Combination of anti-human CD39 antibody, anti-human PD-1 antibody, and chemotherapy in gastric cancer

Abstract

Provided herein are dosing and combination therapies with CD39 antibodies, PD-1 antibodies, and FOLFOX or CAPOX in gastric cancer. Immune checkpoint inhibitors have revolutionized the cancer treatment paradigm. These agents modulate the tumor microenvironment or other aspects of the immune system to overcome the immunosuppression that tumors exert on the host immune system. Anti-PD-1 / programmed cell death ligand-1 (PD-L1) agents target the immunosuppressive pathway and have been shown to be beneficial in many tumor types.

Description

[Technical field]

[0001] Provided herein are dosing and combination therapies with CD39 antibodies, PD-1 antibodies, and FOLFOX or CAPOX in gastric cancer. [Background technology]

[0002] Immune checkpoint inhibitors have revolutionized the cancer treatment paradigm. These agents modulate the tumor microenvironment or other aspects of the immune system to overcome the immunosuppression that tumors exert on the host immune system. Anti-PD-1 / programmed death-ligand-1 (PD-L1) agents target immune suppressive pathways and have been shown to be beneficial in multiple tumor types.

[0003] Research over the past decade has led to the discovery of several new immune-modulating pathways. Among them, the adenosine pathway has emerged as one of the most promising targets in immuno-oncology. Adenosine is an immunosuppressive metabolite that is produced at high levels within the tumor microenvironment. It is mainly generated extracellularly through the sequential dephosphorylation of adenosine triphosphate (ATP) by the ectonucleotidases CD39 and CD73.

[0004] Both CD39 and CD73 are reportedly elevated in hematological neoplasia, such as leukemia and lymphoma, as well as in multiple solid tumor types. In solid tumors, ATP is abundantly released in the extracellular space, achieving concentrations more than 1000-fold higher than in healthy tissues. This is mainly due to cell death, metabolic or hypoxic stress in the tumor core, and proinflammatory signals that stimulate active export of ATP.

[0005] Chemotherapy-induced immunogenic cell death is mediated in part by the release of extracellular ATP. Tumors are adept at converting ATP to adenosine via CD39 and CD73 on malignant cells, regulatory immune cells, and the vasculature. These ectonucleotidases regulate purinergic signaling primarily by scavenging proinflammatory ATP and generating immunosuppressive adenosine.

[0006] CD39 is the main rate-limiting enzyme in the adenosine cascade and plays a key role in tumor progression. Blockade of CD39 enzymatic activity can stimulate antitumor immunity across a broad range of tumors by preventing the production of immunosuppressive adenosine and by promoting the accumulation of ATP in the tumor microenvironment. Thus, CD39 can be viewed as an immunological switch that shifts ATP-driven proinflammatory immune cell activity toward an anti-inflammatory state mediated by adenosine, and is therefore a unique therapeutic target for oncology indications.

[0007] Gastroesophageal cancer (GEC) is the fifth most frequently diagnosed cancer and the third leading cause of cancer-related death worldwide. In 2018, it was estimated that over 1.6 million new GEC cases and approximately 1.3 million related deaths would occur. In the United States, an estimated 45,000 new cases of GEC will be diagnosed in 2019, and there will be approximately 27,000 GEC-related deaths. GEC remains difficult to cure, as most patients present with progressive disease. The prognosis for advanced GEC is poor, with an estimated 5-year overall survival (OS) rate of approximately 5%-20%.

[0008] Treatment of advanced / metastatic GEC is based on human epidermal growth factor receptor 2 (HER2) status. However, unlike breast cancer, the prognostic significance of HER2 status in GEC is unclear. Although further studies are needed to assess the prognostic significance of HER2 status in GEC, the addition of HER2 monoclonal antibodies to chemotherapy regimens has proven to be a promising treatment option for patients with HER2-positive metastatic disease, which accounts for 12%-23% of GEC cases.

[0009] For patients with HER2-negative GEC, chemotherapy is the standard first-line treatment for advanced disease. Currently, fluoropyrimidines (fluorouracil or capecitabine) in combination with platinum (oxaliplatin or cisplatin) are the mainstay of chemotherapy.

[0010] A recent phase 3 trial compared treatment with fluorouracil and cisplatin to treatment with fluorouracil and oxaliplatin (FOLFOX) in 220 patients with previously untreated advanced adenocarcinoma of the stomach or gastroesophageal junction. Results showed that FOLFOX was associated with significantly lower toxicity and a trend toward improved median progression-free survival (PFS) compared with fluorouracil and cisplatin (5.8 vs. 3.9 months, p=0.77). In patients over 65 years of age, FOLFOX resulted in superior response rates (41.3 vs. 16.7%, respectively, p=0.12), time to treatment failure (5.4 vs. 2.3 months, p<0.001), PFS (6.0 vs. 3.1 months, p=0.029), and OS (13.9 vs. 7.2 months) compared with fluorouracil and cisplatin.

[0011] Anti-PD-1 agents are also evolving as frontline treatment for GEC. On April 16, 2021, the US Food and Drug Administration approved a PD-1 antibody in combination with select types of chemotherapy for the initial treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma. First-line treatment with a PD-1 antibody and chemotherapy showed a statistically significant improvement in OS among previously untreated patients with PD-L1-positive advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma compared with chemotherapy alone. The study showed a statistically significant improvement in OS and PFS for patients with a PD-L1 combined positive score (CPS) of 5 or higher.

[0012] Impressive and durable responses have been observed in a subset of patients treated with anti-PD-1 agents, but response rates are rarely above 50%, and for most patients, responses are transient. Thus, synergistic strategies may be beneficial for patients. Co-expression of PD-1 and CD39 is very common on tumor-infiltrating lymphocytes and represents an exhausted effector T cell subset in multiple tumor types. Chemotherapy remains an important treatment option for many cancer patients and has traditionally been thought to directly kill tumor cells through their cytotoxic effects, causing tumor cell death in a non-immunogenic manner.

[0013] What is needed is combination therapy. Summary of the Invention [Means for solving the problem]

[0014] Disclosed herein are dosing and combination therapies with CD39 antibodies, PD-1 antibodies, and FOLFOX or CAPOX.

[0015] A first aspect is a method for treating a subject suffering from gastric cancer, comprising: i) an anti-human CD39 antibody comprising an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) a VH CDR1 having the sequence set forth in SEQ ID NO:1; b) a VH CDR2 having the sequence set forth in SEQ ID NO:5; c) a VH CDR3 having the sequence set forth in SEQ ID NO: 9, VL, a) a VLCDR1 having the sequence set forth in SEQ ID NO: 13; b) a VLCDR2 having the sequence set forth in SEQ ID NO: 17; c) an anti-human CD39 antibody comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO: 21; ii) an anti-human PD-1 antibody comprising an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) a VH CDR1 having the sequence set forth in SEQ ID NO:2; b) a VH CDR2 having the sequence set forth in SEQ ID NO:6; c) a VH CDR3 having the sequence set forth in SEQ ID NO: 10, VL, a) a VLCDR1 having the sequence set forth in SEQ ID NO: 14; b) a VLCDR2 having the sequence set forth in SEQ ID NO: 18; c) an anti-human PD-1 antibody comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO:22; and iii) administering to a subject a pharmaceutical composition comprising FOLFOX or CAPOX.

