investigator to be experiencing clinical benefit could continue treatment beyond initial RECIST 1.1-defined PD, with sponsor approval, if they met the following criteria for clinical stability:

[0214] - Lack of clinical signs and symptoms suggestive of PD (including worsening of laboratory values).

[0215] - ECOG status (Appendix A) not downgraded due to underlying malignancy

[0216] - The patient tolerates the study drug; and continued treatment will not prevent or delay treatment that could prevent serious disease complications.

[0217] Duration of treatment

[0218] Part 1: Patients received up to 3 doses of botencilimab (3 cycles) at the allocated dose according to SoC (Table 4) in combination with gemcitabine (1000 mg / m 2 ) / albumin-bound paclitaxel (125 mg / m 2 After 3 doses of botencilimab, patients continued gemcitabine / nab-paclitaxel according to SoC until disease progression, unacceptable toxicity, or patient discontinuation of study treatment for any reason.

[0219] Part 2: Patients in Group A (combination) received up to 3 doses of dapoxetine combined with gemcitabine (1000 mg / m 2 ) / albumin-bound paclitaxel (125 mg / m 2 After 3 doses of botencilimab, patients continued gemcitabine / nab-paclitaxel according to SoC until disease progression, unacceptable toxicity, or the patient discontinued study treatment for any reason.

[0220] According to SoC (Table 4), gemcitabine (1000 mg / m 2) / albumin-bound paclitaxel (125 mg / m 2 ) Patients in treatment group B (SoC) were followed until disease progression, unacceptable toxicity, or patients discontinued study treatment for any reason. After treatment discontinuation, patients were followed for safety at 30 (± 7) days and 90 (± 7) days, and long-term follow-up was performed every 3 months from the last administration for 12 months.

[0221] If patients remained eligible to continue on the study despite discontinuation of study treatment (eg, due to toxicity), they continued with scheduled imaging assessments and concurrent clinic visits.

[0222] If the study is not terminated for the reasons provided in Section 9.4, the entire trial will end approximately 12 months after the last randomized patient completes the last dose of botencilimab, withdraws from the trial, or is lost to follow-up (i.e., the patient cannot be contacted by the investigator).

[0223] Prohibited medications and treatments

[0224] During the study, no medications or vaccinations specifically prohibited by the exclusion criteria were permitted. If any medication or vaccination specifically prohibited during the study became clinically indicated, study treatment or vaccination would need to be discontinued. The final decision regarding any supportive care or vaccination rested with the investigator and / or the patient's attending physician. However, the decision to continue study treatment required the mutual agreement of the investigator, sponsor, and patient.

[0225] Specific restrictions on concomitant treatment established during the course of the study are listed below:

[0226] - Antitumor systemic chemotherapy or biological therapy other than SoC.

[0227] - Unspecified immuno-oncology therapy in the agreement.

[0228] - Study medication other than assigned study treatment.

[0229] - Systemic glucocorticoids (>10 mg prednisone equivalents for >1 week) for any purpose other than treatment of immune-related adverse events. NOTE: Prophylactic corticosteroid use to avoid allergic reactions (e.g., IV contrast or blood transfusions) is permitted, as is the use of inhaled steroids or intranasal or topical corticosteroids.

[0230] -The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. Caution should be exercised when nab-paclitaxel is coadministered with drugs known to inhibit or induce CYP2C8 or CYP3A4.

[0231] Patients who were clinically managed with any prohibited medication (excluding the exceptions listed above) were removed from the study. All treatments deemed necessary for the patient's welfare by the investigator were administered at the investigator's discretion in accordance with community standard medical care. All concomitant medications were recorded on the electronic case report form (eCRF), including all prescriptions, over-the-counter products, herbal supplements, and IV medications and fluids. If changes occurred during the study, the medication dose, frequency, route, and date were recorded in the eCRF.

[0232] Surgery and radiation therapy

[0233] If patients require surgery for progressive malignant disease, they should discontinue study treatment. In the case of surgery for intestinal obstruction, patients will continue to receive study treatment if there is no confirmed PD. Palliative radiation therapy to non-target lesions is permitted based on specific clinical circumstances and after discussion with the sponsor.

[0234] Permanent discontinuation of study drug treatment

[0235] Botencilimab was permanently discontinued for any of the following reasons:

[0236] - Occurrence of immune-related adverse events meeting discontinuation criteria.

