Combination of anti-galectin-9 antibodies with chemotherapeutic agents for use in the treatment of cancer - Patents.com

Abstract

Disclosed herein is a combination therapy for treating a solid tumor (e.g., pancreatic ductal adenocarcinoma (PDAC), colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), cholangiocarcinoma (CAA), renal cell carcinoma (RCC), urothelial carcinoma, head and neck cancer, breast cancer, lung cancer, or other gastrointestinal solid tumors), comprising an antibody that binds to human galectin-9 (anti-Gal9 antibody, e.g., G9.2-17) and one or more chemotherapeutic agents, such as gemcitabine, paclitaxel, or a combination thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application No. 63 / 182,519, filed April 30, 2021, U.S. Provisional Application No. 63 / 193,381, filed May 26, 2021, and U.S. Provisional Application No. 63 / 313,882, filed February 25, 2022, each of which is incorporated by reference herein in its entirety.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on April 25, 2022, is named 112174-0212-NP010WO1_SEQ.txt and is 89,162 bytes in size. [Background technology]

[0003] Galectin-9 is a tandem repeat lectin consisting of two carbohydrate recognition domains (CRDs) and was first discovered and described in 1997 in patients suffering from Hodgkin's lymphoma (HL) (Tureci et al., J. Biol. Chem. 1997, 272, 6416-6422). It exists in three isoforms and can be located intracellularly or extracellularly. Elevated levels of galectin-9 have been observed in a wide range of cancers, including melanoma, Hodgkin's lymphoma, hepatocellular carcinoma, pancreatic cancer, gastric cancer, colon cancer, and renal clear cell carcinoma (Wdowiak et al. Int. J. Mol. Sci. 2018, 19, 210). In renal cancer, patients with high galectin-9 expression showed larger tumor size and more advanced disease progression (Kawashima et al.; BJU Int. 2014; 113: 320-332). In melanoma, galectin-9 is expressed in 57% of tumors and was significantly increased in the plasma of patients with advanced melanoma compared to healthy controls (Enninga et al., Melanoma Res. 2016 Oct;26(5):429-441). Many studies have demonstrated the utility of galectin-9 as a prognostic marker and, more recently, as a potential drug target (Enninga et al., 2016; Kawashima et al. BJU Int 2014;113:320-332; Kageshita et al., Int J Cancer. 2002 Jun 20;99(6):809-16, and references therein).

[0004] Galectin-9 has been described to play an important role in many cellular processes, such as adhesion, cancer cell aggregation, apoptosis, and chemotaxis. Recent studies have shown a role for galectin-9 in tumor-supportive immune regulation, for example, through negative regulation of Th1-type responses, Th2 polarization, and polarization of macrophages toward the M2 phenotype. This includes studies showing that galectin-9 is involved in the direct inactivation of T cells through its interaction with the T cell immunoglobulin and mucin protein 3 (TIM-3) receptor (Dardalhon et al., J Immunol., 2010, 185, 1383-1392; Sanchez-Fueyo et al., Nat Immunol., 2003, 4, 1093-1101).

[0005] Galectin-9 also plays a role in polarizing T cell differentiation towards a tumor suppressor phenotype, as well as promoting tolerogenic macrophage programming and adaptive immune suppression (Daley et al., Nat Med., 2017, 23, 556-567). In mouse models of pancreatic ductal adenocarcinoma (PDAC), blocking the checkpoint interaction between galectin-9 and its receptor Dectin-1, found on innate immune cells in the tumor microenvironment (TME), has been shown to increase antitumor immune responses in the pancreatic TME and slow tumor progression (Daley et al., Nat Med., 2017, 23, 556-567). Galectin-9 has also been shown to bind to CD206, a surface marker of M2 macrophages, resulting in reduced secretion of CVL22 (MDC), a macrophage-derived chemokine that is associated with improved survival and reduced risk of recurrence in lung cancer (Enninga et al, J Pathol. 2018 Aug;245(4):468-477). Summary of the Invention

[0006] The present disclosure is based on the unexpected discovery in animal models that synergistic effects are observed in combination therapies including both an exemplary anti-galectin-9 antibody (e.g., G9.2-17(IgG4)) and chemotherapeutic agents such as gemcitabine and paclitaxel (e.g., nanoparticle albumin-bound paclitaxel, i.e., nab-paclitaxel). Alternatively or additionally, the present disclosure is based, at least in part, on the unexpected discovery that the anti-galectin-9 antibody G9.2-17(IgG4) has a faster clearance rate in human subjects compared to other antibody therapeutics. Thus, a treatment regimen has been developed that includes a weekly dosing schedule that ensures suitable plasma concentrations, e.g., therapeutic systemic exposure levels, of the anti-galectin-9 antibody (anti-Gal-9 antibody) to achieve a therapeutic effect.

[0007] Thus, provided herein are methods of treating solid tumors comprising the combination of an anti-galectin-9 antibody (e.g., G9.2-17 or a functional variant thereof) with one or more chemotherapeutic agents (e.g., gemcitabine, paclitaxel, such as protein-bound paclitaxel (e.g., nab-paclitaxel, i.e., Abraxane®), or a combination thereof). In some cases, the anti-Gal-9 antibodies disclosed herein, such as G9.2-17(IgG4), may be administered on a weekly dosing schedule.

[0008] In some embodiments, the methods of treating solid tumors disclosed herein may comprise administering to a subject in need thereof an effective amount of an antibody that binds to human galectin-9 (anti-Gal-9 antibody). The anti-Gal-9 antibody may have the same heavy chain complementarity determining regions (CDRs) as antibody G9.2-17 and the same light chain CDRs as antibody G9.2-17. The subject may be undergoing anti-cancer therapy that includes one or more chemotherapeutic agents.

[0009] In some embodiments, the methods of treating solid tumors disclosed herein may comprise administering to a subject in need thereof an effective amount of an antibody that binds to human galectin-9 (anti-Gal-9 antibody) and an effective amount of one or more chemotherapeutic agents. The anti-Gal-9 antibody may have the same heavy chain complementarity determining regions (CDRs) as antibody 9.2-17 and the same light chain CDRs as antibody 9.2-17.

[0010] In some embodiments, the methods of treating solid tumors disclosed herein may comprise administering to a subject in need thereof an effective amount of one or more chemotherapeutic agents. The subject may be receiving a treatment comprising an antibody that binds to human galectin-9 (anti-Gal-9 antibody), the antibody having the same heavy chain complementarity determining regions (CDRs) as antibody G9.2-17 and the same light chain CDRs as antibody G9.2-17.

[0011] Any of the methods disclosed herein can be applied to the treatment of metastatic solid tumors. In some instances, the solid tumor is pancreatic ductal adenocarcinoma (PDAC), such as metastatic PDAC.

[0012] In some embodiments, subjects treated with any of the methods disclosed herein meet the following characteristics: (i) no resectable cancer, (ii) no SARS-CoV-2 infection, and (iii) no active brain or leptomeningeal metastases. In some instances, the solid tumor is pancreatic ductal adenocarcinoma (PDAC) and the subject does not have locally advanced PDAC without distant organ metastatic deposits.

[0013] In some embodiments, one or more chemotherapeutic agents included in any of the methods disclosed herein may include an antimetabolite (e.g., a nucleoside analog), a microtubule inhibitor, or a combination thereof. In some instances, the nucleoside analog is gemcitabine and / or the microtubule inhibitor is paclitaxel, e.g., nanoparticle albumin-bound paclitaxel (e.g., Abraxane®).

[0014] In some embodiments, the anti-galectin-9 antibody is administered to the subject at a dose of about 0.2 mg / kg to about 32 mg / kg (e.g., about 0.2 mg / kg to about 16 mg / kg, 0.5 mg / kg to about 16 mg / kg, about 2 mg / kg to about 32 mg / kg, or about 2 mg / kg to about 16 mg / kg, or about 0.2 mg / kg to about 15 mg / kg, or about 0.2 to about 16 mg / kg or more).

[0015] In some embodiments, the anti-Gal-9 antibody is administered to the subject once a week. In some embodiments, the anti-Gal-9 antibody may be administered to the subject once a week at a dose of about 0.2 mg / kg to about 32 mg / kg. In some embodiments, the anti-Gal-9 antibody may be administered to the subject once a week at a dose of about 10 mg / kg to about 16 mg / kg. Alternatively, the anti-Gal-9 antibody disclosed herein, such as G9.2-17(IgG4), may be administered to the subject once a week at a dose of about 650 mg to about 1120 mg. For example, the anti-Gal-9 antibody may be administered to the subject once a week at a dose of 10 mg / kg, or once a week at a fixed dose of about 650 to 700 mg. Alternatively, the anti-galectin-9 antibody may be administered to the subject at a dose of 16 mg / kg once weekly, or at a flat dose of about 1040-1120 mg once weekly.

[0016] In some embodiments, the anti-galectin-9 antibody is administered to the subject once every two or three weeks. In some embodiments, the anti-galectin-9 antibody is administered to the subject at a dose selected from 0.2 mg / kg, 0.6 mg / kg, 0.63 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 6.3 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, or 16 mg / kg or more. In some embodiments, the anti-galectin-9 antibody is administered to the subject at a dose selected from 2 mg / kg, 4 mg / kg, 8 mg / kg, 12 mg / kg, or 16 mg / kg or more. In some embodiments, the anti-galectin-9 antibody is administered to the subject at a dose selected from 0.2 mg / kg, 0.6 mg / kg, 0.63 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 6.3 mg / kg, 10 mg / kg, or 16 mg / kg or more. In some embodiments, the anti-galectin-9 antibody is administered to the subject once every two weeks at a dose selected from 0.2 mg / kg, 0.63 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 6.3 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, or 16 mg / kg. In some embodiments, the anti-galectin-9 antibody is administered once every two weeks. In some embodiments, the anti-galectin-9 antibody is administered to the subject once every two weeks at a dose selected from 2 mg / kg, 4 mg / kg, 8 mg / kg, 12 mg / kg, or 16 mg / kg or more. In some embodiments, the anti-galectin-9 antibody is administered once every two weeks. In some embodiments, the anti-galectin-9 antibody is administered to the subject once every two weeks at a dose selected from 0.2 mg / kg, 0.6 mg / kg, 0.63 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 6.3 mg / kg, 10 mg / kg, or 16 mg / kg or more.

[0017] In some embodiments, the anti-Gal-9 antibody, such as G9.2-17(IgG4), may be administered to the subject at a dose of about 650 mg to about 1120 mg once every 2 to 6 weeks, for example, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In some examples, the anti-Gal-9 antibody is administered to the subject at a dose of about 650 mg to about 700 mg once every 2 to 6 weeks, for example, once every 2 weeks, once every 3 weeks, or once every 4 weeks. In other examples, the anti-Gal-9 antibody is administered to the subject at a dose of about 1040 mg to about 1120 mg once every 2 to 6 weeks, for example, once every 2 weeks, once every 3 weeks, or once every 4 weeks.

[0018] In some embodiments, the anti-Gal-9 antibody is administered once every two weeks for one cycle, once every two weeks for two cycles, once every two weeks for three cycles, once every two weeks for four cycles, or once every two weeks for more than four cycles. In some embodiments, the treatment period is 0-3 months, 0-6 months, 3-6 months, 6-12 months, 12-24 months, or more. In some embodiments, the treatment period is 12-24 months or more. In some embodiments, the cycle spans a period of 3 months to 6 months, or 6 months to 12 months, or 12 months to 24 months, or more. In some embodiments, the length of the cycle is modified, e.g., temporarily or permanently, to a longer period, e.g., 3 weeks, or 4 weeks, or 6 weeks.

[0019] In some embodiments, the anti-Gal-9 antibody is administered to the subject by intravenous infusion. In some embodiments, the cancer is PDAC. In some embodiments, the cancer is metastatic cancer. In some instances, the subject may be administered multiple doses of the anti-galectin-9 antibody, with later doses being higher than earlier doses.

[0020] In some embodiments, the anti-Gal-9 antibody may be administered to the subject by intravenous infusion at a dose of about 0.5 mg / kg to about 32 mg / kg once every two weeks. In some embodiments, the anti-Gal-9 antibody may be administered to the subject by intravenous infusion at a dose of about 0.2 mg / kg to about 32 mg / kg once every two weeks. In some embodiments, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 0.5 mg / kg once every two weeks. In some embodiments, the anti-Gal-9 antibody may be administered to the subject by intravenous infusion at a dose of about 2 mg / kg to about 16 mg / kg once every two weeks. In some embodiments, the anti-Gal-9 antibody may be administered to the subject by intravenous infusion at a dose of about 0.2 mg / kg to about 16 mg / kg once every two weeks. In some embodiments, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 0.2 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 0.6 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 0.63 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 2 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 4 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 6 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 6.3 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 8 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 10 mg / kg once every two weeks.In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 12 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 16 mg / kg or more once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject by intravenous infusion at a dose of about 32 mg / kg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to the subject at a dose of about 10 mg / kg to about 16 mg / kg once every week. It may also be administered to the subject at a dose of about 10 mg / kg to about 16 mg / kg once every week.

[0021] In any of the methods disclosed herein, the one or more chemotherapeutic agents comprise antimetabolites, microtubule inhibitors, or combinations thereof.For example, the antimetabolites can be gemcitabine.Alternatively, or in addition, the microtubule inhibitor can be paclitaxel.In some cases, the paclitaxel is protein-bound paclitaxel, for example nanoparticle albumin-bound paclitaxel.In some embodiments, the one or more chemotherapeutic agents comprise the combination of gemcitabine and paclitaxel.

[0022] In some embodiments, the method includes a 28 day cycle in which the anti-Gal9 antibody is administered to the subject on days 1 and 15, and gemcitabine and paclitaxel (e.g., nanoparticle albumin-bound paclitaxel) are administered to the subject on days 1, 8, and 15. In some examples, the paclitaxel is administered at 125 mg / m 2 In some embodiments, the gemcitabine is administered intravenously to the subject at a dose of 1000 mg / m 2 is administered to the subject.

[0023] Optionally, the methods disclosed herein may include a 28 day cycle in which the anti-Gal-9 antibody is administered to the subject on days 1, 8, 15, and 22, and gemcitabine and paclitaxel are administered to the subject on days 1, 8, and 15. In some examples, the paclitaxel is administered at 125 mg / m 2 Alternatively, or in addition, the gemcitabine is administered intravenously to the subject at a dose of 1000 mg / m 2 is administered to the subject.

[0024] In some embodiments, the anti-galectin-9 antibody comprises a light chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:1, a light chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:2, and a light chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:3, and / or a heavy chain complementarity determining region 1 (CDR1) set forth as SEQ ID NO:4, a heavy chain complementarity determining region 2 (CDR2) set forth as SEQ ID NO:5, and a heavy chain complementarity determining region 3 (CDR3) set forth as SEQ ID NO:6.

[0025] In some embodiments, the anti-Gal9 antibody comprises a heavy chain variable region (V) comprising the amino acid sequence of SEQ ID NO:7. H ), and a light chain variable region (V L ). In some examples, the anti-Gal9 antibody may be an IgG molecule, such as an IgG4 molecule. In certain examples, the anti-Gal9 antibody may comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:19 and a light chain comprising the amino acid sequence of SEQ ID NO:15.

[0026] In some embodiments, the one or more chemotherapeutic agents may be administered to the subject on the same day that the subject receives the anti-galectin-9 antibody. Alternatively, the administration of the one or more chemotherapeutic agents and the administration of the anti-galectin-9 antibody may occur on two consecutive days. In some examples, the administration of the one or more chemotherapeutic agents may occur prior to the administration of the anti-Gal-9 antibody, e.g., on the first administration day, with the anti-galectin-9 antibody being administered the following day.

[0027] In any of the methods disclosed herein, the subject may be a human patient. In some embodiments, the subject may contain galectin-9 positive cancer cells or immune cells. In some cases, the subject's level of galectin-9 may be elevated compared to a control value. For example, the subject's serum or plasma level of galectin-9 may be elevated compared to the control value.

[0028] In some embodiments, the subject may have received at least one line of systemic anti-cancer therapy, hi other embodiments, the subject may have had no prior therapy comprising gemcitabine and / or paclitaxel, or the subject received prior therapy comprising gemcitabine and / or paclitaxel at least 6 months prior to administration of the anti-Gal-9 antibody.

[0029] In some cases, the subject may be monitored for the following features before, during, and / or after treatment: (a) one or more tumor markers in a tumor biopsy sample from the subject (optionally, the one or more tumor markers include CA15-3, CA-125, CEA, CA19-9, and / or alpha fetoprotein); (b) cytokine profile; (c) serum / plasma levels of Galectin-9; d) peripheral blood mononuclear cell immunophenotyping; e) multiplexed immunophenotyping of tumor tissue biopsy / resection specimen; f) Galectin-9 expression levels and patterns of tumor tissue biopsy / resection specimen; g) any other immune score test, such as PDL-1 immunohistochemistry, tumor mutation burden (TMB), tumor microsatellite instability status, and any other immune score test, such as Immunoscore®-HalioDx, ImmunoSEQ-Adaptive Biotechnologies, NanoString nCounter® Gene Expression System, 18-gene signature, PanCancer IO The subject may be tested for one or more panels, such as the TIS (NanoString Technologies) panel, developed based on the 360™ assay. Other suitable biomarkers specific to the target tumor may also be tested.

[0030] Any of the methods disclosed herein may further include monitoring the occurrence of one or more adverse effects in the subject. In some cases, the one or more adverse effects include liver damage, hematologic toxicity, neurotoxicity, skin toxicity, gastrointestinal toxicity, or a combination thereof.

[0031] In some embodiments, the method may further comprise reducing the dose of the anti-Gal9 antibody, the dose of the one or more chemotherapeutic agents, or both, if adverse effects are observed. For example, the method may further comprise reducing the dose of the anti-Gal-9 antibody, the dose of gemcitabine, the dose of paclitaxel, or a combination thereof, if moderate to severe liver damage is observed in the subject. In one particular example, a reduction in the dose of the anti-Gal-9 antibody is performed according to the clinician's assessment or by at least 30%. In another example, a reduction of 30% or 50% of the previous dose level is performed. If necessary, another dose reduction of 30% of dose level-1 (the level at the first dose reduction) is performed (dose level-2, the level at the second dose reduction). In another example, another dose reduction of 50% of dose level-1 is performed (dose level-2). In some embodiments, one or more dose reductions of about 10% to about 80% of the previous dose level are performed. In some embodiments, one or more dose reductions of about 10% to about 20%, about 20% to about 30%, about 30% to about 40%, about 40% to about 50%, about 50% to about 60% reduction, or about 70% to about 80% of the previous level are implemented. In some embodiments, one or more dose reductions of 10% to 20%, 20% to 30%, 30% to 40%, 40% to 50%, 50% to 60%, or 70% to 80% of the previous level are implemented. In some embodiments, one or more dose reductions of about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, or about 80% of the previous level are implemented. In some embodiments, one or more dose reductions of 10%, 20%, 30%, 40%, 50%, 60%, 70%, or 80% of the previous level are implemented. In some cases, the administration of paclitaxel is withheld if the subject has an aspartate transaminase (AST) level greater than 10 times the upper limit of normal (ULN), a bilirubin level greater than 5 times the ULN, or both.

[0032] Optionally, the method may further comprise reducing the dose of the anti-Gal-9 antibody, the dose of gemcitabine, the dose of paclitaxel, or a combination thereof if moderate to severe liver damage is observed. In other examples, the method may further comprise reducing or ceasing the administration of the anti-Gal-9 antibody, the gemcitabine, the paclitaxel, or a combination thereof if severe hematologic, neurologic, cutaneous, and / or gastrointestinal toxicity is observed. In some examples, the dose of paclitaxel is 100 mg / m 2 ~75mg / m 2 In another embodiment, the dose of gemcitabine is reduced to 800 mg / m 2 ~600mg / m 2 is reduced to

[0033] Also within the scope of the disclosure are pharmaceutical compositions for use in the treatment of solid tumors (e.g., solid tumors described herein and including metastatic solid tumors), and the use of any of the above-described anti-galectin-9 antibodies in combination with one or more chemotherapeutic agents, also disclosed herein, for the manufacture of a medicament for treating said solid tumors.

[0034] The details of one or more embodiments of the invention are set forth in the description below. Other features or advantages of the invention will be apparent from the following drawings and detailed description of certain embodiments, as well as from the appended claims.

[0035] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure, which can be better understood by reference to the drawings in combination with the detailed description of specific embodiments presented herein. [Brief description of the drawings]

[0036] [Figure 1A]Figure 1 includes graphs showing Kaplan-Meier survival curves and log-rank tests for orthotopic mPA6115 pancreatic cancer xenograft mouse models grouped by treatment regimen: Group 1 = untreated, Group 2 = saline vehicle control for chemotherapy, Group 3 = isotype IgG1 mice, Group 4 = anti-Gal9 mAb, Group 5 = gemcitabine / Abraxane, and Group 6 = anti-Gal9 mAb and gemcitabine / Abraxane. Survival curves for all six groups are shown. [Figure 1B] Figure 1 includes graphs showing Kaplan-Meier survival curves and log-rank tests for orthotopic mPA6115 pancreatic cancer xenograft mouse models grouped by treatment regimen: Group 1 = untreated, Group 2 = saline vehicle control for chemotherapy, Group 3 = isotype IgG1 mice, Group 4 = anti-Gal9 mAb, Group 5 = gemcitabine / Abraxane, and Group 6 = anti-Gal9 mAb and gemcitabine / Abraxane. Survival curves for groups 1, 5, and 6 are shown. [Figure 1C] Figure 1 includes graphs showing Kaplan-Meier survival curves and log-rank tests for orthotopic mPA6115 pancreatic cancer xenograft mouse models grouped by treatment regimen: Group 1 = untreated, Group 4 = anti-Gal9 mAb, Group 5 = gemcitabine / Abraxane, and Group 6 = anti-Gal9 mAb and gemcitabine / Abraxane. Survival curves for groups 1, 4, and 6 are shown. [Figure 1D] Figure 1 includes graphs showing Kaplan-Meier survival curves and log-rank tests for orthotopic mPA6115 pancreatic cancer xenograft mouse models grouped by treatment regimen: Group 1 = untreated, Group 4 = anti-Gal9 mAb, Group 5 = gemcitabine / Abraxane, and Group 6 = anti-Gal9 mAb and gemcitabine / Abraxane. Survival curves for groups 1, 4, 5, and 6 are shown. [Diagram 2]Graph showing hazard ratios (HRs) and their 95% confidence intervals (95% CIs) for groups 4-6 versus groups 1, 2, and 3, respectively, calculated from Cox regression analysis, where group 1=untreated orthotopic mPA6115 mice, group 2=orthotopic mPA6115 mice treated with saline, which is the vehicle control for chemotherapy agents, group 3=orthotopic mPA6115 mice treated with isotype IgG1 mice, group 4=orthotopic mPA6115 mice treated with anti-Gal9 mAb, group 5=orthotopic mPA6115 mice treated with gemcitabine / Abraxane, and group 6=orthotopic mPA6115 mice treated with anti-Gal9 mAb and gemcitabine / Abraxane. [Diagram 3] Figure includes a graph of the average body weight of each treatment group, measured twice weekly during the study period, where: Group 1 = untreated orthotopic mPA6115 mice; Group 2 = orthotopic mPA6115 mice treated with saline, a vehicle control for chemotherapy agents; Group 3 = orthotopic mPA6115 mice treated with isotype IgG1 mice; Group 4 = orthotopic mPA6115 mice treated with anti-Gal9 mAb; Group 5 = orthotopic mPA6115 mice treated with gemcitabine / Abraxane; Group 6 = orthotopic mPA6115 mice treated with anti-Gal9 mAb and gemcitabine / Abraxane. [Figure 4] FIG. 1 is a schematic diagram showing an exemplary study scheme. CRM: Reevaluation method; RP2D: Recommended second dose; PK: Pharmacokinetics; PD: Pharmacodynamics; PDAC: Pancreatic ductal adenocarcinoma; CRC: Colorectal cancer; CCA: Cholangiocarcinoma; TBD: To be determined. [Diagram 5] Includes graphs showing the effect of G2.9-17 on TGF-β1 secretion measurements in whole blood of an exemplary healthy human donor. TGF-β1 release from cryopreserved macrophages of donors incubated in the presence of M2 polarizing cocktail. IgG4 isotype is a negative control antibody. Data represent mean + SEM of triplicate determinations. Significance was determined by two-way ANOVA with Dunnett's multiple comparison test. *p<0.05 [Figure 6]Includes graphs showing the effect of G2.9-17 on IL-10 secretion in whole blood of an exemplary healthy human donor. IL-10 release from cryopreserved macrophages of donors incubated in the presence of M2 polarizing cocktails (IL-4 / IL-13 or Gal-9). IgG4 isotype is a negative control antibody. Data represent the mean (±SEM) of triplicates. Significance was determined by two-way ANOVA with Tukey's multiple comparison test (*P<0.05). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] Provided herein are methods of combining anti-galectin-9 antibodies, e.g., G9.2-17, with gemcitabine and paclitaxel (e.g., protein-bound paclitaxel, such as nanoparticle albumin-bound paclitaxel) to treat solid tumors, e.g., pancreatic ductal adenocarcinoma (PDAC). In some embodiments, the solid tumor is metastatic. In some embodiments, the methods disclosed herein provide specific doses and / or administration schedules. In some cases, the methods disclosed herein are directed to specific patient populations, e.g., patients who have been previously treated and have shown disease progression through the previous treatment, or who are resistant (de novo or acquired) to the previous treatment.

[0038] In some embodiments, the methods disclosed herein provide a particular dose and / or administration schedule of an anti-Gal-9 antibody disclosed herein (e.g., G9.2-17(IgG4)) in combination with a chemotherapeutic agent also disclosed herein (e.g., gemcitabine and paclitaxel), e.g., 0.2 mg / kg to 16 mg / kg of the antibody once a week to once every four weeks (e.g., 0.2 mg / kg, 0.63 mg / kg, 2 mg / kg, 6.3 mg / kg, 10 mg / kg, or 16 mg / kg once a week or once every two weeks). In some examples, the administration schedule of the anti-Gal9 antibody, such as G9.2-17(IgG4), may be 10 mg / kg or 16 mg / kg once a week. In some embodiments, the anti-Gal9 antibody may be administered to the subject at a dose of about 10 mg / kg to about 16 mg / kg once a week.

[0039] Alternatively, the anti-Gal-9 antibody disclosed herein, such as G9.2-17(IgG4), may be administered to the subject at a fixed dose, e.g., about 650 mg to about 1120 mg (e.g., about 650-700 mg or about 1040-1120 mg), once a week to once every four weeks, e.g., once a week or once every two weeks. The clearance rate of G9.2-17(IgG4) in human subjects was found to be unexpectedly rapid compared to conventional antibody therapeutics. Thus, to ensure systemic exposure levels of the anti-Gal-9 antibody that achieve therapeutic efficacy, a treatment regimen was developed that includes a weekly administration schedule.

[0040] The tandem repeat lectin, galectin-9, is a β-galactoside-binding protein that has been shown to play a role in regulating cell-cell and cell-matrix interactions. It has been found to be strongly overexpressed in Hodgkin's disease tissues and other pathological conditions. In some cases, it has also been found circulating within the tumor microenvironment (TME).

[0041] Galectin-9 interacts with Dectin-1, an innate immune receptor highly expressed on macrophages and cancer cells in PDAC (Daley, et al. Nat Med. 2017;23(5):556-6). Regardless of the source of Galectin-9, disruption of its interaction with Dectin-1 has been shown to reprogram CD4+ and CD8+ cells into essential mediators of anti-tumor immunity. Thus, Galectin-9 serves as a valuable therapeutic target to block Dectin-1-mediated signaling. Thus, in some embodiments, the anti-Galectin-9 antibodies described herein disrupt the interaction between Galectin-9 and Dectin-1.

[0042] Galectin-9 interacts with TIM-3, a type I cell surface glycoprotein expressed on the surface of leukemic stem cells in all types of acute myeloid leukemia (except M3 (acute promyelocytic leukemia)), but not on normal human hematopoietic stem cells (HSCs). TIM-3 signaling resulting from ligation of galectin-9 has been shown to have pleiotropic effects on immune cells, inducing apoptosis of Th1 cells (Zhu et al., Nat Immunol., 2005, 6:1245-1252) and stimulating the secretion of tumor necrosis factor alpha (TNF-α), which leads to maturation of monocytes into dendritic cells that trigger innate immune inflammation (Kuchroo et al., Nat Rev Immunol., 2008, 8:577-580). Furthermore, galectin-9 / TIM-3 signaling has been found to co-activate NF-κB and β-catenin signaling, two pathways that promote LSC self-renewal (Kikushige et al., Cell Stem Cell, 2015, 17(3):341-352). Anti-galectin-9 antibodies that interfere with galectin-9 / TIM-3 binding may have therapeutic value, particularly with respect to leukemia and other hematological malignancies. Thus, in some embodiments, the anti-galectin-9 antibodies described herein disrupt the interaction between galectin-9 and TIM-3.

[0043] Furthermore, galectin-9 interacts with CD206, a mannose receptor highly expressed on M2-polarized macrophages, thereby promoting tumor survival (Enningaetal., JPathol. 2018Aug;245(4):468-477). Tumor-associated macrophages expressing CD206 are mediators of tumor immunosuppression, angiogenesis, metastasis, and recurrence (see, e.g., Scodeller et al., Sci Rep. 2017 Nov 7;7(1):14655, and references therein). Specifically, M1 (also called classically activated macrophages) are induced by Th1-associated cytokines and bacterial products, express high levels of IL-12, and are tumoricidal. In contrast, M2 (so-called alternatively activated macrophages) are activated with Th2-associated factors, express high levels of anti-inflammatory cytokines such as IL-10, and promote tumor progression (Biswas and Mantovani; Nat Immunol. 2010 Oct; 11(10): 889-96). The tumor-promoting effects of M2 include promoting angiogenesis, progression of invasion and metastasis, and protecting tumor cells from chemotherapy-induced apoptosis (Hu et al., Tumor Biol. 2015 Dec; 36(12): 9119-9126 and references therein). Tumor-associated macrophages are of an M2-like phenotype and are thought to have a pro-tumor role. Galectin-9 has been shown to mediate the differentiation of myeloid cells into the M2 phenotype (Enninga et al., Melanoma Res. 2016 Oct; 26(5): 429-41). Binding of galectin-9 to CD206 may potentially reprogram TAMs to an M2 phenotype, similar to what has previously been shown for dectin. Without wishing to be bound by theory, blocking the interaction of galectin-9 with CD206 may provide one mechanism by which anti-galectin-9 antibodies, such as the G9.2-17 antibody, may be therapeutically beneficial. Thus, in some embodiments, the anti-galectin-9 antibodies described herein disrupt the interaction between galectin-9 and CD206.