[0016] A second aspect is a pharmaceutical composition for treating a subject suffering from gastric cancer, comprising: i) an anti-human CD39 antibody comprising an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) a VH CDR1 having the sequence set forth in SEQ ID NO:1; b) a VH CDR2 having the sequence set forth in SEQ ID NO:5; c) a VH CDR3 having the sequence set forth in SEQ ID NO: 9, VL, a) a VLCDR1 having the sequence set forth in SEQ ID NO: 13; b) a VLCDR2 having the sequence set forth in SEQ ID NO: 17; c) an anti-human CD39 antibody comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO: 21; ii) an anti-human PD-1 antibody comprising an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) a VH CDR1 having the sequence set forth in SEQ ID NO:2; b) a VH CDR2 having the sequence set forth in SEQ ID NO:6; c) a VH CDR3 having the sequence set forth in SEQ ID NO: 10, VL, a) a VLCDR1 having the sequence set forth in SEQ ID NO: 14; b) a VLCDR2 having the sequence set forth in SEQ ID NO: 18; c) an anti-human PD-1 antibody comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO:22; and iii) providing a pharmaceutical composition comprising or consisting of FOLFOX or CAPOX.

[0017] In some embodiments, the anti-human CD39 antibody is administered at a dosage of 0.5 mg / kg to 40.0 mg / kg, hi some embodiments, the anti-human CD39 antibody is administered at a dosage of 20.0 mg / kg.

[0018] In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 500 mg. In some embodiments, FOLFOX is administered at the following dosage: 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovarin, and 400 mg / m 2 bolus injection of 2400 mg / m 2 In some embodiments, the FOLFOX comprises mFOLFOX6.

[0019] In some embodiments, the gastric cancer comprises locally advanced or metastatic gastric cancer. In some embodiments, the gastric cancer comprises Her2 - It is.

[0020] In some embodiments, the step of administering any of the antibodies or FOLFOX or CAPOX comprises intravenous administration. In some embodiments, the pharmaceutical composition may be administered intravenously.

[0021] In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 40.0 mg / kg. In some embodiments, one week after administration of the loading dose, an anti-human CD39 antibody is administered to a subject at a dosage of 20.0 mg / kg every two weeks.

[0022] In some embodiments, the anti-human PD-1 antibody is administered to the subject at a dosage of 500 mg every 4 weeks. In some embodiments, the FOLFOX comprises mFOLFOX6, and the mFOLFOX6 is administered every 2 weeks.

[0023] In some embodiments, the anti-human CD39 antibody is an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), where the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 25 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 29. In some embodiments, the anti-human CD39 antibody is an antibody comprising a heavy chain and a light chain, where the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 33 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 34.

[0024] In some embodiments, the anti-human PD-1 antibody is an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), where the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO:26 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 30. In some embodiments, the anti-human PD-1 antibody is an antibody comprising a heavy chain and a light chain, where the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO:35 or SEQ ID NO:36, and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO:37.

[0025] In some embodiments, the subject has a partial or complete response. In some embodiments, the method or pharmaceutical composition results in an OS of 40%, 50%, 60%, 70%, or 80%. In some embodiments, the method or pharmaceutical composition increases PFS or DFS. [Brief description of the drawings]

[0026] [Figure 1] CD39 monotherapy dose escalation and expansion are shown. [Diagram 2] This shows eligibility, patient background, and disease characteristics for treatment with CD39 antibody, anti-PD-1 antibody (budigalimab), and FOLFOX for metastatic gastroesophageal cancer. [Figure 3A] FIG. 3 shows patient responses following treatment with CD39 antibody, budigalimab, and FOLFOX for metastatic gastroesophageal cancer. FIG. 3A shows treatment duration swim plots, and FIG. 3B shows swim lanes by CPS score. [Figure 3B] Same as above. [Figure 4] 1 shows maximum change from baseline for treatment with CD39 antibody, budigalimab, and FOLFOX for metastatic gastroesophageal cancer. [Diagram 5] 1 shows the onset of tumor response for treatment with CD39 antibody, budigalimab, and FOLFOX for metastatic gastroesophageal cancer. [Figure 6A] Figure 6A shows that combination treatment results in an increase in PD-L1 and CD8 T cells. Figure 6B shows that combination treatment results in an increase in CD8 cells. Figure 6C shows that combination treatment affects CD39 stromal therapy. [Figure 6B] Same as above. [Figure 6C] Same as above. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] 1.Definition Unless otherwise defined, all terms, designations, and other scientific terms of the art used herein are intended to have the meanings commonly understood by those skilled in the art to which the present invention pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or ease of reference, and the inclusion of such definitions herein should not necessarily be interpreted as representing a difference from what is commonly understood in the art. The techniques and procedures described or referenced herein are generally well understood and commonly used with conventional methodologies by those skilled in the art, such as the widely used molecular cloning methodologies described in, for example, Sambrook et al., Molecular Cloning: A Laboratory Manual 2nd ed. (1989) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. Where appropriate, procedures involving the use of commercially available kits and reagents are generally performed according to manufacturer-defined protocols and / or parameters unless otherwise specified.

[0028] The terms "CD39" and "CD39 antigen" and "cluster of differentiation 39" are used interchangeably herein. CD39 is also known as ectonucleoside triphosphate diphosphohydrolase-1 (gene: ENTPDJ, protein: NTPDase1, see www.ncbi.nlm.nih.gov / gene / 953). CD39 has also been referred to as ATPDase and SPG64.

[0029] The terms "PD-1," "programmed cell death protein 1," and "cluster of differentiation 279" are used interchangeably herein.

[0030] As used herein, "FOLFOX" refers to a combination chemotherapy that includes leucovorin, fluorouracil, and oxaliplatin. There are several different FOLFOX regimens, including FOLFOX-4, FOLFOX-6, modified FOLFOX-6 (mFOLFOX-6), and FOLFOX-7. They differ in the doses and manner in which the three drugs are given.

[0031] As used herein, "CAPOX" refers to a combination chemotherapy that includes oxaliplatin and capecitabine. CAPOX may also be referred to as XELOX, CAPE-OX, and OxCap.

[0032] As used herein, "RP2D" refers to the recommended phase 2 dose of one or more agents as determined by dose-limiting toxicity. In oncology, it is defined as the dose level that results in approximately 20% of dose-limiting toxicity. In North America, the maximum tolerated dose is the RP2D, while in other parts of the world, the MTD is considered a dose greater than the RP2D. The RPTD is often selected by the sponsor in consultation with the principal investigator for the dose expansion arm, based on safety, tolerability, efficacy, pharmacokinetic, and pharmacokinetic data collected during the dose escalation portion of the study.

