Anti- CD73, Anti-PD - l1 antibodies and chemotherapies for treating tumors

Abstract

To provide a method for treating a tumor in a human patient.SOLUTION: The present invention relates to monoclonal antibodies or antigen-binding fragments thereof directed against CD73 and the use of such antibodies or antigen-binding fragments thereof in the treatment of tumors. The present invention also relates to methods of treatment of tumors comprising administering to patients in need thereof anti-programmed death antibodies or antigen binding fragments thereof in combination with monoclonal antibodies or antigen binding fragments thereof directed against CD73 ligand 1 (PD - L1) (also known as B7 homolog 1 (B7 - H1)). The present invention also relates to methods of treating tumors comprising administering to a subject in need thereof anti- CD73 antibodies or antigen-binding fragments thereof in combination with PD - L1 antibodies or antigen-binding fragments thereof and chemotherapies.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 62 / 828,177, filed April 2, 2019, the entire contents of which are incorporated by reference.

[0002] The present disclosure relates to monoclonal antibodies or antigen-binding fragments thereof directed against anti-cluster differentiation [CD]73 (CD73) and the use of such antibodies or antigen-binding fragments thereof in the treatment of tumors. The present disclosure also relates to methods of treating tumors comprising administering to a patient in need thereof an anti-CD73 antibody or antigen-binding fragment thereof in combination with a monoclonal antibody or antigen-binding fragment thereof directed against programmed death-ligand 1 (PD-L1) (also known as B7 homolog 1 (B7-H1)). The present disclosure also relates to methods of treating tumors comprising administering to a patient in need thereof an anti-CD73 antibody or antigen-binding fragment thereof in combination with a PD-L1 antibody or antigen-binding fragment thereof and / or chemotherapy. [Background technology]

[0003] CD73, or ecto-5'-nucleotidase (5'-NT), is ubiquitously expressed in several tissues. This protein is anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) linkage, has ectoenzymatic activity, and plays a role in signal transduction. The primary function of CD73 is to convert extracellular nucleotides (e.g., 5'-AMP), which are generally cell-impermeable, into their corresponding nucleosides (e.g., adenosine), which can readily enter most cells. CD73 generation of adenosine by AMP dephosphorylation has been shown to regulate adenosine receptor ligation in many tissues, suggesting that adenosine functions in cytoprotection, cell proliferation, angiogenesis, and immunosuppression, as well as playing a role in tumorigenesis.

[0004] Expression of CD73 on tumor cells has been reported in several types of cancer, including colorectal cancer, pancreatic cancer, bladder cancer, leukemia, lymphoma, glioma, glioblastoma, melanoma, ovarian cancer, thyroid cancer, esophageal cancer, prostate cancer, and breast cancer. Increased expression of CD73 has also been associated with tumor invasion, metastasis, and shortened patient survival. CD73 creates an immunosuppressive environment characterized by increased adenosine levels, which promotes cancer development and progression. In particular, CD73 expression is associated with a prometastatic phenotype in melanoma and breast cancer.

[0005] Programmed death-ligand 1 (PD-L1), also known as B7H1, is a 40-kDa transmembrane protein that represents a major obstacle in anti-cancer immunity. Binding to the programmed death receptor (PD-1) inactivates T cells, protecting tumor cells and suppressing immune system detection, allowing cancer cells to grow unchecked. PD-L1 also binds to the costimulatory molecule CD80. A wide range of tumorigenic and activated immune cell types naturally express PD-L1, including antigen-presenting cells, macrophages, monocytes, B cells, T cells, and non-hematopoietic cells. Furthermore, inflammatory cytokines induce PD-L1 expression, including interferon gamma (IFNγ). Activated T cells produce IFNγ, the most potent inducer of PD-L1. IFNγ then induces PD-L1 expression, promoting tumor protection. This mechanism is known as adaptive immune tolerance. Summary of the Invention [Problem to be solved by the invention]

[0006] Immune checkpoint inhibitors have great potential as cancer therapeutics. Nevertheless, clinical benefit from immune checkpoint inhibition has been modest. One possible explanation is that tumors use non-overlapping immunosuppressive mechanisms to promote immune escape. Therefore, improved compositions and methods for reducing tumor-mediated immunosuppression are needed. [Means for solving the problem]

[0007] The present disclosure provides a method of treating a tumor in a human patient, the method comprising administering oleclumab or an antigen-binding fragment thereof to the patient. In certain embodiments, the oleclumab or antigen-binding fragment thereof is administered at a dose of 750 to 3000 mg. In certain embodiments, the oleclumab or antigen-binding fragment thereof is administered at a dose of 40 mg / kg.