[0044] Galectin-9 has also been shown to interact with protein disulfide isomerase (PDI) and 4-1BB (Bi S, et al. Proc Natl Acad Sci US A. 2011; 108(26): 10650-5; Madireddi et al. J Exp Med. 2014; 211(7): 1433-48).

[0045] Anti-galectin-9 antibodies may function as therapeutic agents for treating diseases associated with galectin-9 (e.g., those involving galectin-9 signaling). Without being bound by theory, anti-galectin-9 antibodies may block signaling pathways mediated by galectin-9. For example, the antibodies may interfere with the interaction between galectin-9 and its binding partners (e.g., Dectin-1, TIM-3, or CD206), thereby blocking signaling caused by galectin-9 / ligand interactions. Alternatively or additionally, anti-galectin-9 antibodies may also exert their therapeutic effect by inducing blocking and / or cytotoxicity, e.g., ADCC, CDC, or ADCP, against pathological cells expressing galectin-9. Pathological cells refer to cells that directly or indirectly contribute to the initiation and / or development of a disease. See, e.g., WO2019 / 084553, WO2020 / 198390, WO2020 / 0223702, and WO2021022256, the relevant disclosures of each of which are incorporated by reference with respect to the subject matter and purposes referenced herein.

[0046] The anti-galectin-9 antibodies disclosed herein can inhibit galectin-9 mediated signaling (e.g., galectin-9 / Dectin-1 or galectin-9 / Tim-3 mediated signaling pathways) or eliminate pathological cells expressing galectin-9, e.g., by ADCC. Thus, the anti-galectin-9 antibodies described herein can be used to inhibit any of galectin-9 signaling and / or eliminate galectin-9 positive pathological cells, thereby providing benefits in the treatment of diseases associated with galectin-9. See, e.g., WO2019 / 084553, PCT / US2020 / 024767, and PCT / US2020 / 031181, the relevant disclosures of each of which are incorporated by reference for purposes and subject matter referenced herein.

[0047] As described herein, combination therapy of a representative anti-Gal9 antibody (G9.2-17, such as G9.2-17(IgG4)) with chemotherapeutic agents (gemcitabine and nab-paclitaxel) successfully extended survival in the animal models disclosed herein. A synergistic effect on survival of a representative anti-Gal9 antibody with gemcitabine and nab-paclitaxel was observed in the animal models. These results demonstrate that the anti-tumor methods disclosed herein, including the combination of an anti-galectin-9 antibody with a chemotherapeutic agent, such as those disclosed herein, will achieve a superior therapeutic effect against a target solid tumor than either the antibody or the chemotherapeutic agent alone.

[0048] Thus, described herein are therapeutic uses of anti-galectin-9 antibodies and chemotherapeutic agents to treat certain solid tumors disclosed herein.

[0049] Antibodies that bind to galectin-9 The present disclosure provides the anti-Gal-9 antibody G9.2-17 and functional variants thereof for use in the therapeutic methods disclosed herein.

[0050] Antibodies (used interchangeably in the plural) are immunoglobulin molecules capable of specifically binding to targets, e.g., carbohydrates, polynucleotides, lipids, polypeptides, etc., through at least one antigen recognition site located in the variable region of the immunoglobulin molecule. As used herein, the term "antibody", e.g., anti-galectin-9 antibody, encompasses not only intact (e.g., full-length) polyclonal or monoclonal antibodies, but also antigen-binding fragments thereof (e.g., Fab, Fab', F(ab')2, Fv), single chain (scFv), variants thereof, antibody portions, humanized antibodies, chimeric antibodies, diabodies, nanobodies, linear antibodies, single chain antibodies, multispecific antibodies (e.g., bispecific antibodies), as well as fusion proteins comprising immunoglobulin molecules of any other modified configuration that contains an antigen recognition site of the required specificity, including glycosylation variants of antibodies, amino acid sequence variants of antibodies, and covalently modified antibodies. Antibodies, e.g., anti-galectin-9 antibodies, include antibodies of any class, such as IgD, IgE, IgG, IgA, or IgM (or subclasses thereof), and do not have to be of any particular class. Depending on the antibody amino acid sequence of the constant domain of the heavy chain, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy chain constant domains corresponding to the various classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of the various classes of immunoglobulins are well known.

[0051] A typical antibody molecule consists of a heavy chain variable region (V H ) and the light chain variable region (V L ), which are usually involved in antigen binding. H and V LThe regions can be further subdivided into regions of hypervariability, also known as "complementarity determining regions" ("CDRs"), interspersed with regions that are more conserved, known as "framework regions" ("FRs"). H and V L is typically composed of three CDRs and four FRs, arranged from amino terminus to carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The extent of framework regions and CDRs can be precisely identified using methodologies known in the art, for example, by the Kabat definition, the Chothia definition, the AbM definition, the EU definition, the "Contact" numbering scheme, the "IMGT" numbering scheme, the "AHo" numbering scheme, and / or the contact definition, all of which are well known in the art. See, e.g., EA, et al. (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, USDepartment of Health and Human Services, NIH Publication No. 91-3242, Chothia et al., (1989) Nature 342:877; Chothia, C. et al. al.(1987)J.Mol.Biol.196:901-917,Al-lazikani et al(1997)J.Molec.Biol.273:927-948;Edelman et al.,Proc Natl Acad Sci USA.1969 May;63(1):78-85; and Almagro, J.Mol.Recognit.17:132-143(2004);MacCallum et al., J. Mol. Biol. 262:732-745 (1996), Lefranc MP et al., Dev Comp Immunol, 2003 January;27(1):55-77; and Honegger A and Pluckthun A, J Mol Biol, 2001 June.8;309(3):657-70. See also: hgmp.mrc.ac.uk and bioinf.org.uk / abs).

[0052] In some embodiments, the anti-Galectin-9 antibodies described herein are full-length antibodies containing two heavy chains and two light chains, each of which comprises a variable domain and a constant domain. Alternatively, the anti-Galectin-9 antibodies may be antigen-binding fragments of full-length antibodies. Examples of binding fragments encompassed within the term "antigen-binding fragment" of a full-length antibody include: (i) a Fab fragment (V L , V H , C L , and C H (ii) F(ab')2 fragment (a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region); (iii) V H and C H (iv) a single-domain Fd fragment of an antibody; L and V H (v) Fv fragment consisting of V domains; H (iv) isolated complementarity determining regions (CDRs) that retain function. In addition, two domains of the Fv fragment, the V L and V H Although the V and VL are encoded by separate genes, they can be joined using recombinant methods with a synthetic linker that can be made into a single protein chain. L Area and V H The regions pair to form monovalent molecules known as single-chain Fvs (scFvs). See, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883.

[0053] Any of the antibodies described herein, for example, anti-galectin-9 antibodies, can be either monoclonal or polyclonal. A "monoclonal antibody" refers to a homogeneous population of antibodies, whereas a "polyclonal antibody" refers to a heterogeneous population of antibodies. These two terms do not limit the source of the antibody or the method by which the antibody is made.

[0054] Reference antibody G9.2-17 refers to an antibody capable of binding to human galectin-9 and comprises a heavy chain variable region of SEQ ID NO: 7 and a light chain variable domain of SEQ ID NO: 8, both of which are provided below. In some embodiments, the anti-galectin-9 antibody used in the methods disclosed herein is a G9.2-17 antibody. In some embodiments, the anti-galectin-9 antibody used in the methods disclosed herein is an antibody that has the same heavy chain complementarity determining regions (CDRs) as the reference antibody G9.2-17 and / or the same light chain complementarity determining regions as the reference antibody G9.2-17. H and / or V L Two antibodies having CDRs mean that their CDRs are identical when determined by the same approach (e.g., the Kabat approach, the Chothia approach, the AbM approach, the Contact approach, or the IMGT approach known herein, see, e.g., bioinf.org.uk / abs / ).

[0055] The heavy and light chain CDRs of the reference antibody G9.2-17 are presented below in Table 1 (determined using the Kabat method). [Table 1]

[0056] In some examples, anti-galectin-9 antibodies used in the methods disclosed herein may comprise (according to the Kabat scheme) a heavy chain complementarity determining region 1 (CDR1) set forth in SEQ ID NO: 4, a heavy chain complementarity determining region 2 (CDR2) set forth in SEQ ID NO: 5, and a heavy chain complementarity determining region 3 (CDR3) set forth in SEQ ID NO: 6, and / or a light chain complementarity determining region 1 (CDR1) set forth in SEQ ID NO: 1, a light chain complementarity determining region 2 (CDR2) set forth in SEQ ID NO: 2, and a light chain complementarity determining region 3 (CDR3) set forth in SEQ ID NO: 3. Anti-galectin-9 antibodies, including the reference antibody G9.2-17, may be in any format disclosed herein, e.g., full length antibody or Fab. As used herein, the term "G9.2-17(Ig4)" refers to a G9.2-17 antibody that is an IgG4 molecule. Similarly, the term "G9.2-17(Fab)" refers to a G9.2-17 antibody that is a Fab molecule.

[0057] In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises a heavy chain variable region and a light chain variable region, and the CDR1, CDR2, and CDR3 amino acid sequences of the light chain variable region have at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and any increment therein) sequence identity to the amino acid sequences of the light chain variable region CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 1, 2, and 3, respectively. In some embodiments, the anti-galectin-9 antibody or binding portion thereof comprises a heavy chain variable region and a light chain variable region, and the CDR1, CDR2, and CDR3 amino acid sequences of the heavy chain variable region have at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, and any increment therein) sequence identity to the amino acid sequences of the heavy chain variable region CDR1, CDR2, and CDR3 set forth in SEQ ID NOs: 4, 5, and 6, respectively.

[0058] Additional galectin-9 antibodies (e.g., those that bind to the CRD1 and / or CRD2 regions of galectin-9) are described in co-pending U.S. patent application Ser. No. 16 / 173,970 and co-pending international patent applications PCT / US18 / 58028 and PCT / US2020 / 024767, the contents of each of which are incorporated by reference in their entirety.

[0059] In some embodiments, the anti-galectin-9 antibodies disclosed herein have the corresponding V H Alternatively or additionally, in some embodiments, the anti-galectin-9 antibody comprises a light chain CDR that has, individually or collectively, at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to the corresponding V CDRs of reference antibody G9.2-17. H The heavy chain CDRs have, individually or collectively, at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to the CDRs.

[0060] The "percent identity" of two amino acid sequences is determined using the algorithm of Karlin and Altschul Proc. Natl. Acad. Sci. USA 87:2264-68, 1990, modified as in Karlin and Altschul Proc. Natl. Acad. Sci. USA 90:5873-77, 1993. Such an algorithm is incorporated into the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. J. Mol. Biol. 215:403-10, 1990. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3, to obtain amino acid sequences homologous to the protein molecules of the invention. When gaps exist between the two sequences, gapped BLAST can be utilized as described in Altschul et al., Nucleic Acids Res. 25(17):3389-3402, 1997. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (eg, XBLAST and NBLAST) can be used.

[0061] In other embodiments, the anti-galectin-9 antibodies described herein comprise a V CDR comprising HC CDR1, HC CDR2, and HC CDR3. H which collectively comprise up to 8 amino acid residue variations (8, 7, 6, 5, 4, 3, 2, or 1 variations) including additions, deletions, and / or substitutions compared to the HC CDR1, HC CDR2, and HC CDR3 of the reference antibody G9.2-17. Alternatively or additionally, in some embodiments, the anti-galectin-9 antibodies described herein comprise a V CDR1, a V CDR2, and a V CDR3 comprising LC CDR1, LC CDR2, and LC CDR3. H which collectively contain up to 8 amino acid residue diversity (8, 7, 6, 5, 4, 3, 2, or 1 diversity(s) including additions, deletions, and / or substitutions) compared to the LC CDR1, LC CDR2, and LC CDR3 of reference antibody G9.2-17.

[0062] In one example, the amino acid residue diversity is a conservative amino acid residue substitution. As used herein, "conservative amino acid substitution" refers to an amino acid substitution that does not change the relative charge or size characteristics of the protein in which the amino acid substitution is made. Diversity can be adjusted according to methods for modifying polypeptide sequences known to those skilled in the art, such as those found in references that summarize such methods, for example, Molecular Cloning: A Laboratory Manual, J. Sambrook, et al., eds., Second Edition, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1989, or Current Protocols in Molecular Biology, FMAusubel, et al., eds., John Wiley & Sons, Inc., New York. Conservative amino acid substitutions include substitutions made between amino acids within the following groups: (a) M, I, L, V; (b) F, Y, W; (c) K, R, H; (d) A, G; (e) S, T; (f) Q, N; and (g) E, D.

[0063] In some embodiments, the anti-galectin-9 antibodies disclosed herein having heavy chain CDRs disclosed herein are H The fragments include framework regions derived from a subclass of the germline V HRegions are well known in the art. See, for example, the IMGT database (www.imgt.org) or www.vbase2.org / vbstat.php. Examples include the IGHV1 subfamily (e.g., IGHV1-2, IGHV1-3, IGHV1-8, IGHV1-18, IGHV1-24, IGHV1-45, IGHV1-46, IGHV1-58, and IGHV1-69), the IGHV2 subfamily (e.g., IGHV2-5, IGHV2-26, and IGHV2-70), the IGHV3 subfamily (e.g., IGHV3-7, IGHV3-9, IGHV3-11, IGHV3-13, IGHV3-15, IGHV3-20, IGHV3-21, IGHV3-23, IGHV3-30, IGHV3- 33, IGHV3-43, IGHV3-48, IGHV3-49, IGHV3-53, IGHV3-64, IGHV3-66, IGHV3-72, and IGHV3-73, IGHV3-74), IGHV4 subfamily (e.g., IGHV4-4, IGHV4-28, IGHV4-31, IGHV4-34, IGHV4-39, IGHV4-59, IGHV4-61, and IGHV4-B), IGHV subfamily (e.g., IGHV5-51, or IGHV6-1), and IGHV7 subfamily (e.g., IGHV7-4-1).

[0064] Alternatively or additionally, in some embodiments, an anti-galectin-9 antibody having a light chain CDR disclosed herein comprises a framework region derived from a germline VK fragment. Examples include an IGKV1 framework (e.g., IGKV1-05, IGKV1-12, IGKV1-27, IGKV1-33, or IGKV1-39), an IGKV2 framework (e.g., IGKV2-28), an IGKV3 framework (e.g., IGKV3-11, IGKV3-15, or IGKV3-20), and an IGKV4 framework (e.g., IGKV4-1). In other cases, an anti-galectin-9 antibody comprises a light chain variable region comprising a framework derived from a germline V fragment. Examples include IGλ1 frameworks (e.g., IGλV1-36, IGλV1-40, IGλV1-44, IGλV1-47, IGλV1-51), IGλ2 frameworks (e.g., IGλV2-8, IGλV2-11, IGλV2-14, IGλV2-18, IGλV2-23), IGλ3 frameworks (e.g., IGλV3-1, IGλV3-9, IGλV3-10, IGλV3-12, IGλV3-16, IGλV3-19, IGλV3-21, IGλV3-25, IGλV3-27), I Examples of such frameworks include IGλ4 frameworks (e.g., IGλV4-3, IGλV4-60, IGλV4-69), IGλ5 frameworks (e.g., IGλV5-39, IGλV5-45), IGλ6 frameworks (e.g., IGλV6-57), IGλ7 frameworks (e.g., IGλV7-43, IGλV7-46), IGλ8 frameworks (e.g., IGλV8-61), IGλ9 frameworks (e.g., IGλV9-49), or IGλ10 frameworks (e.g., IGλV10-54).

[0065] In some embodiments, the anti-galectin-9 antibody used in the methods disclosed herein has the same heavy chain variable region (V H ) and / or the same light chain variable region (V L ), and V H and V L The amino acid sequence of the region is provided below: VH : [ka] V L : [ka]

[0066] In some embodiments, the anti-Galectin-9 antibody has at least 80% sequence identity (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) with the heavy chain variable region of SEQ ID NO: 7. Alternatively or additionally, the anti-Galectin-9 antibody has at least 80% sequence identity (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity) with the light chain variable region of SEQ ID NO:8.

[0067] In some cases, the anti-galectin-9 antibodies disclosed herein are functional variants of the reference antibody G9.2-17. The functional variants may be structurally similar to the reference antibody (e.g., including a limited number of amino acid residue variations in one or more of the heavy and / or light chain CDRs as G9.2-17 disclosed herein, or sequence identity with the heavy and / or light chain CDRs of G9.2-17 disclosed herein) that have substantially similar binding affinity to human galectin-9 (e.g., having KD values ​​in the same order).

[0068] In some embodiments, the anti-galectin-9 antibodies described herein are capable of binding to and inhibiting the activity of galectin-9 by at least 20% (e.g., 31%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). The apparent inhibition constant (Ki) provides a measure of the potency of an inhibitor. app Or Ki ,app) is related to the concentration of inhibitor required to reduce enzyme activity and is independent of enzyme concentration. The inhibitory activity of the anti-galectin-9 antibodies described herein can be measured by routine methods known in the art.

[0069] Antibody K i, app The K value can be determined by measuring the inhibitory effect of different concentrations of antibody on the extent of the reaction (e.g., enzyme activity); fitting the change in the pseudo-first-order rate constant (v) as a function of inhibitor concentration to a modified Morrison equation (Equation 1) provides an estimate of the apparent K value. For competitive inhibitors, the K app is the K with respect to the substrate concentration i, app can be obtained from the y-intercept extracted from the linear regression analysis of the plot of

number

[0070] In some embodiments, the anti-galectin-9 antibody inhibits Dectin-1 signaling in tumor-infiltrating immune cells, such as macrophages. In some embodiments, the anti-galectin-9 antibody inhibits Galectin-9-induced Dectin-1 signaling by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). Such inhibitory activity can be measured by conventional methods, such as routine assays. Alternatively or additionally, the anti-galectin-9 antibody inhibits Galectin-9-initiated T cell immunoglobulin mucin-3 (TIM-3) signaling. In some embodiments, the anti-galectin-9 antibody inhibits T cell immunoglobulin mucin-3 (TIM-3) signaling, e.g., in tumor infiltrating immune cells, e.g., in some embodiments, by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). Such inhibitory activity can be measured by conventional methods, such as routine assays.

[0071] In some embodiments, the anti-galectin-9 antibody inhibits CD206 signaling, for example, in tumor-infiltrating immune cells. In some embodiments, the anti-galectin-9 antibody inhibits galectin-9-induced CD206 signaling by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). Such inhibitory activity can be measured by conventional methods, such as a routine assay. In some embodiments, the anti-galectin-9 antibody blocks or inhibits galectin-9 binding to CD206 by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). Such inhibitory activity can be measured by conventional methods, such as a routine assay.

[0072] In some embodiments, the anti-galectin-9 antibody induces cytotoxicity, such as ADCC, in a target cell expressing galectin-9, e.g., the target cell is a cancer cell or an immunosuppressive immune cell. In some embodiments, the anti-galectin-9 antibody induces apoptosis of an immune cell, such as a T cell, or a cancer cell by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). Such inhibitory activity can be measured by conventional methods, such as routine assays. In some embodiments, any of the anti-galectin-9 antibodies described herein induces cytotoxicity, such as complement-dependent cytotoxicity (CDC), in a target cell expressing galectin-9.

[0073] Antibody-dependent cell-mediated phagocytosis (ADCP) is an important mechanism of action of antibodies that mediate some or all of their actions through phagocytosis, where antibodies mediate the uptake of specific antigens by antigen-presenting cells. ADCP can be mediated by monocytes, macrophages, neutrophils, and dendritic cells via FcγRIIa, FcγRI, and FcγRIIIa, with FcγRIIa (CD32a) on macrophages representing the major pathway.

[0074] In some embodiments, the anti-galectin-9 antibody induces cellular phagocytosis of target cells, e.g., cancer cells or immunosuppressive immune cells expressing galectin-9 (ADCP). In some embodiments, the anti-galectin-9 antibody increases phagocytosis of target cells, e.g., cancer cells or immunosuppressive immune cells, by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein).

[0075] In some embodiments, the anti-galectin-9 antibodies described herein induce cytotoxicity, such as complement dependent cytotoxicity (CDC), against target cells, e.g., cancer cells or immunosuppressed immune cells. In some embodiments, the anti-galectin-9 antibodies increase CDC against target cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein).

[0076] In some embodiments, the anti-galectin-9 antibody induces T cell activation, i.e., directly or indirectly suppresses Galectin-9-mediated inhibition of T cell activation, e.g., in tumor-infiltrating T cells. In some embodiments, the anti-galectin-9 antibody enhances T cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). T cell activation can be measured by conventional methods such as assays (e.g., measuring CD44, TNF-alpha, IFN-gamma, and / or PD-1). In some embodiments, the anti-galectin-9 antibody enhances CD4+ cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces CD44 expression in CD4+ cells. In some embodiments, the anti-galectin-9 antibody increases CD44 expression in CD4+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces IFN-gamma expression in CD4+ cells. In some embodiments, the anti-galectin-9 antibody increases IFN-gamma expression in CD4+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces TNFα expression in CD4+ cells. In some embodiments, the anti-galectin-9 antibody increases IFN-alpha expression in CD4+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein).

[0077] In some embodiments, the anti-galectin-9 antibody enhances CD8+ cell activation by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces CD44 expression in CD8+ cells. In some embodiments, the anti-galectin-9 antibody increases CD44 expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces IFN-gamma expression in CD8+ cells. In some embodiments, the anti-galectin-9 antibody increases IFN-gamma expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein). In a non-limiting example, the anti-galectin antibody induces TNFα expression in CD8+ cells. In some embodiments, the anti-galectin-9 antibody increases IFN-alpha expression in CD8+ cells by at least 30% (e.g., 31%, 35%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more, including any increment therein).

[0078] In some embodiments, the anti-galectin-9 antibodies described herein have suitable binding affinity for a target antigen (e.g., galectin-9) or an antigenic epitope thereof. As used herein, "binding affinity" refers to the apparent binding constant or K A Refers to. A is the dissociation constant (K D The anti-galectin-9 antibodies described herein have a binding affinity of at least 10 to a target antigen or antigen epitope. -5 , 10 -6 , 10 -7 , 10 -8 , 10 -9 , 10 -10 Binding affinity (K D The increase in binding affinity can be expressed as K DThis corresponds to a decrease in the binding affinity (or binding specificity). Binding affinity (or binding specificity) can be determined in a variety of ways, including equilibrium dialysis, equilibrium binding, gel filtration, ELISA, surface plasmon resonance, or spectroscopy (e.g., using a fluorescence assay). Exemplary conditions for assessing binding affinity are in HBS-P buffer (10 mM HEPES (pH 7.4), 150 mM NaCl, 0.005% (v / v) surfactant P20).

[0079] These techniques can be used to measure the concentration of bound binding protein as a function of the concentration of target protein. Under certain conditions, the fractional concentration of bound binding protein ([bound] / [total]) is generally related to the concentration of total target protein ([target]) by the following formula: [Binding] / [Total]=[Target] / (Kd+[Target])

[0080] Not necessarily, K A Although it is not necessary to precisely determine K, it is sometimes sufficient to obtain a quantitative measure of affinity (e.g., as determined using methods such as ELISA or FACS analysis). A The affinity of the antibody can be proportional to the affinity of the antibody, and can be used to compare, e.g., to determine whether the affinity is high, e.g., 2-fold higher, to obtain a qualitative measure of affinity or to obtain an estimate of affinity, e.g., by activity in a functional assay, e.g., in vitro or in vivo assay. In some cases, in vitro binding assays indicate in vivo activity. In other cases, in vitro binding assays do not necessarily indicate in vivo activity. In some cases, tight binding is beneficial, but in other cases, tight binding is not desirable in vivo and antibodies with lower binding affinity are more desirable.

[0081] In some embodiments, the heavy chain of any of the anti-galectin-9 antibodies described herein further comprises a heavy chain constant region (CH) or a portion thereof (e.g., CH1, CH2, CH3, or a combination thereof). The heavy chain constant region can be of any suitable origin, e.g., human, mouse, rat, or rabbit. In one particular example, the heavy chain constant region is derived from human IgG (gamma heavy chain) of any of the IgG subfamilies described herein.

[0082] In some embodiments, the heavy chain constant regions of the antibodies described herein comprise a single domain (e.g., CH1, CH2, or CH3), or any combination of single domains, of the constant regions (e.g., SEQ ID NOs: 10, 12-14, and 21). In some embodiments, the light chain constant regions of the antibodies described herein comprise a single domain (e.g., CL) of the constant region. Exemplary light and heavy chain sequences are described below. Exemplary light and heavy chain sequences are described below. The hIgG1 LALA sequence contains two mutations L234A and L235A (EU numbering) that inhibit FcgR binding, and a P329G mutation (EU numbering) that abolishes complement C1q binding, thereby abolishing all immune effector functions. The hIgG4 Fab group replacement mutant sequence contains a mutation (S228P; EU numbering) that inhibits Fab group replacement. An IL2 signal sequence (MYRMQLLSCIALSLALVTNS; SEQ ID NO: 9) may be located at the N-terminus of the variable region. This is used in expression vectors, where it is cleaved during secretion and therefore not in the mature antibody molecule. The mature proteins (after secretion) begin with "EVQ" for the heavy chain and "DIM" for the light chain. Exemplary heavy chain constant region amino acid sequences are provided below: hIgG1 heavy chain constant region (SEQ ID NO: 10) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK* hIgG1 heavy chain constant region (SEQ ID NO: 12)

Chem.

[0083] In some cases, the heavy chain constant region of an anti-galectin-9 antibody disclosed herein (e.g., G9.2-17) may have the C-terminal lysine (K) residue removed, e.g., for manufacturing purposes. The corresponding amino acid sequence without the terminal K residue is provided below: hIgG1 heavy chain constant region without the C-terminal lysine (SEQ ID NO:24) ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGV EVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG* hIgG1 LALA heavy chain constant region without the C-terminal lysine (SEQ ID NO:25) [ka] hIgG4 heavy chain constant region without the C-terminal lysine (SEQ ID NO:26) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSPG* hIgG4 heavy chain constant region without the C-terminal lysine (SEQ ID NO:27) ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVE VHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG* hIgG4 mutant heavy chain constant region without the C-terminal lysine (SEQ ID NO:28) [ka] hIgG4 mutant heavy chain constant region without the C-terminal lysine (SEQ ID NO:29) [ka]

[0084] In some embodiments, an anti-Galectin-9 antibody having any of the above light chain constant regions is paired with a light chain having the following light chain constant region: Light chain constant region (SEQ ID NO: 11) TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0085] Exemplary full length anti-galectin-9 antibodies are provided below: G9.2-17 hIgG1 heavy chain (SEQ ID NO: 16) [ka] G9.2-17 hIgG1 heavy chain without the C-terminal lysine residue (SEQ ID NO:30) [ka] G9.2-17 hIgG1 LALA heavy chain (SEQ ID NO: 17) [ka] G9.2-17 hIgG1 LALA heavy chain without the C-terminal lysine residue (SEQ ID NO:31) [ka] G9.2-17 hIgG4 heavy chain (SEQ ID NO: 18) [ka] G9.2-17 hIgG4 heavy chain without the C-terminal lysine residue (SEQ ID NO:32) [ka] G9.2-17 hIgG4 heavy chain (SEQ ID NO:22) [ka] G9.2-17 hIgG4 heavy chain without the C-terminal lysine residue (SEQ ID NO:33) [ka] G9.2-17 hIgG4 Fab group substitution mutant heavy chain (SEQ ID NO: 19) [ka] G9.2-17 hIgG4 Fab group substitution mutant heavy chain without the C-terminal lysine residue (SEQ ID NO:34) [ka] G9.2-17 hIgG4 Fab group substitution mutant heavy chain (SEQ ID NO: 23) [ka] G9.2-17 hIgG4 Fab group substitution mutant heavy chain without the C-terminal lysine residue (SEQ ID NO:35) [ka]

[0086] Any of the above heavy chains may be combined with a light chain as shown below (SEQ ID NO:15). [ka]

[0087] In some embodiments, the anti-galectin-9 antibody comprises a heavy chain IgG1 constant region having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 10. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG1 constant region comprising SEQ ID NO: 13. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region consisting of SEQ ID NO: 10.

[0088] In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 13. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region comprising SEQ ID NO: 13. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region consisting of SEQ ID NO: 13.

[0089] In some embodiments, the constant region is derived from human IgG4. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO:20. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region comprising SEQ ID NO:20. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region consisting of SEQ ID NO:20.

[0090] In any of these embodiments, the anti-galectin-9 antibody comprises a light chain constant region having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 11. In some embodiments, the anti-galectin-9 antibody comprises a light chain constant region comprising SEQ ID NO: 11. In some embodiments, the anti-galectin-9 antibody comprises a light chain constant region consisting of SEQ ID NO: 11.

[0091] In some embodiments, the IgG is a variant with minimal Fc receptor engagement. In one example, the constant region is derived from human IgG1 LALA. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG1 constant region having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 12. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG1 constant region comprising SEQ ID NO: 12. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG1 constant region consisting of SEQ ID NO: 12.

[0092] In some embodiments, the anti-galectin-9 antibody comprises a modified constant region. In some embodiments, the anti-galectin-9 antibody comprises a modified constant region that is immunologically inert, e.g., does not induce complement-mediated lysis or stimulate antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC activity can be assessed using the methods disclosed in U.S. Pat. No. 5,500,362. In other embodiments, the constant region is modified as described in Eur. J. Immunol. (1999) 29:2613-2624; PCT Application No. PCT / GB99 / 01441; and / or UK Patent Application No. 9809951.8. In some embodiments, the IgG4 constant region is a mutant with reduced heavy chain substitution. In some embodiments, the constant region is derived from the human IgG4 Fab group substitution mutant S228P.

[0093] In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 14. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region comprising SEQ ID NO: 14. In one embodiment, the constant region of the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region consisting of SEQ ID NO: 14.

[0094] In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 21. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region comprising SEQ ID NO: 21. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain IgG4 constant region consisting of SEQ ID NO: 21.

[0095] In some embodiments, the anti-galectin-9 antibody has a light chain corresponding to SEQ ID NO: 15; exemplary heavy chain amino acid sequences correspond to SEQ ID NOs: 10 (hIgG1); 12 (hIgG1 LALA); 13 (hIgG4); 20 (hIgG4); 14 (hIgG4 mutant); and 21 (hIgG4 mutant).