[0033] As used herein, "overall survival" or "OS" refers to the time starting at the time of diagnosis (or initiation of treatment) and ending at the time of death.

[0034] As used herein, "disease-free survival" or "DFS" or "recurrence-free survival" or "RFS" refers to the length of time after treatment for cancer has ended that a patient survives without any signs or symptoms of cancer.

[0035] As used herein, "progression-free survival" or "PFS" refers to the time from a participant's first dose of study treatment to the earliest date of disease progression or death, whichever occurs first.

[0036] "Duration of response" and "DOR" shall refer to the time from the first documentation of disease response (CR or PR) to the first documentation of disease progression or death from any cause, whichever occurs first.

[0037] "Objective response rate" or "ORR" refers to the percentage of subjects with unconfirmed and confirmed CR or unconfirmed and confirmed PR.

[0038] "Complete response" or "CR" refers to the disappearance of all target lesions and any pathological lymph nodes (whether target or non-target lesions) must have a reduction in size to less than 10 mm in the short axis.

[0039] A "partial response" or "PR" refers to at least a 30% reduction in the sum of the diameters of the target lesions, the reference being the baseline diameter.

[0040] As used herein, "SD" in "stable disease" refers neither to a shrinkage compared to baseline sufficient to qualify for a partial response nor to an increase (with reference to the smallest summated diameter during the study) sufficient to qualify for PD.

[0041] As used herein, "progression" or "PD" refers to at least a 20% increase in the sum of the diameters of the target lesions, referenced to the smallest sum in the study (which includes the baseline sum if it is the smallest sum in the study). In addition to the 20% relative increase, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

[0042] As used herein, "DCR," "disease control rate," "CBR," and "clinical benefit rate" refer to the percentage of patients with advanced or metastatic cancer who achieve CR, PR, and SD.

[0043] As used herein, "CPS" refers to the total number of PD-L1 staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells multiplied by 100.

[0044] As used herein, "BOR" or "best overall response" refers to the single best response at any evaluation time point before receiving non-protocol therapy or before PD.

[0045] As used herein, the term "subject" means a mammalian subject. In some embodiments, the subject is a human.

[0046] 2. Method Disclosed herein are combination and dosing regimens and compositions that combine CD39 antibodies, PD-1 antibodies, and FOLFOX or CAPOX.

[0047] A first aspect is a method for treating a subject suffering from gastric cancer, comprising: i) an anti-human CD39 antibody comprising an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) a VH CDR1 having the sequence set forth in SEQ ID NO:1; b) a VH CDR2 having the sequence set forth in SEQ ID NO:5; c) a VH CDR3 having the sequence set forth in SEQ ID NO: 9, VL, a) a VLCDR1 having the sequence set forth in SEQ ID NO: 13; b) a VLCDR2 having the sequence set forth in SEQ ID NO: 17; c) an anti-human CD39 antibody comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO: 21; ii) an anti-human PD-1 antibody comprising an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) a VH CDR1 having the sequence set forth in SEQ ID NO:2; b) a VH CDR2 having the sequence set forth in SEQ ID NO:6; c) a VH CDR3 having the sequence set forth in SEQ ID NO: 10, VL, a) a VLCDR1 having the sequence set forth in SEQ ID NO: 14; b) a VLCDR2 having the sequence set forth in SEQ ID NO: 18; c) an anti-human PD-1 antibody comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO:22; and iii) administering to a subject a pharmaceutical composition comprising FOLFOX or CAPOX.

[0048] In some embodiments, the anti-human CD39 antibody is administered at a dosage of 0.5 mg / kg to 40.0 mg / kg, hi some embodiments, the anti-human CD39 antibody is administered at a dosage of 20.0 mg / kg.

[0049] In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 500 mg. In some embodiments, FOLFOX is administered at the following dosage: 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovarin, and 400 mg / m 2 bolus injection of 2400 mg / m 2 In some embodiments, the FOLFOX comprises mFOLFOX6.

[0050] In some embodiments, the gastric cancer comprises locally advanced or metastatic gastric cancer. In some embodiments, the gastric cancer comprises Her2 - It is.

[0051] In some embodiments, the step of administering any of the antibodies and / or FOLFOX or CAPOX comprises intravenous administration. In some embodiments, the pharmaceutical composition may be administered intravenously.

[0052] In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 40.0 mg / kg. In some embodiments, one week after administration of the loading dose, an anti-human CD39 antibody is administered to a subject at a dosage of 20.0 mg / kg every two weeks.

[0053] In some embodiments, the anti-human PD-1 antibody is administered to the subject at a dosage of 500 mg every 4 weeks. In some embodiments, the FOLFOX comprises mFOLFOX6, and the mFOLFOX6 is administered every 2 weeks.

[0054] In some embodiments, the anti-human CD39 antibody is an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), where the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 25 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 29. In some embodiments, the anti-human CD39 antibody is an antibody comprising a heavy chain and a light chain, where the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 33 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO: 34.

[0055] In some embodiments, the anti-human PD-1 antibody is budigalimab comprising a heavy chain variable region (VH) and a light chain variable region (VL), where the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO:26 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 30. In some embodiments, the budigalimab comprises a heavy chain and a light chain, where the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO:35 or SEQ ID NO:36 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO:37.

[0056] Other anti-human PD-1 antibodies may be used. For example, in some embodiments, the anti-human PD-1 antibody is nivolumab and comprises or consists of an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) VHCDR1 having the sequence set forth in SEQ ID NO:3; b) a VHCDR2 having the sequence set forth in SEQ ID NO:7, and c) comprising or consisting of a VH CDR3 having the sequence set forth in SEQ ID NO: 11; VL is a) VLCDR1 having the sequence set forth in SEQ ID NO: 15; b) VLCDR2 having the sequence set forth in SEQ ID NO: 19, and c) comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO:23.

[0057] In some embodiments, the anti-human PD-1 antibody is an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), where the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO:27 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO:31. In some embodiments, the anti-human PD-1 antibody is an antibody comprising a heavy chain and a light chain, where the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO:38 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO:39.

[0058] In some embodiments, the anti-human PD-1 antibody is pembrolizumab and comprises or consists of an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) VHCDR1 having the sequence set forth in SEQ ID NO:4, b) a VHCDR2 having the sequence set forth in SEQ ID NO:8, and c) comprising or consisting of a VH CDR3 having the sequence set forth in SEQ ID NO: 12, VL is a) VLCDR1 having the sequence set forth in SEQ ID NO: 16; b) VLCDR2 having the sequence set forth in SEQ ID NO: 20, and c) comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO:24.

[0059] In some embodiments, the anti-human PD-1 antibody is an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), where the heavy chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO:28 and the light chain variable region comprises or consists of a molecule having a sequence comprising or consisting of SEQ ID NO: 32. In some embodiments, the anti-human PD-1 antibody is an antibody comprising a heavy chain and a light chain, where the heavy chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO:40 and the light chain comprises or consists of one or more molecules having a sequence comprising or consisting of SEQ ID NO:41.