[0237] - A confirmed diagnosis of PD unless the investigator believes the patient is deriving clinical benefit from treatment, the patient is clinically stable, and approval is obtained from the sponsor.

[0238] - Clinical progression in the absence of radiologic progression according to RECIST 1.1 as shown by one or more of the following:

[0239] o Signs and / or symptoms consistent with progression of clinically significant disease, including worsening of laboratory values,

[0240] Appearance of new lesions / worsening of lesions best seen clinically, etc.

[0241] - Missed two or more consecutive doses of study treatment due to non-adherence unless otherwise approved by the Sponsor.

[0242] Tumor flare, defined as localized pain, irritation, or rash at the site of a known or suspected tumor, does not require discontinuation of treatment.

[0243] Definition of the end of the study

[0244] If the study is not terminated for the reasons listed above, the overall study ends 24 months after the last patient completes the 90-day safety follow-up visit; if the last patient withdraws from the study before the 90-day safety follow-up visit or is lost to follow-up (i.e., the researcher cannot contact the patient), the study ends approximately 24 months from the date of this event.

[0245] B. Research Group

[0246] Inclusion Criteria

[0247] To participate in the study, patients must meet all of the following inclusion criteria:

[0248] 1. Voluntarily agree to participate by signing, dating, and submitting a written informed consent form prior to any study-specific procedures.

[0249] 2. Age ≥ 18 years old.

[0250] 3. Histological confirmation of the diagnosis of pancreatic ductal adenocarcinoma.

[0251] 4. Must have had disease progression on any version of FOLFIRINOX for metastatic disease.

[0252] 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0253] 6. Life expectancy is at least 3 months.

[0254] 7. Measurable disease on baseline imaging according to RECIST 1.1 criteria.

[0255] 8. Pre-existing peripheral neuropathy < Grade 2 according to NCICTCAE, Version 5.0.

[0256] 9. Acceptable coagulation status as indicated by INR ≤ 1.5 times the institutional upper limit of normal (ULN), except for anticoagulated patients who may be included at the discretion of the investigator.

[0257] 10. Adequate organ function, defined as the following laboratory values ​​within 7 days prior to the first dose of study drug, unless

[0258] The following explains:

[0259] a. Neutrophils >1500 / μL (stable on any growth factor within 4 weeks prior to the first dose of study drug).

[0260] b. Platelets>100×10 3 / μL (no blood transfusions were allowed to achieve this level within 2 weeks before the first dose of study drug).

[0261] c. Hemoglobin >9.0 g / dL (no blood transfusions were allowed to achieve this level within 2 weeks prior to the first dose of study drug).

[0262] d. Creatinine clearance ≥ 30 mL / min (measured or calculated according to institutional standards).

[0263] e. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) <3.0×ULN.

[0264] f. Direct bilirubin <1.5×ULN (except for patients with Gilbert's syndrome, whose total bilirubin level must be <3.0×ULN).

[0265] g. Serum albumin ≥3.0 g / dL (must be confirmed within 3 days before the first dose of study drug).

[0266] 11. Female patients of childbearing potential (WOCBP) must have a negative urine or serum pregnancy test at screening (within 72 hours of 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. Non-childbearing potential is defined as:

[0267] a. Aged ≥ 50 years and has not had menstruation for more than 1 year.

[0268] b. Amenorrhea for ≥ 2 years, without hysterectomy and bilateral oophorectomy, and follicle-stimulating hormone value within the postmenopausal range at the pre-study (screening) evaluation.

[0269] c. Patients undergoing hysterectomy, bilateral oophorectomy, or tubal ligation.

[0270] 12. Male patients with female partners of childbearing potential must agree to use highly effective contraception throughout the study, starting from the screening visit and ending 90 days after the last dose of study drug. Male patients with pregnant partners must agree to use condoms; pregnant partners do not need additional contraceptive methods.

[0271] 13. Willing and able to comply with the requirements of the Agreement.

[0272] Exclusion criteria

[0273] Participants will be excluded from the trial if any of the following criteria apply:

[0274] 1. Received more than one prior regimen (i.e., FOLFIRINOX) for their metastatic disease.

[0275] 2. History of central nervous system (CNS) metastasis.

[0276] 3. Concurrent malignancy requiring treatment within 2 years prior to the first dose of study drug (present during screening) or a history of active prior malignancy (i.e., patients with a history of prior malignancy are eligible if treatment was completed at least 2 years prior to the first dose of study drug and the patient has no evidence of disease). Patients with a history of prior early-stage basal / squamous cell skin cancer or non-invasive or in situ carcinoma that has been definitively treated at any time are also eligible.