[0096] In some embodiments, the anti-galectin-9 antibody has a light chain comprising, consisting essentially of, or consisting of SEQ ID NO: 15. In some embodiments, the anti-galectin-9 antibody has a heavy chain comprising, consisting essentially of, or consisting of any one of the sequences selected from the group consisting of SEQ ID NOs: 16-19, 22, and 23. In some embodiments, the anti-galectin-9 antibody has a light chain comprising, consisting essentially of, or consisting of SEQ ID NO: 15 and a heavy chain comprising, consisting essentially of, or consisting of any one of the sequences selected from the group consisting of SEQ ID NOs: 16-19. In some embodiments, the anti-galectin-9 antibody has a light chain comprising, consisting essentially of, or consisting of SEQ ID NO: 15 and a heavy chain comprising, consisting essentially of, or consisting of any one of the sequences selected from the group consisting of SEQ ID NOs: 16-19, 22, and 23. In some embodiments, the anti-galectin-9 antibody has a light chain comprising, consisting essentially of, or consisting of SEQ ID NO: 15 and a heavy chain comprising, consisting essentially of, or consisting of any one of the sequences selected from the group consisting of SEQ ID NOs: 16-19, 22, and 23. In some embodiments, the anti-galectin-9 antibody has a light chain consisting of SEQ ID NO: 15 and a heavy chain consisting of any one of the sequences selected from the group consisting of SEQ ID NOs: 16-19, 22, and 23. In one specific embodiment, the anti-galectin-9 antibody has a light chain consisting essentially of SEQ ID NO: 15 and a heavy chain consisting essentially of SEQ ID NO: 19. In another specific embodiment, the anti-galectin-9 antibody has a light chain consisting essentially of SEQ ID NO: 15 and a heavy chain consisting essentially of SEQ ID NO: 20.

[0097] In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 16. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence comprising SEQ ID NO: 16. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence consisting of SEQ ID NO: 16.

[0098] In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 17. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence comprising SEQ ID NO: 17. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence consisting of SEQ ID NO: 17.

[0099] In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 18. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence comprising SEQ ID NO: 18. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence consisting of SEQ ID NO: 18.

[0100] In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 22. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence comprising SEQ ID NO: 22. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence consisting of SEQ ID NO: 22.

[0101] In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 19. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence comprising SEQ ID NO: 19. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence consisting of SEQ ID NO: 19.

[0102] In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 23. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence comprising SEQ ID NO: 23. In one embodiment, the anti-galectin-9 antibody comprises a heavy chain sequence consisting of SEQ ID NO: 23.

[0103] In any of these embodiments, the anti-galectin-9 antibody comprises a light chain sequence having at least 80% (e.g., 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% and any increment therein) sequence identity to SEQ ID NO: 15. In some embodiments, the anti-galectin-9 antibody comprises a light chain sequence comprising SEQ ID NO: 15. In some embodiments, the anti-galectin-9 antibody comprises a light chain sequence consisting of SEQ ID NO: 15.

[0104] In specific examples, the anti-galectin-9 antibody used in the therapeutic methods disclosed herein has a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 15. In some embodiments, the anti-galectin-9 antibody used in the therapeutic methods disclosed herein is G9.2-17 IgG4. In some examples, such anti-galectin-9 antibodies do not have a C-terminal lysine residue in the heavy chain.

[0105] Preparation of anti-galectin-9 antibody Antibodies capable of binding to galectin-9 as described herein can be made by any method known in the art, including but not limited to recombinant techniques, an example of which is provided below.

[0106] The nucleic acids encoding the heavy and light chains of the anti-galectin-9 antibody described herein can be cloned into one expression vector, with each nucleotide sequence operably linked to a suitable promoter. In one example, each of the nucleotide sequences encoding the heavy and light chains is operably linked to a separate promoter. Alternatively, the nucleotide sequences encoding the heavy and light chains can be operably linked to a single promoter, such that both the heavy and light chains are expressed from the same promoter. If necessary, an internal ribosome entry site (IRES) can be inserted between the heavy and light chain coding sequences.

[0107] In some instances, the nucleotide sequences encoding the two chains of an antibody are cloned into two vectors, which can be introduced into the same or different cells. When the two chains are expressed in different cells, each of them can be isolated from a host cell expressing such a chain, and the isolated heavy and light chains can be mixed and incubated under suitable conditions to allow the formation of the antibody.

[0108] In general, the nucleic acid sequence encoding one or all chains of the antibody can be operably linked to a suitable promoter and cloned into a suitable expression vector using methods known in the art. For example, the nucleotide sequence and the vector can be contacted with a restriction enzyme to generate complementary ends on each molecule that can pair with each other and join with a ligase under suitable conditions. Alternatively, synthetic nucleic acid linkers can be ligated to the ends of the gene. These synthetic linkers contain nucleic acid sequences that correspond to specific restriction sites in the vector. The choice of expression vector / promoter will depend on the type of host cell used to produce the antibody.

[0109] A variety of promoters can be used to express the antibodies described herein, including, but not limited to, the cytomegalovirus (CMV) intermediate-early promoter, viral LTRs, such as Rous sarcoma virus LTR, HIV-LTR, HTLV-1 LTR, Simian Virus 40 (SV40) early promoter, E. coli lac UV5 promoter, and herpes simplex tk virus promoter.

[0110] Regulatable promoters can also be used, including those that use the lac repressor from E. coli as a transcriptional modulator to regulate transcription from mammalian cell promoters with the lac operator [Brown, M. et al., Cell, 49:603-612 (1987)], and those that use the tetracycline repressor (tetR) [Gossen, M., and Bujard, H., Proc. Natl. Acad. Sci. USA 89:5547-5551 (1992); Yao, F. et al., Human Gene Therapy, 9:1939-1950 (1998); Shockelt, P., et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)]. Other systems include FK506 dimers, VP16, or p65 using astroradiol, RU486, diphenol murislerone, or rapamycin. Inducible systems are available from Invitrogen, Clontech, and Ariad.

[0111] Regulatable promoters containing repressors with operons can be used. In one embodiment, the lac repressor from E. coli can function as a transcription regulator to regulate transcription from mammalian cell promoters with lac operators (M. Brown et al., Cell, 49:603-612 (1987); Gossen and Bujard (1992); M. Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551 (1992)). The tetracycline repressor (tetR) is combined with a transcription activator (VP16) to create a tetR mammalian cell transcription activator fusion protein, tTa (tetR-VP 16), in combination with a minimal promoter with tetO from the human cytomegalovirus (hCMV) major immediate early promoter to create a tetR-tet operator system to control gene expression in mammalian cells. In one embodiment, a tetracycline-inducible switch is used. The tetracycline repressor (tetR) instead of the tetR mammalian cell transcription factor fusion derivative can function as a powerful transmodulator to regulate gene expression in mammalian cells when the tetracycline operator is appropriately placed downstream of the TATA element of the CMVIE promoter (Yao et al., Human Gene Therapy, 10(16):1392-1399 (2003)). One particular advantage of this tetracycline-inducible switch is that it does not require the use of tetracycline repressor-mammalian cell transactivator or repressor fusion proteins, which in some cases may be toxic to cells, to achieve its regulatable effect (Gossen et al., Natl. Acad. Sci. USA, 89:5547-5551 (1992); Shockett et al., Proc. Natl. Acad. Sci. USA, 92:6522-6526 (1995)).

[0112] In addition, the vectors may contain, for example, some or all of the following: a selectable marker gene, such as a neomycin gene, for selection of stable or transient transfectants in mammalian cells; an enhancer / promoter sequence from the immediate early gene of human CMV for high levels of transcription; transcription termination and RNA processing signals from SV40 for mRNA stability; an SV40 polyoma origin of replication and ColE1 for proper episomal replication; an internal ribosome binding site (IRES), a versatile multiple cloning site; and T7 and SP6 RNA promoters for in vitro transcription of sense and antisense RNA. Suitable vectors and methods for generating vectors containing transgenes are well known and available in the art.

[0113] Examples of polyadenylation signals useful in carrying out the methods described herein include, but are not limited to, the human collagen I polyadenylation signal, the human collagen II polyadenylation signal, and the SV40 polyadenylation signal.

[0114] One or more vectors (e.g., expression vectors) containing a nucleic acid encoding any of the antibodies can be introduced into a suitable host cell for producing the antibody. The host cells can be cultured under conditions suitable for expression of the antibody or any of its polypeptide chains. Such antibodies or their polypeptide chains can be recovered from the cultured cells (e.g., from the cells or culture supernatant) by conventional methods, e.g., affinity purification. If desired, the antibody polypeptide chains can be incubated under suitable conditions for a suitable period of time to allow for production of the antibody.

[0115] In some embodiments, the method for preparing the antibodies described herein includes a recombinant expression vector encoding both the heavy and light chains of an anti-galectin-9 antibody, as also described herein. The recombinant expression vector can be introduced into a suitable host cell (e.g., dhfr-CHO cells) by conventional methods, for example, calcium phosphate-mediated transfection. Positively transformed host cells can be selected and cultured under suitable conditions that allow the expression of the two polypeptide chains that form the antibody, which can be recovered from the cells or the medium. If necessary, the two chains recovered from the host cells can be incubated under suitable conditions that allow the formation of the antibody.

[0116] In one example, two recombinant expression vectors are provided, one encoding the heavy chain of an anti-galectin-9 antibody and the other encoding the light chain of an anti-galectin-9 antibody. Both of the two recombinant expression vectors can be introduced into a suitable host cell (e.g., dhfr-CHO cells) by conventional methods, such as calcium phosphate-mediated transfection. Alternatively, each of the expression vectors can be introduced into a suitable host cell. Positive transformants can be selected and cultured under suitable conditions that allow the expression of the antibody polypeptide chains. When the two expression vectors are introduced into the same host cell, the antibody produced therein can be recovered from the host cell or medium. If necessary, the polypeptide chains can be recovered from the host cell or medium and then incubated under suitable conditions that allow the formation of the antibody. When the two expression vectors are introduced into different host cells, each of them can be recovered from the corresponding host cell or the corresponding medium. The two polypeptide chains can then be incubated under suitable conditions for the formation of the antibody.

[0117] Standard molecular biology techniques are used to prepare the recombinant expression vector, transfect the host cells, select for transformants, culture the host cells, and recover the antibody from the culture medium. For example, some antibodies can be isolated by affinity chromatography using a Protein A or Protein G-bound matrix.

[0118] Any of the nucleic acids encoding the heavy chain, the light chain, or both, of the anti-galectin-9 antibodies described herein, vectors containing same (e.g., expression vectors), and host cells containing the vectors are within the scope of the disclosure.

[0119] Anti-galectin-9 antibodies thus prepared can be characterized using methods known in the art to detect and / or measure the reduction, amelioration, or neutralization of Galectin-9 biological activity. For example, in some embodiments, ELISA-type assays are suitable for the qualitative or quantitative measurement of Galectin-9 inhibition of Dectin-1 or TIM-3 signaling.

[0120] The biological activity of anti-galectin-9 antibodies can be verified by incubating the candidate antibody with Dectin-1 and Galectin-9 and monitoring any one or more of the following properties: (a) binding and inhibiting signal transduction mediated by the binding between Dectin-1 and Galectin-9; (b) preventing, ameliorating, or treating any aspect of solid tumors; (c) blocking or reducing Dectin-1 activation; (d) inhibiting (reducing) the synthesis, production, or release of Galectin-9. Alternatively, TIM-3 can be used to verify the biological activity of anti-galectin-9 antibodies using the above protocol. Alternatively, CD206 can be used to verify the biological activity of anti-galectin-9 antibodies using the above protocol.

[0121] In some embodiments, biological activity or efficacy is assessed in a subject, for example, by measuring peripheral and intratumoral T cell ratios, T cell activation, or by macrophage phenotyping.

[0122] Additional assays for determining the biological activity of anti-galectin-9 antibodies include measuring CD8+ and CD4+ (conventional) T cell activation (e.g., inflammatory cytokine levels, e.g., IFN gamma, TNF alpha, CD44, ICOS granzyme B, perforin, IL2 (upregulated), CD26L and IL-10 (downregulated)); measuring macrophage reprogramming (in vitro or in vivo), e.g., from an M2 to an M1 phenotype (e.g., increased MHCII, decreased CD206, increased TNF-α and iNOS), or assessing the level of ADCC, e.g., in an in vitro assay as described herein.

[0123] Cancer Combination Therapy The present disclosure provides methods of treating solid tumors, such as pancreatic ductal adenocarcinoma (PDAC), colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), cholangiocarcinoma (CAA), renal cell carcinoma (RCC), urothelial, head and neck, breast cancer, lung cancer, or other gastrointestinal solid tumors, using any of the above-described anti-galectin antibodies, such as G9.2-17 (e.g., G9.2-17(IgG4)), in combination with one or more chemotherapeutic agents, such as gemcitabine and / or paclitaxel (e.g., Abraxane®).

[0124] Without wishing to be bound by theory, it is believed that anti-galectin-9 antibodies may reprogram the immune response against tumor cells through their inhibition of Dectin-1, e.g., by inhibiting the activity of γδ T cells infiltrating the tumor microenvironment and / or enhancing immune surveillance against tumor cells, e.g., by activating CD4+ and / or CD8+ T cells. Thus, combination of anti-galectin-9 antibodies with one or more chemotherapeutic agents, such as those described herein, is expected to significantly enhance anti-tumor efficacy.

[0125] (A) Examples of solid tumors that can be targeted therapeutically In some embodiments, the present disclosure provides methods of treating solid tumors, such as PDAC, CRC, HCC, cholangiocarcinoma, renal cell carcinoma (RCC), urothelial carcinoma, head and neck cancer, breast cancer, lung cancer, or other gastrointestinal solid tumors. The therapeutic methods disclosed herein include combination therapy with an anti-Gal9 antibody, such as G9.2-17(IgG4), and one or more chemotherapeutic agents (e.g., gemcitabine and paclitaxel as disclosed herein).

[0126] Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with few long-term survivors (Yadav et al., Gastroenterology, 2013, 144, 1252-1261). Inflammation is paramount in PDAC progression, as oncogenic mutations alone are insufficient for tumorigenesis in the absence of concomitant inflammation (Guerra et al., Cancer Cell, 2007, 11, 291-302). Innate and adaptive immunity cooperate to drive tumor progression in PDAC. In particular, specific innate immune subsets within the tumor microenvironment (TME) are well suited to educate adaptive immune effector cells toward a tumor-permissive phenotype. Antigen-presenting cell (APC) populations, including M2-polarized tumor-associated macrophages (TAMs) and myeloid dendritic cells (DCs), induce the generation of immunosuppressive Th2 cells in favor of tumor-protective Th1 cells (Ochi et al., J of Exp Med., 2012, 209, 1671-1687; Zhu et al., Cancer Res., 2014, 74, 5057-5069). Similarly, myeloid-derived suppressor cells (MDSCs) mediate the generation of antitumor CD8+ / - cells in PDAC. + It has been shown to counteract cytotoxic T lymphocyte (CTL) responses and promote metastatic progression (Connolly et al., J Leuk Biol., 2010, 87, 713-725; Pylayeva-Gupta et al., Cancer Cell, 2012, 21, 836-847; Bayne et al., Cancer Cell, 2012, 21, 822-835).

[0127] Colorectal cancer (CRC), also known as intestinal cancer, colon cancer, or rectal cancer, is any cancer that affects the colon and rectum. CRC is known to be caused by genetic alterations in tumor cells and is also influenced by tumor-host interactions. Recent reports have demonstrated a direct correlation between the density of specific T lymphocyte subpopulations and favorable clinical outcomes in CRC, supporting the key role of T cell-mediated immunity in suppressing tumor progression in CRC.

[0128] Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. HCC occurs most frequently in people with chronic liver disease, such as cirrhosis caused by hepatitis B or C infection. HCC is usually accompanied by cirrhosis with extensive lymphocytic infiltration due to chronic viral infection. Many studies have demonstrated that tumor-infiltrating effector CD8+ T cells and Th17 cells correlate with improved survival after surgical resection of tumors. However, tumor-infiltrating effector T cells fail to control tumor growth and metastasis (Pang et al., Cancer Immunol Immunother 2009;58:877-886).

[0129] Cholangiocarcinoma is a group of cancers that arise in the bile duct. Cholangiocarcinomas are usually classified by their location in relation to the liver. For example, intrahepatic cholangiocarcinoma accounts for less than 10% of all cholangiocarcinoma cases and arises in the small bile ducts within the liver. In another example, perihilar cholangiocarcinoma (also known as Kratskin tumor), which accounts for more than half of cholangiocarcinoma cases, begins at the hilum where the two main bile ducts leave the liver after joining it. Others are classified as distal cholangiocarcinomas, which begin in the bile ducts outside the liver.

[0130] In some embodiments, the disclosed methods increase anti-tumor activity (e.g., reduce cell proliferation, tumor growth, tumor volume, and / or tumor mass or weight, or reduce the number of metastatic lesions over time) by at least about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, or more compared to pre-treatment or control subject levels. In some embodiments, the reduction is measured by comparing the cell proliferation, tumor growth, and / or tumor volume of the subject before and after administration of the pharmaceutical composition. In some embodiments, the methods of treating or ameliorating cancer in a subject can improve one or more symptoms of the cancer by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more. In some embodiments, before, during, and after administration of the pharmaceutical composition, the subject's cancerous cells and / or biomarkers are measured in a biological sample, such as blood, serum, plasma, urine, ascites, and / or biopsy, from a tissue or organ. In some embodiments, a method of reducing the volume, size, weight, or mass of a tumor in a subject to an undetectable size or to less than about 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, or 90% of the size, weight, or mass of the tumor in the subject before treatment includes administering a composition of the invention. In other embodiments, the methods include administering a composition of the invention to reduce the subject's cell proliferation rate or tumor growth rate to an undetectable rate or to less than about 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, or 90% of the rate before treatment. In other embodiments, the methods of reducing the incidence of metastatic lesions or the number or size of metastatic lesions in a subject to an undetectable rate or to less than about 1%, 2%, 5%, 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, or 90% of the rate before treatment include administering a composition of the invention.

[0131] The term "about" or "approximately" means within an acceptable error range of a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within an acceptable standard deviation, as practiced in the art. Alternatively, "about" can mean within a range of up to ±20%, preferably up to ±10%, more preferably up to ±5%, and even more preferably up to ±1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 2-fold, of a value. When a particular value is described in the application and claims, unless otherwise indicated, the term "about" is implicit in this context to mean within an acceptable error range of the particular value.

[0132] As used herein, the term "treating" refers to the application or administration of a composition comprising one or more active agents to a subject having a target disease or disorder, a symptom of a disease / disorder, or a predisposition to a disease / disorder, for the purpose of curing, curing, mitigating, alleviating, altering, treating, ameliorating, ameliorating, or affecting the disorder, the symptom of a disease or disorder, or the predisposition to a disease or disorder.

[0133] Alleviating the target disease / disorder includes delaying the onset or progression of the disease, or reducing the severity of the disease, or prolonging survival. Alleviating the disease or prolonging survival does not necessarily require a therapeutic effect. As used herein, "delaying" the onset of the target disease or disorder means postponing, hindering, slowing down, inhibiting, stabilizing, and / or postponing the progression of the disease. This delay can vary in time depending on the disease being treated and / or the medical history of the individual. A method of "delaying" or alleviating the onset of a disease, or a method of delaying the onset of a disease, is a method that reduces the probability of developing one or more symptoms of the disease within a given time frame and / or reduces the severity of symptoms in a given time frame compared to not using the method. Such comparisons are usually based on clinical studies using a sufficient number of subjects to obtain statistically significant results.

[0134] "Onset" or "progression" of a disease refers to the initial symptoms and / or subsequent progression of a disease. Onset of a disease can be detected and assessed using standard clinical techniques well known in the art. However, development also refers to progression that may be undetectable. For purposes of this disclosure, onset or progression refers to the biological course of a condition. "Onset" includes occurrence, recurrence, and onset. As used herein, "onset" or "onset" of a target disease or disorder includes initial onset and / or recurrence.

[0135] (B) Exemplary patient populations to be treated Subjects with a target solid tumor, e.g., PDAC, as disclosed herein, can be identified by routine medical examination, e.g., clinical tests, organ function tests, genetic tests, interventional procedures (biopsy, surgery), any and all relevant imaging modalities. In some embodiments, the subjects to be treated with the methods described herein are human cancer patients who have undergone or are undergoing anti-cancer therapy, e.g., chemotherapy, radiation therapy, immunotherapy, tumor treating fields (TTFields), or surgery, in any combination or sequence of the therapies outlined.

[0136] In some embodiments, the subject has previously received an immunomodulatory anti-tumor agent. Non-limiting examples of such immunomodulatory agents include, but are not limited to, anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-OX40, anti-CD137, anti-TIGIT, anti-PVRIG, platinum-based agents, and the like. Non-limiting examples of platinum-based agents include cisplatin, carboplatin, oxaliplatin, nedaplatin, and lobaplatin. In some embodiments, the subject exhibits disease progression throughout treatment. In other embodiments, the subject is resistant to treatment (either de novo or acquired). In some embodiments, such a subject is documented to be suffering from an advanced malignant tumor (e.g., inoperable or metastatic). Alternatively or additionally, in some embodiments, the subject has no standard treatment options available or is ineligible for standard treatment options, which refers to therapies commonly used in clinical settings to treat the corresponding solid tumor.

[0137] Tumor Treating Electric Fields (TTFields) are a cancer treatment modality that uses alternating electric fields of intermediate frequency (approximately 100-500 kHz) and low intensity (1-3 V / cm) to disrupt cell division. In any of the embodiments described herein, the anti-galectin-9 antibody in combination with a chemotherapeutic agent described herein may be administered prior to, concurrently with, or following a Tumor Treating Electric Fields (TTFields) regimen. In any of the embodiments described herein, the anti-galectin-9 antibody in combination with a chemotherapeutic agent described herein may be administered prior to, concurrently with, or following a reverse-thermal hydrogel technology based therapy.

[0138] In some cases, the subject may be a human patient suffering from refractory disease, for example, refractory PDAC. As used herein, "refractory" refers to a tumor that does not respond to treatment or becomes resistant to it. In some cases, the subject may be a human patient suffering from recurrent disease, for example, recurrent PDAC. As used herein, "relapsed" or "recurring" refers to a tumor that recurs or progresses after a period of improvement (for example, partial or complete response) by treatment.

[0139] In some embodiments, a human patient to be treated with the methods disclosed herein meets one or more of the inclusion and exclusion criteria disclosed in Example 2 below. For example, the human patient may be over 18 years old and may have histologically unresectable metastatic cancer (e.g., adenocarcinoma and squamous cell carcinoma). The patient may have measurable disease according to RECIST v.1.1. In some cases, the human patient may have a recent archival tumor sample (e.g., obtained within the last 5 years) available for biomarker analysis (e.g., galectin-9 tumor tissue expression, which may be assessed by IHC). In some cases, the human patient is a PDAC patient who has undergone at least one series of systemic therapy in the metastatic setting. Such patients may be gemcitabine-containing regimen naive or at least 6 months since being treated with a gemcitabine-containing regimen. The patient may have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 and / or a Karnofsky score of >70. Patients should have adequate hematologic and end-organ function, e.g., neutrophil count ≥ 1 × 10 9 / L, platelet count ≥100×10 9 / L, HCC in part 1 ≥ 50 × 10 9 / L; without transfusion in the previous week, hemoglobin ≥ 9.0 g / dL, creatinine ≤ 1.5 x ULN, AST (SGOT) ≤ 3 x ULN (≤ 5 x ULN if HCC or liver metastases present), ALT (SGPT) ≤ 3 x ULN (≤ 5 x ULN if HCC or liver metastases present), bilirubin ≤ 1.5 x ULN (patients with known Gilbert's disease may have bilirubin ≤ 3.0 x ULN), albumin ≥ 3.0 g / dL, INR and PTT ≤ 1.5 x ULN; and / or amylase and lipase ≤ 1.5 x ULN. In some cases, human patients show no evidence of active infection or infection requiring parenteral antibiotics, nor any severe infection within 4 weeks prior to initiation of treatment. Pancreatic, biliary, or enteric fistulas are permitted if they are appropriately non-infectious and controlled with patent drains.

[0140] Alternatively, or in addition, human patients receiving any of the treatments disclosed herein may be free of: (i) metastatic cancer of unknown primary site; (ii) clinically significant active uncontrollable bleeding, any bleeding diathesis (e.g., active peptic ulcer disease); (iii) radiation therapy within 4 weeks of the first dose of treatment; (iv) fungal tumor mass or locally advanced PDAC; (v) CTCAE grade 3 or higher toxicity from prior cancer treatment (excluding alopecia and vitiligo); (v) history of a second malignancy; (vi) evidence of severe or uncontrollable systemic disease, New York Heart Association (NYHA) class ≥2 congestive heart failure, or myocardial infarction (MI) within 6 months; (vii) severe non-healing wounds, active ulcers, or untreated fractures; (viii) uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage procedures; (ix ) history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins;(x) history of significant vascular disease within 6 months of treatment (e.g., aortic aneurysm or recent arterial thrombosis requiring surgical repair), history of pulmonary embolism, stroke, or transient ischemic attack within 3 months prior to treatment, and / or history of abdominal fistula or gastrointestinal perforation within 6 months prior to treatment;(xi) active autoimmune disease (excluding type I diabetes mellitus, hypothyroidism requiring hormone replacement only, vitiligo, psoriasis, or alopecia);(xii) requirement of systemic immunosuppressive treatment;(xii) tumor-related pain (greater than grade 3) unresponsive to extensive analgesic interventions (oral and / or patch);(xiii) uncontrollable hypercalcemia despite use of bisphosphonates;(xiv) received organ transplant(s).

[0141] In some cases, the subject is a human patient with an elevated level of galectin-9 compared to a control level. The level of galectin-9 can be the plasma or serum level of galectin-9 in the human patient. In other examples, the level of galectin-9 can be the level of cell surface galectin-9, e.g., the level of galectin-9 on cancer cells. In one example, the level of galectin-9 can be the level of surface galectin-9 expressed on cancer cells in patient-derived organotypic tumor spheroids (PDOTs), which can be prepared, for example, by the methods disclosed in the Examples below. The control level can refer to the level of galectin-9 in a corresponding sample of a homogenous subject (e.g., human) that does not have a solid tumor. In some examples, the control level represents the level of galectin-9 in a healthy subject.

[0142] To identify such subjects, a suitable biological sample can be obtained from a subject suspected of suffering from a solid tumor, and the biological sample can be analyzed to determine the level of galectin-9 contained therein (e.g., free, cell surface expressed, or total) using conventional methods, such as ELISA or FACS. In some embodiments, organoid cultures are prepared, for example, as described herein, and used to evaluate the level of galectin-9 in a subject. Single cells derived from a particular fraction obtained as part of the organoid preparation process are also suitable for evaluating the level of galectin-9 in a subject. In some cases, the assay for measuring the level of free form or cell surface expressed galectin-9 includes the use of an antibody that specifically binds to galectin-9 (e.g., specifically binds to human galectin-9). Any of the anti-galectin-9 antibodies known in the art can be tested for suitability in any of the above assays, and then used in such assays in a predetermined manner. In some embodiments, the antibodies described herein (e.g., G9.2-17 antibody) can be used in such assays. In some embodiments, the antibody is described in co-pending U.S. patent application Ser. No. 16 / 173,970 and co-owned, co-pending International application PCT / US18 / 58028, the relevant disclosures of each of which are incorporated by reference for the purposes and subject matter referenced herein. In some examples, the anti-galectin-9 antibody is a Fab molecule. Assay methods for determining galectin-9 levels as disclosed herein are also within the scope of this disclosure.

[0143] (C) Exemplary Treatment Conditions In some embodiments, an antibody described herein, e.g., G9.2-17 (such as an IgG4 form thereof), is administered to a subject in need of treatment in an amount sufficient to suppress Galectin-9 (and / or Dectin-1 or TIM-3 or CD206) activity on immunosuppressive immune cells of a tumor in vivo by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more). In other embodiments, an antibody described herein, e.g., G9.2-17, is administered in an amount effective to reduce Galectin-9 (and / or Dectin-1 or TIM-3 or CD206) activity levels on immunosuppressive immune cells by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more) (compared to levels before treatment or in a control subject). In some embodiments, an antibody described herein, e.g., G9.2-17, is administered to a subject in need of treatment in an amount sufficient to promote M1-like programming in TAMs in vivo (compared to pre-treatment or control subject levels) by at least 20% (e.g., 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).

[0144] Conventional methods known to those skilled in the art can be used to administer the pharmaceutical composition to a subject, depending on the type of disease or site of disease to be treated, hi some embodiments, the anti-galectin-9 antibody may be administered to the subject by intravenous infusion.

[0145] Injectable compositions may contain various carriers, such as vegetable oils, dimethylactamide, dimethylformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (such as glycerol, propylene glycol, and liquid polyethylene glycol). For intravenous infusion, water-soluble antibodies may be administered by drip infusion, in which a pharmaceutical formulation containing the antibody and a physiologically acceptable excipient is injected. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution, or other suitable excipients. Intramuscular preparations, for example, a sterile formulation of a suitable soluble salt form of the antibody, may be administered by dissolving it in a pharmaceutical excipient, such as water for injection, 0.9% saline, or 5% glucose solution.

[0146] In some embodiments, the method is provided, wherein the anti-galectin-9 antibody is administered simultaneously with one or more chemotherapeutic agents. In some embodiments, the anti-galectin-9 antibody is administered before or after the one or more chemotherapeutic agents. In some embodiments, the one or more chemotherapeutic agents are administered systemically. In some embodiments, the one or more chemotherapeutic agents are administered locally. In some embodiments, the one or more chemotherapeutic agents are administered intravenously (e.g., as a bolus or by continuous infusion over a period of time), intramuscularly, intraperitoneally, intracerebrospinal, subcutaneously, intra-arterial, intra-articular, intravesical, intrasynovial, intrathecal, intratumor, suburothelial, oral, inhaled, or topically. In one embodiment, the one or more chemotherapeutic agents are administered to the subject by intravenous infusion. In some embodiments, the anti-galectin-9 antibody described herein is administered to a patient currently undergoing or who has previously undergone an anti-cancer therapy, e.g., chemotherapy.