[0060] 3. Pharmaceutical Compositions A second aspect is a pharmaceutical composition for treating a subject suffering from gastric cancer, comprising: i) an anti-human CD39 antibody comprising an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) a VH CDR1 having the sequence set forth in SEQ ID NO:1; b) a VH CDR2 having the sequence set forth in SEQ ID NO:5; c) a VH CDR3 having the sequence set forth in SEQ ID NO: 9, VL, a) a VLCDR1 having the sequence set forth in SEQ ID NO: 13; b) a VLCDR2 having the sequence set forth in SEQ ID NO: 17; c) an anti-human CD39 antibody comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO: 21; ii) an anti-human PD-1 antibody comprising an antibody comprising a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH is a) a VH CDR1 having the sequence set forth in SEQ ID NO:2; b) a VH CDR2 having the sequence set forth in SEQ ID NO:6; c) a VH CDR3 having the sequence set forth in SEQ ID NO: 10, VL, a) a VLCDR1 having the sequence set forth in SEQ ID NO: 14; b) a VLCDR2 having the sequence set forth in SEQ ID NO: 18; c) an anti-human PD-1 antibody comprising or consisting of a VLCDR3 having the sequence set forth in SEQ ID NO:22; and iii) providing a pharmaceutical composition comprising or consisting of FOLFOX or CAPOX.

[0061] Each of the pharmaceutical compositions for the antibody and FOLFOX or CAPOX contains one or more active agents and may further contain solvents, buffers, diluents, carriers, and other excipients to aid in the administration, solubility, absorption or bioavailability, and / or stability of the active agent or the overall composition. Each of the antibody and FOLFOX or CAPOX can be provided in a suitable pharmaceutical composition and administered by any suitable route of administration. Suitable routes of administration for each of the antibody and FOLFOX or CAPOX include, but are not limited to, inhalation, intraarterial, intradermal, intramuscular, intraperitoneal, intravenous, nasal, parenteral, pulmonary, and subcutaneous routes. Each composition may contain one or more pharmaceutical excipients. Any suitable pharmaceutical excipient may be used, and one of skill in the art may select a suitable pharmaceutical excipient. Additional pharmaceutical excipients include, for example, those described in Handbook of Pharmaceutical Excipients, Rowe et al. (Eds.) 6th Ed. (2009), which is incorporated by reference in its entirety.

[0062] 4. Dosage form A physician will determine the dosing regimen which he deems most appropriate depending on the age, weight, condition, and other factors specific to the subject being treated, including available guidance on recommended dosages.

[0063] In some embodiments, the anti-human CD39 antibody is administered at a dosage of 0.5 mg / kg to 60 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 0.5 mg / kg to 1 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 1 mg / kg to 5 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 5 mg / kg to 10 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 10 mg / kg to 15 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 15 mg / kg to 20 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 20 mg / kg to 25 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 25 mg / kg to 30 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 30 mg / kg to 35 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 35 mg / kg to 40 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 40 mg / kg to 45 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 45 mg / kg to 50 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 50 mg / kg to 55 mg / kg. In some embodiments, the anti-human CD39 antibody is administered at a dosage of 55 mg / kg to 60 mg / kg.

[0064] In some embodiments, the anti-human CD39 antibody is administered at a dosage of 30 mg / kg Q3W or 20 mg / kg Q2W.

[0065] In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 1 mg to 1 g. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 50 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 100 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 150 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 200 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 250 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 300 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 350 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 400 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 450 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 500 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 550 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 600 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 650 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 700 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 750 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 800 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 850 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 900 mg. In some embodiments, the anti-human PD-1 antibody is administered at a dosage of 950 mg.

[0066] In some embodiments, the anti-human PD-1 antibody is administered at a flat dose of 275 mg Q2W, a flat dose of 375 mg Q3W, or a flat dose of 500 mg Q4W.

[0067] In some embodiments, treatment or prevention can be initiated with one or more loading doses of an antibody or composition provided herein, followed by one or more maintenance doses. In some embodiments, the one or more loading doses include one or more loading doses of an anti-human CD39 antibody. In some embodiments, the one or more loading doses are administered at a dosage between 5 mg / kg and 100 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 5.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 10.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 15.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 20.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 25.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 30.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 35.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 40.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 45.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 50.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 55.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 60.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 65.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 70.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 75.0 mg / kg.In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 80.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 85.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 90.0 mg / kg. In some embodiments, a single loading dose of an anti-human CD39 antibody is administered to a subject at a dosage of 95.0 mg / kg.

[0068] In some embodiments, FOLFOX is administered in the following amounts: 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovarin, and 400 mg / m 2 bolus injection of 2400 mg / m 2 In some embodiments, the FOLFOX comprises mFOLFOX6.

[0069] In certain embodiments, a dose of an antibody or composition provided herein can be administered to achieve a steady state concentration of the antibody in the blood or serum of a subject. The steady state concentration can be determined by measurement according to techniques available to those of skill in the art, or can be based on the subject's physical characteristics, such as height, weight, and age.

[0070] 5. Scheduling The frequency and dosage will also vary depending on factors specific to each subject, depending on the particular therapy administered, as well as the subject's age, weight, response, and past medical history. Additionally, it is noted that the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with the subject's response.

[0071] In some embodiments, the combination is assembled in the subject to be treated, whether they are administered at the same time or at different times, hi some embodiments, the components of the combination are mixed together at the clinical site prior to administration.

[0072] In some embodiments, the CD39 antibody, the PD-1 antibody, and FOLFOX or CAPOX are administered on the same schedule. In some embodiments, the CD39 antibody, the PD-1 antibody, and FOLFOX or CAPOX are administered on different schedules. In some embodiments, the CD39 antibody and the PD-1 antibody are administered on the same schedule, but FOLFOX or CAPOX is administered on a different schedule.

[0073] In some embodiments, the CD39 antibody is administered once a week. In some embodiments, the CD39 antibody is administered every other week. In some embodiments, the CD39 antibody is administered every three weeks. In some embodiments, the CD39 antibody is administered every four weeks. In some embodiments, the CD39 antibody is administered every five weeks. In some embodiments, the CD39 antibody is administered every six weeks. In some embodiments, the CD39 antibody is administered every seven weeks. In some embodiments, the CD39 antibody is administered every eight weeks.

[0074] In some embodiments, the dose and dosing frequency of the CD39 antibody is 20 mg / kg every 2 weeks. In some embodiments, the dose and dosing frequency of the CD39 antibody is 30 mg / kg every 3 weeks. In some embodiments, the dose and dosing frequency of the CD39 antibody is 40 mg / kg every 4 weeks.

[0075] In some embodiments, the PD-1 antibody is administered once a week. In some embodiments, the PD-1 antibody is administered every other week. In some embodiments, the PD-1 antibody is administered every three weeks. In some embodiments, the PD-1 antibody is administered every four weeks. In some embodiments, the CD39 antibody is administered every five weeks. In some embodiments, the PD-1 antibody is administered every six weeks. In some embodiments, the PD-1 antibody is administered every seven weeks. In some embodiments, the PD-1 antibody is administered every eight weeks.