[0277] 4. Uncontrolled concurrent illness, including but not limited to clinically significant (i.e., active) cardiovascular disease: cerebrovascular accident / stroke or myocardial infarction within 6 months of enrollment, unstable angina, congestive heart failure (New York Heart Association class ≥III), or severe uncontrolled arrhythmia requiring medication.

[0278] 5. Active, uncontrolled infection requiring systemic intravenous anti-infective treatment within 2 weeks before the first dose of study drug.

[0279] 6. Major surgery within 4 weeks before signing the informed consent form (ICF).

[0280] 7. Previous treatment with immune checkpoint inhibitors.

[0281] 8. Refractory ascites was defined as the need for 2 or more therapeutic paracentesis in the last 4 weeks before signing the ICF, or ≥ 4 in the last 90 days or ≥ 1 in the last 2 weeks, or the need for diuretics within 2 weeks of signing the ICF.

[0282] 9. Partial or complete intestinal obstruction, signs / symptoms of intestinal obstruction, or known radiological evidence of impending obstruction within the last 3 months prior to signing the ICF.

[0283] 10. Clinically significant gastrointestinal (GI) disorders including:

[0284] a. GI perforation or non-healing ulcer < 6 months prior to signing the ICF. Patients must have documented evidence of complete healing of the previous perforation or ulcer area (e.g., upper endoscopy, colonoscopy).

[0285] b. Clinically significant GI bleeding < 3 months before signing the ICF.

[0286] c. History of active Crohn's disease or ulcerative colitis.

[0287] 11. Treatment with one of the following drug categories within the defined time window before the first dose of study drug:

[0288] a. Cytotoxic agents within 3 weeks.

[0289] b. Monoclonal antibodies, antibody-drug conjugates, radioimmunoconjugates, or investigational drugs within 4 weeks or 5 half-lives, whichever is shorter.

[0290] c. Small molecule / tyrosine kinase inhibitors within 14 days.

[0291] 12. Previous 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) before the first dose of study drug.

[0292] 13. SARS-CoV-2 vaccine <7 days before the first dose of study drug.

[0293] 14. Known allergy or hypersensitivity to any study drug or any study drug excipient.

[0294] 15. Symptomatic interstitial lung disease (ILD), history of ILD, or any lung disease that may interfere with the detection and management of new immune-related pulmonary toxicity.

[0295] 16. History of allogeneic organ transplantation.

[0296] 17. Psychiatric or substance abuse disorders that would interfere with cooperation with research requirements.

[0297] 18. Patients with a condition requiring systemic treatment with corticosteroids (>10 mg prednisone equivalents per day) within 14 days prior to the first dose of study drug or another immunosuppressive drug within 30 days. Inhaled or topical steroids and adrenal replacement steroid doses (≤10 mg prednisone equivalents per day) are permitted in the absence of active autoimmune disease.

[0298] 19. Active autoimmune disease or history of autoimmune disease requiring systemic treatment (i.e., use of disease-modifying or immunosuppressive drugs) within 2 years prior to the first dose of study drug.

[0299] 20. Pregnant or breastfeeding patients.

[0300] 21. Uncontrolled HIV infection. Patients must be receiving stable highly active antiretroviral therapy (HAART) with an undetectable viral load and normal CD4 count for at least 6 months prior to signing the ICF. HIV serological testing is not required at screening.

[0301] 22. Patients who are known to be positive for hepatitis B (HBV) surface antigen, or any other positive test for acute or chronic HBV infection. Patients who are currently receiving or have received anti-HBV treatment and have undetectable HBV DNA for at least 6 months prior to signing the ICF. Serological testing for HBV is not required at screening.

[0302] 23. Known active hepatitis C (HCV) as determined by positive serology and confirmed by polymerase chain reaction (PCR). Patients who are currently receiving or have been receiving antiretroviral therapy are eligible, provided they have been virus-free by PCR for at least 6 months prior to signing the ICF. Serology testing for HCV is not required at screening.

[0303] 24. Dependence on total parenteral nutrition.

[0304] 25. Patients with diarrhea > Grade 1 at the time of randomization despite optimal treatment with SoC pancreatic enzymes.

[0305] 26. Known active or latent tuberculosis (not required to be tested at screening).