[0147] An effective amount of the pharmaceutical compositions described herein can be administered to a subject (e.g., a human) in need of treatment via a suitable route, either systemically or locally. In some embodiments, the anti-galectin-9 antibody is administered intravenously, e.g., as a bolus or by continuous infusion over a period of time, by intramuscular, intraperitoneal, intracerebrospinal, subcutaneous, intra-arterial, intra-articular, intrasynovial, intrathecal, intratumoral, suburothelial, oral, inhalation, or topical routes. In one embodiment, the anti-galectin-9 antibody is administered to the subject by intravenous infusion. In one embodiment, the anti-galectin-9 antibody is administered to the subject intraperitoneally. As used herein, "effective amount" refers to the amount of each active agent, alone or in combination with one or more other active agents, required to confer a therapeutic effect on the subject. In some embodiments, the therapeutic effect is a decrease in galectin-9 activity and / or amount / expression, a decrease in Dectin-1 signaling, a decrease in TIM-3 signaling, a decrease in CD206 signaling, or an increase in an anti-tumor immune response in the tumor microenvironment. Non-limiting examples of increased anti-tumor response include increased activation levels of effector T cells or switching of TAMs from M2 phenotype to M1 phenotype. In some cases, anti-tumor response includes increased ADCC reaction. Determining whether the amount of antibody achieves a therapeutic effect will be clear to those skilled in the art. As recognized by those skilled in the art, effective amounts will vary depending on the specific condition being treated, the severity of the condition, individual patient parameters including age, physical condition, size, sex, and weight, duration of treatment, nature of concomitant therapy (if any), specific route of administration, and similar factors within the knowledge and expertise of medical practitioners. These factors are well known to those skilled in the art and can be addressed with only routine experimentation. In general, it is preferred to use the maximum dose of each component or combination thereof, i.e., the highest safe dose according to sound medical judgment.

[0148] Generally, empirical considerations such as half-life contribute to the determination of dosage. For example, antibodies compatible with the human immune system, such as humanized antibodies or fully human antibodies, are sometimes used to extend the half-life of the antibody and prevent the antibody from being attacked by the host's immune system. The frequency of administration can be determined and adjusted over the course of treatment, and is generally, but not necessarily, based on the treatment and / or suppression and / or improvement and / or delay of the target disease / disorder. Alternatively, a sustained release formulation of the antibody may be appropriate. Various formulations and devices for achieving sustained release are known in the art.

[0149] In one example, the dosage of the antibody described herein is empirically determined in an individual who is administered one or more doses of the antibody. The individual is given increasing doses of the antagonist. To evaluate the effectiveness of the antagonist, indicators of the disease / disorder can be followed.

[0150] Treatment with anti-galectin-9 antibody Any of the anti-galectin-9 antibodies described herein can be used in the methods described herein. In some embodiments, the anti-galectin-9 antibody is G9.2-17. The G9.2-17 can be an IgG4 molecule (G9.2-17(IgG4)) disclosed herein. In a particular example, the anti-galectin-9 antibody (G9.2-17) used herein has a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 15. The anti-Gal9 antibody can be formulated as disclosed herein and administered to a subject in need of the treatment by any suitable route, for example, intravenous infusion.

[0151] In some examples, an anti-galectin-9 antibody disclosed herein (eg, G9.2-17, such as G9.2-17(IgG4)) may be administered to a subject at an appropriate dose, for example, from about 0.2 to about 32 mg / kg. Examples include 0.2 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 2 mg / kg, 2 mg / kg to 3 mg / kg, 3 mg / kg to 4 mg / kg, 4 mg / kg to 6 mg / kg, 4 mg / kg to 6.3 mg / kg, 6 mg / kg to 8 mg / kg, 6.3 mg / kg to 8 mg / kg, 4 mg / kg to 8 mg / kg, 8 mg / kg to 12 mg / kg, 8 mg / kg to 10 mg / kg, 10 mg / kg to 12 mg / kg, 12 mg / kg to 16 mg / kg, 16 mg / kg to 20 mg / kg, 20 mg / kg to 24 mg / kg, 24 mg / kg to 28 mg / kg, or 28 mg / kg to 32 mg / kg (e.g., 0.2 mg / kg , 0.5mg / kg, 1mg / kg, 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, 6.3mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 11mg / kg, 12mg / kg, 13mg / kg, 14mg / kg, 15mg / kg, 16mg / kg, 17mg / kg, 18mg / kg, 19mg / kg, 20mg / kg, 21mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg, 27mg / kg, 28mg / kg, 29mg / kg, 30mg / kg, 31mg / kg, or 32mg / kg), or any value between these ranges.In some embodiments, the antibody is administered at a dose of about 0.2 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, about 1 mg / kg to 2 mg / kg, about 2 mg / kg to 4 mg / kg, about 4 mg / kg to 8 mg / kg, 4 mg / kg to 6 mg / kg, 4 mg / kg to 6.3 mg / kg, 6 mg / kg to 8 mg / kg, 6.3 mg / kg to 8 mg / kg, about 8 mg / kg to 12 mg / kg, about 12 mg / kg to 16 mg / kg, about 16 mg / kg to 20 mg / kg, about 20 mg / kg to 24 mg / kg, about 24 mg / kg to 28 mg / kg, or about 28 mg / kg to 32 mg / kg (e.g., about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, about 1 mg / kg, g, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 6.3 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, or about 32 mg / kg), or any value therebetween within these ranges.

[0152] In some embodiments, the anti-Gal-9 antibody, such as G9.2-17(IgG4), is administered at 0.2 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 0.6 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 0.63 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 2 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 4 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 6 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 6.3 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 8 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 10 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 12 mg / kg. In some embodiments, the anti-Gal-9 antibody is administered at 16 mg / kg. In some cases, multiple administrations of the anti-galectin-9 antibody may be administered to the subject at appropriate intervals or cycles, for example, once a week, once every 2 to 4 weeks (e.g., once every 2, 3, or 4 weeks). The treatment may be continued for an appropriate period of time, for example, up to 3 months, up to 6 months, or up to 12 months, or up to 24 months or more. In some embodiments, the anti-Gal-9 antibody may be administered to the subject once every week at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-Gal-9 antibody is administered to the subject once every week at a dose of 10 mg / kg. Alternatively, the anti-Gal-9 antibody is administered to the subject once every week at a dose of 16 mg / kg.

[0153] In some cases, an anti-Gal-9 antibody, such as G9.2-17(IgG4) disclosed herein, may be administered to a subject at a fixed dose, e.g., about 650 mg to about 1120 mg, once every week to once every four weeks. In some examples, the anti-Gal-9 antibody is administered to a subject at about 650 mg to about 700 mg once every week. In some examples, the anti-Gal-9 antibody is administered to a subject at about 650 mg to about 700 mg once every two weeks. In some examples, the anti-Gal-9 antibody is administered to a subject at about 1040 mg to about 1120 mg once every week. In some examples, the anti-Gal-9 antibody is administered to a subject at about 1040 mg to about 1120 mg once every two weeks.

[0154] In some examples, the anti-Gal-9 antibody, such as the G9.2-17 (IgG4) antibody, is administered to a human patient having a solid tumor (e.g., PDAC) disclosed herein at a dose of about 3 mg / kg by intravenous infusion once every two weeks. In other examples, the anti-Gal-9 antibody is administered to a human patient having the target solid tumor at a dose of about 15 mg / kg by intravenous infusion once every two weeks. In other examples, the anti-Gal-9 antibody is administered to a human patient having the target solid tumor at a dose of about 0.2 mg / kg by intravenous infusion once every two weeks. In other examples, the anti-Gal-9 antibody is administered to a human patient having the target solid tumor at a dose of about 0.6 mg / kg by intravenous infusion once every two weeks. In other examples, the anti-Gal-9 antibody is administered to a human patient having the target solid tumor at a dose of about 0.63 mg / kg by intravenous infusion once every two weeks. In another example, the anti-Gal-9 antibody is administered to the human patient having the target solid tumor by intravenous infusion at a dose of about 2 mg / kg once every two weeks. In another example, the anti-Gal-9 antibody is administered to the human patient having the target solid tumor by intravenous infusion at a dose of about 4 mg / kg once every two weeks. In another example, the anti-Gal-9 antibody is administered to the human patient having the target solid tumor by intravenous infusion at a dose of about 6 mg / kg once every two weeks. In another example, the anti-Gal-9 antibody is administered to the human patient having the target solid tumor by intravenous infusion at a dose of about 6.3 mg / kg once every two weeks. In another example, the anti-Gal-9 antibody is administered to the human patient having the target solid tumor by intravenous infusion at a dose of about 8 mg / kg once every two weeks. In another example, the anti-Gal-9 antibody is administered to the human patient having the target solid tumor by intravenous infusion once every two weeks at a dose of about 10 mg / kg. In another example, the anti-Gal-9 antibody is administered to the human patient having the target solid tumor by intravenous infusion once every two weeks at a dose of about 12 mg / kg. In another example, the anti-Gal-9 antibody is administered to the human patient having the target solid tumor by intravenous infusion once every two weeks at a dose of about 16 mg / kg.

[0155] In another example, the anti-Gal-9 antibody is administered to a human patient having the target solid tumor by intravenous infusion once every two weeks at a dose selected from 0.2 mg / kg, 0.63 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 6.3 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, and 16 mg / kg or more. In some embodiments, the anti-Gal-9 antibody may be administered to the patient once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the patient once weekly at a dose of 10 mg / kg or once weekly at a fixed dose of 650-700 mg. Alternatively, the anti-galectin-9 antibody is administered to the patient once weekly at a dose of 16 mg / kg or once weekly at a fixed dose of 1040-1120 mg.

[0156] In some examples, about 2 mg / kg to 16 mg / kg of an anti-Gal9 antibody (e.g., G9.2-17 in IgG4 form) may be administered to a subject in need of the treatment once every two weeks. In some examples, about 0.2 mg / kg to 16 mg / kg of an anti-Gal9 antibody (e.g., G9.2-17 in IgG4 form) may be administered to a subject in need of the treatment once every two weeks. In some examples, the anti-Gal9 antibody (e.g., G9.2-17 in IgG4 form disclosed herein having a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 15) is administered to the subject by intravenous infusion once every two weeks at a dose of about 0.5 mg / kg, 0.6 mg / kg, 0.63 mg / kg, 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, 6.3 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg, or any value therebetween. In some embodiments, the anti-Gal9 antibody may be administered to the subject once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 10 mg / kg, or once weekly at a fixed dose of 650-700 mg. Alternatively, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 16 mg / kg, or once weekly at a fixed dose of 1040-1120 mg.

[0157] In some examples, the anti-Gal9 antibody (e.g., G9.2-17 in IgG4 form disclosed herein having a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 15) is administered to the subject by intravenous infusion at a dose of about 0.2 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 0.6 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 0.63 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 2 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 4 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 6 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 6.3 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 8 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 10 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 12 mg / kg once every two weeks. In some examples, the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 16 mg / kg once every two weeks. In some embodiments, the anti-Gal9 antibody may be administered to the subject once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 10 mg / kg, or once weekly at a fixed dose of 650-700 mg. Alternatively, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 16 mg / kg, or once weekly at a fixed dose of 1040-1120 mg.

[0158] In some examples, the anti-Gal9 antibody (e.g., G9.2-17 in IgG4 form disclosed herein having a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 15) is administered to the subject at a dose of about 0.2 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, about 1 mg / kg to 2 mg / kg, about 3 mg / kg to 4 mg / kg, about 4 mg / kg to 6 mg / kg, about 4 mg / kg to 6.3 mg / kg, or about 5 mg / kg to 7 mg / kg. , about 4 mg / kg to 8 mg / kg, about 8 mg / kg to 10 mg / kg, about 8 mg / kg to 12 mg / kg, about 10 mg / kg to 12 mg / kg, about 12 mg / kg to 16 mg / kg, about 16 mg / kg to 20 mg / kg, about 20 mg / kg to 24 mg / kg, about 24 mg / kg to 28 mg / kg, or about 28 mg / kg to 32 mg / kg (e.g., about 0.2 mg / kg, about 0.6 mg / kg , about 0.63mg / kg, about 0.5mg / kg, about 1mg / kg, about 2mg / kg, about 3mg / kg, about 4mg / kg, about 5mg / kg, about 6mg / kg, about 6.3mg / kg, about 7mg / kg, Approximately 8mg / kg, approximately 9mg / kg, approximately 10mg / kg, approximately 11mg / kg, approximately 12mg / kg, approximately 13mg / kg, approximately 14mg / kg, approximately 15mg / kg, approximately 16mg / kg, approximately 17mg / kg, approximately The anti-Gal9 antibody may be administered by intravenous infusion once weekly at a dose of about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, or 32 mg / kg), or any value between these. In some embodiments, the anti-Gal9 antibody may be administered to the subject once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 10 mg / kg, or at a flat dose of 650 to 700 mg. Alternatively, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 16 mg / kg or at a flat dose of 1040-1120 mg once weekly.

[0159] In some examples, the anti-Gal9 antibody (e.g., G9.2-17 in IgG4 form disclosed herein having a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 15) is administered to the subject at a dose of 0.2 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 2 mg / kg, 3 mg / kg to 4 mg / kg, about 4 mg / kg to 6 mg / kg, about 4 mg / kg to 6.3 mg / kg, 4 mg / kg to 8 mg / kg, 8 mg / kg to 12 mg / kg, 8 mg / kg to 10 mg / kg, 10 mg / kg to 12 mg / kg, 12 mg / kg to 16 mg / kg, 16 mg / kg to 20 mg / kg, 20 mg / kg to 24 mg / kg, 24 mg / kg to 28 mg / kg, or 28 mg / kg to 32 mg / kg (e.g., 0.2 mg / kg, 0.6 mg / kg, 0.63 mg / kg, 0.5 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 6.3 mg / kg, about 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, or 32 mg / kg), or any numerical value between these ranges, administered by intravenous infusion once weekly. In some embodiments, the anti-Gal9 antibody may be administered to the subject once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 10 mg / kg, or once weekly at a fixed dose of 650-700 mg. Alternatively, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 16 mg / kg, or once weekly at a fixed dose of 1040-1120 mg.

[0160] In some examples, the anti-Gal9 antibody (e.g., G9.2-17 in IgG4 form disclosed herein having a heavy chain of SEQ ID NO: 19 and a light chain of SEQ ID NO: 15) is administered to the subject by intravenous infusion once a week at a dose of about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, 6.3 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg, or any value therebetween. In some embodiments, the anti-Gal9 antibody may be administered to the subject once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 10 mg / kg, or at a flat dose of 650-700 mg. Alternatively, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 16 mg / kg, or at a flat dose of 1040-1120 mg.

[0161] In other embodiments, an anti-galectin-9 antibody such as G9.2-17(IgG4) may be administered to a human patient once a week at a suitable dose (e.g., a dose disclosed herein). For example, 2.0 mg / kg of G9.2-17(IgG4) may be administered to a human patient once a week. For example, 6.3 mg / kg of G9.2-17(IgG4) may be administered to a human patient once a week. In another example, 10 mg / kg of G9.2-17(IgG4) may be administered to a human patient once a week. Alternatively, 12 mg / kg of G9.2-17(IgG4) may be administered to a human patient once a week. In yet another example, 16 mg / kg of G9.2-17(IgG4) may be administered to a human patient once a week.

[0162] In some cases, the anti-galectin-9 antibody may be administered to the human patient for at least two cycles, at least three cycles, at least four cycles, at least five cycles, at least six cycles, or more. In some cases, the treatment period may be from 6 months to 12 months. In other cases, the treatment period may be from 12 months to 24 months. In other cases, the treatment period may be greater than 24 months.

[0163] In some embodiments, the anti-galectin-9 antibody disclosed herein (e.g., G9.2-17 IgG4) is administered intravenously with an infusion period of 30 minutes to 6 hours. In some examples, the intravenous infusion of the anti-galectin-9 antibody may be performed for 30 minutes to 2 hours. In other examples, the anti-galectin-9 antibody may be administered with a prolonged infusion period, such as, for example, about 2 to 6 hours, such as, for example, about 2 to 4 hours or about 4 to 6 hours. In certain examples, the anti-galectin-9 antibody may be infused intravenously for a period of about 3 hours, about 4 hours, about 5 hours, or about 6 hours.

[0164] In certain embodiments, the interval or cycle is one week. In certain embodiments, the interval or cycle is two weeks. In some embodiments, the regimen is once every two weeks for one cycle, once every two weeks for two cycles, once every two weeks for three cycles, once every two weeks for four cycles, or once every two weeks for four or more cycles. In some embodiments, the treatment is once every two weeks for one to three months, once every two weeks for three to six months, once every two weeks for six to twelve months, or once every two weeks for twelve to twenty-four months or more.

[0165] In certain embodiments, the interval or cycle is 3 weeks. In some embodiments, the regimen is once every 3 weeks for 1 cycle, once every 3 weeks for 2 cycles, once every 3 weeks for 3 cycles, once every 3 weeks for 4 cycles, or once every 3 weeks for 4 cycles or more. In some embodiments, the treatment is once every 3 weeks for 1-3 months, once every 3 weeks for 3-6 months, once every 3 weeks for 6-12 months, or once every 3 weeks for 12-24 months or more.

[0166] In certain embodiments, the interval or cycle is 4 or more weeks. In some embodiments, the regimen is 1 cycle of 4 or more weeks, 2 cycles of 4 or more weeks, 3 cycles of 4 or more weeks, 4 cycles of 4 or more weeks, or 4 or more cycles of 4 or more weeks. In some embodiments, the treatment is 1-3 months of 4 or more weeks, 3-6 months of 4 or more weeks, 6-12 months of 4 or more weeks, or 12-24 months of 4 or more weeks. In some embodiments, the treatment is a combination of treatments at various times, e.g., 2 weeks, 3 weeks, 4 or more weeks. In some embodiments, the treatment interval is adjusted according to the patient's response to the treatment. In some embodiments, the dose(s) is adjusted according to the patient's response to the treatment. In some embodiments, the dose is altered during the treatment interval. In some embodiments, the treatment may be temporarily stopped. In some embodiments, the treatment with anti-galectin-9 is temporarily stopped. In some embodiments, chemotherapy is temporarily stopped. In some embodiments, both are temporarily suspended. In any of these embodiments, the anti-Gal9 antibody may be G9.2-17, an IgG4 form disclosed herein, having a heavy chain of SEQ ID NO:19 and a light chain of SEQ ID NO:15.

[0167] Alternatively, human patients may be started on a low dose of an anti-galectin-9 antibody, such as G9.2-17(IgG4) disclosed herein, e.g., 0.2 mg / kg, 0.63 mg / kg, or 2 mg / kg. If no side effects are observed, the dose of the antibody may be increased, e.g., to 6.3 mg / kg, 10 mg / kg, or 16 mg / kg.

[0168] chemotherapy The one or more chemotherapeutic agents can include antimetabolites, microtubule (e.g., tubulin) inhibitors, platinum agents, or combinations thereof.Antimetabolites include, for example, folate antagonists (e.g., methotrexate) and nucleotide analogs such as pyrimidine antagonists (e.g., 5-fluorouracil, floxuricine, cytarabine, capecitabine, and gemcitabine), purine antagonists (e.g., 6-mercaptopurine and 6-thioguanine), and adenosine deaminase inhibitors (e.g., cladribine, fludarabine, and pentostatin).Microtubule inhibitors (MIT) include, for example, paclitaxel (e.g., Taxol®), docetaxel, vinblastine, vincristine, and vinorelbine.

[0169] In some examples, the antimetabolite used in the methods disclosed herein is gemcitabine, which may be administered by intravenous infusion. The amount of gemcitabine administered to a subject will depend on many factors, such as height and weight, general health or other health concerns, and the type of cancer being treated, but will be within the knowledge of a physician following guidelines provided by the Food and Drug Administration (see, for example, the drug labeling of approved gemcitabine products). In some examples, a subject will receive gemcitabine at a dose of 1000 mg / m 2Gemcitabine may be administered by intravenous infusion over 30 minutes at a dose of 0.01 mg / kg once weekly for up to 7 weeks, optionally followed by a week off treatment. Subsequent cycles may consist of weekly infusions for 3 consecutive weeks every 4 weeks. If one or more adverse effects occur, the dose of gemcitabine may be reduced or treatment may be withheld. Further details regarding management of adverse effects associated with gemcitabine treatment are provided in Example 2 below.

[0170] Microtubule inhibitors are certain compounds that inhibit the formation of microtubules in cells, thus blocking cell proliferation. In some instances, the microtubule inhibitor is a stabilizer that promotes microtubule polymerization. Examples include taxanes and epothilones. In other instances, the microtubule inhibitor is a destabilizer that promotes microtubule depolymerization. Examples include vinca alkaloids. In some instances, the microtubule inhibitor used in the methods disclosed herein is paclitaxel. Optionally, the paclitaxel is in free form. In other instances, the paclitaxel is bound to a protein, such as albumin. In certain instances, the paclitaxel is Abraxane®, which is paclitaxel bound to nanoparticle albumin.

[0171] The amount of paclitaxel, e.g., protein-bound paclitaxel such as nab-paclitaxel, administered to a subject will depend on many factors, such as height and weight, general health or other health concerns, and the type of cancer being treated, but will be within the knowledge of a physician following guidelines provided by the Food and Drug Administration (see, e.g., drug labeling for approved gemcitabine products). For example, paclitaxel bound to nanoparticle albumin (nab-paclitaxel, e.g., Abraxane®) can be administered at 260 mg / m 2It can be administered by intravenous infusion over 30 minutes at 100 mg / m once every 3 weeks. If severe adverse effects (e.g., neutropenia or severe sensory neuropathy) are observed, the dose of paclitaxel may be reduced. Optionally, the dose of nab-paclitaxel can be increased to 180 mg / m 2 When combined with the anti-Gal9 antibody, the dose of paclitaxel may be reduced to 125 mg / m 2 If necessary, the dose of paclitaxel may be increased to 100 mg / m 2 or 75 mg / m 2 Further details regarding management of adverse effects associated with paclitaxel are provided in Example 2 below.

[0172] Optionally, the chemotherapeutic agent used in combination with the anti-Gal-9 antibody may include a platinum agent, such as cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, or satraplatin.

[0173] Combination therapy Combination therapies provided herein include any of the anti-galectin-9 antibody therapeutics disclosed herein (e.g., including the antibody G9.2-17 (IgG4)) and any of the chemotherapeutic agents disclosed herein (e.g., including a combination of gemcitabine and paclitaxel).

[0174] In some specific examples, the anti-Gal9 antibody (e.g., G9.2-17 in IgG4 form), gemcitabine, and paclitaxel (e.g., paclitaxel bound to nanoparticle albumin, i.e., Abraxane®) may be administered to a subject in need of the treatment according to the treatment regimen and administration schedule set forth in Example 2 below. For example, the treatment may include one or more cycles, each of 28 days. In each cycle, the anti-Gal9 antibody (e.g., G9.2-17(IgG4)) is administered to the subject (e.g., a human patient with PDAC) by intravenous infusion once every two weeks (e.g., on days 1 and 15) at a dose of about 2 mg / kg to 16 mg / mg (e.g., about 2 mg / kg, about 4 mg / kg, about 8 mg / kg, about 12 mg / kg, or about 16 mg / kg). In some embodiments, in each cycle, the anti-Gal9 antibody (e.g., G9.2-17(IgG4)) is administered to the subject (e.g., a human patient with PDAC) at a dose of about 0.2 mg / kg to 16 mg / mg (e.g., about 0.2 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, about 2 mg / kg, about 4 mg / kg, about 6 mg / kg, about 6.3 mg / kg, about 10 mg / kg, or about 16 mg / kg) by intravenous infusion once every two weeks (e.g., on days 1 and 15). Gemcitabine and paclitaxel (e.g., paclitaxel conjugated to a protein such as Abraxane®) may be administered to the subject once a week for three weeks (e.g., on days 1, 8, and 15 of a 28-day cycle) followed by one week off treatment, using doses and administration schedules approved by the FDA. For example, gemcitabine was administered to the above subjects at 1000 mg / m 2 once weekly by intravenous infusion, and paclitaxel was administered to the subjects at a dose of 125 mg / m 2 If necessary, the dose of gemcitabine may be 800 mg / m 2 or 600 mg / m 2 Alternatively, or in addition, the dose of paclitaxel may be reduced to 100 mg / m 2 or 75 mg / m2 may be reduced to

[0175] In some embodiments, the methods of treating solid tumors (e.g., PDAC) described herein include one or more 28 day treatment cycles, in which the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 0.2 mg / kg to about 32 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)), and gemcitabine and paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) are administered to the subject on days 1, 8, and 15. In some examples, paclitaxel is administered to the subject at a dose of 125 mg / m 2 In some examples, gemcitabine is administered intravenously (e.g., intravenous infusion) to the subject at a dose of 1000 mg / m 2 Gemcitabine is administered intravenously (e.g., by intravenous infusion) at a dose of 800 mg / m 2 or 600 mg / m 2 Alternatively, or in addition, the dose of paclitaxel may be reduced to 100 mg / m 2 or 75 mg / m 2 may be reduced to

[0176] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) The anti-Gal9 antibody is administered to the subject at a dose of about 0.2 mg / kg to 0.5 mg / kg, about 0.5 mg / kg to 1 mg / kg, about 1 mg / kg to 2 mg / kg, about 3 mg / kg to 4 mg / kg, about 4 mg / kg to 8 mg / kg, about 4 mg / kg to 6 mg / kg, about 4 mg / kg to 6.3 mg / kg, about 6 mg / kg to 8 mg / kg, about 6.3 mg / kg to 8 mg / kg, or about 8 mg / kg to 12 mg. / kg, about 8 mg / kg to 10 mg / kg, about 10 mg / kg to 12 mg / kg, about 12 mg / kg to 16 mg / kg, about 16 mg / kg to 20 mg / kg, about 20 mg / kg to 24 mg / kg, about 24 mg / kg to 28 mg / kg, or about 28 mg / kg to 32 mg / kg (e.g., about 0.2 mg / kg, about 0.5 mg / kg, about 0.63 mg / kg, about 0.63 mg / kg, about 1 mg / kg, 2mg / kg, about 3mg / kg, about 4mg / kg, about 5mg / kg, about 6mg / kg, about 6.3mg / kg, about 7mg / kg, about 8mg / kg, about 9mg / kg, about 10mg / kg, about 1 1mg / kg, about 12mg / kg, about 13mg / kg, about 14mg / kg, about 15mg / kg, about 16mg / kg, about 17mg / kg, about 18mg / kg, about 19mg / kg, about 20mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, or about 32 mg / kg), or any value therebetween, administered by intravenous infusion on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15. Optionally, the dose of gemcitabine is 800 mg / m 2 or 600 mg / m 2 may be reduced to (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2is administered intravenously (e.g., intravenous infusion) on days 1, 8, and 15 at a dose of 100 mg / m 2 or 75 mg / m 2 may be reduced to

[0177] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) The anti-Gal9 antibody is administered to the subject at a dose of 0.2 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 2 mg / kg, 3 mg / kg to 4 mg / kg, 4 mg / kg to 8 mg / kg, 4 mg / kg to 6 mg / kg, 4 mg / kg to 6.3 mg / kg, 6 mg / kg to 8 mg / kg, 6.3 mg / kg to 8 mg / kg, 8 mg / kg to 12 mg / kg, 8 mg / kg to 10 mg / kg, 10 mg / kg to 12 mg / kg, 12 mg / kg to 16 mg / kg, 16 mg / kg to 20 mg / kg, 20 mg / kg to 24 mg / kg, 24 mg / kg to 28 mg / kg, or 28 mg / kg to 32 mg / kg (e.g., 0.2 mg / kg, 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, g, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 6.3 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, or 32 mg / kg), or any numerical value therebetween; (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15. Optionally, the dose of gemcitabine is 800 mg / m 2 or 600 mg / m 2may be reduced to (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 is administered intravenously (e.g., intravenous infusion) on days 1, 8, and 15 at a dose of 100 mg / m 2 or 75 mg / m 2 may be reduced to

[0178] In some embodiments, the methods for treating solid tumors (e.g., PDAC) described herein include one or more 28-day treatment cycles, in which the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 2 mg / kg to about 16 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)), and gemcitabine and paclitaxel (e.g., paclitaxel conjugated to nanoparticle albumin) are administered to the subject on days 1, 8, and 15. In some embodiments, the methods of treating solid tumors (e.g., PDAC) described herein include one or more 28 day treatment cycles, in which the anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 0.2 mg / kg to about 16 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)), and gemcitabine and paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) are administered to the subject on days 1, 8, and 15. In some examples, paclitaxel is administered to the subject at a dose of 125 mg / m 2 In some examples, gemcitabine is administered intravenously (e.g., intravenous infusion) to the subject at a dose of 1000 mg / m 2 Gemcitabine is administered intravenously (e.g., by intravenous infusion) at a dose of 800 mg / m 2 or 600 mg / m 2 Alternatively, or in addition, the dose of paclitaxel may be reduced to 100 mg / m 2 or 75 mg / m 2 may be reduced to

[0179] In some embodiments, the methods of treating a solid tumor (e.g., PDAC) described herein include one or more 28 day treatment cycles, wherein the anti-Gal9 antibody is administered to the subject at a dose of about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 6.3 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, or about 12 mg / kg. , about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg, or any value therebetween, by intravenous infusion on days 1 and 15 (i.e., once every two weeks (q2w)), and gemcitabine and paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) are administered to the subject on days 1, 8, and 15. In some examples, paclitaxel is administered to the subject at a dose of 125 mg / m 2 In some examples, gemcitabine is administered intravenously (e.g., intravenous infusion) to the subject at a dose of 1000 mg / m 2 Gemcitabine is administered intravenously (e.g., by intravenous infusion) at a dose of 800 mg / m 2 or 600 mg / m 2 Alternatively, or in addition, the dose of paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) may be reduced to 100 mg / m 2 or 75 mg / m 2 may be reduced to