[0076] In some embodiments, the dose and dosing frequency of the PD-1 antibody is 100 mg to 300 mg every week. In some embodiments, the dose and dosing frequency of the PD-1 antibody is 200 mg to 400 mg every 2 weeks. In some embodiments, the dose and dosing frequency of the PD-1 antibody is 300 mg to 500 mg every 3 weeks. In some embodiments, the dose and dosing frequency of the PD-1 antibody is 400 mg to 600 mg every 4 weeks. In some embodiments, the dose and dosing frequency of the PD-1 antibody is 500 mg to 700 mg every 5 weeks. In some embodiments, the dose and dosing frequency of the PD-1 antibody is 600 mg to 800 mg every 6 weeks. In some embodiments, the dose and dosing frequency of the PD-1 antibody is 700 mg to 900 mg every 7 weeks. In some embodiments, the dose and dosing frequency of the PD-1 antibody is 800 mg to 1 g every 8 weeks.

[0077] In some embodiments, the anti-human CD39 antibody is administered on days 1 and 15 of a 28 day cycle. In some embodiments, the anti-human PD1 antibody is administered to the subject at a dose of 500 mg every 4 weeks. In some embodiments, the mFOLFOX6 is administered on days 1 and 15 of a 28 day cycle.

[0078] In some embodiments, the dosing regimen further comprises an initial loading dose of 40 mg / kg one week prior to beginning the repeat portion (maintenance dose) of the dosing regimen.

[0079] In some embodiments, the dosing regimen further comprises an initial loading dose of 10 mg / kg to 90 mg / kg. In some embodiments, the loading dose is 10 mg / kg. In some embodiments, the loading dose is 20 mg / kg. In some embodiments, the loading dose is 30 mg / kg. In some embodiments, the loading dose is 40 mg / kg. In some embodiments, the loading dose is 50 mg / kg. In some embodiments, the loading dose is 60 mg / kg. In some embodiments, the loading dose is 70 mg / kg. In some embodiments, the loading dose is 80 mg / kg. In some embodiments, the loading dose is 90 mg / kg.

[0080] These dosage regimens are generally sufficient to maintain the trough concentration of anti-human CD39 antibody at or above 50 μg / ml. Other trough concentrations can be achieved by adjusting the dosage accordingly. Although these particular regimens offer the benefit of relatively convenient outpatient treatment, other dosage regimens with smaller doses administered more frequently can also be used, up to and including continuous intravenous infusion (IV drip). Any of these dosage regimens can be referred to as a means or step for maintaining the serum trough concentration of CD39 binding protein at or above a threshold level, or at or above a threshold level in 85% of subjects. In some embodiments, the threshold level is 10, 20, 30, 40, 50, or 60 μg / mL.

[0081] 6.RECIST and response Tumor burden assessment is an important criterion of evaluation. Any method can be used to assess response. Some embodiments provide for using RECIST criteria to assess response (see https: / / recist.eortc.org / recist-1-1-2 / and New response evaluation criteria in solid tumors: Revised RECIST guideline (version 1.1), European Journal of Cancer 45 (2009) 228-247, which are incorporated herein by reference in their entirety).

[0082] To demonstrate efficacy, subjects treated with the method or composition should have an objective response rate of greater than 25%, or greater than 30%. In some embodiments, the efficacy of the treatment includes a median DOR of 6 months or greater (i.e., at least 6 months, at least 8 months, and / or at least 10 months). Other efficacy endpoints include PFS, OS, and / or an acceptable safety and tolerability profile.

[0083] In some embodiments, the methods or pharmaceutical compositions provide a partial or complete response. In some embodiments, the methods or pharmaceutical compositions provide a 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, results in an OS of 75%, 80%, 85%, or 90%. In some embodiments, the method or pharmaceutical composition increases PFS or DFS.

[0084] Different methods can be used to measure tumors. Some internal cancer tumors show up on an x-ray or CT scan and can be measured with a ruler. Blood tests can be done, including those that measure organ function. Tumor marker tests can be done for certain cancers.

[0085] Regardless of the test used, whether a blood test, cell count, or tumor marker test, it is repeated at specific intervals so that the results can be compared to earlier tests of the same type.

[0086] Other measures of effectiveness of cancer treatment include overall survival (i.e., the time to death from any cause, measured from diagnosis or from the start of the treatment being evaluated), cancer-free survival (i.e., the time to death from any cause after a complete response), and genomic function. These measures include progression-free survival (i.e., the length of time that resumed tumor growth remains undetectable after disease stabilization or partial response), and progression-free survival (i.e., the length of time that resumed tumor growth remains undetectable after disease stabilization or partial response).

[0087] In some embodiments, there is a treatment-induced increase in the CPS score. The baseline CPS score may correlate with response to a treatment regimen containing an anti-PD-1 or anti-PD-L1 agent. More specifically, the CPS score may correlate with improved ORR, PFS, or OS when combined with chemotherapy in gastric cancer as exemplified herein.

[0088] In some embodiments, the subject has a CPS score. In some embodiments, the CPS score is less than 1. In some embodiments, the CPS score is greater than or equal to 1 and less than 5. In some embodiments, the CPS is greater than or equal to 5.

[0089] In some embodiments, treatment induces an increase in CPS score. Changes in CPS score can reflect increased anti-tumor immune activity and can correlate with clinical response. Changes in CPS can predict clinical response before radiological assessment.

[0090] In some embodiments, the treatment induces an increase in CD8 T cells, which are known to mediate anti-tumor immunity, and increased CD8 T cells can correlate with clinical response.

[0091] In some embodiments, the treatment induces an increase in CD39 along with an increase in CD8 T cells. Expression of CD39 on CD8 T cells is known to enrich tumor-reactive T cells and differentiate them from bystander T cells. [Table S-1] [Table S-2] [Table S-3] [Table S-4] EXAMPLES

[0092] Example 1: Inclusion and Exclusion and Dose Specifications Inclusion criteria included male or female subjects aged 18 years or older at screening (or 19 years or older at screening in Korea), fresh and / or archival tumor tissue, body weight ≥35 kg, evidence of measurable disease by computed tomography (CT), CT positron emission tomography (PET), or magnetic resonance imaging (MRI) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, life expectancy >12 weeks, and Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

[0093] Inclusion criteria also included adequate organ and bone marrow function, defined as follows: Absolute neutrophil count ≥ 1.5k / μL, platelets ≥ 75k / μL (platelets ≥ 100k / μL in the chemotherapy arm), hemoglobin ≥ 8g / dL (hemoglobin ≥ 9g / dL in the chemotherapy arm). b. Serum creatinine <= 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 40 mL / min. Note: Subjects eligible for Cohort 10 may have a CrCl < 40 mL / min after approval by the Medical Monitor. c. Aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5xULN (or ≤ 5xULN for liver metastases). d. Total bilirubin ≤ 2xULN (or ≤ 3xULN in Gilbert's syndrome). e. Prothrombin time (PT) / international normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≦1.2xULN, fibrinogen ≧150mg / dL. f. Serum albumin ≥ 3.0 g / dL. Subjects also had to have had at least 14 days since the last dose of chemotherapy or biologic therapy or tyrosine kinase inhibitor or high-dose (e.g., >10 mg prednisone or equivalent per day) steroid therapy, or other second generation hormonal therapy, prior to the loading dose / first dose of study treatment. Resolution of adverse effects from any prior chemotherapy, immunotherapy, or prior systemic anticancer therapy, radiation therapy, or surgery to grade 1 or baseline (excluding grade 2 alopecia and grade 2 sensory neuropathy) was also required. Subjects with a history of congestive heart failure were required to have an echocardiogram or multi-gated acquisition scan showing a left ventricular ejection fraction of 45% or greater within 21 days prior to the loading dose / first dose of study treatment.