[0306] 27. Any situation that the principal investigator believes may interfere with the patient's participation in the study or the assessment of study results.

[0307] 28. Unwilling or unable to comply with the procedures required by this Agreement.

[0308] C. Research Assessment and Procedures

[0309] All screening assessments were completed and reviewed to confirm that potential patients met all eligibility criteria. Investigators maintained a screening log to record details of all patients screened and to confirm eligibility or document reasons for screening failure, if applicable.

[0310] Procedures performed as part of the patient's routine clinical management (e.g., blood counts) and obtained before signing the informed consent form (ICF) are used for screening or baseline purposes, provided that the procedure meets the protocol-specified criteria and is performed within the timeframe of other baseline assessments.

[0311] Duplicate or unplanned samples and images were taken for safety reasons or technical issues with the samples.

[0312] filter

[0313] The researcher or a qualified designee obtains written informed consent from each potential patient before participation in a clinical study. After the patient signs the ICF, they are assigned a unique, sequential patient number. Once a number is assigned, it cannot be reassigned if the original patient is found to be ineligible or withdraws consent.

[0314] Patients who met all inclusion criteria and had no exclusion criteria were included in the study. Patients who did not meet the inclusion and exclusion criteria were considered screening failures, and their demographic information and reasons for screening failure were recorded.

[0315] During screening, attention was paid to washout periods of prior treatments and prohibited medications.

[0316] Treatment and evaluation period

[0317] Patients continued to receive all assessments while they were actively receiving treatment.

[0318] Treatment cessation visit

[0319] Discontinuation visits that occurred during the time of study treatment (≤7 days after the last dose) were discontinued for any reason. If the discontinuation visit occurred approximately 30 days after the last dose of study treatment, the procedure was not repeated at the mandatory 30-day safety follow-up visit.

[0320] 30-day safety follow-up visit

[0321] All patients underwent a mandatory 30-day safety follow-up visit 30 days (±7 days) after the last dose of study treatment or before starting new anti-tumor therapy, whichever came first. Patients with AE grade >1 were further followed until the AE resolved to grade 0 to 1, or until new anti-tumor therapy was started, whichever occurred first. Patients with ongoing TRAEs at the time of the safety visit were followed until the TRAE resolved, became stable, or was deemed clinically insignificant by the investigator.

[0322] All patients who discontinued treatment for any reason will also have a 90-day safety follow-up visit (±7 days).

[0323] Efficacy follow-up (discontinued treatment, on study)

[0324] Patients who discontinued study treatment for reasons other than PD continued to have scheduled visits and imaging assessments.

[0325] Survival follow-up

[0326] For patients who no longer continued with study visits and imaging (e.g., after starting subsequent anti-tumor therapy), patients were contacted by telephone every 12 weeks (±14 days) to assess survival status until the end of the overall study. Survival data were obtained from public records for patients lost to follow-up.

[0327] Studying post-cancer treatment

[0328] The investigator or 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, the 30-day safety follow-up visit occurred before the first dose of the new therapy. Once a new anticancer therapy was initiated, the patient entered survival follow-up.

[0329] Efficacy evaluation

[0330] Response assessments were performed according to RECIST 1.1 (Eisenhauer 2009). For all patients, tumor response assessments were obtained by radiographic imaging with CT (preferred) or MRI (if CT was contraindicated) assessment of C / A / P (plus other areas as required for the specific tumor type or disease history). Generally, lesions detected at baseline were followed up at subsequent tumor assessment visits using the same imaging method and preferably the same imaging equipment.

[0331] After an initial objective response (PR or CR according to RECIST 1.1), a confirmatory imaging study was obtained 4 to 6 weeks later. Confirmation of PD was confirmed by imaging 4 to 6 weeks (but not later) after diagnosis and progression by review by a central radiologist before discontinuation of study treatment.

[0332] Tumor response to treatment was assigned based on response assessments of targets, non-target tumors, and new lesions according to RECIST 1.1 (all measurements were recorded in metric notation). To assess objective response, tumor burden was estimated at baseline and used for comparison with subsequent measurements. At baseline, tumor lesions were divided into target and non-target lesions. The results of these assessments were recorded with the greatest possible specificity, so that pre- and post-treatment results provided the best opportunity for accurate assessment of tumor response.

[0333] If a patient discontinued treatment but remained on study, scans were performed according to the corresponding assessment schedule. Additional imaging was performed if clinically indicated at the investigator's discretion.