[0180] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) The anti-Gal9 antibody is administered to the subject at a dose of about 0.2 mg / kg to 0.5 mg / kg, about 0.5 mg / kg to 1 mg / kg, about 1 mg / kg to 2 mg / kg, about 3 mg / kg to 4 mg / kg, about 4 mg / kg to 8 mg / kg, about 4 mg / kg to 6 mg / kg, about 4 mg / kg to 6.3 mg / kg, about 6 mg / kg to 8 mg / kg, about 6.3 mg / kg to 8 mg / kg, or about 8 mg / kg to 12 mg. / kg, about 8 mg / kg to 10 mg / kg, about 10 mg / kg to 12 mg / kg, about 12 mg / kg to 16 mg / kg, about 16 mg / kg to 20 mg / kg, about 20 mg / kg to 24 mg / kg, about 24 mg / kg to 28 mg / kg, or about 28 mg / kg to 32 mg / kg (e.g., about 0.2 mg / kg, about 0.5 mg / kg, about 0.63 mg / kg, about 0.63 mg / kg, about 1 mg / kg, 2mg / kg, about 3mg / kg, about 4mg / kg, about 5mg / kg, about 6mg / kg, about 6.3mg / kg, about 7mg / kg, about 8mg / kg, about 9mg / kg, about 10mg / kg, about 1 1mg / kg, about 12mg / kg, about 13mg / kg, about 14mg / kg, about 15mg / kg, about 16mg / kg, about 17mg / kg, about 18mg / kg, about 19mg / kg, about 20mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, or about 32 mg / kg), or any value therebetween, administered by intravenous infusion on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0181] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) The anti-Gal9 antibody is administered to the subject at a dose of 0.2 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 2 mg / kg, 3 mg / kg to 4 mg / kg, 4 mg / kg to 8 mg / kg, 4 mg / kg to 6 mg / kg, 4 mg / kg to 6.3 mg / kg, 6 mg / kg to 8 mg / kg, 6.3 mg / kg to 8 mg / kg, 8 mg / kg to 12 mg / kg, 8 mg / kg to 10 mg / kg, 10 mg / kg to 12 mg / kg, 12 mg / kg to 16 mg / kg, 16 mg / kg to 20 mg / kg, 20 mg / kg to 24 mg / kg, 24 mg / kg to 28 mg / kg, or 28 mg / kg to 32 mg / kg (e.g., 0.2 mg / kg, 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, g, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 6.3 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, or 32 mg / kg), or any numerical value therebetween; (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0182] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) The anti-Gal9 antibody is administered to the subject at about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 6.3 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 20 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, or about 32 mg / kg), or any value therebetween, administered by intravenous infusion on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0183] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion on days 1 and 15 (i.e., once every two weeks (q2w)) at a dose of about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 6.3 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg, or any value therebetween; (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0184] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 0.2 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0185] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 0.6 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0186] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 0.63 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0187] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 2 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0188] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 4 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0189] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 6 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0190] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 6.3 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0191] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 8 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0192] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 10 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0193] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 12 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0194] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 16 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0195] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion at a dose of about 32 mg / kg on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered to the above subjects at a dose of 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 125 mg / m 2on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0196] In any of the above administration method embodiments, optionally the dose of gemcitabine is 800 mg / m 2 or 600 mg / m 2 or, alternatively, or in addition, the dose of paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) may be reduced to 100 mg / m 2 or 75 mg / m 2 may be reduced to

[0197] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) The anti-Gal9 antibody is administered to the subject at a dose of about 0.2 mg / kg to 0.5 mg / kg, about 0.5 mg / kg to 1 mg / kg, about 1 mg / kg to 2 mg / kg, about 3 mg / kg to 4 mg / kg, about 4 mg / kg to 8 mg / kg, about 4 mg / kg to 6 mg / kg, about 4 mg / kg to 6.3 mg / kg, about 6 mg / kg to 8 mg / kg, about 6.3 mg / kg to 8 mg / kg, or about 8 mg / kg to 12 mg. / kg, about 8 mg / kg to 10 mg / kg, about 10 mg / kg to 12 mg / kg, about 12 mg / kg to 16 mg / kg, about 16 mg / kg to 20 mg / kg, about 20 mg / kg to 24 mg / kg, about 24 mg / kg to 28 mg / kg, or about 28 mg / kg to 32 mg / kg (e.g., about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, about 1 mg / kg, kg, 2mg / kg, about 3mg / kg, about 4mg / kg, about 5mg / kg, about 6mg / kg, about 6.3mg / kg, about 7mg / kg, about 8mg / kg, about 9mg / kg, about 10mg / kg, about 1 1mg / kg, about 12mg / kg, about 13mg / kg, about 14mg / kg, about 15mg / kg, about 16mg / kg, about 17mg / kg, about 18mg / kg, about 19mg / kg, about 20mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, or about 32 mg / kg), or any value therebetween, administered by intravenous infusion on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered at 800 mg / m 2 , 600 mg / m 2 , or 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 100 mg / m 2 , 75 mg / m 2 , or 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0198] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) The anti-Gal9 antibody is administered to the subject at a dose of 0.2 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 2 mg / kg, 3 mg / kg to 4 mg / kg, 4 mg / kg to 8 mg / kg, 4 mg / kg to 6 mg / kg, 4 mg / kg to 6.3 mg / kg, 6 mg / kg to 8 mg / kg, 6.3 mg / kg to 8 mg / kg, 8 mg / kg to 12 mg / kg, 8 mg / kg to 10 mg / kg, 10 mg / kg to 12 mg / kg, 12 mg / kg to 16 mg / kg, 16 mg / kg to 20 mg / kg, 20 mg / kg to 24 mg / kg, 24 mg / kg to 28 mg / kg, or 28 mg / kg to 32 mg / kg (e.g., 0.2 mg / kg, 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg , 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 6.3 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, 20 mg / kg, 21 mg / kg, 22 mg / kg, 23 mg / kg, 24 mg / kg, 25 mg / kg, 26 mg / kg, 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, or 32 mg / kg), or any numerical value therebetween, administered by intravenous infusion on days 1 and 15 (i.e., once every two weeks (q2w)); (2) Gemcitabine was administered at 800 mg / m 2 , 600 mg / m 2 , or 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 100 mg / m 2 , 75 mg / m 2 , or 125 mg / m 2on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0199] In some embodiments, the method comprises one or more 28 day treatment cycles, (1) an anti-Gal9 antibody is administered to the subject by intravenous infusion on days 1 and 15 (i.e., once every two weeks (q2w)) at a dose of about 0.2 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 6.3 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg, or any value therebetween; (2) Gemcitabine was administered at 800 mg / m 2 , 600 mg / m 2 , or 1000 mg / m 2 on days 1, 8, and 15, (3) Paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) is administered to the subject at a dose of 100 mg / m 2 , 75 mg / m 2 , or 125 mg / m 2 on days 1, 8, and 15 at a dose of 0.01 mg / kg / day, and administered intravenously (eg, intravenous infusion) on days 1, 8, and 15.

[0200] In any of the above administration methods, the treatment cycle may last for a period of 12 to 24 months.

[0201] In any of the embodiments of the methods described herein, the anti-galectin-9 antibody may be administered once per week, once every two weeks for one cycle, once every two weeks for two cycles, once every two weeks for three cycles, once every two weeks for four cycles, or once every two weeks for more than four cycles (alone or in combination with one or more chemotherapeutic agents, e.g., gemcitabine and nab-paclitaxel, e.g., in doses described herein). In some embodiments, the treatment is for 1-3 months, 3-6 months, 6-12 months, 12-24 months, or more. In some embodiments, the treatment is for 1-3 months once per two weeks, 3-6 months once per two weeks, 6-12 months once per two weeks, or 12-24 months, or more.

[0202] In some embodiments, the methods of treating a solid tumor (e.g., PDAC) described herein include one or more 28 day treatment cycles, and the anti-Gal9 antibody is administered to the subject at a dose of about 0.2 mg / kg to 0.5 mg / kg, about 0.5 mg / kg to 1 mg / kg, about 1 mg / kg to 2 mg / kg, about 3 mg / kg to 4 mg / kg, about 4 mg / kg to 8 mg / kg, about 4 mg / kg to 6 mg / kg, about 4 mg / kg to 6.3 mg / kg, about 6 mg / kg to 8 mg / kg, about ... mg / kg to 8 mg / kg, about 8 mg / kg to 12 mg / kg, about 8 mg / kg to 10 mg / kg, about 10 mg / kg to 12 mg / kg, about 12 mg / kg to 16 mg / kg, about 16 mg / kg to 20 mg / kg, about 20 mg / kg to 24 mg / kg, about 24 mg / kg to 28 mg / kg, or about 28 mg / kg to 32 mg / kg (e.g., about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, about 1 mg / kg, about 2 mg / kg, g, about 3mg / kg, about 4mg / kg, about 5mg / kg, about 6mg / kg, about 6.3mg / kg, about 7mg / kg, about 8mg / kg, about 9mg / kg, about 10mg / kg, about 11mg / kg, about 12mg / kg, about 13mg / kg, about 14mg / kg, approximately 15mg / kg, approximately 16mg / kg, approximately 17mg / kg, approximately 18mg / kg, approximately 19mg / kg, approximately 20mg / kg, approximately 21mg / kg, approximately 22mg / kg, approximately 23mg / kg, approximately 24mg / kg, approximately 25mg / k g, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, or about 32 mg / kg), or any value therebetween, by intravenous infusion on days 1, 7, 15, and 21 (i.e., once weekly (q1w)), and gemcitabine and paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) are administered to the subject on days 1, 8, and 15. In some examples, paclitaxel is administered to the subject at a dose of 125 mg / m 2 In some examples, gemcitabine is administered intravenously (e.g., intravenous infusion) to the subject at a dose of 1000 mg / m 2 Gemcitabine is administered intravenously (e.g., by intravenous infusion) at a dose of 800 mg / m2 or 600 mg / m 2 Alternatively, or in addition, the dose of paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) may be reduced to 100 mg / m 2 or 75 mg / m 2 In some embodiments, the anti-Gal9 antibody may be administered to the subject once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 10 mg / kg, or once weekly at a fixed dose of 650-700 mg. Alternatively, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 16 mg / kg, or once weekly at a fixed dose of 1040-1120 mg.

[0203] In some embodiments, the methods of treating a solid tumor (e.g., PDAC) described herein include one or more 28 day treatment cycles, and the anti-Gal9 antibody is administered to the subject at a dose of 0.2 mg / kg to 0.5 mg / kg, 0.5 mg / kg to 1 mg / kg, 1 mg / kg to 2 mg / kg, 3 mg / kg to 4 mg / kg, 4 mg / kg to 8 mg / kg, 4 mg / kg to 6 mg / kg, 4 mg / kg to 6.3 mg / kg, 6 mg / kg to 8 mg / kg, 6.3mg / kg to 8mg / kg, 8mg / kg to 12mg / kg, 8mg / kg to 10mg / kg, 10mg / kg to 12mg / kg, 12mg / kg to 16mg / kg, 16mg / kg to 20mg / kg, 20mg / kg to 24mg / kg, 24mg / kg to 28mg / kg, or 28mg / kg to 32mg / kg (e.g., about 0.2mg / kg, 0.5mg / kg, 0.6mg / kg, 0.63mg / kg, 1mg / kg, 2mg / kg, 3mg / kg, 4mg / kg, 5mg / kg, 6mg / kg, approximately 6.3mg / kg, 7mg / kg, 8mg / kg, 9mg / kg, 10mg / kg, 11mg / kg, 12mg / kg, 13mg / kg, 14mg / kg, 15mg / kg, 16mg / kg, 17mg / kg, 18mg / kg, 19mg / kg, 20mg / kg, 21mg / kg, 22mg / kg, 23mg / kg, 24mg / kg, 25mg / kg, 26mg / kg , 27 mg / kg, 28 mg / kg, 29 mg / kg, 30 mg / kg, 31 mg / kg, or 32 mg / kg), or any numerical value between these ranges, is administered by intravenous infusion on days 1, 7, 15, and 21 (i.e., once weekly (qlw)), and gemcitabine and paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) are administered to the subject on days 1, 8, and 15.

[0204] In some instances, paclitaxel is administered to the subject at a dose of 125 mg / m 2 In some examples, gemcitabine is administered intravenously (e.g., intravenous infusion) to the subject at a dose of 1000 mg / m 2 Gemcitabine is administered intravenously (e.g., by intravenous infusion) at a dose of 800 mg / m 2or 600 mg / m 2 Alternatively, or in addition, the dose of paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) may be reduced to 100 mg / m 2 or 75 mg / m 2 In some embodiments, the anti-Gal9 antibody may be administered to the subject once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 10 mg / kg, or once weekly at a flat dose of 650-700 mg. Alternatively, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 16 mg / kg, or once weekly at a flat dose of 1040-1120 mg.

[0205] In some embodiments, the methods of treating a solid tumor (e.g., PDAC) described herein include one or more 28 day treatment cycles, wherein the anti-Gal9 antibody is administered to the subject at about 0.2 mg / kg, about 0.5 mg / kg, about 0.6 mg / kg, about 0.63 mg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 6.3 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 14 mg / kg, about 16 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about In some instances, the subject is administered a dose of about 125 mg / m2, about 13 mg / m2, about 14 mg / m2, about 15 mg / m2, about 16 mg / m2, about 17 mg / m2, about 18 mg / m2, about 19 mg / m2, or about 20 mg / m2, or any value therebetween, by intravenous infusion on days 1, 7, 15, and 21 (i.e., once weekly (qlw)), and gemcitabine and paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) are administered to the subject on days 1, 8, and 15. In some instances, paclitaxel is administered to the subject at a dose of 125 mg / m2, about 13 mg / m2, about 14 mg / m2, about 15 mg / m2, about 16 mg / m2, about 17 mg / m2, about 18 mg / m2, about 19 mg / m2, or any value therebetween. 2 In some examples, gemcitabine is administered intravenously (e.g., intravenous infusion) to the subject at a dose of 1000 mg / m 2 Gemcitabine is administered intravenously (e.g., by intravenous infusion) at a dose of 800 mg / m 2or 600 mg / m 2 Alternatively, or in addition, the dose of paclitaxel (e.g., paclitaxel bound to nanoparticle albumin) may be reduced to 100 mg / m 2 or 75 mg / m 2 In some embodiments, the anti-Gal9 antibody may be administered to the subject once weekly at a dose of about 10 mg / kg to about 16 mg / kg. For example, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 10 mg / kg, or once weekly at a fixed dose of 650-700 mg. Alternatively, the anti-galectin-9 antibody is administered to the subject once weekly at a dose of 16 mg / kg, or once weekly at a fixed dose of 1040-1120 mg.

[0206] In some cases, Gal-9 antibody treatment may be initiated simultaneously with chemotherapy (e.g., gemcitabine and nab-paclitaxel). Alternatively, Gal-9 antibody treatment may be initiated after a chemotherapy regimen (e.g., gemcitabine and nab-paclitaxel) has already begun. In some cases, Gal-9 antibody treatment is administered simultaneously with chemotherapy (e.g., gemcitabine and nab-paclitaxel), after which chemotherapy is discontinued. In some instances where chemotherapy is discontinued, administration of the anti-Gal-9 antibody treatment regimen may continue.

[0207] In any of the above embodiments, the interval or cycle may be once a week. In any of the above embodiments, the interval or cycle may be once every two weeks. In some embodiments, the regimen may be once every two weeks for one cycle, once every two weeks for two cycles, once every two weeks for three cycles, once every two weeks for four cycles, or once every two weeks for more than four cycles. In some embodiments, the treatment may be once every two weeks for one to three months, once every two weeks for three to six months, once every two weeks for six to twelve months, or once every two weeks for 12 to 24 months or more.

[0208] In any of the above embodiments, the interval or cycle may be 3 weeks. In some embodiments, the regimen may be once every 3 weeks for 1 cycle, once every 3 weeks for 2 cycles, once every 3 weeks for 3 cycles, once every 3 weeks for 4 cycles, or once every 3 weeks for 4 or more cycles. In some embodiments, the treatment may be once every 3 weeks for 1-3 months, once every 3 weeks for 3-6 months, once every 3 weeks for 6-12 months, or once every 3 weeks for 12-24 months or more.

[0209] In any of the above embodiments, the interval or cycle may be 4 or more weeks. In some embodiments, the regimen is 1 cycle of 4 or more weeks, 2 cycles of 4 or more weeks, 3 cycles of 4 or more weeks, 4 cycles of 4 or more weeks, or 4 or more cycles of 4 or more weeks. In some embodiments, the treatment may be 1-3 months of 4 or more weeks, 3-6 months of 4 or more weeks, 6-12 months of 4 or more weeks, or 12-24 months of 4 or more weeks. In some embodiments, the treatment is a combination of treatments at various times, e.g., 2 weeks, 3 weeks, 4 or more weeks. In some embodiments, the treatment interval is adjusted according to the patient's response to the treatment. In some embodiments, the dose(s) is adjusted according to the patient's response to the treatment. In some embodiments, the dose is altered during the treatment interval. In some embodiments, the treatment may be temporarily stopped. In some embodiments, the treatment with anti-galectin-9 is temporarily stopped. In some embodiments, chemotherapy is temporarily stopped, hi some embodiments, both are temporarily stopped.

[0210] In any of the combination therapies disclosed herein, the one or more chemotherapeutic agents (e.g., gemcitabine and nab-paclitaxel) and the anti-galectin-9 antibody (e.g., G9.2-17 IgG4) may be administered on the same day. In that case, the one or more chemotherapeutic agents may be administered to the subject prior to administration of the anti-galectin-9 antibody. In another example, the one or more chemotherapeutic agents (e.g., gemcitabine and nab-paclitaxel) and the anti-galectin-9 antibody (e.g., G9.2-17 IgG4) may be administered to the subject on two consecutive days. The chemotherapeutic agents may be administered on the first day of administration, and the anti-galectin-9 antibody may be administered the following day.

[0211] In other examples, a checkpoint inhibitor, such as any of the chemotherapeutic agents disclosed herein (e.g., gemcitabine and nab-paclitaxel), may be administered about 1 to 7 days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days) prior to administration of an anti-galectin 9 antibody disclosed herein, such as G9.2-17.

[0212] In some examples, the anti-galectin-9 antibody may be administered to the subject prior to administration of the chemotherapeutic agent. In other examples, the administration of the anti-galectin-9 antibody and the administration of the chemotherapeutic agent are performed on two consecutive days. The anti-galectin-9 antibody may be administered to the subject on the first day of administration, and the chemotherapeutic agent may be administered to the subject on the following day. In other examples, the anti-galectin-9 antibody disclosed herein, such as G9.2-17, may be administered about 1-7 days (e.g., 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days) prior to administration of the chemotherapeutic agent, such as gemcitabine and nab-paclitaxel.

[0213] In some embodiments, methods are provided herein, for example, where an anti-gal-9 antibody is administered in combination with a chemotherapeutic agent (e.g., gemcitabine and nab-paclitaxel) to improve overall response (e.g., at 3, 6, or 12 months) compared to baseline levels before treatment was initiated. In some embodiments, methods are provided herein to achieve complete response, partial response, or stable disease (SD) (e.g., measured at 3, 6, or 12 months or later according to RECIST or iRECIST criteria). Such response may be temporary or durable over a period of time. In some embodiments, the methods may improve the likelihood of complete response, partial response, or SD (e.g., measured at 3, 6, or 12 months) compared to baseline levels before treatment was initiated. Such response may be temporary or durable over a period of time.

[0214] In some embodiments, treatment may result in longer survival, i.e., a higher chance of survival, for example at a particular time point, e.g., 6 or 12 months, or thereafter.

[0215] In any of the methods described herein, partial response, SD, complete response, partial response, SD, progressive disease, disease progression (e.g., measured at 3 months, 6 months, or 12 months or later), may be assessed according to RECIST criteria or iRECIST criteria. Response to treatment, e.g., treatment of a solid tumor as described herein, can be evaluated according to RECIST or RECIST 1.1 criteria and / or irRC, irRECIST, iRECIST, imRECISTPDAC as described in Eisenhower et al., New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1);European Journal Of Cancer 45 (2009) 228-247;or Borcoman et al., Annals of Oncology 30: 385-396, 2019;Nishino et al., Clin Cancer Res 2013;19(14): 3936-3943, the contents of each of which are incorporated herein by reference in their entirety.

[0216] In some embodiments, methods are described herein for improving quality of life and symptom control (e.g., measured at 3 months, 6 months, or 12 months, or later) compared to a baseline before treatment began. In some embodiments, improvement can be measured on the ECOG scale, as described in Example 2 herein.

[0217] In some embodiments, the present disclosure provides methods for reducing or maintaining, either permanently or for more than a minimum period of time, tumor size in a subject, including a human subject, compared to a baseline tumor size before the initiation of treatment in the subject (e.g., measured at 3, 6, or 12 months or later), comprising administering to the subject a therapeutically effective amount of an anti-galectin-9 antibody disclosed herein. In some embodiments, the present disclosure provides methods for improving the likelihood of reducing or maintaining, either permanently or for more than a minimum period of time, tumor size in a subject, including a human subject, compared to, for example, a baseline level before the initiation of treatment (e.g., measured at 3, 6, or 12 months or later). In some embodiments, the present disclosure provides methods for reducing or maintaining, either permanently or for more than a minimum period of time, tumor burden in a subject, including a human subject, compared to a baseline level before the initiation of treatment (e.g., measured at 3, 6, or 12 months or later). Thus, in some embodiments, tumor size and / or tumor burden are measured with regularly scheduled reclassification scans (e.g., CT with contrast, MRI with contrast, PET-CT (diagnostic CT) and / or X-ray).

[0218] In some embodiments, provided herein are methods for extending the time to disease progression, i.e., progression-free survival (e.g., measured at 6 months), comprising administering an anti-gal-9 antibody in combination with a chemotherapeutic agent (e.g., gemcitabine and nab-paclitaxel). In some embodiments, the methods may result in a higher likelihood of progression-free survival (e.g., measured at 3, 6, or 12 months or longer after initiation of treatment). In some embodiments, provided herein are methods for improving the duration and depth of response according to RECIST 1.1 criteria (e.g., measured at 3, 6, or 12 months or longer after initiation of treatment), comprising administering an anti-gal-9 antibody in combination with a chemotherapeutic agent (e.g., gemcitabine and nab-paclitaxel).

[0219] In some embodiments, the methods provided herein, in which an anti-gal-9 antibody is administered in combination with a chemotherapeutic agent (e.g., gemcitabine and nab-paclitaxel), may improve quality of life and / or symptom control (e.g., measured using the ECOG scale at 1 month, 3 months, 6 months, or 12 months, or later) compared to a baseline prior to initiation.

[0220] Alternatively, or in addition, the anti-galectin-9 antibody may be combined with a regimen including UGN-102, UGN-201, or UGN-302. In one embodiment, UGN-102, UGN-201, or UGN-302 is formulated in a hydrogel, such as a hydrogel based on reverse-thermal hydrogel technology. In some examples, the anti-galectin-9 antibody may be administered prior to UGN-102, UGN-201, or UGN-302. In some examples, the anti-galectin-9 antibody may be administered simultaneously with UGN-102, UGN-201, or UGN-302. In some examples, the anti-galectin-9 antibody may be administered after UGN-102, UGN-201, or UGN-302.

[0221] (iv) Monitoring Treatment Response A patient's response to any of the treatments disclosed herein can be monitored by routine practices or as disclosed herein.

[0222] In some embodiments, the response to treatment may also be characterized by blood and tumor immunophenotype, cytokine profile (serum), soluble galectin-9 levels in blood (serum or plasma), immunohistochemistry (tumor, stroma, immune cells), tumor mutational burden (TMB), PDL-1 expression (e.g., by immunohistochemistry), mismatch repair status, or galectin-9 tumor tissue expression levels and expression patterns (e.g., measured at about 3 months, 6 months, or 12 months, or thereafter, or at any other time point as clinically indicated) by tumor markers associated with the disease. Non-limiting examples of such tumor markers include CA15-3, CA-125, CEA, CA19-9, alpha-fetoprotein. These parameters may be compared to baseline levels before the start of treatment.

[0223] In any of the methods disclosed herein, the subject may be tested for one or more of the following features before, during, and / or after treatment: (a) one or more tumor markers in a blood sample from the subject, optionally the one or more tumor markers include CA15-3, CA-125, CEA, CA19-9, and / or alpha fetoprotein, as well as any other tumor type specific tumor marker; (b) a cytokine profile; and (c) Galectin-9 serum / plasma levels; (d) peripheral blood mononuclear cell immunophenotyping, (e) multiplexed immunophenotyping of tumor tissue biopsy / resection specimens, (f) Galectin-9 expression levels and patterns of tumor tissue biopsy / resection specimens, (g) any other immunoscore tests, such as PDL-1 immunohistochemistry, tumor mutation burden (TMB), tumor microsatellite instability status, and panels, such as Immunoscore®-HalioDx, ImmunoSeq-Adaptive Biotechnologies, NanoString TIS developed based on the nCounter® Gene Expression System, 18-gene signature, PanCancer IO 360™ Assay (NanoString Technologies), etc. Other suitable biomarkers specific to target tumors such as PDAC may also be used.

[0224] Thus, in some embodiments, methods of modulating a therapeutic condition are contemplated herein based on one or more of the characteristics disclosed herein.

[0225] In some embodiments, the increase in overall immune response, e.g., overall inflammatory immune response, is measured by a reduction in tumor weight, tumor size, or tumor burden, or any of the RECIST criteria described herein. In some embodiments, the increase in overall immune response is measured by an increase in the level(s) of one or more inflammatory cytokines (including, e.g., two or more, three or more, or most anti-inflammatory cytokines) (one or more, two or more, or most anti-inflammatory cytokines and / or immunosuppressive cytokines and / or one or more of the most potent anti-inflammatory or immunosuppressive cytokines either decrease or remain constant). In some embodiments, the increase in overall immune response is measured by an increase in the level of one or more of the most potent inflammatory cytokines (one or more anti-inflammatory and / or immunosuppressive cytokines, including one or more of the most potent cytokines either decrease or remain constant). In some embodiments, an increase in the overall immune response is measured by a decrease in the levels of one or more (including most) immunosuppressive and / or anti-inflammatory cytokines (wherein the levels of one or more or most inflammatory cytokines (including, for example, the most potent inflammatory cytokines) either increase or remain constant). In some embodiments, an increase in the overall immune response is measured by an increase in the levels of one or more most potent anti-inflammatory and / or immunosuppressive cytokines (wherein the levels of one or more or most inflammatory cytokines (including, for example, the most potent inflammatory cytokines) either increase or remain constant). In some embodiments, an increase in the overall immune response is measured by any combination of the above. Also, an increase (or upregulation) of one type of immune response parameter may result in a corresponding decrease (or downregulation) of another type of immune response parameter. For example, an increase in the production of a particular inflammatory cytokine may result in the downregulation of a particular anti-inflammatory and / or immunosuppressive cytokine, and vice versa.

[0226] (D) Regulation of immune responses In some embodiments, the methods described herein, in which Gal-9 antibodies are administered with chemotherapeutic agents, such as gemcitabine and nab-paclitaxel, may modulate the levels of immune cells and immune cell markers in blood or tumors. Such changes can be measured in patient blood and tissue samples using methods known in the art, such as multiplex flow cytometry and multiplex immunohistochemistry. For example, a panel of phenotypic and functional PBMC immune markers can be assessed at baseline before the start of treatment and at various time points during treatment. Table 2 lists non-limiting examples of markers useful for these assessment methods. Flow cytometry (FC) is a technique of choice that provides fast and informative information for analyzing cellular phenotype and function, and has gained attention in immune phenotypic surveillance. FC allows characterization of many subsets of cells, including rare subsets, in complex mixtures such as blood, and FC is a representative method for rapidly acquiring large amounts of data. The advantages of FC are speed, sensitivity, and specificity. Standardized antibody panels and procedures can be used to analyze and classify immune cell subtypes. Multiplex IHC is a powerful investigative tool that provides objective quantitative data describing the immune landscape of a tumor in terms of both the number and location of immune subsets, allowing the assessment of multiple markers in a single tissue section. Computer algorithms can be used to combine chromogenic IHC methods and staining with digital pathology approaches to quantify IHC-based biomarker content from whole-slide images of patient biopsies. [Table 2]

[0227] In some embodiments, the present disclosure provides methods for modulating an immune response in a subject, including a human subject (e.g., measured at 3 months, 6 months, or 12 months, or thereafter), the method comprising administering to the subject a therapeutically effective amount of an anti-galectin-9 antibody disclosed herein. In some embodiments, the present disclosure provides methods for modulating levels of immune cells and immune cell markers, including but not limited to those set forth in Table 2 herein, in the blood or tumor of a subject, including a human subject, the method comprising administering to the subject a therapeutically effective amount of an anti-galectin-9 antibody disclosed herein. In some embodiments, the overall result of the modulation is upregulation of proinflammatory immune cells and / or downregulation of immunosuppressive immune cells.

[0228] Thus, in some embodiments, the methods described herein in which anti-gal9 antibodies are administered in combination with chemotherapy may modulate immune activation markers, such as those in Table 2. In some embodiments, the methods described herein in which anti-gal9 antibodies are administered alone or in combination with checkpoint inhibitor therapy result in one or more of: (1) an increase in the number of CD8 cells in plasma or tumor tissue; (2) a decrease in regulatory T cells (Tregs) in plasma or tumor tissue; (3) an increase in M1 macrophages in plasma or tumor tissue; (4) a decrease in MDSCs in plasma or tumor tissue; and (5) a decrease in M2 macrophages in plasma or tumor tissue (e.g., measured at 3 months, 6 months, or 12 months or later). In some embodiments, the markers evaluated using the techniques described above or known in the art are selected from CD4, CD8, CD14, CD11b / c, and CD25. These parameters may be compared to baseline levels before the start of treatment.

[0229] In some embodiments, treatment as described herein results in changes in pro-inflammatory and anti-inflammatory cytokines. In some embodiments, methods are provided herein for one or more of: (1) increasing the level of IFN-gamma in plasma or tumor tissue; (2) increasing the level of TNF-alpha in plasma or tumor tissue; and (3) decreasing the level of IL-10 in plasma or tumor tissue (e.g., measured at 3, 6, or 12 months or later). These parameters may be compared to baseline levels before the start of treatment.

[0230] In some embodiments, changes in cytokines or immune cells may be assessed between one tumor biopsy prior to administration and a repeat biopsy at a time when feasible. In some embodiments, changes in cytokines or immune cells may be assessed between two repeat biopsies. In some embodiments, described herein are methods for modulating one or more soluble galectin-9 levels in blood (serum or plasma) or galectin-9 expression levels and expression patterns in tumor tissue by immunohistochemistry (tumor, stroma, immune cells) (e.g., measured at 3 months, 6 months, or 12 months, or later). In some embodiments, described herein are methods for reducing one or more soluble galectin-9 levels in blood (serum or plasma) or galectin-9 expression levels and expression patterns in tumor tissue by immunohistochemistry (tumor, stroma, immune cells) (e.g., measured at 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months, or later). These galectin-9 levels may be compared to baseline levels before the start of treatment. In some embodiments, measurements are collected at 2 months.