[0094] Inclusion criteria also included a histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction with HER2-negative disease (HER2 0 or 1 by IHC, or HER2 2+ by IHC, and no HER2 gene amplification by in situ hybridization (ISH)). Subjects had histologically or cytologically confirmed HER2-negative disease (HER2 0 or 1 by IHC, or HER2 2+ by IHC, and no HER2 gene amplification by ISH) in their primary or metastatic tumors. Patients were required to have no prior treatment for metastatic disease and no prior (neo)adjuvant therapy within 6 months of study entry.

[0095] Exclusion criteria included a history of allergy or hypersensitivity to any component of the study treatment. Subjects with a history of severe hypersensitivity reactions (defined as any grade 3 reaction lasting 48 hours or more despite optimal therapy) to any monoclonal antibody were excluded. Subjects were excluded if they had used study medication within 14 days prior to the loading dose / first dose of study treatment and throughout the study, chemotherapy, radiation therapy, biologic therapy, herbal therapy, or any study therapy within 14 days prior to the loading dose / first dose of study treatment. Palliative radiation therapy for non-target lesions was permitted.

[0096] Subjects who received high-dose (e.g., >10 mg prednisone or equivalent per day) systemic steroid therapy or any other form of immunosuppressive therapy within 14 days of the loading / first dose of study treatment were excluded, but inhaled, intranasal, intraocular, topical, and intra-articular steroids are permitted. Transient steroid administration as antiemetics or chemotherapy preconditioning (e.g., paclitaxel) was also permitted. Subjects who received therapeutic anticoagulation were excluded. Prophylactic anticoagulation with low molecular weight heparin, factor Xa inhibitors, and low-dose aspirin was permitted. Patients with a history of systemic treatment requiring systemic steroids or immunosuppressants or an autoimmune disease requiring transplantation within the past 2 years (e.g., rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease) were excluded. Patients with a history of vitiligo, autoimmune thyroiditis, or mild psoriasis were permitted.

[0097] Subjects were excluded if they had a known history of HIV or other chronic immune deficiencies. Also excluded were subjects with uncontrolled intercurrent illnesses, including but not limited to: - Uncontrolled diabetes mellitus. - Ongoing or active bacterial, viral, or fungal infection requiring systemic treatment. - Clinically significant congestive heart failure as defined by New York Heart Association Class 3 or Class 4. - Unstable angina, arrhythmia, or myocardial infarction within 6 months prior to screening. - Uncontrolled tumor-related pain. (Subjects requiring narcotic analgesics had to be on a stable regimen at the time of study enrollment). - Poorly controlled hypertension, defined as blood pressure consistently >150 / 90mmHg despite optimal medical management. - Uncontrolled pleural, pericardial, or ascites effusion requiring repeat drainage ≥2 times every 28 days. Indwelling drainage catheters (e.g., PleurX®) were permitted. - Active or chronic viral hepatitis B or C infection. Subjects who were positive for hepatitis B surface antigen or hepatitis C antibody were excluded. If hepatitis B core antibody was positive, subjects had to have a negative PCR result prior to enrollment. Those with a positive PCR were excluded. - Uncontrolled thyroid disease. - Known history of active tuberculosis. - Active infection requiring 4 or more days of systemic therapy (grade ≥ 2) within 1 week of dosing.

[0098] Subjects with active or untreated central nervous system metastases were excluded. Subjects with brain metastases were eligible provided they could demonstrate clinical and radiographic SD for at least 4 weeks after targeted therapy and had not used steroids (>10 mg / day prednisone or equivalent) for at least 4 weeks prior to the loading / first dose of study treatment. Subjects with a history of any other malignancy within the past 3 years were excluded (except for successfully treated non-melanoma skin cancer or localized carcinoma in situ that was considered cured or adequately treated by the investigator). Subjects with completely resected cutaneous melanoma (early stage), basal cell carcinoma, cutaneous squamous cell carcinoma, cervical carcinoma in situ, breast carcinoma in situ, and localized prostate cancer were eligible.

[0099] Pregnant or lactating women were excluded. Subjects who had received a live vaccine within 28 days prior to the loading / first dose of study drug were excluded. Subjects with a history of pneumonia or interstitial lung disease (except in the setting of PD-(L)1 therapy) or ongoing pneumonia, idiopathic pulmonary fibrosis, organizing pneumonia, bronchiolitis obliterans, drug-induced pneumonia, or idiopathic pneumonia were excluded. Subjects previously treated with an anti-PD-(L)1 targeted agent were excluded if they had any of the following during the course of their therapy: Immune-mediated toxicity of grade 3 or greater severity. b. Any ocular or neurotoxicity. c. Any hypersensitivity to a PD-(L)1 targeted agent for subjects in the budigalimab- and pembrolizumab-containing cohorts.

[0100] Subjects were excluded if judged by the principal investigator to have evidence of ongoing hemolysis on a hemolysis panel (total, direct, and unconjugated serum bilirubin, peripheral blood smear, D-dimer, and serum haptoglobin). Subjects who underwent major surgery by the principal investigator within 28 days prior to the loading dose / first dose of study drug and had not completely healed surgical wounds were excluded. Diagnostic or research biopsies did not exclude subjects from enrollment, and placement of a vascular access device such as a Port-A-Cat was not considered a major surgery. Subjects were excluded if they had a history of a major immunologic reaction (grade 3–4) to any IgG-containing agent. Subjects were excluded if they had a history of primary immunodeficiency, bone marrow transplant, chronic lymphocytic leukemia, solid organ transplant, or a previous clinical diagnosis of tuberculosis. Subjects were excluded if they had Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), or drug reaction with eosinophilia and systemic symptoms (DRESS).

[0101] Exclusion criteria also included inability to receive a port or peripherally inserted central catheter, known hypersensitivity to 5-FU, oxaliplatin, or other platinum agents, known hypersensitivity to mFOLFOX6 or any of its excipients, known dihydropyrimidine dehydrogenase deficiency (no testing required), and baseline peripheral neuropathy / paresthesia grade >1.