[0334] Tumor imaging

[0335] Initial tumor imaging was performed during the screening period to establish a baseline for disease burden. Scans performed as part of routine clinical management could be used as screening scans if they were of adequate quality and were ≤ 21 days prior to the first dose.

[0336] If clinically indicated at the investigator's discretion, investigators performed scans in addition to the scheduled study scans. Study imaging was performed on calendar days and was not adjusted for delays in treatment administration or visits. The same imaging technique was used for patients throughout the study to maintain consistency.

[0337] Brain imaging

[0338] MRI, with and without contrast, is the preferred brain imaging modality; however, if MRI is clinically contraindicated, CT is acceptable. Patients with a history of CNS metastases undergo brain imaging on the same schedule as chest / abdomen / pelvis imaging.

[0339] During the study period, brain CT / MRI scans were performed if new clinical symptoms developed.

[0340] Safety assessment

[0341] The safety profile of the study treatment was assessed by recording, reporting, and analyzing baseline medical conditions, AEs, physical examination results (including vital signs), and laboratory tests. A comprehensive assessment of any significant toxicity experienced by patients was conducted from the time the patient signed the informed consent form and throughout the study. Any AEs, whether observed by the investigator or reported by the patient, were reported by study site personnel.

[0342] Main efficacy analysis

[0343] PFS is defined as the time from randomization to progression or death (whichever comes first) assessed by the IRC according to RECIST 1.1. Patients who did not have an event (death or PD) on the analysis cutoff date were censored at the last tumor assessment or the date of starting a new anticancer treatment. If estimated, median PFS and its 95% CI were constructed using the generalized Brookmeyer and Crowley method (Brookmeyer 1982). The cumulative probability of PFS at 3-month intervals for each treatment group was calculated using the Kaplan-Meier method and expressed with a two-sided 95% CI using the Greenwood formula. The PFS review rules follow the FDA's industry clinical trial endpoint guidance (Food and Drug Administration 2007) for approval of cancer drugs and biologics. At the last adequate tumor assessment, data for patients who did not have disease progression or death at the time of analysis were reviewed. When it was known that the patient had no progression, data for patients who lost follow-up before the recorded disease progression were reviewed on the last adequate tumor assessment date. Data for patients who began receiving new anticancer treatment were reviewed on the last adequate tumor assessment date before the introduction of a new therapy.

[0344] In the final analysis, the PFS distribution between group A and group B was compared descriptively using the log-rank test. Hazard ratios between the groups and their 2-sided 95% confidence intervals were estimated from the Cox regression model. Further details of the PFS analysis and review are provided in the SAP.

[0345] The final analysis, which was the primary analysis of the study, was conducted after approximately 46 PFS events were observed according to IRC review or 12 months after the last patient was randomized, whichever occurred earlier. Additional analyses included updated efficacy and safety data after the study was completed.

[0346] Secondary Efficacy Analyses

[0347] Objective response rate (ORR)

[0348] ORR is defined as the proportion of patients with a best overall response (BOR) with an objective response (CR or PR). BOR is defined as the best response documented from randomization to data cutoff, disease progression, or initiation of new anticancer therapy. Patients without a post-baseline response assessment are considered non-responders for BOR. Confirmed ORR, as assessed by the IRC according to RECIST 1.1, is summarized using the same methods described for CRR.

[0349] Duration of response (DOR)

[0350] DOR is defined as the time from the initial objective response until the first progression record or death (whichever comes first) assessed by the IRC according to RECIST 1.1. DOR was summarized using the Kaplan-Meier method only in responders. All censoring rules for PFS analysis were also applied to DOR. The cumulative probability of DOR at 3-month intervals was calculated and expressed as a two-sided 95% CI.

[0351] Overall survival (OS)

[0352] OS (defined as the time to death from any cause) was analyzed in the ITT analysis set; patients were censored at the date of the last known patient alive or the data cutoff date, whichever came first. Median OS and cumulative probability of OS were estimated at 6-month intervals using Kaplan-Meier estimates for each treatment group and are presented with two-sided 95% confidence intervals. Descriptive comparisons of OS between groups at the time of the final analysis were similar to those for PFS.

[0353] Complete response (CR)

[0354] Complete responses were assessed by the IRC according to RECIST v1.1 criteria and a decrease in CA 19-9 (or CA 125 or CEA, if not an expresser of CA 19-9) to normal limits (from at least >2×ULN) at the time of CR assessment by the IRC.