[0231] In some embodiments, methods are described herein for modulating the level of PD-L1 expression (e.g., as assessed by immunohistochemistry). In some embodiments, the present disclosure provides, for example, a method for modulating PD-L1 expression (e.g., as assessed by immunohistochemistry) (e.g., measured at 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months, or later), comprising administering to the subject a therapeutically effective amount of an anti-galectin-9 antibody disclosed herein. In some embodiments of the method, PD-L1 expression (e.g., as assessed by immunohistochemistry) remains unchanged. PD-L1 levels may be compared to baseline levels before treatment begins. In some embodiments, the methods provided herein reduce PD-L1 expression (e.g., as assessed by immunohistochemistry). PD-L1 levels can be measured using routine methods known in the art. In one non-limiting example, a Ventana OptiView PD-L1 (SP263) can be used to detect PD-L1 in cancer tissue using immunohistochemistry. In some embodiments, provided herein are methods for modulating (increasing or decreasing) one or more tumor markers associated with the disease (e.g., measured at 3, 6, or 12 months or later). Non-limiting examples of such tumor markers include Cal5-3, CA-125, CEA, CA19-9, alpha-fetoprotein. These parameters may be compared to baseline levels before treatment begins. In some embodiments, the methods provided herein reduce the occurrence of one or more tumor markers associated with the disease.

[0232] In some embodiments, the present disclosure provides a method of modulating PD-L1 expression (e.g., as assessed by immunohistochemistry) (e.g., measured at 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months, or later), comprising administering to the subject a therapeutically effective amount of an anti-galectin-9 antibody disclosed herein. In some embodiments of the method, PD-L1 expression (e.g., as assessed by immunohistochemistry) remains unchanged. PD-L1 levels may be compared to baseline levels before treatment begins. In some embodiments, the methods provided herein reduce PD-L1 expression (e.g., as assessed by immunohistochemistry).

[0233] In some embodiments, the present disclosure provides a method of modulating (increasing or decreasing) one or more biomarkers associated with the disease (e.g., measured at 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 6 months, or 12 months or later), comprising administering to the subject a therapeutically effective amount of an anti-galectin-9 antibody disclosed herein. Levels of biomarkers in clinical tissue from patients can be measured using conventional methods, such as multiplex immunofluorescence (mIF) techniques, as described in the Examples herein. Exemplary panels of biomarkers can include CD3, CD4, CD8, CD45RO, FoxP3, CD11b, CD14, CD15, CD16, CD33, CD68, CD163, HLA-DR, Arginase 1, Granzyme B, Ki67, PD-1, PD-L1, F4 / 80, Ly6G / C, and PanCK.

[0234] These markers may be compared to baseline levels before treatment began (e.g., at specific intervals, e.g., 3 months, 6 months, or 12 months). In some embodiments, the cytokine profile is modulated.

[0235] In some embodiments, the present disclosure provides a method of modulating an immune response in a subject. The immune response may be a T cell-mediated and / or B cell-mediated immune response, which is affected by modulating immune cell activity, e.g., T cell activation. In one embodiment of the present disclosure, the immune response is T cell-mediated. As used herein, the term "modulate" means to change or alter, and includes both upregulation and downregulation. For example, "modulating an immune response" means to change or modify the state of one or more immune response parameters. Exemplary parameters of a T cell-mediated immune response include the level of T cells (e.g., an increase or decrease in effector T cells) and the level of T cell activation (e.g., an increase or decrease in the production of a particular cytokine). Exemplary parameters of a B cell-mediated immune response include an increase in B cell levels, B cell activation, and B cell-mediated antibody production.

[0236] When immune response is regulated, some immune response parameters may decrease and other immune response parameters may increase.For example, in some cases, regulating immune response increases (or upregulates) one or more immune response parameters and decreases (or downregulates) one or more other immune response parameters, resulting in an increase in overall immune response, for example, an increase in overall inflammatory immune response.In another example, regulating immune response increases (or upregulates) one or more immune response parameters and decreases (or downregulates) one or more other immune response parameters, resulting in a decrease in overall immune response, for example, a decrease in overall inflammatory response.

[0237] In some embodiments, provided herein are methods for modulating soluble galectin-9 levels in blood (serum or plasma) or expression levels and patterns of galectin-9 in tumor tissue by immunohistochemistry (tumor, stromal, immune cells) (e.g., measured at 3 months, 6 months, or 12 months, or later) in a subject comprising administering an anti-Gal9 antibody in combination with chemotherapy. Galectin-9 levels in the subject may be compared to baseline levels before treatment begins.

[0238] In some embodiments, provided herein are methods for reducing the levels of one or more soluble galectin-9 in blood (serum or plasma) or galectin-9 expression levels and expression patterns in tumor tissues by immunohistochemistry (tumor, stromal, immune cells) (e.g., measured at 3 months, 6 months, or 12 months, or later).

[0239] In some embodiments, methods are provided herein for modulating (increasing or decreasing) one or more tumor markers associated with the disease (e.g., measured at 3, 6, or 12 months or later), comprising administering an anti-Gal9 antibody in combination with chemotherapy. Non-limiting examples of such tumor markers include Cal5-3, CA-125, CEA, CA19-9, alpha-fetoprotein. These parameters may be compared to baseline levels before treatment begins.

[0240] Kits for use in combination therapy of solid tumors - Patents.com The present disclosure also provides kits for use in treating or ameliorating a solid tumor, such as PDA, CRC, HCC, or cholangiocarcinoma, and other solid tumors described herein. Such kits may include one or more containers containing an anti-galectin-9 antibody, such as any of the antibodies described herein above (e.g., G9.2-17(IgG4)), and, optionally, one or more chemotherapeutic agents, also as described herein (e.g., gemcitabine and / or clitaxel), in combination with the anti-galectin-9 antibody.

[0241] In some embodiments, the kit may include instructions for use according to any of the methods described herein. The included instructions may include instructions for administering the anti-galectin-9 antibody and the one or more chemotherapeutic agents to treat, delay the onset of, or alleviate a target disease described herein. In some embodiments, the kit further includes instructions for selecting an individual suitable for treatment, e.g., based on applying a diagnostic method described herein to identify whether the individual has the target disease. In yet other embodiments, the instructions include instructions for administering the antibody to an individual at risk for the target disease.

[0242] The instructions for use of the anti-galectin-9 antibody and the one or more chemotherapeutic agents will typically include information regarding dosage, administration schedule, and route of administration for the intended treatment. The containers may be unit doses, bulk packages (e.g., multi-dose packages), or sub-unit doses. The instructions provided in the kits of the invention will typically be written instructions on a label or package insert (e.g., a paper sheet contained in the kit), although machine-readable instructions (e.g., instructions recorded on a magnetic or optical memory disk) are also acceptable.

[0243] The label or package insert indicates that the composition is used for treating, delaying the onset of, and / or ameliorating a solid tumor. In some embodiments, instructions for practicing any of the methods described herein are provided.

[0244] The kit of the present invention is in suitable packaging. Suitable packaging includes, but is not limited to, vials, bottles, jars, flexible packaging (e.g., sealed Mylar or plastic bags), and the like. Packages for use in combination with certain devices, such as inhalers, nasal administration devices (e.g., atomizers), or injection devices, such as mini-pumps, are also contemplated. In some embodiments, the kit has a sterile access port (e.g., the container may be an intravenous solution bag or vial with a stopper that can be punctured by a hypodermic needle). In some embodiments, the container also has a sterile access port (e.g., the container is an intravenous solution bag or vial with a stopper that can be punctured by a hypodermic needle). At least one active agent in the composition is an anti-galectin-9 antibody as described herein.

[0245] The kit may optionally provide additional components such as buffers and interpretive information. Typically, the kit comprises a container and a label or package insert(s) on or associated with the container. In some embodiments, the invention provides an article of manufacture comprising the contents of the kit described above.

[0246] Common methods The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry, and immunology, which are within the skill of the art. Such techniques are fully explained in, for example, Molecular Cloning: A Laboratory Manual, second edition (Sambrook, et al., 1989) Cold Spring Harbor Press; Oligonucleotide Synthesis (M. J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; Cell Biology: A Laboratory Notebook (J. E. Elis, ed., 1998) Academic Press; Animal Cell Culture (R. I. Freshney, ed., 1987); Introduction to Cell and Tissue Culture (J. P. Mather and P. E. Oberts, 1998) Plenum Press; Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B. Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons; Methods in Enzymology (Academic Press, Inc.); Handbook of Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); Gene Transfer Vectors for Mammalian Cells (JMMiller and MP Calos, eds., 1987); Current Protocols in Molecular Biology (FMAusubel, et al., eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis, et al., eds., 1994); Current Protocols in Immunology (JEColigan et al., eds.,1991);Short Protocols in Molecular Biology(Wiley and Sons,1999);Immunobiology(CAJaneway and P.Travers,1997);Antibodies(P.Finch,1997);Antibodies: a practical approach(D.Catty.,ed.,IRL Press,1988-1989);Monoclonal antibodies: a practical approach(P.Shepherd and C.Dean, eds.,Oxford University Press,2000);Using antibodies: a laboratory manual(E.Harlow and D.Lane(Cold Spring Harbor Laboratory Press,1999);The Antibodies(M.Zanetti and JDCapra,eds.,Harwood Academic Publishers,1995).

[0247] Without further elaboration, it is believed that one skilled in the art can utilize the present invention to its fullest extent based on the above description. Accordingly, the following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way. All publications cited herein are incorporated by reference for the purpose or subject matter referenced herein. EXAMPLES

[0248] Although the present disclosure has been described with reference to specific embodiments thereof, those skilled in the art should understand that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the present disclosure. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step(s) to the objective, spirit and scope of the present disclosure. All such modifications are intended to be within the scope of the present disclosure.

[0249] Example 1: In vitro study of anti-galectin-9 antibody in combination with chemotherapeutic agents for cancer treatment in a mouse model of pancreatic cancer A preclinical evaluation of an anti-galectin-9 IgG4 fully human antibody (G9.2-17(IgG4)) (as a single agent or in combination with other systemic chemotherapy anticancer agents) for the treatment of refractory solid tumors was performed in a mouse model of pancreatic cancer.

[0250] The specific animal used was an orthotopic mPA6115 pancreatic cancer xenograft model in female C57BL / 6 mice. To generate this model, tumors were first obtained from mPA6115 mice, a mouse allograft model of human pancreatic ductal adenocarcinoma (PDAC) that retains morphological similarity to PDAC. The mPA6115 mouse strain expresses a conditional mutant Kras (Kras LSL-G12D / WT ), with constitutive deletion of Trp53 (P53KO / KO), and Cre driven by the promoter of the Pdx1 gene, developed severe PDAC tumors at 8 weeks of age.

[0251] At that time, mPA6115 mice with palpable tumors were sacrificed and their pancreatic tumors were harvested. The harvested tumor tissue was cut into small pieces (approximately 2 mm 3 ) and transplanted subcutaneously (SC) into syngeneic recipient C57BL / 6 mice. These seed tumors were transplanted into the oocytes when the seed tumor volume was 700-1000 mm. 3 The seed tumors were subcutaneously maintained in C57BL / 6 mice until they reached a desired volume. When the seed tumors reached a desired volume, the tumors were harvested and were then cultured to a size of approximately 2 mm in diameter. 3The tumors were then washed with ice-cold Roswell Park Memorial Institute (RPMI) 1640 medium (without serum) to remove adjacent non-tumor tissue. The tumor pieces were then stored in ice-cold RPMI 1640 medium until orthotopic implantation. On the same day that the seed tumors were harvested, 6-7 week old female C57BL / 6 mice were subjected to orthotopic implantation of the pancreas. In detail, after the animals were fully anesthetized, a small longitudinal incision was made in the lower left thorax to expose the spleen and the pancreas below the spleen. One seed tumor piece per mouse was sewn into the pancreas with 6-0 silk suture. The tissues around the tumor pieces were then sutured with 6-0 silk suture, and the tumor pieces were encased in pancreatic tissue. The abdomen was then closed with 4-0 silk suture. After tumor implantation, the animals were placed in a warm cage and returned to the animal room after fully recovering from anesthesia.

[0252] On the day of implantation, the implanted mice were randomly divided into 6 groups based on the weight of the mice, and randomization was performed based on the "Matched distribution" method (StudyDirector™ software, version 3.1.399.19). The day of randomization was designated as day 0. Three days after implantation, the animals began their dosing regimen according to group number. The dosing regimen for each group is shown in Table 3 below. [Table 3]

[0253] Anti-Galectin-9 mouse IgG1 was used for these studies. This antibody (referred to as anti-Gal9 mAb) is a mouse IgG1 version of the human G9.2-17 antibody, which binds to the same carbohydrate binding domain 2 (CRD2) on Galectin-9 as G9.2-17 and has the same VH and VL regions as G9.2-17. Thus, data obtained using anti-Gal9 mAb correlates with the efficacy of G9.2-17 in humans. In addition to treating mice with anti-Gal9 mAb alone (group 4), transplanted mice in groups 5 and 6 were also treated with standard of care chemotherapy (gemcitabine / Abraxane regimen) or a combination of anti-Gal9 mAb and chemotherapy.

[0254] After orthotopic pancreatic implantation, mice in groups 1-7 were monitored daily for morbidity and mortality. During regular monitoring, any effects of tumor growth and treatment on the following characteristics were noted: mobility, food and water intake, weight gain or loss, loss of eye / hair maturity, and other abnormalities. Body weight and tumor volume were measured twice weekly after randomization using StudyDirector™ software (version 3.1.399.19). Measurements and monitoring data were collected as described from day 0 until day 66, when the last mouse was found dead. Blood, plasma, spleen, and tumor were collected from each mouse at the time of death. Table 4 below shows the average life span of mice per experimental group. The longest survival time in all control groups (groups 1, 2, and 3) was 33 days, whereas the last mouse died in groups 4 (anti-galectin-9 IgG1), 5 (gemcitabine / Abraxane), and 6 (combination therapy) on days 55, 41, and 66, respectively. [Table 4]

[0255] The primary endpoint regarding the survival of animals implanted with orthotopic KPC tumors was evaluated by estimating the survival curves of each group considered separately using the Kaplan-Meier method and statistically compared using the log-rank test. In detail, the Kaplan-Meier survival curves / log-rank test (SPSS18) were used. The Kaplan-Meier survival curves and the log-rank test are shown in Figure 1A-B and Figure 1C-D. The results of the log-rank test are shown in Table 5. [Table 5]

[0256] Cox regression analysis (coxph function in the survival R package) was used to calculate the hazard ratios (HRs) and their 95% confidence intervals (95% CIs) of groups 4 to 6 relative to groups 1, 2, and 3, respectively. We also used Cox regression analysis to calculate the hazard ratios (HRs) and their 95% confidence intervals (95% CIs) of groups 5 and 6 relative to group 4. Finally, we used Cox regression analysis to calculate the hazard ratios (HRs) and their 95% confidence intervals (95% CIs) of group 6 relative to group 5. The results of the Cox regression analysis are shown in Figure 2 and Table 6. [Table 6]

[0257] In the Cox regression analysis using group 1 as the criterion, the hazard ratios for groups 4 and 6 were significantly lower than group 1, while the hazard ratios for groups 2 and 3 were not significantly different from group 1. In the Cox regression analysis using group 2 as the criterion, the hazard ratio for group 6 was significantly lower than group 2. However, the hazard ratio for group 3 was not significantly different from group 2. In the Cox regression analysis using group 3 as the criterion, the hazard ratios for groups 4, 5, and 6 were not significantly different from group 3. In the Cox regression analysis using group 4 as the criterion, the hazard ratios for groups 5 and 6 were not significantly different from group 4. Finally, the Cox regression analysis using group 5 as the criterion showed that the hazard ratio for group 6 was not significantly different from group 5.

[0258] These data demonstrated that the combination of the anti-galectin-9 antibody with gemcitabine / Abraxane was well tolerated, could be administered over a long period of time (up to 16 doses for the anti-galectin-9 IgG1 antibody (mouse IgG1 version) and 10 doses for gemcitabine / Abraxane) and provided a survival advantage compared to untreated animals (6 vs. 1 group: Cox analysis, HR=0.336, HR(95%CI)=(0.14, 0.806), p=0.015; and p=0.051 log-rank test of mean survival). Anti-galectin-9 IgG1 alone also provided a survival advantage compared to untreated animals (4 vs. 1 group: Cox analysis, HR=0.348, HR(95%CI)=(0.146, 0.83), p=0.017).

[0259] When the last mouse in group 6 was found dead on day 66, no tumors were found in its pancreas and the study was terminated. Previous data showed that the engraftment rate of the orthotopic mPA6115 model in the vehicle-treated group was 100%. Thus, the last mouse in group 6 demonstrated a complete response to the anti-galectin-9 / gemcitabine / Abraxane combination regimen.

[0260] Mice implanted with orthotopic KPC tumors were weighed twice weekly after implantation / randomization (day 0) until all mice were euthanized or died. Figure 3 shows the body weight measurements collected over the course of the study, measured using StudyDirector™ software (version 3.1.399.19). The last mouse in group 4 became moribund and was euthanized on day 55, at which time the tumor weight was 2544.6 mg (TV=1877.07 mm). 3 Between days 51 and 55, only one mouse was left in each of the four groups, with a weight change of 12.36% to -2.25% compared to the weight on the first day of treatment. This weight loss was most likely associated with disease induced by tumor growth.

[0261] Overall, the data from this example confirmed the safety and efficacy of the anti-galectin-9 regimen and the anti-galectin-9 / gemcitabine / Abraxane combination regimen in the orthotopic pancreatic cancer xenograft model mPA6115.

[0262] Example 2: A Phase 1 / 2, Open-Label, Multicenter Study of the Safety, Pharmacokinetics, and Antitumor Activity of an Anti-Galectin-9 Monoclonal Antibody Alone and in Combination with Chemotherapy Agents in Patients with Metastatic Solid Tumors Galectin-9 is a molecule that is overexpressed in many solid tumors, including pancreatic, colorectal, and hepatocellular carcinoma solid tumors. Furthermore, galectin-9 is expressed on tumor-associated macrophages, as well as intratumoral immunosuppressive gamma delta T cells, thereby acting as a potent mediator of cancer-associated immunosuppression.

[0263] G9.2-17(IgG4) is a fully human IgG4 monoclonal antibody (mAb) that targets the galectin-9 (-gal-9) protein. Gal-9 functions as an immunosuppressant, conferring immune privilege to tumor cells and negating immune-mediated cancer attack by controlling the susceptibility of cancer cells to macrophage, T cell, myeloid-derived suppressor cells, and cytotoxic T cell-induced cell death. Based on available data, blockade of gal-9 by G9.2-17(IgG4) interferes with the immunosuppressive function of gal-9, thereby resulting in effective immune activation and tumor growth inhibition across multiple preclinical models.

[0264] Gal-9 can be overexpressed and / or secreted in many solid tumor types, including pancreatic adenocarcinoma, cholangiocarcinoma (CCA), colorectal carcinoma (CRC), breast cancer, bladder cancer, ovarian cancer, non-small cell and small cell lung cancer, nasopharyngeal carcinoma, melanoma, ovarian cancer, etc., and high levels of tissue and / or circulating Gal-9 correlate with aggressive tumor characteristics and adverse survival outcomes.

[0265] Thus, the target indication for G9.2-17(IgG4) is relapsed or refractory metastatic solid tumors, and G9.2-17(IgG4) will be tested as a single agent and in combination with checkpoint inhibitors (programmed cell death 1 [PD1] antibodies).

[0266] Dose escalation (Part 1) will be performed in all comer solid tumors to establish the safety and tolerability profile of G9.2-17 (IgG4), evaluate its immunogenic potential, establish the pharmacokinetic (PK) and pharmacodynamic (PD) profile, and arrive at a recommended Phase 2 dose (RP2D), which may be the maximum tolerated dose (MTD). Expansion cohorts (Part 2) are planned in first-line metastatic pancreatic ductal adenocarcinoma (PDAC), in combination with gemcitabine / nab-paclitaxel, and in CRC and CCA, e.g., as single agents.

[0267] There are no other therapeutic agents that target gal-9 that are currently approved or known to be in clinical trials for any indication.

[0268] No significant toxicity has been observed in non-clinical studies conducted to date, at doses approximately 500 times greater than those intended for administration to humans. Furthermore, G9.2-17(IgG4) has been shown to be highly specific for gal-9 and has been demonstrated to be effective in multiple animal models of cancer. The enrolled patient population is at a late stage of disease and has failed standard treatments prior to enrollment in this study. G9.2-17(IgG4) is expected to provide benefits in the treatment of malignancies, such as malignant solid tumors, when administered either alone or in combination with one or more chemotherapeutic agents, such as gemcitabine and paclitaxel, as described herein.

[0269] Objectives and Endpoints [Table 7] [Table 8]

[0270] Test Design This is an open-label, uncontrolled, multicenter Phase 1 / 2 study (dose escalation phase (part 1) and cohort expansion phase (part 2)) in patients with relapsed / refractory metastatic solid tumors. The study will be conducted at up to 20 centers in the United States. The study duration is estimated to be 12-24 months. Survival follow-up will continue for up to 2 years. The study scheme is presented in Figure 4.

[0271] Treatment Duration and Treatment Periods Treatment Duration Administration of the study drug will continue until disease progression, unacceptable toxicity, or withdrawal from the study. Patients who discontinue the study drug before disease progression and are not being treated with other systemic anti-cancer therapy(ies) will be followed in the study until disease progression.

[0272] Treatment Periods The study consisted of the following periods in both Part 1 and Part 2: Screening period: Up to 4 weeks prior to first dose (day -28 to day -1) Treatment duration: 28-day treatment cycles as presented in the evaluation schedule (SoA; Tables 13 and 14) Post-treatment period: 30 days after last treatment (end of treatment visit / visit for early discontinuation) Follow-up: Long-term follow-up for up to 2 years (visits every 3 months) for patients who discontinued treatment for reasons other than disease progression and did not receive additional systemic anticancer therapy.

[0273] Part 1: Dose Escalation Phase A dose-finding study will be conducted using the continuous reassessment method (CRM) (O'Quigley et al., 1990) to establish DLT and RP2D. Two to six patients will be assigned per treatment cohort 1-6 to receive IV injections of successively higher concentrations of G9.2-17 (IGG4) every 2 weeks (Q2W) on days 1 and 15 of each 28-day cycle, starting with a dose of 0.2 mg / kg. Patients assigned to a particular dose-escalation cohort will receive the test dose corresponding to that cohort. They will receive the study drug at one of eight dose levels until disease progression, unacceptable toxicity, or withdrawal from the study for other reasons. Patients will be replaced only if they withdraw during the first treatment cycle for reasons other than toxicity or tolerability issues.

[0274] Cohorts 1-6 will be dosed two patients at a time based on CRM design. Dose escalation is based on analysis of patient safety data focusing on occurrence of DLTs at previous dose levels and other relevant safety and dosing data from previous cohorts. Dose escalation may occur after at least 28 days (1 cycle). Skipping dose levels is not permitted.

[0275] After completion of cohort 6 under the CRM design, the once weekly (QW) G9.2-17 (IgG4) dosing scheme will be evaluated within the CRM design, provided that the RP2D has not been reached. Cohorts 7 and 8 will not be evaluated in the CRM design. Patients will only be allowed to enter cohort 7 if no DLTs have been identified.

[0276] Cohorts 7 and 8 will be dosed four patients at a time per cohort. Four patients per dose level in cohorts 7 and 8 will be assigned to receive sequentially higher concentration IV injections of G9.2-17 (IgG4) on days 1, 8, 15, and 22 of each 28-day cycle every week (QW). Starting with the first four patients in cohort 7, dose escalation to the next cohort will occur only if no DLTs are identified. If a single DLT is recorded in cohort 7, no further patients will be dosed within that cohort and cohort 8 will not be activated.

[0277] Approximately 36 patients will be enrolled in cohorts 1-8 of Part 1. Within the CRM design, a total of six dosage levels will be evaluated: Dose escalation cohort 1 = 0.2 mg / kg Q2W Dose escalation cohort 2 = 0.63mg / kg Q2W Dose Escalation Cohort 3 = 2mg / kg Q2W Dose Escalation Cohort 4 = 6.3mg / kg Q2W Dose Escalation Cohort 5 = 10mg / kg Q2W Dose Escalation Cohort 6 = 16mg / kg Q2W Two additional dosage levels are included to account for the RP2D. Dose Escalation Cohort 7 = 10mg / kg QW Dose Escalation Cohort 8 = 16mg / kg QW

[0278] Patients who received treatment in the initial cohort before the RP2D was identified will be allowed to dose escalate to the highest dose level cleared. Dose escalation may occur at least 28 days (1 cycle) after a complete cycle. Dose escalation may not occur mid-cycle. Patients may continue to escalate to the highest approved dose level until discontinued due to toxicity or disease progression, or other reasons (e.g., the patient chooses to discontinue the study).

[0279] Dose escalation is based on the occurrence of DLT in patients treated at the previous dose level. For each dose cohort, the previous DLT probability is identified from GLP-compliant toxicity studies and preclinical models. For a given target DLT rate and total number of dose levels, a skeleton of the power model d^exp(a) is generated following the approach of Lee and Cheung using the previous MTD adjusted with PK / PD data, with dose level median and interval measures at delta = 0.05 (Lee and Cheung, 2011). The prior distribution of parameter "a" has a mean zero normal distribution with the least information on the prior variance. If the lower limit of the Agresti and Coull binomial confidence interval (CI) for the lowest tested dose level exceeds the target DLT rate, the study is stopped for safety (Agresti and Coull, 1998). The RP2D is the MTD dose derived from part 1.

[0280] If any patient experienced a DLT during the first 28 days of treatment, the patient would be permanently discontinued from the study drug.

[0281] In patients who experience toxicity (including IMAR) outside the DLT window, dose reductions are permitted only if clinical benefit is anticipated and may be obtained by continuing with a lower dose of G9.2-17(IgG4). The dose of G9.2-17(IgG4) will be initially reduced by 50% and then further reduced by 50% as defined in the dose modification guidance presented in Table 7. No further dose reductions are permitted. [Table 9-1] [Table 9-2]

[0282] Part 1 Complete Part 1 will be completed when up to six patients have received the dose identified as the RP2D, which is based in part on the continuous reassessment method (CRM) study design, PK and PD data parameters, additional safety and efficacy data, and any other factors considered.

[0283] Backfill Cohort The purpose of the backfill cohort is to evaluate the safety, tolerability, and biological effects of G9.2-17(IGG4) in patients whose tumors are gal-9 positive. The gal-9 status of the RP2D cohort will be determined retrospectively. If there are fewer than six patients with gal-9 positive tumors treated at the RP2D, patients assigned to the backfill cohort will require prospective assessment of gal-9 tumor status by IHC. Up to six additional patients whose tumors are gal-9 positive may be enrolled to enroll the cohort at the RP2D dose level.

[0284] Part 2: Cohort expansion phase The second part of the protocol will employ the Simon two-stage optimal design, which will include approximately 223 patients. Based on the implementation of expansion cohorts and tumor-specific considerations for clinical trial endpoints, it is planned to expand the cohorts to PDAC, CRC, and CCA and / or potentially other solid tumor types. The rationale behind this approach is to ensure feasibility of recruitment and capture clinical needs for specific indications.

[0285] CRC and CCA patients will receive one of two treatments (four treatment arms in total): G9.2-17 (IgG4) as a single agent PDAC patients will receive G9.2-17 (IgG4) in combination with gemcitabine / nab-paclitaxel.

[0286] For all patients receiving combination therapy (gemcitabine / nab-paclitaxel + G9.2-17(IgG4)), multiple therapeutic agents may be administered on the same day. Gemcitabine / nab-paclitaxel should be administered prior to G9.2-17(IgG4). If for any reason same-day administration is not feasible, gemcitabine / nab-paclitaxel should be administered on the first day and G9.2-17(IgG4) should be administered the next day.

[0287] CRC and CCA patients Treatment of CRC and CCA patients with single agent or combination agent cohorts may be performed in parallel.

[0288] G9.2-17 (IgG4) monotherapy The starting dose of G9.2-17 (IgG4) in monotherapy is the RP2D specified in Part 1. In the CRC and CCA monotherapy arms, an optimal 2-stage design (Stage I and II) will be used to test the null hypothesis that ORR3 is ≤5% versus the alternative hypothesis that ORR3 is ≥15% in the monotherapy arms.

[0289] If, after testing the investigational agent in 23 patients in stage I, 1 or fewer patients respond, that arm will be stopped. If the trial progresses to stage II of the Simon optimal design, approximately 33 additional patients will be treated in each of the single-agent arms. If the total number of responding patients is 5 or fewer, the investigational agent in that arm will be rejected. If 6 or more patients have a confirmed ORR3, a part 3 expansion cohort for that arm will be activated and described in the protocol amendment.

[0290] Dose reductions may be expected if clinical benefit is expected and subsequently induced with lower doses of G9.2-17(IgG4). The dose of G9.2-17(IgG4) will be initially reduced by 50% and may be further reduced by 50% as defined in the dose modification guidance provided in the protocol. No further dose reductions will be permitted.

[0291] PDAC patient Part 2 cohort of patients with metastatic PDAC will require combination treatment with G9.2-17 (IgG4) in first-line metastatic cases.

[0292] The dose of G9.2-17 (IgG4) is the RP2D-1 dose, which is the dose level in the cohort immediately preceding the RP2D dose identified in Part 1. To ensure patient safety, a run-in will be conducted in which the first 8 patients will be dosed and the treatment arm will continue if 2 or less patients develop DLTs below the 25% target toxicity level (TTL). If 3 or more patients develop DLTs, the combination treatment arm will be discontinued. In this combination treatment run-in cohort, patients who withdraw for reasons other than toxicity or tolerability issues will only be replaced during the first treatment cycle. If a DLT occurs during any of the 8 safety runs for a patient during the first 28 days of treatment, the patient will be permanently discontinued from receiving the study drug.

[0293] In patients who experience toxicity outside the DLT window, dose reductions are permitted only if clinical benefit is anticipated and may be obtained by continuing with a lower dose of G9.2-17(IgG4). The dose of G9.2-17(IgG4) will be initially reduced by 50% and may be reduced by a further 50%. No further dose reductions are permitted. Dose modifications of gemcitabine and / or nab-paclitaxel are permitted.

[0294] If IMAR occurs / recurs uncontrolled by dose reduction of either agent, both study drugs must be discontinued.

[0295] The primary efficacy endpoint is PFS6 in patients. In first-line metastatic cancer treatment with gemcitabine / nab-paclitaxel, PFS6 has been reported to be 50% (von Hoff et al., 2013). After testing the G9.2-17(IGG4) / chemotherapy combination in 11 patients in the first stage of the Simon two-stage design, if 6 or fewer patients have a PFS of 6 months or more, the trial will be terminated. If the trial proceeds to the second stage of the Simon two-stage design, approximately 14 more patients will be treated. If the total number of patients with a PFS-6 response is 16 or fewer, the study arm will be rejected.

[0296] Part 2 Complete Completion of part 2 will depend on patients achieving ORR3 for CRC and CCA patients and PFS6 for PDAC.