[0008] The present disclosure further provides a method of treating a tumor in a human patient, the method comprising administering oleclumab or an antigen-binding fragment thereof and durvalumab or an antigen-binding fragment thereof to the patient.

[0009] The present disclosure further provides a method of treating a tumor in a human patient, the method comprising administering oleclumab or an antigen-binding fragment thereof and chemotherapy to the patient.

[0010] In some embodiments, the method of treating a tumor in a human patient comprises administering oleclumab or an antigen-binding fragment thereof to the patient.

[0011] In some embodiments, a method of treating a tumor in a human patient comprises administering oleclumab or an antigen-binding fragment thereof and durvalumab or an antigen-binding fragment thereof to the patient.

[0012] In some embodiments, a method of treating a tumor in a human patient comprises administering oleclumab or an antigen-binding fragment thereof and chemotherapy to the patient. In some embodiments, the method further comprises administering durvalumab or an antigen-binding fragment thereof.

[0013] In some embodiments, olecullab or an antigen-binding fragment thereof is administered in a dose of 750 mg to 3000 mg. In some embodiments, olecullab or an antigen-binding fragment thereof is administered in a dose of 750 mg. In some embodiments, olecullab or an antigen-binding fragment thereof is administered in a dose of 1500 mg. In some embodiments, olecullab or an antigen-binding fragment thereof is administered in a dose of 2250 mg. In some embodiments, olecullab or an antigen-binding fragment thereof is administered in a dose of 3000 mg. In some embodiments, olecullab or an antigen-binding fragment thereof is administered in a dose of 2250 mg, followed by a dose of 3000 mg. In some embodiments, olecullab or an antigen-binding fragment thereof is administered in four doses of 2250 mg, followed by a dose of 3000 mg.

[0014] In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 14 to 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 14 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 14 days for at least two doses, and then every 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 14 days for four doses, and then every 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 21 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 21 days for at least two doses, and then every 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 21 days for at least two doses, and then every 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 21 days for two to four doses, and then every 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered every 21 days for two doses and then once every 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered once every 21 days for four doses and then once every 28 days.

[0015] In some embodiments, oleclumab or an antigen-binding fragment thereof is administered at a dose of 2250 mg once every 21 days for two doses, and then at a dose of 3000 mg once every 28 days. In some embodiments, oleclumab or an antigen-binding fragment thereof is administered at a dose of 2250 mg once every 21 days for four doses, and then at a dose of 3000 mg once every 28 days.

[0016] In some aspects, oleclumab or an antigen-binding fragment thereof is administered intravenously.

[0017] In some embodiments, durvalumab or an antigen-binding fragment thereof is administered in a dose of 1500 mg.

[0018] In some embodiments, durvalumab or an antigen-binding fragment thereof is administered every 21 to 28 days. In some embodiments, durvalumab or an antigen-binding fragment thereof is administered every 28 days. In some embodiments, durvalumab or an antigen-binding fragment thereof is administered every 21 days. In some embodiments, durvalumab or an antigen-binding fragment thereof is administered every 21 days for at least two doses, and then every 28 days. In some embodiments, durvalumab or an antigen-binding fragment thereof is administered every 21 days for four doses, and then every 28 days.

[0019] In some embodiments, durvalumab or an antigen-binding fragment thereof is administered at a dose of 1500 mg every 21 days for four doses, and then at a dose of 1500 mg every 28 days.

[0020] In some aspects, durvalumab or an antigen-binding fragment thereof is administered intravenously.