[0102] Six subjects with a variety of advanced solid tumors received the following combination regimens: -Anti-human CD39 antibody (40 mg / kg 7 days before day 1 of cycle 1, followed by 20 mg / kg Q2W). -Budigalimab (500 mg every 4 weeks [Q4W]). -mFOLFOX6 (oxaliplatin 85mg / m 2 IV, leucovorin 400 mg / m 2 IV for 2 hours plus 5-FU 400 mg / m 2 IV bolus and 2400 mg / m 2 Continuous infusion Q2W for 46 hours). Example 2: Anti-human PD-1 antibody and anti-human CD39 antibody combined with chemotherapy in subjects with advanced gastroesophageal cancer

[0103] Figure 1 shows the monotherapy dose escalation and expansion and study design for treatment with CD39 antibody, PD-1 antibody (budigalimab), and FOLFOX for metastatic gastroesophageal cancer. Figure 2 shows eligibility and demographic and disease characteristics for treatment with CD39 antibody, budigalimab, and FOLFOX for metastatic gastroesophageal cancer.

[0104] Seventy response-evaluable subjects with human epidermal growth factor receptor 2 (HER2)-negative metastatic gastroesophageal cancer (GEC) were administered the doses listed below. 1. Arm A: anti-human CD39 antibody + mFOLFOX6 (n=6). 2. Cohort 3 arm B: anti-human CD39 antibody + budigalimab + mFOLFOX6 (n=40). 3. Budigalimab + mFOLFOX6 (n=24).

[0105] Inclusion criteria included a histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction with HER2-negative disease (HER2 0 or 1 by IHC, or HER2 2+ by IHC, and no HER2 gene amplification by in situ hybridization (ISH)). Subjects were required to have histologically or cytologically confirmed HER2-negative disease (HER2 0 or 1 by IHC, or HER2 2+ by IHC, and no HER2 gene amplification by ISH) in their primary or metastatic tumors. Subjects were also required to have had no prior treatment for metastatic disease and no prior (neo)adjuvant therapy within 6 months of study enrollment.

[0106] The RP2D of the anti-human CD39 antibody was determined to be a loading dose of 40 mg / kg 7 days prior to Day 1 of Cycle 1, followed by either 30 mg / kg Q3W or 20 mg / kg Q2W. Doses up to 40 mg / kg were determined to be well tolerated, as described below.

[0107] PK demonstrated that the 40 mg / kg Q3W dose achieved minimal functional trough levels based on the activity of the anti-human CD39 antibody in preclinical human functional assays (i.e., enhancement of IL-2 from PBMCs and inflammasome activation). The half-life was 18.9 days. After completion of the dose escalation portion of the study, the totality of the PK data was used for RP2D PK modeling. Based on the simulation, it was determined that a loading dose of 40 mg / kg 1 week prior to cycle 1, day 1 dosing of 30 mg / kg Q3W or 20 mg / kg Q2W would provide minimal functional trough levels in greater than 80% of subjects prior to cycle 1, day 1 and in subsequent cycles.

[0108] Based on observed safety, PK, pharmacodynamic, and efficacy data, the RP2D for the anti-human PD-1 antibody was determined to be a flat dose of 250 mg Q2W, 375 mg Q3W, or 500 mg Q4W. The RP2D was also supported by population PK modeling and simulations, which showed that exposures achieved at the 250 mg Q2W, 375 mg Q3W, or 500 mg Q4W doses resulted in saturation of PD-1 positive CD4 central memory T cells and significant PD-L1 blockade, without further impact on safety.

[0109] mFOLFOX6 was administered according to standard clinical practice (oxaliplatin 85 mg / m 2 IV, leucovorin 400 mg / m 2 IV over 2 hours plus 5-FU 400 mg / m 2 IV bolus and 2400 mg / m 2 (Continuous infusion was administered Q2W over 46 hours.) Changes to mFOLFOX6 (i.e., dose reductions or combination modifications) may be permitted per institutional guidelines.

[0110] Anti-human CD39 antibody and anti-human PD-1 antibody were administered over at least 60 minutes during a 28-day cycle, for example. mFOLFOX6 was administered over 48 hours.

[0111] Figure 3 shows patient response to treatment with CD39 antibody, budigalimab, and FOLFOX for metastatic gastroesophageal cancer. Figure 3A shows the treatment duration swim plot, and Figure 3B shows the swimlanes by CPS score.

[0112] Figure 4 shows waterfall plots of maximum change from baseline and CPS score for treatment with CD39 antibody, budigalimab, and FOLFOX for metastatic gastroesophageal cancer. Figure 4 shows tumor response across different PD-L1 levels at baseline.

[0113] The BOR (RECIST) criteria for the total evaluable population N=40 are shown in Table 1. [Table 1]

[0114] ORR (RECIST) criteria for the subpopulation with known CPS N=37 are shown in Table 2. [Table 2]

[0115] FIG. 5 shows the onset of tumor response for treatment with CD39 antibody, budigalimab, and FOLFOX for metastatic gastroesophageal cancer.

[0116] Figure 6 shows that combination treatment results in an increase in PD-L1 and CD8 T cells. Figure 6A shows that combination treatment results in an increase in PD-L1 CPS score and CD8 T cells. Figure 6B shows that combination treatment results in an increase in CD8 cells. Figure 6C shows that combination treatment affects CD39 stromal therapy.

[0117] The terms "a," "an," "the," and similar referents as used in the context of describing the present invention (particularly in the context of the claims that follow) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. All methods described herein can be performed in any suitable order, unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended merely to better elucidate the invention and does not impose limitations on the scope of the invention as otherwise claimed. No language in the specification should be construed as indicating any non-claimed element essential to the practice of the invention.

[0118] Certain embodiments disclosed herein may be further limited in the claims using the language consisting of or consisting essentially of. When used in a claim, whether as filed or added per amendment, the transitional term "consisting of" excludes any element, step, or ingredient not specified in the claim. The transitional term "consisting essentially of" limits the claim to the specified materials or steps, and those that do not materially affect the basic and novel characteristics. The embodiments of the invention so claimed are essentially or explicitly described and enabled herein.

[0119] All patents, patent publications, and other publications referenced or identified in this specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of this application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by reason of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents are based on the information available to the applicants and do not constitute an admission as to the accuracy of the dates or contents of these documents.

Claims

1. 1. A combination for use in a method for treating a subject suffering from gastric cancer, said combination comprising: i) an anti-human CD39 antibody consisting of a heavy chain amino acid sequence SEQ ID NO: 33 and a light chain amino acid sequence SEQ ID NO: 34; ii) an anti-human PD-1 antibody consisting of a heavy chain amino acid sequence of SEQ ID NO: 35 and a light chain amino acid sequence of SEQ ID NO: 36; iii) mFOLFOX6 consisting of oxaliplatin, leucovorin, and fluorouracil (5FU), wherein the method comprises administering the combination to the subject.