[0297] Part 3: Expansion If promising efficacy signals are identified within one or more of the trial arms, expansion cohorts will be initiated to confirm the findings as described above. The sample size for each expansion arm will be determined based on the point estimates determined in Part 2, combined with a predefined level of precision for the 95% CIs around ORR / OS and PFS. A protocol amendment will be submitted with details on the expansion population, treatment regimen, and statistical analysis plan prior to initiating Part 3.

[0298] Dose-limiting toxicity criteria Dose-limiting toxicities evaluated in this study were defined as clinically significant hematologic and / or nonhematologic AEs or abnormal laboratory values ​​assessed as unrelated to metastatic tumor disease progression, intercurrent illness, or contemporaneous medications that were possibly or were related to the study drug and occurred during the first cycle (28 days) of the study. Patients who experience a DLT in Part 1 or Part 2 during the first 28 days of treatment will be permanently discontinued from receiving study drug.

[0299] A DLT is a toxicity that meets any of the following criteria: Any death without an underlying disease or external cause Signs of potential drug-induced liver injury (Highe's Law): ALT or AST >3x the upper limit of normal (ULN) confirmed by repeat testing after 24 hours, and Serum total bilirubin (TBL) > 2 × ULN (confirmed by repeat testing after 24 hours) No other explanation can be found for the elevation of TBL and / or AT, e.g., viral hepatitis (A, B, or C), alcoholic or autoimmune hepatitis, pre-existing or acute liver disease, gallbladder obstruction or bile duct disease, Gilbert's syndrome, disease progression, or another drug that may be causing the observed effects. Any grade 4 non-hematologic or hematologic toxicity of any duration All grade 3 non-hematologic and hematologic toxicities. Exceptions include: Grade 3 nausea, vomiting, and diarrhea that can be managed to ≤ Grade 2 within 48 hours with supportive care without requiring hospitalization or total parenteral nutrition support. Grade 3 electrolyte abnormalities are corrected to Grade 2 or less within 24 hours. o Grade 3 electrolyte abnormalities that last less than 24-72 hours, are clinically uncomplicated, and resolve spontaneously or respond to conventional medical intervention. Amylase or lipase grade 3 or higher without symptoms or clinical signs of pancreatitis.

[0300] Definition of Exam Completion The end of Part 1 of the study will be defined as the time when all patients are receiving treatment with G9.2-17 (IgG4) until RP2D is identified and disease progression is confirmed.

[0301] End of study part 2 was defined for each of the three tumor types following completion of the Simon two-stage optimal design, with all enrolled patients receiving treatment with G9.2-17(IGG4) (alone or in combination) until confirmed disease progression.

[0302] In both Part 1 and Part 2, patients will be followed for OS for up to 2 years after their last dose of G9.2-17(IgG4), if they discontinue treatment for reasons other than disease progression and are not receiving additional systemic anticancer therapy.

[0303] The end of the study will be defined as the date of the last patient's last visit.

[0304] Clinical trial suspension rules Part 1 If the lower limit of Agresti and Coull's CI for the lowest tested dose level exceeds the target DLT rate, the trial will be stopped for safety (Agresti and Coull, 1998).

[0305] Part 2 After testing the investigational drug in 23 patients in Stage I of the Simon optimal design for the monotherapy arms of CRC and CCA, each arm is stopped if 1 or fewer patients respond. If the trial proceeds to Stage II of the Simon optimal design, an arm is stopped if the total number of patients in that arm who respond is 5 or fewer.

[0306] For the PDAC G9.2-17(IgG4)+gemcitabine / nab-paclitaxel combination arm, the Simon optimal design similarly guides the study to stop. After testing the G9.2-17(IgG4) / chemotherapy agent in 11 stage I patients, the study arm is stopped if 6 or fewer patients show a PFS of 6 months or more. If the study proceeds to stage II, the study arm is stopped if the total number of patients responding with a PFS of 6 months or more is 16 or fewer.

[0307] To ensure patient safety in both combination arms, a safety run-in will be conducted in which the first 8 patients are dosed. For each cancer type (e.g., CCA, CRC, and / or PDAC), enrollment will continue only if 2 or fewer patients develop DLTs, which are below the target toxicity level (TTL) of 25%. If 3 or more patients with a given cancer type develop DLTs in the combination arm, enrollment will be halted for that cancer type in that arm.

[0308] Study population Inclusion criteria Participants are eligible to be enrolled in the study only if they meet all of the following criteria: Part 1 and Part 2 1. Written informed consent (mentally normal patients, able to understand and willing to sign the informed consent form) 2. Age 18 or older, male or non-pregnant female 3. Histologically confirmed unresectable metastatic carcinoma (adenocarcinoma and squamous cell carcinoma are acceptable). Patients with resectable disease will be excluded. 4. Ability to comply with study protocols Life expectancy of over 5.3 months 6. Eastern Cooperative Oncology Group (ECOG) performance status 0–1 7. Coronavirus SARS-CoV-2 (COVID-19) negative patients 8. Patients able and willing to undergo pre-treatment and intra- / post-treatment biopsies. Planned biopsies should not expose patients to significantly increased risk of complications. Every effort will be made to biopsy the same lesions during repeat biopsies. 9. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. It should be noted that the lesion intended for biopsy should not be the target lesion. 10. Adequate hematologic and end-organ function as defined by the following laboratory test results obtained prior to the first dose of investigational treatment: A neutrophil count ≥ 1 x 10 9 / L b. Platelet count ≧100×10 9 / L; Part 1 hepatocellular carcinoma (HCC) ≥ 50 × 10 9 For / L C. Hemoglobin ≥ 9.0 g / dL without transfusion in the previous week Creatinine ≤ 1.5 x upper limit of normal (ULN) e. Aspartate aminotransferase (AST) ≤ 3 × ULN (≤ 5 × ULN if HCC or liver metastases are present) f. Alanine aminotransferase (ALT [SGPT]) ≤ 3 × ULN (≤ 5 × ULN if HCC or liver metastasis is present) g. Bilirubin ≦1.5×ULN (patients with known Gilbert's disease may have bilirubin ≦3.0×ULN) h. Albumin ≥ 3.0 g / dL i. International normalized ratio (INR) and partial thromboplastin time (PTT) ≦ 1.5 x ULN j. Amylase and lipase ≦1.5 x ULN 11. No evidence of active infection or infection requiring parenteral antibiotics and no serious infection within 4 weeks prior to study initiation. 12. Females of childbearing potential must have a negative pregnancy test result within 72 hours prior to starting treatment. For females of childbearing potential: Agree to remain abstinent (abstain from heterosexual intercourse) or use a method of contraception with a failure rate of less than 1% per year during treatment and for at least 180 days after the last study treatment. A woman is of childbearing potential if she has had her first menstrual period, has not yet reached postmenopausal status (amenorrhea for 12 or more consecutive months with no identified cause other than menopause), and has not been surgically sterilized (removal of the ovaries and / or uterus). Examples of contraceptive methods with failure rates of less than 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the patient's preferred usual lifestyle. Periodic abstinence (e.g., calendar, ovulation, symptom-temperature, or postovulatory methods) and withdrawal are not acceptable contraceptive methods. Males of reproductive potential must practice an effective method of contraception during the trial unless evidence of infertility is present. 13. Four (4) weeks or five half-lives (whichever is shorter) since the last dose of anticancer therapy prior to the first dose of G9.2-17(IgG4) 14. Continuation of bisphosphonate therapy (e.g., zoledronic acid) or denosumab for bone metastases that have been stable for at least 6 months prior to C1D1 is permitted. 15. Biliary or gastric outlet obstruction is permitted, provided it can be effectively evacuated by endoscopic, surgical, or interventional means. 16. Pancreatic, biliary, or enteric fistulas are permitted provided they are managed with an appropriate, patent, non-infected drain (if a drain or stent is in situ, patency must be confirmed prior to study initiation). Additionally, for part 1 only: 17.Patient: a. Have already received at least one prior line of systemic therapy for metastatic disease, or b. Those with tumor types for which there are no available standard treatment options. Additionally, for part 2 only: 18. PDAC expansion cohort: 1st-line metastatic patients who have not received a gemcitabine-containing regimen or have been previously treated with a gemcitabine-containing regimen in the neoadjuvant or adjuvant / local advanced care setting for at least 3 months 19. CRC and CCA expansion cohort - Patients who have received at least one prior line of treatment in the metastatic setting.

[0309] Exclusion criteria Participants will be excluded from the study if they meet any of the following criteria: 1. Patient is unwilling or unable to comply with the requirements of the protocol 2.Patients diagnosed with metastatic cancer of unknown primary site 3. Previous or current illegal drug addiction (medical and recreational cannabis / cannabidiol (CBD) / tetrahydrocannabinol (THC) would not be considered "illegal"). 4. Any patient with clinically significant active uncontrolled bleeding and a bleeding diathesis (e.g., active peptic ulcer disease). Prophylactic or therapeutic use of anticoagulants is permitted. 5. Pregnant and / or breastfeeding women 6. Receiving any other investigational drug, or participating in any other clinical trial involving another investigational drug for the treatment of solid tumors within 4 weeks prior to Cycle 1, Day 1 of the trial, or within 5 half-lives of the administered drug (whichever is shorter), or other investigational therapy or major surgery within 4 weeks of the date of consent, or surgery scheduled within 4 weeks of the anticipated start of the trial (this includes dental surgery). 7. Radiation therapy within 4 weeks of first dose of investigational drug, except palliative radiation therapy to limited areas such as for the treatment of bone pain or locally painful tumor masses, that does not jeopardize measurable disease necessary for response evaluation (RECIST v1.1). 8.Patients with fungal tumor masses 9. Patients with locally advanced PDAC without distant organ metastatic deposits 10. Grade 4 immune-mediated toxicity from a prior checkpoint inhibitor. Grade 2 or Grade 3 pneumonitis or other Grade 3 checkpoint inhibitor-related toxicity that led to discontinuation of treatment with the immunotherapy agent. Low-grade (<grade 3) toxicities, e.g., neuropathy from prior therapy, manageable electrolyte abnormalities and lymphopenia, alopecia, and vitiligo, are acceptable. 11. History of secondary malignancies (excluding those previously treated with curative intent for ≥5 years with no or low chance of recurrence (e.g., nonmelanotic skin cancer, cervical carcinoma in situ, early (or localized) prostate cancer, or superficial bladder cancer)) 12. Active brain or leptomeningeal metastases. Patients with brain metastases are eligible if they have clinically and radiographically stable disease (SD) at least 4 weeks after definitive treatment and have not used steroids (≥10 mg / day prednisone or equivalent) for at least 4 weeks prior to the first dose of study drug. 13. Severe or uncontrolled systemic disease, congestive heart failure > New York Heart Association (NYHA) class 2, myocardial infarction (MI) within 6 months, or evidence of laboratory findings that would preclude the patient from participating in the trial. 14. Any significant medical condition compromising patient safety or compromising the interpretation of the G9.2-17 (IgG4) toxicity assessment 15. Serious non-healing wounds, ongoing ulcers, or untreated fractures 16. Uncontrolled pleural, pericardial, or ascites requiring repeated drainage procedures. For the purposes of this trial, "recurrence" is defined as 3 or more drains in the past 30 days. 17. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins 18. Significant vascular disease within 6 months of Cycle 1, Day 1 (e.g., aortic aneurysm requiring surgical repair, or recent arterial thrombosis) 19. History of pulmonary embolism, stroke, or transient ischemic attack within 3 months prior to Cycle 1, Day 1 20. History of abdominal fistula or gastrointestinal perforation within 6 months prior to Cycle 1, Day 1 21. Active autoimmune disease (excluding diabetes mellitus type I / II, hypothyroidism requiring hormone replacement only, vitiligo, psoriasis, or alopecia areata) 22. Requires systemic immunosuppressive therapy, including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents. Patients who have received or are receiving acute low-dose systemic immunosuppressants (e.g., 10 mg / day or less of prednisone or equivalent) may be enrolled. Replacement therapy (e.g., thyroxine, insulin, physiological corticosteroid replacement therapy [e.g., 10 mg / day or less of prednisone equivalent] for adrenal or pituitary insufficiency) is not considered a form of systemic treatment. Use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone), topical steroids, intranasal steroids, intra-articular steroids, and ophthalmic steroids is permitted. 23. Severe tumor-related pain (grade 3 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) v.5.0) unresponsive to extensive analgesic interventions (oral and / or patch) 24. Hypercalcemia (grade 3 according to CTCAE v5.0) despite use of bisphosphonates 25. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of the investigational product or that gives reasonable suspicion of a disease or condition that may affect the interpretation of the results or place the patient at high risk of complications of treatment. 26. Administered organ transplant(s) 27. Patients undergoing dialysis 28. In Part 1, hormonal androgen deprivation therapy will be permitted to continue for men with metastatic castration-resistant prostate cancer. 29. Any ablative therapy (radiofrequency ablation or percutaneous ethanol injection) for HCC within 6 weeks prior to study entry 30. Hepatic encephalopathy or severe hepatic adenoma 31. Child-Pugh score ≥ 7 Additionally, for part 2 only: 32. Hypersensitivity to the active substance or any of the excipients of gemcitabine / nab-paclitaxel

[0310] Investigational Drugs and Other Interventions Investigational intervention(s) are defined as the investigational drug(s), marketed product(s), placebo, or medical device(s) intended to be administered / used to study participants according to the study protocol.

[0311] Drugs administered in combination with G9.2-17 (IgG4) Gemcitabine + Nab-paclitaxel Gemcitabine is a nucleoside metabolic inhibitor indicated for the treatment of multiple cancer types, alone or in combination with other therapeutic agents. Nab-paclitaxel (Abraxane® (protein-bound paclitaxel)) is also a microtubule inhibitor indicated for the treatment of multiple tumor types. In particular, Nab-paclitaxel is indicated as a first-line treatment for metastatic PDAC, in combination with gemcitabine. Gemcitabine is administered at 1000 mg / m on days 1, 8, and 15 of each 28-day cycle. 2 Nab-paclitaxel is administered at a dose of 125 mg / m over 30 minutes on days 1, 8, and 15 of each 28-day cycle. 2 Administer over 3 to 40 minutes at a dose of

[0312] Adverse events attributable to the combination of gemcitabine + Nab-paclitaxel are shown in Table 8 below. [Table 10]

[0313] Limiting the infusion of nab-paclitaxel to 30 minutes reduces the chance of infusion-related reactions.

[0314] Premedication to prevent hypersensitivity reactions prior to administration of nab-paclitaxel is generally not required. Gemcitabine is contraindicated in patients with hypersensitivity to gemcitabine.

[0315] Abraxane causes bone marrow suppression, which can lead to neutrophil counts of 1,500 cells / mm 3Do not use in patients with less than 18 mg / kg / day of chemotherapy. Abraxane is known to cause severe hypersensitivity reactions. Do not administer gemcitabine to patients with known sensitivity to gemcitabine.

[0316] Tables 9-11 below show recommended dose modifications for Gemcitabine + Nab-paclitaxel in patients with PDAC. [Table 11] [Table 12] [Table 13]

[0317] Clinical Trial Intervention Management All patients will receive G9.2-17(IgG4), administered by IV infusion weekly or every 2 weeks until disease progression, unacceptable toxicity, or withdrawal of consent.

[0318] In Part 1, patients will receive G9.2-17 (IgG4) alone at escalating doses starting at 0.2 mg / kg.

[0319] In Part 2, patients will receive G9.2-17(IgG4) RP2D (determined in Part 1) as a single agent or G9.2-17(IgG4)RP2D-1 in combination with gemcitabine / Nab-paclitaxel as follows: Patients with CRC or CCA G9.2-17 (IgG4) in CRC G9.2-17 (IgG4) in CCA PDAC patients ○G9.2-17(IgG4)+Gemcitabine / Nab-paclitaxel Other solid tumor types (based on data from Part 1) G9.2-17 (IgG4) as a single agent and / or in combination with checkpoint inhibitors or chemotherapy as determined based on each tumor type

[0320] See Table 12 for a summary description of each study intervention.

[0321] Patients who experience a DLT in Part 1 will not resume treatment. Patients who experience a DLT in Part 2 will have treatment discontinued. If clinical benefit is achieved, treatment may be resumed with the same or reduced dose of G9.2-17(IgG4). [Table 14]

[0322] Preparation of G9.2-17 (IgG4) The manufacture and packaging of Investigational Medicinal Product (IMP) G9.2-17 (IgG4) follows applicable current Good Manufacturing Practice (cGMP) and the product meets the standards applicable for human use.

[0323] The G9.2-17 (IgG4) formulation is diluted to the target dose prior to administration. All dilutions should be performed in a controlled, sterile environment (patient doses are prepared and administered by IV infusion over approximately 60 minutes).

[0324] G9.2-17(IgG4) is a sterile liquid and should be stored at 2°C to 8°C, protected from light.

[0325] Dose reduction Continuation of G9.2-17(IgG4) dose for patients in the G9.2-17(IgG4)+gemcitabine / Nab-paclitaxel cohort If the patient is experiencing clinical benefit according to G9.2-17(IgG4) and protocol efficacy criteria, and the patient is experiencing an adverse reaction not attributable to G9.2-17(IgG4), then treatment with G9.2-17(IgG4) alone may be continued while gemcitabine / Nab-paclitaxel is dose modified / discontinued.

[0326] The following, i.e. ● the patient's clinical condition is not rapidly deteriorating; and A concomitant medication is discontinued due to an AE solely attributable to that medication. In such cases, G9.2-17 (IgG4) may be continued.

[0327] If IMAR occurs / recurs and cannot be managed by dose reduction of either drug, both study drugs must be discontinued.

[0328] Nab-paclitaxel is not recommended for patients with total bilirubin >5xULN or AST >10xULN. In addition, Nab-paclitaxel is not recommended for patients with metastatic adenocarcinoma of the pancreas with moderate to severe hepatic impairment (total bilirubin >1.5xULN and AST ≤10xULN). For patients with moderate or severe hepatic impairment, the starting dose should be reduced.

[0329] Discontinuation of study intervention In rare cases, it may be necessary for a patient to permanently discontinue the investigational intervention. If the investigational intervention is permanently discontinued for reasons other than disease progression and the patient is not being treated with other anti-cancer therapy(ies), the patient will continue to be evaluated for disease progression for up to 2 years. See SoA for data to be collected at the time of discontinuation of investigational intervention and follow-up, and any further optional evaluations that need to be completed.

[0330] Investigators must make every effort to continue patients on investigational treatment until one of the reasons for discontinuing investigational treatment is met (disease progression, investigational drug-related toxicity, withdrawal of consent). If a patient has radiographic progression, the patient may continue on investigational treatment if there is no clear clinical progression and no alternative treatment is initiated. However, if a patient has clear clinical progression in the absence of radiographic progression, the investigational treatment should be stopped and the patient has been advised of available treatment options.

[0331] Patients may be discontinued prior to disease progression for any of the following reasons: • DLT per definition in Section 3.4.4. The AE occurs / recurs outside the DLT window requiring discontinuation of study treatment(s). - Occurrence / recurrence of IMAR requiring discontinuation of study treatment(s) ●Completion of research by PureTech Health, LLC Any intercurrent illness or medical condition that may prevent further administration of treatment or jeopardize the patient's safety if continued on investigational treatment. Pregnancy Use of non-protocol anticancer therapy

[0332] Patients may also be discontinued prior to disease progression for any of the following reasons: -Significant deviation from protocol on the part of the patient (including lack of compliance)

[0333] An explanation of why a patient is discontinuing study treatment should be documented in the Case Report Form (CRF). If a patient discontinues study treatment due to toxicity, "dose-limiting toxicity" or "adverse event" will be recorded as the primary reason for withdrawal. If a patient is prematurely discontinued from the study at any time due to an AE or serious adverse event (SAE), the patient must be followed until recovery to grade 2 or less, unless improvement is unlikely due to the underlying condition.

[0334] Combination therapy Any medications or vaccines (including over-the-counter or formulated drugs, recreational drugs, vitamins, and / or herbal supplements) that participants are receiving at the time of enrollment or will be receiving during the study must be recorded with the following information: ●Reason for use Date of administration, including start and end dates Dosage information, including dosage and frequency

[0335] Permitted medicines The following contemporaneous medications are permitted: • Standard of care premedication for patients on combination treatment regimens. • Bisphosphonate therapy (e.g., zoledronic acid) or continuation of denosumab for bone metastases has been stable for at least 6 months prior to treatment (C1D1). • Use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone), topical steroids, intranasal steroids, intra-articular steroids, and ophthalmic steroids. Prophylactic or therapeutic use of anticoagulants Vaccination against COVID-19, common influenza, and / or other common clinically indicated indications (e.g., tetanus, pneumococcal, HBV, etc.) is permitted prior to or during the study period. Timing and type of vaccination must be recorded.

[0336] Prohibited Substances The following medications are not permitted during this study: - Concomitant administration of other investigational drugs other than G9.2-17 (IGG4) for any indication. Systemic immunosuppressive treatments, including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents. However, patients are permitted to take acute low doses of systemic immunosuppressants (e.g., up to 10 mg / day of prednisone or equivalent). • Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy [e.g., prednisone equivalent 10 mg / day or less] for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.

[0337] supportive care Patients should receive full supportive care during the study, including transfusion of blood and blood products; treatment with antibiotics, antiemetics, antidiarrheals, and analgesics; and other treatments as deemed appropriate and in accordance with institutional guidelines.

[0338] Evaluation Schedule [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4] [Table 15-5] [Table 15-6] [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5]

[0339] Test Evaluation and Procedures A signed, written ICF approved by the Institutional Review Board (IRB) must be obtained prior to potential patients participating in any study-specific procedures, including study-specific screening procedures.

[0340] Patients are enrolled in the study if they complete all screening procedures and are deemed to meet all eligibility criteria. Part 1, Cohorts 1-6, study procedures and respective timing are summarized in the SoA (Table 13). Part 1, Cohorts 7 and 8, study procedures and respective timing are summarized in the SoA (Table 14). Protocol waivers or exemptions will not be permitted. Compliance with all study requirements, including those specified in the SoA, is essential and mandatory for the conduct of the study. Immediate safety concerns must be discussed as soon as they arise or are recognized to determine the need for intervention or trial discontinuation. All screening assessments must be completed and outlined to ensure potential participants meet all eligibility criteria. A screening log will be maintained to record details of all participants screened and, where applicable, confirm eligibility or record the reasons for screening failure. • Procedures performed as part of the participant's routine clinical management (e.g., blood counts) and obtained prior to signing the ICF may be utilized for screening or baseline purposes only if they meet the criteria specified in the protocol and the procedure was performed within the time frame defined in the SoA.

[0341] Evaluation for each visit The SoA (Tables 13 and 14) present a list of assessments to be performed during the screening period (up to 28 days), the treatment period (shown as 28-day cycles), the end of treatment / early discontinuation period, the IMAR follow-up, and the long-term follow-up period. If medically indicated, optional visits are permitted during each treatment cycle, during which study evaluations may be performed.

[0342] During the COVID-19 pandemic, many governments have mandated social distancing for their citizens and more vulnerable populations have been advised to self-isolate. These types of constraints may impact the ability to conduct this clinical trial as originally intended. Planned site visits may be adjusted to allow the trial to continue safely during the pandemic. Possible modifications may include: Postponement of medical visits and / or clinical trial procedures ● Substitute by phone / video call(s) Alternative to home visits ● Visits to alternative clinics Visits by medical providers other than the study team ●Clinic visits and / or clinical trial procedures have been cancelled entirely.

[0343] Screening Period (between Day 28 and Day 1) The following procedures must be performed within 4 weeks of starting treatment: Study Procedures and Exams ● Written informed consent ● Check inclusion and exclusion criteria for patient eligibility Patient demographics Medical history Previous and contemporaneous medications ●ECHO / Multi-Gated Acquisition Scan (MUGA) ● 12-lead ECG (QT interval corrected using Fridericia's formula [QTcF]) Physical Examination – For patients with stable, treated brain metastases, a neurological examination should be performed. ECOG performance status Vital signs Tumor imaging evaluation (computed tomography [CT] or magnetic resonance imaging [MRI] with or without contrast, or positron emission tomography [PET]-CT, with CT with contrast preferred) Clinical Laboratory Pregnancy testing for women of childbearing potential (WOCBP) ●Hematology Serum Chemistry Thyroid stimulating hormone (TSH), free T4 or thyroxine (fT4), serum lipase, amylase, parathyroid hormone (PTH), follicle stimulating hormone (FSH), luteinizing hormone (LH), free cortisol ●Blood coagulation Urine tests Pharmacodynamics and Pharmacokinetics Tumor biopsy o If a biopsy is deemed dangerous to the patient, the biopsy may be omitted. If a biopsy is not available, the institution will make every effort to obtain an archival tumor tissue specimen available as a formalin-fixed, paraffin-embedded (FFPE) block. Acceptable archival specimens include specimens obtained by core needle biopsy or excision surgery within the past 5 years. dMMR-MSI-H status (if the patient's MMR and MSI status has not been previously determined, testing should be performed at a local laboratory) Tumor type-related biomarkers

[0344] Duration of treatment Each treatment cycle is 28 days in duration.

[0345] Treatment procedure on day 1 of each cycle (CXD1; ±2 days from the start of cycle 2) The following procedure is performed on Day 1 of each treatment cycle. Test procedures and inspections Concurrent medication ●AE ●12-lead ECG (QTcF) Physical Examination ECOG performance status Vital signs Clinical Laboratory Pregnancy testing for WOCBP ●Hematology Serum Chemistry ●TSH, fT4, lipase, amylase, PTH, FSH, LH, free cortisol ●Blood coagulation Urine tests PK / PD assessment ●PD blood sampling ●PK blood sampling ●ADA blood collection Tumor type-related biomarkers Administration of investigational drug • Administer only after all pre-administration evaluations and procedures have been completed. In addition, starting on Day 1 of Cycle 3, the following assessments will be performed every 8 weeks: Tumor imaging evaluation (CT or MRI, with or without contrast; or PET-CT, preferably CT with contrast) In addition, starting on Day 1 of Cycle 4, the following assessments will be performed every 3 months: ●ECHO / MUGA Cohorts 1-6: Treatment procedures on days 2 and 8 of cycle 1 and cycle 3 (CXD2 ± 1 days and CXD8 ± 1 days) Test procedures and inspections Concurrent medication ●AE PK / PD assessment ●PD blood sampling ●PK blood sampling Cohorts 1-6: Treatment procedure on day 15 of each cycle (CXD15 ± 1 days for cycle 1 and ± 2 days for the start of cycle 2)

[0346] The following procedure is performed on day 15 of each treatment cycle. Test procedures and inspections Concurrent medication ●AE Physical Examination ECOG performance status Vital signs Clinical Laboratory ●Hematology Serum Chemistry ●Blood coagulation Urine tests PK / PD assessment ● PD blood sampling only on C1D15 and C3D15 ●PK blood sampling for C1D15 and C3D15 only Tumor type-related biomarkers Tumor biopsy on C3D15±7 (Cycle 3 only; may be omitted if deemed too high risk for patient) Administration of investigational drug • Administer only after all pre-administration evaluations and procedures have been completed. Cohorts 7 and 8: Treatment procedures on day 3 of cycle 1 and cycle 3 (C1D3±1 days and C3D3±1 days) Test procedures and inspections Concurrent medication ●AE PK / PD assessment ●PD blood sampling ●PK blood sampling Cohorts 7 and 8: Treatment procedure on day 8 of each cycle (CXD8 ± 1 days) Test procedures and inspections Concurrent medication ●AE Physical Examination ECOG performance status Vital signs Clinical Laboratory ●Hematology Serum Chemistry ●Blood coagulation Urine tests PK / PD assessment ●PD blood sampling PK blood sampling only in odd-numbered cycles Administration of investigational drug • Administer only after all pre-administration evaluations and procedures have been completed. Cohorts 7 and 8: Treatment procedures on days 15 and 22 of each cycle (CXD15 ± 1 day in cycle 1 and ± 2 days at the start of cycle 2)

[0347] The following procedures will be performed on days 15 and 22 of each treatment cycle. Test procedures and inspections Concurrent medication ●AE Physical Examination ECOG performance status Vital signs Clinical Laboratory ●Hematology Serum Chemistry ●Blood coagulation Urine tests PK / PD assessment ● PD blood sampling only on C1D15 and C3D15 PK blood sampling only in odd-numbered cycles Tumor type-related biomarkers Tumor biopsy on C3D15±7 (Cycle 3 only; may be omitted if deemed too high risk for patient) ●ADA blood collection for C1D15 and C2D15 only Administration of investigational drug • Administer only after all pre-administration evaluations and procedures have been completed.

[0348] Additional treatment after cycle 4 Treatment cycles beyond cycle 4 may be repeated as indicated in the SoA (Tables 13 and 14). If patients are experiencing clinical benefit, they may continue treatment even if they have progressed radiologically.

[0349] Procedures for Terminating or Early Discontinuation of Treatment The following procedures will be performed 30 days (± 3 days) after the last dose, including for patients who are discontinuing treatment early. Test procedures and inspections Concurrent medication ●AE Physical Examination ECOG Vital signs • Tumor imaging evaluation: confirmatory scan if study completion is >8 weeks from previous scan. Clinical Laboratory Pregnancy testing for WOCBP ●Hematology Serum Chemistry ●TSH, fT4, lipase, amylase, PTH, FSH, LH, free cortisol ●Blood coagulation Urine tests PD evaluation ●PD blood sampling ●ADA blood collection Tumor type-related biomarkers

[0350] Long-term follow-up OS will be assessed every 3 months for up to 2 years after patients complete / prematurely discontinue treatment. Tumor imaging evaluation will continue if patients are able to discontinue treatment for reasons other than disease progression and are not receiving additional systemic anti-cancer therapy.

[0351] Survival data and information on new anticancer therapies initiated after disease progression will be collected at least every 3 months. They may be collected more frequently to aid in data cleaning or regulatory submission efforts. Follow-up may be conducted by telephone interview, electronic messaging, or chart review and will be reported on the CRF. During the follow-up period, cause of death, regardless of causality, will be collected and reported within 24 hours of discovery or notification of the event.

[0352] RECIST v1.1 criteria for tumor assessment For screening tumor assessment, tumor lesions / lymph nodes are classified as measurable or non-measurable, and measurable tumor lesions are recorded according to the longest diameter of the measurement surface (excluding pathological lymph nodes, which are measured in their shortest axis). If multiple measurable lesions are present at screening, a total of up to five total lesions (and a maximum of two lesions per organ) representing all involved organs should be identified as target lesions. Target lesions should be selected based on their size (lesions with the longest diameter). The sum of the diameters of all target lesions is calculated and reported as the baseline sum diameter.