[0021] In some embodiments, the chemotherapy comprises at least one of cisplatin, pemetrexed, nab-paclitaxel, carboplatin, gemcitabine, cisplatin, oxaliplatin, leucovorin, 5-fluorouracil, and docetaxel.

[0022] In some embodiments, the chemotherapy includes oxaliplatin, leucovorin, and 5-fluorouracil.

[0023] In some embodiments, oxaliplatin is 85 mg / m 2 In some embodiments, the oxaliplatin is administered every two weeks.

[0024] In some embodiments, the leucovorin is 400 mg / m 2 In some embodiments, the leucovorin is administered every two weeks.

[0025] In some embodiments, 5-fluorouracil is 2400 mg / m 2 In some embodiments, the 5-fluorouracil is administered by continuous intravenous infusion for 46-48 hours. In some embodiments, the 5-fluorouracil is administered over 46-48 hours every two weeks.

[0026] In some embodiments, chemotherapy is 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 2400 mg / m 2 Contains 5-fluorouracil.

[0027] In some embodiments, the method further comprises administering bevacizumab or an antigen-binding fragment thereof. In some embodiments, the bevacizumab or antigen-binding fragment thereof is administered at a dose of 5 mg / kg. In some embodiments, the bevacizumab or antigen-binding fragment thereof is administered every two weeks. In some embodiments, the bevacizumab or antigen-binding fragment thereof is administered intravenously.

[0028] In some embodiments, the chemotherapy includes (a) nab-paclitaxel and carboplatin; (b) gemcitabine and cisplatin; (c) gemcitabine and carboplatin; (d) pemetrexed and carboplatin; and (e) pemetrexed and cisplatin.

[0029] In some embodiments, nab-paclitaxel is administered at 100 mg / m 2 In some embodiments, nab-paclitaxel is administered on days 1, 8, and 15 of a 21-day cycle.

[0030] In some embodiments, gemcitabine is administered at 1000 mg / m 2 or 1250 mg / m 2 In some embodiments, gemcitabine is administered on days 1 and 8 of a 21-day cycle.

[0031] In some embodiments, pemetrexed is administered at 500 mg / m 2 In some embodiments, pemetrexed is administered every three weeks.

[0032] In some embodiments, carboplatin is administered at a dose of AUC 5 or 6. In some embodiments, carboplatin is administered every 3 weeks.

[0033] In some embodiments, cisplatin is administered at 75 mg / m 2 In some embodiments, cisplatin is administered every three weeks.

[0034] In some embodiments, the chemotherapy is 1000 mg / m 2 of gemcitabine and 125 mg / m 2 Contains nab-paclitaxel.

[0035] In some embodiments, chemotherapy is administered every 7 to 28 days, hi some embodiments, chemotherapy is administered every 14 days.

[0036] In some embodiments, administration of oleculab or an antigen-binding fragment thereof results in a partial response. In some embodiments, administration of oleculab or an antigen-binding fragment thereof results in a complete response.

[0037] In some embodiments, the tumor is a solid tumor. In some embodiments, the solid tumor is breast cancer, ovarian cancer, head and neck cancer, prostate cancer, bladder cancer, colorectal cancer, non-small cell lung cancer (NSCLC), glioblastoma, renal cell carcinoma, or pancreatic cancer. In some embodiments, the pancreatic cancer is pancreatic ductal adenocarcinoma. In some embodiments, the tumor is a resectable NSCLC tumor. In some embodiments, the tumor is an early stage NSCLC tumor. In some embodiments, the tumor is a stage IV NSCLC tumor. In some embodiments, the colorectal cancer is metastatic microsatellite stable.

[0038] In some embodiments, the tumor has high PD-L1 expression. The tumor with high PD-L1 expression may be an NSCLC tumor.

[0039] In some embodiments, the tumor has low PD-L1 expression. The tumor with low PD-L1 expression may be an NSCLC tumor.

[0040] In some embodiments, the tumor lacks an activating epidermal growth factor receptor (EGFR) mutation and / or an anaplastic lymphoma kinase (ALK) fusion. The tumor lacking an EGFR mutation and / or an ALK fusion can be an NSCLC tumor.