2. The combination according to claim 1, wherein the anti-human CD39 antibody is administered intravenously at a dose of 0.5 mg / kg to 40.0 mg / kg.

3. The combination according to claim 2, wherein the anti-human CD39 antibody is administered intravenously at a dose of 20.0 mg / kg.

4. The combination according to claim 1, wherein the anti-human PD-1 antibody is administered intravenously at a dose of 500 mg.

5. mFOLFOX6 in the following amounts: 85 mg / m ２ of oxaliplatin, 400 mg / m ２ of leucovarin, and 400 mg / m ２ bolus injection of 2400 mg / m ２ 2. The combination according to claim 1, characterized in that it is administered intravenously with a continuous infusion of 5-FU.

6. 2. The combination of claim 1, wherein the gastric cancer comprises locally advanced or metastatic gastric cancer.

7. 7. The combination of claim 6, wherein the gastric cancer is advanced unresectable or metastatic Her-2 adenocarcinoma of the stomach or gastroesophageal junction.

8. The combination according to claim 1, wherein the anti-human CD39 antibody is administered on days 1 and 15 of a 28-day cycle.

9. 2. The combination of claim 1, wherein the mFOLFOX6 is administered on days 1 and 15 of a 28-day cycle.

10. 9. The combination of claim 8, wherein a single loading dose of the anti-human CD39 antibody is administered to the subject at a dosage of 40.0 mg / kg one week prior to starting the repeat portion (maintenance dose) of the dosing regimen.

11. 2. The combination of claim 1, wherein the anti-human PD1 antibody is administered to the subject at a dose of 500 mg every four weeks.

12. 2. The combination of claim 1, wherein the subject has a partial or complete response.

13. 10. The combination of claim 1, wherein the method results in an OS of 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

14. 2. The combination of claim 1, wherein the method increases PFS or DFS.

15. 1. A combination for use in a method for treating a subject suffering from gastric cancer, said combination comprising: i) an anti-human CD39 antibody consisting of a heavy chain amino acid sequence SEQ ID NO: 33 and a light chain amino acid sequence SEQ ID NO: 34; ii) an anti-human PD-1 antibody consisting of a heavy chain amino acid sequence of SEQ ID NO: 35 and a light chain amino acid sequence of SEQ ID NO: 36; iii) CAPOX, wherein the method comprises administering the combination to the subject.

16. The combination according to claim 15, wherein the anti-human CD39 antibody is administered intravenously at a dose of 0.5 mg / kg to 40.0 mg / kg.

17. The combination according to claim 16, wherein the anti-human CD39 antibody is administered intravenously at a dose of 20.0 mg / kg.

18. The combination according to claim 15, wherein the anti-human PD-1 antibody is administered intravenously at a dose of 500 mg.

19. 16. The combination of claim 15, wherein the gastric cancer comprises locally advanced or metastatic gastric cancer.

20. 20. The combination of claim 19, wherein the gastric cancer is advanced unresectable or metastatic Her-2 adenocarcinoma of the stomach or gastroesophageal junction.

21. The combination according to claim 15, wherein the anti-human CD39 antibody is administered on days 1 and 15 of a 28-day cycle.

22. 16. The combination of claim 15, wherein the anti-human PD1 antibody is administered to the subject at a dose of 500 mg every four weeks.

23. 16. The combination of claim 15, wherein the subject has a partial or complete response.

24. 16. The combination of claim 15, wherein the method results in an OS of 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, or 90%.

25. 16. The combination of claim 15, wherein the method increases PFS or DFS.

26. 10. A combination according to any preceding claim, wherein the subject has a CPS score of less than 1, 1 to 5, or 5 or greater.

27. A pharmaceutical composition for treating a subject suffering from gastric cancer, said pharmaceutical composition comprising an anti-human CD39 antibody consisting of a heavy chain amino acid sequence of SEQ ID NO: 33 and a light chain amino acid sequence of SEQ ID NO: 34; i) an anti-human PD-1 antibody consisting of a heavy chain amino acid sequence of SEQ ID NO: 35 and a light chain amino acid sequence of SEQ ID NO: 36; and ii) A pharmaceutical composition administered in combination with mFOLFOX6 consisting of oxaliplatin, leucovorin, and fluorouracil (5FU).

28. A pharmaceutical composition for treating a subject suffering from gastric cancer, said pharmaceutical composition comprising an anti-human PD-1 antibody consisting of a heavy chain amino acid sequence of SEQ ID NO: 35 and a light chain amino acid sequence of SEQ ID NO: 36; i) an anti-human CD39 antibody consisting of a heavy chain amino acid sequence SEQ ID NO: 33 and a light chain amino acid sequence SEQ ID NO: 34; and ii) A pharmaceutical composition administered in combination with mFOLFOX6 consisting of oxaliplatin, leucovorin, and fluorouracil (5FU).

29. A pharmaceutical composition for treating a subject suffering from gastric cancer, the pharmaceutical composition comprising mFOLFOX6, consisting of oxaliplatin, leucovorin, and fluorouracil (5FU); i) an anti-human CD39 antibody consisting of a heavy chain amino acid sequence SEQ ID NO: 33 and a light chain amino acid sequence SEQ ID NO: 34; and ii) A pharmaceutical composition, characterized in that it is administered in combination with an anti-human PD-1 antibody consisting of heavy chain amino acid sequence SEQ ID NO: 35 and light chain amino acid sequence SEQ ID NO:

36.

30. A pharmaceutical composition for treating a subject suffering from gastric cancer, said pharmaceutical composition comprising an anti-human CD39 antibody consisting of a heavy chain amino acid sequence of SEQ ID NO: 33 and a light chain amino acid sequence of SEQ ID NO: 34; i) an anti-human PD-1 antibody consisting of a heavy chain amino acid sequence of SEQ ID NO: 35 and a light chain amino acid sequence of SEQ ID NO: 36; and ii) A pharmaceutical composition, characterized in that it is administered in combination with CAPOX.

31. A pharmaceutical composition for treating a subject suffering from gastric cancer, said pharmaceutical composition comprising an anti-human PD-1 antibody consisting of a heavy chain amino acid sequence of SEQ ID NO: 35 and a light chain amino acid sequence of SEQ ID NO: 36; i) an anti-human CD39 antibody consisting of a heavy chain amino acid sequence SEQ ID NO: 33 and a light chain amino acid sequence SEQ ID NO: 34; and ii) A pharmaceutical composition, characterized in that it is administered in combination with CAPOX.

32. A pharmaceutical composition for treating a subject suffering from gastric cancer, the pharmaceutical composition comprising CAPOX; i) an anti-human CD39 antibody consisting of a heavy chain amino acid sequence SEQ ID NO: 33 and a light chain amino acid sequence SEQ ID NO: 34; and ii) A pharmaceutical composition, characterized in that it is administered in combination with an anti-human PD-1 antibody consisting of heavy chain amino acid sequence SEQ ID NO: 35 and light chain amino acid sequence SEQ ID NO: 36.

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