[0353] All other lesions (or sites of disease), including pathological lymph nodes, should be identified as non-target lesions and also recorded at screening. No measurements are required and these lesions should be tracked as "present," "absent," or "definite progression."

[0354] Tumor target lesions will be assessed according to RECIST v1.1 guidelines (Eisenhauer et al., 2009) using the following disease response measures:

[0355] Target Lesion Assessment: ● Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether targeted or non-targeted) must have a reduction of less than 10 mm in the short axis. ●Partial response (PR): At least a 30% reduction in the sum of the diameters of the target lesions, based on the baseline sum diameter. ● Progressive Disease: The sum of the diameters of the target lesions increases by at least 20% with reference to the study minimum sum (for the study minimum, this includes the baseline sum). In addition to the relative increase of 20%, the sum must also show an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). ● Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, based on the smallest total diameter on study.

[0356] Non-target lesion assessment: CR: All non-target lesions disappear and tumor marker levels normalize. All lymph nodes must be non-pathological in size (short axis <10 mm). • Non-CR / non-progressive disease (non-PD): persistence of one or more non-target lesion(s) and / or maintenance of tumor marker levels above normal limits. ● Progressive disease: clear progression of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression).

[0357] A summary is provided in Table 15 below. [Table 17]

[0358] Measurement of disease response at various time points allows for the calculation of: • Disease control rate (DCR), defined as the proportion of patients achieving CR, PR, and SD. ●Objective response rate (ORR), defined as the percentage of patients who experience a predetermined amount of reduction in tumor size (≥30% tumor shrinkage). Progression-free survival (PFS) is defined as the time from initiation of investigational treatment to disease progression (tumor growth ≥ 30%). Duration of response (DoR), defined as the length of time the tumor continues to respond to treatment without the cancer growing or spreading. Overall survival (OS) is defined as the time from start of study drug treatment to death from any cause.

[0359] Safety assessment Physical Examination The medical and physical examination must be performed by a licensed physician, nurse practitioner, or physician assistant and must include a thorough examination of all body systems. In addition, height (at screening only) and weight will be measured.

[0360] Vital signs Vital signs are measured after 5 minutes of rest in the supine position and include temperature, blood pressure (systolic and diastolic), heart rate, and respiratory rate.

[0361] electro-cardiogram A 12-lead ECG is obtained as outlined in the SoA (see Tables 13 and 14) using an ECG machine that automatically calculates heart rate and measures heart rate, PR interval, QRS duration, the time distance in the ECG tracing from the start of the QRS complex to the end of the T wave (QT) interval, and the QTcF interval.

[0362] Clinical safety evaluation in laboratory tests Patients will have blood samples drawn (approximately 5 mL at each time point) for routine laboratory tests according to the SoA (Tables 13 and 14); additional tests may be performed at any time during the study if deemed necessary.

[0363] Clinical laboratory parameters will be analyzed in the on-site clinical laboratory. Laboratory evaluations completed include hematology and serum chemistry, defined as follows: ● Serum chemistry: Includes glucose, total protein, albumin, electrolytes [sodium, potassium, chloride, magnesium, phosphorus], calcium, bilirubin (total, direct), SGPT (ALT) or SGOT (AST), alkaline phosphatase, gamma glutamyl transferase (gamma GT), lactate dehydrogenase (LDH), creatinine, hemoglobin A1c (HgbA1c) (only if there is a history of type 1 or type 2 diabetes), blood urea nitrogen, and creatine phosphokinase (CPK). ○TSH, fT4, lipase, amylase, PTH, FSH, LH, and free cortisol at designated visits Fasting blood glucose levels are assessed only when clinically indicated. • Hematology: Includes complete blood count, differential, platelets, and hemoglobin. ● Coagulation: includes prothrombin time (PT) and PTT, activated partial thromboplastin time (APTT) and INR (with tolerated anticoagulants), C-reactive protein (CRP), and troponin. Urinalysis: The patient collects a urine specimen for routine urinalysis, including color, appearance, and specific gravity gauges, protein, leukocyte esterase, glucose, ketones, urobilinogen, nitrites, white blood cell count (WBC), red blood cell count (RBC), and pH, as well as urine culture (if the patient is clinically symptomatic). If clinically significant values ​​do not return to normal / baseline or grade 1 within a reasonable time period, an etiology must be identified. All protocol required laboratory tests must be performed in accordance with the laboratory manuals and SoAs (Tables 13 and 14). ● If a non-protocol-specified clinical test result performed in the site's local laboratory requires a change in the participant's management or is deemed clinically important (e.g., an SAE or AE or dose modification), the result must be recorded.

[0364] Pregnancy test Only WOCBP after menstrual period has been confirmed and a high-sensitivity urine or serum pregnancy test has been negative should be included.

[0365] Additional pregnancy testing should be performed according to the SoA (Tables 13 and 14) during treatment and at end-of-treatment / early discontinuation visits, as appropriate for local need.

[0366] A pregnancy test is performed whenever a menstrual cycle is late or if pregnancy is otherwise suspected.

[0367] If the patient has a history of bilateral salpingo-oophorectomy and / or hysterectomy, record these surgical procedures; pregnancy testing is not required for these patients.

[0368] Pharmacokinetic evaluation If possible, the following serum PK parameters will be calculated for G9.2-17(IgG4): ●AUC 0-336h ●C max ●T max ●t 1 / 2 Serum concentration vs. time profile

[0369] Approximately 5 mL blood samples will be collected and processed to serum at each time point specified in the SoA (Tables 13 and 14).

[0370] PK schedule for cohorts 1-6: Day 1 of Cycle 1 and Cycle 3 Before administration ●End of injection (EOI) ●2 hours (±30 minutes) from EOI ● 4 hours (± 30 minutes) from EOI Day 15 of Cycle 1 and Cycle 3 Before administration ●At EOI Days 2 and 8 (non-treatment days) of Cycle 1 and Cycle 3 At any point during the visit Day 1 of Cycle 2 and Cycle 4 Before administration ●At EOI Day 1 of every 2 cycles after Cycle 4 (i.e., C6D1, C8D1, etc.) Before administration ●At EOI

[0371] PK schedule for cohorts 7 and 8: Day 1 of every odd-numbered cycle (i.e., C1D1, C3D1, etc.) Before administration ●End of injection (EOI) ● 1 hour after EOI (±15 minutes) Day 3 of every odd-numbered cycle (i.e., C1D3, C3D3, etc.) At any point during the visit Days 8, 15, and 22 of every odd-numbered cycle (i.e., C1D8, C3D8, etc.) Before administration ●At EOI Day 1 of every even-numbered cycle (i.e., C2D1, C4D1, etc.) Before administration ●At EOI

[0372] If a decision is made to interrupt study drug administration, additional PK and safety assessment data will be collected when dosing is resumed; additional PK assessments may be performed during the interruption. If the dose of study drug is reduced, additional PK assessment data will be collected prior to administration of the reduced dose (within 2 hours prior to dosing) and 2-4 hours after initiation of reduced study drug administration. Additional PK and other hematological assessments may be performed as clinically indicated. In sites where COVID-19 restrictions prevent patients from staying for more than 2 hours after dosing, only samples at EOI and 2 hours after dosing will be tested.

[0373] Instructions for collection and handling of biospecimens will be provided. The actual date and time (24-hour clock time) of each sample will be recorded.

[0374] Samples are used to assess serum concentration levels of total G9.2-17 (IgG4) and free / partially free G9.2-17 (IGG4) by a routine laboratory. Concentrations are measured using a validated assay. At least two 50 μL aliquots of serum are required to measure total G9.2-17 (IgG4) concentration. At least two 100 μL aliquots of serum are required to measure free and partially free G9.2-17 (IGG4) concentrations as well as a third aliquot of residual serum. Samples collected for analysis of G9.2-17 (IgG4) plasma concentrations may also be used to assess safety or efficacy aspects related to concerns arising during or after the clinical trial.

[0375] No genetic analysis will be performed on these blood samples. Participant confidentiality will be maintained. At visits where blood samples for safety laboratory determination of PD, ADA, and G9.2-17 (IGG4) are taken, one sample of sufficient quantity may be used.

[0376] Genetics Genetics are not assessed in this test.

[0377] Pharmacodynamic Biomarkers Planned time points for biomarker assessment are provided in the SoA (Tables 13 and 14); sampling may be reduced to every third cycle after 6 months of treatment.

[0378] Collection of biological specimens for other biomarker testing is also part of this trial. The following specimens are required for biomarker testing and will be collected from all participants in this trial as specified in the SoA. A blood sample to be collected prior to administration of the investigational drug (approximately 15 mL prior to administration) Tumor biopsy (tissue sample)

[0379] Samples will be tested for PD biomarkers (by flow cytometry, ELISA, IHC, or multiplexed phenotyping) using validated assays to assess association with observed clinical response to G9.2-17(IGG4).

[0380] The following biomarkers will be evaluated in this trial: Tumor markers (blood): CA15-3, CA-125, carcinoembryonic antigen (CEA), CA19-9, alpha-fetoprotein, neuron specific enolase (NSE), cytokeratin fragment 21 (CYFRA-21) to be assessed pre- and post-cycle as needed for each tumor type. This may be decreased as needed, every 3 cycles after 6 months of treatment, following the same schedule as tumor imaging assessments. PBMC phenotype (blood): e.g., CD3, CD4, CD8, CD45RO, forkhead box protein P3 (FOXP3), CD11B, CD14, CD15, CD16, CD33, CD68, human leukocyte antigen (HLA)DR, CD163, arginase 1, granzyme B, KI67, PD-1, PDL1, pancytokeratin (PAN CK) ● Cytokines (blood): e.g., interferon gamma (IFNγ), IL10, IL12p70, IL13, IL1β, IL2, IL4, IL6, IL8, TNFα, MIP-1b, monocyte chemoattractant protein 1 (MCP-1), MIP-1a, IL17a, IL5, TGFβ Gal-9 in blood and tumor tissues ●PD-L1 (organization) ● Repair Status Mismatch (Organization) Tumor mutation burden (TMB)

[0381] Changes in exploratory biomarkers, if any, will be correlated with safety and response outcomes.

[0382] Samples may be stored for up to 2 years (or according to local regulations) after the last patient's last visit for the trial at selected facilities to allow for further analysis of the effects of G9.2-17(IGG4) on pharmacodynamic biomarkers.

[0383] Immunogenicity assessment Blood samples (approximately 3 mL) will be collected from all participants according to the SoA (Tables 13 and 14) and processed to serum. In addition, serum samples should also be collected at the End of Treatment / Early Discontinuation visit from patients who discontinue the study intervention or withdraw from the study. Cohorts 1-6: Day 1 of Cycle 1-Cycle 4 Before administration Cohorts 1-6: Day 1 of every 2 cycles after Cycle 4 (i.e., C6D1, C8D1, etc.): Before administration Cohorts 7 and 8: Day 1 of each cycle Before administration Cohorts 7 and 8: Day 15 of Cycle 1 and Day 15 of Cycle 2 only Before administration

[0384] At least two 500 μL aliquots of serum each are obtained, and the remaining serum is obtained in a third tube. The samples are shipped to a designated laboratory for analysis using a validated assay. These samples are then tested.

[0385] Serum samples are screened for antibodies that bind to G9.2-17(IgG4)(ADA) and titers of confirmed positive samples are reported. Other analyses may be performed to verify the stability of antibodies to G9.2-17(IgG4) and / or to further characterize the immunogenicity of G9.2-17(IgG4).

[0386] Detection and characterization of antibodies to G9.2-17(IgG4) will be performed using a validated assay. All samples collected for detection of antibodies to the intervention study will be evaluated for G9.2-17(IgG4) serum concentrations to allow interpretation of the antibody data. Antibodies may be further characterized and / or evaluated for their ability to neutralize the activity of the investigational intervention. Samples may be stored for up to 2 years (or in accordance with local regulations) after the last patient's last visit for the study in a suitable facility to allow further analysis of the immune response to G9.2-17(IgG4).

[0387] Other evaluations Patient background At screening, patient demographics are collected, including age, sex, race, and ethnicity.

[0388] Medical history Medical history will include oncology history, surgery / transplant history, radiation therapy history, and COVID19 history and testing. • Personal medical history including previous treatments / surgeries (record of any implants in situ or past implants, previous and / or current use of medical devices, contemporaneous medications (name, indication, dose, route, dose modification with start and end dates if necessary, and reason), pre-existing symptoms, and AEs), family history and genetic disorders of risk based on a complete family history to the best knowledge of the patient). Records of dental treatments performed in the past 12 months • For patients with previously resected pancreatic adenocarcinoma, record whether the primary tumor was located in the head, body, or tail of the pancreas. Bowel habits / typical frequency and consistency ● Record any dietary requirements or preferences (e.g., following a specific dietary regimen: intermittent fasting, keto diet, etc.). - Records of past and current allergies (allergens, severity)

[0389] Previous and contemporaneous medications Previous and contemporaneous medications, including vaccines and complementary therapies / supplements, will be documented for each patient at each scheduled visit (Tables 13 and 14).

[0390] Tumor imaging evaluation Tumor evaluation is performed using CT or MRI with or without contrast; PET-CT studies are performed.

[0391] CT with contrast is the preferred modality (MRI, PET-CT, or other imaging modalities in lieu of or in addition to a CT scan if, at a given site of disease, CT is not feasible or appropriate). Evaluation should include chest / abdomen / pelvis at a minimum and should include other anatomical regions as indicated based on the patient's tumor type and / or medical history. Imaging scans must be de-identified and archived in native format as part of the patient's trial file. The type of scan will be obtained depending on the disease, but the same methodology should be used for the duration of the trial.

[0392] In the trial, evaluations will be performed every 8 weeks ± 7 days according to the SoA (i.e., C3D1, C5D1, C7D1, C9D1, etc.) and at the end of treatment if not evaluated within the past 4-6 weeks. Evaluations may be performed more frequently if clinically indicated. For Part 2 only, a confirmatory scan will be performed after 4 weeks (+7 days) if the scan shows an objective response. After the confirmatory scan, scheduled scans should resume at a frequency of every 8 weeks (± 7 days) from the date of the confirmatory scan.

[0393] Tumor biopsy Pre-treatment and on-treatment biopsies will be collected. A pre-treatment biopsy will be collected during screening. If a pre-treatment biopsy is not available for reasons outlined in the inclusion criteria and the patient is enrolled in the study, archival tumor tissue specimens from the patient will be collected from the primary tumor and / or metastatic deposits. Excision or core biopsies (FFPE tissue block(s) or fresh tissue in formalin) obtained from the primary tumor lesion or metastatic deposit currently or within 5 years prior to study initiation. If both primary and metastatic tissue are available, preference will be given to the use of metastatic deposit tissue. If information on treatment(s) received before and after tissue collection is available, this will also be collected.

[0394] On-treatment biopsies are scheduled for C3D15 ± 7 days and should be performed only after the cycle 3 tumor imaging scan. If the procedure cannot be performed within the protocol-specified time frame, alternatives may be permitted but should be discussed with the Investigator / Medical Oversight. It is recognized that a variety of clinical factors may make it difficult to obtain sufficient specimens. The decision not to complete on-treatment biopsies should be discussed with Medical Oversight.

[0395] ECHO / MUGA ECHO and / or MUGA will be obtained at the time points indicated in the SoA (Tables 13 and 14). Assessments will be repeated every 3 months if clinically indicated.

[0396] ECOG ECOG performance status will be assessed at the time points indicated on the SoA (Tables 13 and 14) using the following grading scale (Oken et al., 1982): Grade 0: Fully active and able to continue all pre-disease performance without restriction Grade 1: Physically strenuous activity is limited, but the patient is able to walk and perform light or sedentary tasks, e.g., light housework, clerical work. Grade 2: Able to walk and perform all self-care activities, but unable to perform any work activities. Active for approximately 50% or more of waking time. Grade 3: Limited self-care capabilities and confined to bed or chair for more than 50% of waking hours. Grade 4: Completely disabled. Unable to continue any self-care. Completely bed or chair confined. Grade 5: Death

[0397] Adverse Events (AEs), Serious Adverse Events (SAEs), and Other Safety Reports An AE is defined in the ICH guidelines for GCP as "an undesirable medical occurrence in a patient receiving a medicinal product or in a clinical trial patient that does not necessarily have a causal relationship to this treatment."

[0398] In this study, the definition of AE is expanded to include any such occurrence (e.g., sign, symptom, or diagnosis) or worsening of a pre-existing medical condition from the time the patient signs informed consent through the time of initiation of investigational drug. Aggravation indicates an increase in the severity, frequency, or duration of symptoms of a pre-existing medical condition (e.g., diabetes, migraine, gout, hypertension, etc.) or association with a significantly worse outcome.

[0399] Serious Adverse Events An SAE is defined as an AE that: Death is caused • Life threatening (putting the patient at risk of immediate death). • Hospitalization or extension of existing hospitalization is required.

[0400] A hospitalization that meets the definition of "serious" is one that includes at least an overnight stay in a health care facility. Inpatient hospitalization does not include rehabilitation facilities, hospice facilities, skilled nursing facilities, nursing homes, routine emergency room admissions, same-day surgery (as an outpatient / same-day / outpatient procedure), or community hospitalizations (e.g., where the patient has no place to sleep). resulting in persistent or significant impairment / incapacity; or ● Whether the child has a birth abnormality / birth defect A significant medical event that is not fatal, life-threatening, or may require hospitalization may be considered an SAE if, based on sound medical judgment, it may endanger the patient and require medical or surgical intervention to prevent one of the outcomes described in this definition. Examples of such medical events include anaphylaxis and allergic bronchospasm that require intensive treatment in the emergency room or at home, blood disorders or convulsions that do not require hospitalization.

[0401] Related For all AEs, sufficient information must be obtained to determine the causality of the AE (e.g., to the study drug or to another disease). The relationship of the AE to the study treatment will be assessed according to the following definitions: • Unrelated: Any event that does not follow a reasonable temporal sequence from administration of the investigational drug and is likely to have been caused by the patient's clinical condition or other treatments administered to the patient. • Low relatedness: Any event that does not follow a reasonable temporal sequence from administration of the investigational drug or that is likely to have been caused by the patient's clinical condition or other treatments administered to the patient. • Potentially related: any response that follows a reasonable temporal sequence from administration of the investigational drug or that follows a known pattern of responses to the drug in question, and any response that cannot be reasonably explained by known features of the patient's clinical condition or other treatments administered to the patient. • Related: A response that follows a reasonable temporal sequence from administration of the investigational drug and that follows a known pattern of response to the suspected drug, recurs with rechallenge, and / or improves with cessation or dose reduction of the drug.

[0402] Adverse Event Management AEs will not be recorded prior to the first dose of study drug. AEs that begin after administration of study drug or worsen relative to medical history will be recorded. AEs should be followed until they resolve, return to baseline, or are determined to be stable or chronic. All SAEs will be collected up to 30 days after the last dose of study drug. All study procedure-related SAEs must be collected from the date of the patient's written consent.

[0403] Immune-Mediated Adverse Reactions Specific IMARs of interest are: ●Immune-mediated hepatitis ●Immune-mediated nephritis ●Immune-mediated pneumonia ●Immune-mediated pneumonia Immune-mediated colitis and diarrhea Immune-mediated endocrine disorders ●Immune-mediated skin reactions • Other immune-mediated adverse reactions: arthritis, encephalitis, rhabdomyolysis, myositis, myocarditis, pancreatitis, and uveitis.

[0404] The monitoring plan is intended to limit the severity and duration of IMARs occurring during combination development and includes scheduled visits for physical examination, vital signs, safety laboratory assessments including hematology, biochemistry, endocrine function assessments every day (pre-dose) 1 of a new dosing cycle, coagulation status assessments, and urinalysis. The evaluation schedule (Tables 13 and 14) also includes evaluation of ejection fraction every 3 months and regular ECGs.

[0405] The management of IMAR caused by G9.2-17(IgG4), alone or in combination with other therapeutic agents, is outlined in Table 16 below. [Table 18-1] [Table 18-2] [Table 18-3] [Table 18-4] [Table 18-5]

[0406] Dose reduction procedures for adverse event management In the event that dose reductions are used for AE management in Part 2 of the study, two dose reductions of 50% each will be allowed. Dose reductions may continue to be followed and guided if clinical benefit is anticipated.

[0407] Evaluation of Laboratory and Other Abnormalities as AEs and SAEs Abnormal laboratory findings (e.g., clinical chemistry, hematology, and urinalysis) or other abnormal evaluations (e.g., ECG or vital signs) that are judged to be clinically significant will be recorded as AEs and SAEs if they meet the definition of an AE or SAE. Clinically significant abnormal laboratory findings or other abnormal evaluations that are detected during the trial or that are present at screening and that have deteriorated significantly after the start of the trial will be reported as an AE or SAE. However, clinically significant abnormal laboratory findings or other abnormal evaluations that are related to the disease being studied or that are present or detected at the start of the trial and do not deteriorate will not be reported as an AE or SAE unless the patient's condition is judged to be more severe than expected.

[0408] Laboratory values ​​that deviate clinically significant from previous measurements may be repeated. If warranted, additional or more frequent testing than specified in the protocol should be performed to provide adequate documentation of and resolution of the AE.

[0409] Duration and frequency of collecting AE and SAE information All AEs and SAEs will be collected at the time points specified in the SoA, from the start of the intervention to the follow-up visit (Tables 13 and 14).

[0410] Medical events that began before the start of the study intervention and after informed consent was obtained will be recorded as a medical history / current condition and not as an AE.

[0411] All SAEs will be recorded and reported immediately and, under no circumstances, should exceed 24 hours.

[0412] Follow-up of AEs and SAEs After the initial AE / SAE report, each participant should be actively followed up at subsequent visits / contacts. All SAEs will be followed until recovery, stabilization, the event is otherwise described, or the participant is lost to follow-up.

[0413] Statistical considerations The study will be completed when the last patient completes their last visit. The database will be locked for the primary analysis after the last patient experiences a primary endpoint event. Final study analysis will be performed after study completion.

[0414] Statistical hypotheses The current study will identify the MTD of G9.2-17 (IgG4) (Part 1) by assessing DLTs, followed by evaluating drug activity (alone or in combination) in the three disease types using a Simon two-stage optimal design. The trial hypotheses for Part 2 are detailed below.

[0415] CRC and CCA G9.2-17 (IgG4) monotherapy group Null hypothesis: ORR3 is ≦5% ●Alternative hypothesis: ORR3 is ≥ 15%

[0416] PDAC G9.2-17 (IgG4) + gemcitabine / nab-paclitaxel combination treatment In first-line treatment of metastatic cancer with gemcitabine / nab-paclitaxel, PFS6 has been reported to be 50% (von Hoff et al., 2013). This study will test: Null hypothesis: PFS6 is ≦50% ●Alternative hypothesis: PFS6 is 75%

[0417] Analysis Set Unless otherwise specified, the intent-to-treat (ITT) population is defined as patients who received at least one dose of study drug. The primary efficacy analysis will be performed on the ITT. Patients will be treated in the ITT.

[0418] The efficacy population is defined as all patients with at least one measurable ORR3 or PFS6 assessment within the ITT population. This population will be used for sensitivity analyses.

[0419] The per-protocol (PP) population is defined as patients who received at least one cycle of G9.2-17 (IGG4) and had no major protocol deviations.

[0420] The safety population (SAF) is defined as all patients who receive at least one dose of study drug. Safety analyses will be performed on the SAF.

[0421] The PK / PD population will be defined as patients receiving at least one cycle of G9.2-17(IGG4).

[0422] Primary endpoint(s) Safety Analysis - Part 1 and Part 2 Unless otherwise specified, all safety analyses will be performed on the SAF.

[0423] Adverse events An investigational emergent adverse event (TEAE) is defined as an event occurring at or after the first dose of an investigational drug. The MedDRA coding dictionary is used to code the AEs. Treatment-related TEAEs, severe or CTCAE grade 3 or grade 4 TEAEs, and TEAEs are summarized by treatment group, overall, by system organ class, and preferred term. These summarize the number of events and the number and percentage of patients with a given event. In addition, the number and percentage of patients with TEAEs are provided by maximum severity. An overview of all TEAEs by system organ class occurring in ≥5% of patients in any treatment group and preferred terms is provided.

[0424] The DLT, MTD, and RP2D are summarized.

[0425] Clinical Laboratory Evaluation All laboratory-based data will be presented as a list of all values ​​and any abnormal results judged to be clinically important (reported as AEs). A numerical summary of all observed findings and changes from baseline screening laboratory assessments, including chemistry, hematology, and urinalysis results, will be provided by visit and treatment group. No inferential comparisons are planned.

[0426] Vital signs Numerical summaries of all observed findings and changes from baseline screening vital signs, including blood pressure, heart rate, respiratory rate, and temperature, will be provided by time point and treatment group. No inferential analyses are planned for vital signs.

[0427] ECG, ECHO / MUGA, and physical examination Physical examination data and changes will be presented as lists. ECG results will be presented as lists and summarized by treatment group and visit based on the incidence of clinically significant abnormalities. No inferential comparisons between treatment groups are planned.

[0428] Primary Efficacy Analysis – Part 2 Disease response will be assessed according to RECIST v1.1 and will be summarized narratively for th...

Claims

1. A pharmaceutical composition for use in the treatment of a solid tumor in a human subject, said pharmaceutical composition comprising an antibody that binds to human galectin-9 (an anti-Gal9 antibody); said pharmaceutical composition for combination with one or more chemotherapeutic agents; The anti-Gal9 antibody, (a) a light chain comprising a light chain (LC) complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO:1, a LC complementarity determining region 2 (CDR2) comprising the amino acid sequence of SEQ ID NO:2, and a light chain variable region (VL) comprising a LC complementarity determining region 3 (CDR3) comprising the amino acid sequence of SEQ ID NO:3, and (b) a heavy chain comprising a heavy chain (HC) complementarity determining region 1 (CDR1) comprising the amino acid sequence of SEQ ID NO: 4, a HC complementarity determining region 2 (CDR2) comprising the amino acid sequence of SEQ ID NO: 5, and a heavy chain variable region (VH) comprising a HC complementarity determining region 3 (CDR3) comprising the amino acid sequence of SEQ ID NO:

6. Including, The pharmaceutical composition, wherein the anti-Gal9 antibody is administered to the subject once a week at a dose of about 0.2-32 mg / kg.

2. The pharmaceutical composition for use according to claim 1, wherein the anti-Gal9 antibody is administered to the subject once a week at a dose of about 10 mg / kg to about 16 mg / kg.

3. The pharmaceutical composition for use according to claim 2 , wherein the anti-Gal9 antibody is administered to the subject once a week at a dose of 10 mg / kg or 16 mg / kg.

4. 2. The pharmaceutical composition for use according to claim 1, wherein the anti-Gal9 antibody is administered to the subject once a week at a dose of about 650 mg to about 1120 mg, or once a week at a dose of about 650 mg to about 700 mg, or once a week at a dose of about 1040 mg to about 1120 mg.

5. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the solid tumor is a metastatic solid tumor.

6. 5. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the solid tumor is pancreatic ductal adenocarcinoma (PDAC), colorectal carcinoma (CRC), hepatocellular carcinoma (HCC), cholangiocarcinoma (CAA), renal cell carcinoma (RCC), urothelial carcinoma, head and neck cancer, breast cancer, lung cancer, or a gastrointestinal (GI) solid tumor.

7. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the anti-Gal9 antibody is administered to the subject by intravenous infusion.

8. The V of the anti-Gal9 antibody Ｌ comprises the amino acid sequence of SEQ ID NO:8, and the V H of said anti-Gal9 antibody comprises the amino acid sequence of SEQ ID NO:

7.

9. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the anti-Gal9 antibody is a human IgG4 molecule having an altered Fc region compared to the wild-type human IgG4 counterpart.

10. The pharmaceutical composition for use according to claim 10, wherein the anti-Gal9 antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 19 and a light chain comprising the amino acid sequence of SEQ ID NO:

15.

11. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein said one or more chemotherapeutic agents comprises an antimetabolite, a microtubule inhibitor, or a combination thereof.

12. A pharmaceutical composition for use according to any one of claims 1 to 4, wherein the one or more chemotherapeutic agents comprise a combination of gemcitabine and paclitaxel.

13. 13. The pharmaceutical composition for use according to claim 12, wherein said paclitaxel is nanoparticulate albumin-bound paclitaxel.

14. The pharmaceutical composition is for use in combination with a combination of gemcitabine and paclitaxel, said use comprising a 28 day cycle; The anti-Gal9 antibody is administered to the subject on days 1 and 15, and the gemcitabine and paclitaxel are administered to the subject on days 1, 8, and 15; or The pharmaceutical composition for use according to claim 11, wherein the anti-Gal9 antibody is administered to the subject on days 1, 8, 15, and 22, and the gemcitabine and paclitaxel are administered to the subject on days 1, 8, and 15.

15. The paclitaxel is 125 mg / m ２ 15. The pharmaceutical composition for use according to claim 14, wherein said Gemcitabine is administered to said subject intravenously at 1000 mg / m2 and said Gemcitabine is administered to said subject at 1000 mg / m2.

16. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the human subject has elevated serum or plasma levels of galectin-9 compared to the control value.

17. The human subject has received at least one line of systemic anti-cancer therapy; the subject has not received prior therapy including gemcitabine and / or paclitaxel, or The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the subject received prior treatment comprising gemcitabine and / or paclitaxel at least 6 months prior to administration of the anti-Gal9 antibody.

18. The human subject has the following characteristics before, during, and / or after treatment: (a) one or more tumor markers in a tumor biopsy sample from the subject; (b) cytokine profile; and (c) Galectin-9 levels The pharmaceutical composition for use according to any one of claims 1 to 4, wherein one or more of the following is tested:

19. The human subject is monitored for the occurrence of one or more adverse effects; the one or more adverse effects include liver toxicity, hematologic toxicity, neurologic toxicity, skin toxicity, gastrointestinal toxicity, or a combination thereof; The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the dose of the anti-Gal9 antibody and / or the doses of gemcitabine and paclitaxel are reduced if adverse effects are observed.

20. The dose of paclitaxel is 100 mg / m ２ ~75mg / m ２ and / or the dose of gemcitabine is reduced to 800 mg / m 2 to 600 mg / m 2 , and / or 20. The pharmaceutical composition for use according to claim 19, wherein if adverse effects are observed, administration of the paclitaxel is withheld if the human subject has an aspartate transaminase (AST) level greater than 10 times the upper limit of normal (ULN), a bilirubin level greater than 5 times the ULN, or both.

21. The pharmaceutical composition for use according to any one of claims 1 to 4, wherein the human subject receives multiple doses of the anti-Gal9 antibody.

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