[0041] In some embodiments, the patient has metastatic pancreatic ductal adenocarcinoma that has not been previously treated. In some embodiments, the patient has metastatic pancreatic ductal adenocarcinoma that has been previously treated with gemcitabine-based therapy.

[0042] In some embodiments, the tumor has not received prior treatment in the recurrent and / or metastatic setting, hi some embodiments, the patient is undergoing anti-PD-1 or anti-PD-L1 containing therapy.

[0043] In some embodiments, the tumor is first-line metastatic pancreatic ductal adenocarcinoma, and oleclumab or an antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every two weeks for four doses, and every four weeks thereafter, and chemotherapy is administered at 1000 mg / m 2 of gemcitabine and 125 mg / m 2 of nab-paclitaxel, with chemotherapy administered on days 1, 8, and 15 of four 28-day cycles and every four weeks thereafter.

[0044] In some embodiments, the tumor is second-line metastatic pancreatic ductal adenocarcinoma, and oleclumab or an antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every two weeks for four doses, and every four weeks thereafter, and chemotherapy is administered at 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 400 mg / m2 of 5-FU followed by 2400 mg / m 2 The chemotherapy includes 5-FU administered on days 1 and 15 of four 28-day cycles and every four weeks thereafter.

[0045] In some embodiments, the method further comprises administering 1500 mg of durvalumab or an antigen-binding fragment thereof every four weeks.

[0046] In some embodiments, the tumor is first-line stage IV NSCLC with high PD-L1 expression, and oleclumab or an antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every two weeks and then every four weeks for two 14-day cycles, and durvalumab or an antigen-binding fragment thereof is administered at 1500 mg every four weeks.

[0047] In some embodiments, the tumor is first-line stage IV NSCLC with low PD-L1 expression, and oleclumab or an antigen-binding fragment thereof is administered (a) at 1500 mg every 3 weeks for four 21-day cycles, and then every 4 weeks; or (b) at 2250 mg every 3 weeks for four 21-day cycles, and then every 4 weeks at 3000 mg; durvalumab or an antigen-binding fragment thereof is administered at 1500 mg every 3 weeks for four 21-day cycles, and then every 4 weeks; and chemotherapy is administered at (a) 100 mg / m on days 1, 8, and 15 of a 21-day cycle for four cycles. 2 of nab-paclitaxel and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for four cycles; (b) 1000 mg / m on days 1 and 8 of a 21-day cycle for four cycles. 2 or 1250 mg / m 2 of gemcitabine and 75 mg / m on day 1 of a 21-day cycle for 4 cycles 2 (c) cisplatin at 1000 mg / m on days 1 and 8 of a 21-day cycle for four cycles 2 or 1250 mg / m 2gemcitabine and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for four cycles; (d) 500 mg / m on day 1 of a 21-day cycle for four cycles 2 of pemetrexed and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for 4 cycles, optionally at 500 mg / m 2 pemetrexed administered every 4 weeks as maintenance therapy after four cycles, pemetrexed and carboplatin; or (e) 500 mg / m on day 1 of a 21-day cycle for four cycles. 2 pemetrexed at 75 mg / m on day 1 of a 21-day cycle for four cycles 2 cisplatin, optionally at 500 mg / m 2 Pemetrexed in the present invention contains pemetrexed and cisplatin, administered every four weeks as maintenance therapy after four cycles.

[0048] In some embodiments, the tumor is a locally advanced unresectable Stage III NSCLC tumor, and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks, and (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every 2 weeks for 2 months and then every 4 weeks.

[0049] In some embodiments, the tumor is a resectable early-stage NSCLC tumor, and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered, and (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every two weeks.

[0050] In some embodiments, the tumor is a metastatic microsatellite-stable colorectal cancer tumor and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks; (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every 2 weeks for 4 doses and then every 4 weeks; (iii) chemotherapy is administered in the form of: (a) 400 mg / m every 2 weeks; 2of folinic acid, (b) 85 mg / m every 2 weeks 2 of oxaliplatin; and (c) 2400 mg / m every 2 weeks 2 of 5-fluorouracil; and (iv) 5 mg / kg of bevacizumab or an antigen-binding fragment thereof administered every two weeks.