[0355] The complete response rate (CRR) for each group was summarized, along with its corresponding Clopper-Pearson 95% CI. In addition, the ORR difference between the groups was calculated with a 95% CI constructed using the Miettinen-Nurminen method.

[0356] Changes in CA 19-9

[0357] Changes in CA 19-9 were assessed from the start of study treatment until progressive disease or death or the date of last tumor assessment or initiation of new anticancer therapy. Normalization of CA 19-9 was defined as a decrease in CA 19-9 values ​​to the normal limits (from at least >2×ULN). CA 125 or CEA were assessed in patients who were not expressers of CA 19-9.

[0358] Security Analysis

[0359] All safety end points were analyzed in the safety analysis set using actual treatment assignment.

[0360] Exposure

[0361] 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 received per patient (mg), dose intensity, and relative dose intensity. The number (percentage) of patients who required dose interruptions, dose delays, and drug discontinuations due to AEs for each study drug was summarized. The frequency of dose modifications and discontinuations was summarized by category.

[0362] Patient data tabulations were provided for all medication administration records and calculated summary statistics.

[0363] Adverse events (AEs)

[0364] All AEs were coded in MedDRA v25.0 or higher and graded by NCICTCAE v5.0. AEs with an onset date or worsening in severity from baseline (pre-treatment) at or after the first dose of study drug and up to 90 days after discontinuation of study treatment (i.e., the last dose of randomized treatment) or until the initiation of the first subsequent anticancer treatment (including radiation therapy, excluding palliative radiation therapy) after discontinuation of study treatment (whichever occurs first) were considered treatment-emergent adverse events (TEAEs) and included in the summary tables. All AEs, whether or not treatment-emergent, were included in the tabulation.

[0365] The incidence of TEAEs is reported as the number (percentage) of patients with TEAEs by system, organ, category, and preferred term. The number (percentage) of patients with TEAEs is also summarized by relationship to study drug. TRAEs include AEs that the investigator assessed as related to study drug or lacking a causal relationship.

[0366] SAEs, deaths, TEAEs with grade ≥3 severity, irAEs leading to treatment discontinuation, dose interruption, or dose delay, TRAEs, and TEAEs are summarized

[0367] D. Goals and End Points

[0368] Table 5: Objectives and endpoints

[0369]

[0370]

[0371] The final analysis, which was the primary analysis of the study, was conducted after approximately 46 PFS events were observed according to IRC review or 12 months after the last patient was randomized, whichever occurred earlier. Additional analyses included updated efficacy and safety data after the study was completed.

[0372] E. Preliminary Results

[0373] A primary analysis was conducted in evaluable patients with metastatic pancreatic cancer who had progressed on FOLFIRINOX and received 150 mg botencilimab Q6W plus gemcitabine (1000 mg / m 2 ) / albumin-bound paclitaxel (125 mg / m 2 All patients had liver metastases. It was found that 80% of the evaluable patients (n=5) experienced a sustained decrease in tumor markers ( Figure 5 ).like Figure 5As shown, four of the patients demonstrated a decrease in tumor marker (CA 19-9 or CEA) changes from baseline. The fifth patient had clinical progression and was removed from the study. Two patients demonstrated partial responses at 16 weeks, with target lesions decreasing by -47% and -37%, respectively. Both responses are ongoing. Two other patients demonstrated stable disease at 8 weeks, with tumors decreasing by -20% and -13%. Further analysis of the study results is ongoing.

[0374] Incorporated by Reference

[0375] All patent and non-patent literature references cited above are incorporated herein by reference in their entirety.

Claims

1. A method of treating pancreatic cancer in a subject in need thereof, the method comprising administering to the subject an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) at a dose of 25 mg to 250 mg, 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.

2. A method for enhancing activation of T cells in a subject with pancreatic cancer, the method comprising administering to the subject an antibody that specifically binds to human CTLA-4 at a dose of 25 mg to 250 mg, 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.

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

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

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

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

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

9. The method of any one of claims 1 to 7, wherein the antibody is administered once every 2 weeks.

10. The method of any one of claims 1 to 7, wherein the antibody is administered once every 3 weeks.

11. The method of any one of claims 1 to 7, wherein the antibody is administered once every 4 weeks.

12. The method of any one of claims 1 to 7, wherein the antibody is administered once every 5 weeks.

13. The method of any one of claims 1 to 7, wherein the antibody is administered once every 6 weeks.

14. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously once every 6 weeks at a dose of 25 mg.

15. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously once every 6 weeks at a dose of 50 mg.

16. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously once every 6 weeks at a dose of 75 mg.

17. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously once every 6 weeks at a dose of 100 mg.

18. The method of any one of claims 1 to 7, wherein the antibody is administered intravenously once every 6 weeks at a dose of 150 mg.

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

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

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

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

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

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

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

26. The method of any one of the preceding claims, wherein the subject has been previously treated with 5-fluorouracil, folinic acid, irinotecan, and oxaliplatin.

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

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

29. The method of claim 28, wherein nab-paclitaxel is administered at a dose of 75 mg / m 2 , 100mg / m 2 or 125 mg / m 2 Dosage administration.

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

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

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

33. The method of claim 32, wherein gemcitabine is administered at 600 mg / m 2 , 800mg / m 2 or 1000 mg / m 2 Dosage administration.

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

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

36. The method of any one of claims 32 to 35, wherein 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 a 6-week cycle.

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

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

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

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

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

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

44. The method of any one of the preceding claims, wherein the method reduces the level of CA19-9, CA 125, or CEA in the subject.

45. The method of any one of the preceding claims, wherein the subject has measurable disease according to RECIST 1.1 on baseline imaging prior to administration of the antibody.

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

47. The method of any one of the preceding claims, wherein prior to administration of the antibody, the subject's predicted life expectancy is ≥ 12 weeks.

48. The method of any one of the preceding claims, wherein prior to administration of the antibody, the subject has adequate organ function as defined by one or more of the following: a) Neutrophils ≥1500 / μL; b) Platelet count ≥100×10 3 / μL; 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, in whom total bilirubin levels must be <3.0×ULN); and / or g) Serum albumin ≥3.0 g / dL.

49. The method of any of the preceding claims, wherein the subject has no partial or complete intestinal obstruction, signs / symptoms of intestinal obstruction, or known radiographic evidence of impending obstruction within the past 3 months.

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

51. The method of any one of the preceding claims, wherein the subject has not received more than one chemotherapy regimen prior to administration of the antibody.

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

53. The method of any of the preceding claims, wherein the subject has no concurrent malignancy requiring treatment or a history of a previous malignancy that was active within 2 years prior to administration of the antibody.

54. The method of any one of the preceding claims, wherein the subject has not received a cytotoxic or targeted therapy within 3 weeks prior to administration of the antibody.

55. The method of any one of the preceding claims, wherein the subject has not received other monoclonal antibody therapy, antibody-drug conjugate therapy, or radioimmunoconjugate therapy within 4 weeks prior to administration of the antibody.

56. The method of any one of the preceding claims, wherein the subject has not received treatment with a small molecule tyrosine kinase inhibitor within 2 weeks prior to administration of the antibody.

57. The method of any of the preceding claims, wherein the subject does not have refractory ascites prior to administration of the antibody, defined as requiring 2 or more therapeutic paracentesis procedures in the last 4 weeks, or ≥4 in the last 90 days, or ≥1 in the last 2 weeks.

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

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

60. The method of any one of the preceding claims, wherein 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.

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

63. 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. 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 treating pancreatic cancer, wherein the treatment is performed according to the method of any one of the preceding claims.

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

67. Use of an antibody that specifically binds to human CTLA-4 for treating pancreatic cancer, wherein the treatment is performed according to the method of any preceding claim.

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

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

70. Use of gemcitabine, nab-paclitaxel, and an antibody that specifically binds to human CTLA-4 for treating pancreatic cancer, wherein the treatment is performed 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, the method comprising administering to the subject gemcitabine, nab-paclitaxel, and an antibody that specifically binds to CTLA-4.

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 increase binding to FcγRIIA and / or FcγRIIIA.

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

75. The method of any one of claims 71 to 74, wherein an antibody that specifically binds to human cytotoxic T-lymphocyte antigen 4 (CTLA-4) is administered at a dose of 25 mg to 250 mg, 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.

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

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

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

80. The method of any one of claims 71 to 79, wherein gemcitabine is administered at 600 mg / m 2 , 800mg / m 2 or 1000 mg / m 2 Dosage administration.

81. The method of any one of claims 71 to 80, wherein nab-paclitaxel is administered at a dose of 75 mg / m 2 , 100mg / m 2 or 125 mg / m 2 Dosage administration.

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

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