[0051] In some embodiments, the tumor is a microsatellite-stable colorectal cancer tumor and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks; (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every 2 weeks for 4 or 5 doses and then every 4 weeks; (iii) chemotherapy is (a) 400 mg / m every 2 weeks 2 folinic acid; (b) 85 mg / m every 2 weeks 2 of oxaliplatin; and (c) 400 mg / m on day 1. 2 of 5-fluorouracil and then 2400 mg / m every 2 weeks 2 Contains 5-fluorouracil.

[0052] In some embodiments, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. [Brief explanation of the drawings]

[0053] [Figure 1] 1 is a graph showing the concentration of free sCD73 in cynomolgus monkeys administered doses of 0 mg / kg (Group 1), 1 mg / kg (Group 2), 10 mg / kg (Group 3), or 107.8 mg / kg (Group 4) of oleclumab (see Example 2). [Figure 2][Figures 2A-2B] oleclumab administration did not dose-dependently enhance keyhole limpet hemocyanin T-dependent antibody responses (KLH TDAR). Figure 2A shows the mean anti-KLH IgM titers after KLH immunization in monkeys administered 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg of oleclumab, and Figure 2B shows the mean anti-KLH IgG titers after KLH immunization in monkeys administered 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg of oleclumab (see Example 2). [Figure 3] [Figures 3A-3B] oleculab administration did not increase ex vivo IFN-γ or IL-2 production after KLH stimulation of peripheral blood mononuclear cells. Figure 3A shows the mean KLH-specific IFN-γ production after KLH immunization in monkeys administered 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg of oleculab, and Figure 3B shows the KLH-specific IL-2 production after KLH immunization in monkeys administered 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg of oleculab (see Example 2). [Figure 4] 1 shows that lymphocryptovirus (LCV) was detected by qPCR in most samples from monkeys administered oleclumab doses of 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg (see Example 2). [Figure 5] Figure 1 shows the model assumptions for the pharmacokinetic / pharmacodynamic model used to predict the therapeutic human dose of oleclumab. A two-compartment model with linear target-mediated pharmacokinetic clearance adequately described the MEDI9447 serum concentration profile. This model was used to describe monkey pharmacokinetic data, and the resulting parameters were then allometrically scaled to humans to predict dose using simulations (see Example 2). [Figure 6][Figures 6A-6B] Cynomolgus monkey pharmacokinetic modeling and human dose prediction. Cynomolgus monkey serum MEDI9447 concentration profiles (Figure 6A) were adequately described for all three different dose levels by a nonlinear model, generally shown in Figure 5. After allometric scaling of the pharmacokinetic parameters derived from this model, human serum concentration profiles were simulated (Figure 6B). A serum exposure target of 52 μg / mL was determined from tumor suppression data in syngeneic mice, and simulations suggested that doses of 15 mg / kg or higher given every 2 weeks (Q2W) would achieve and maintain adequate exposure throughout the entire dosing period expected to result in efficacy (see Example 2). [Figure 7] [FIGS. 7A-7B] Figure 7A shows a study flow diagram for the dose-escalation phase for the oleculab monotherapy arm (pancreatic cancer and microsatellite-stable colorectal cancer (MSS-CRC)). Figure 7B shows a study flow diagram for the dose-expansion and dose-escalation portions of a study administering oleculab (MEDI9447) and durvalumab as combination therapy to human patients with advanced solid tumors (pancreatic cancer and MSS-CRC) (see Example 3). [Figure 8]

[0023] Figure 1 shows the dosing schema for the screening, treatment, and follow-up periods of the study in which human patients are administered olecurumab (MEDI9447) as monotherapy and olecurumab (MEDI9447) / durvalumab combination therapy (see Example 3). [Figure 9] [Figures 9A-9B] The amount of soluble free CD73 observed after administration of oleculab as monotherapy (Figure 9A) or in combination with durvalumab (Figure 9B). sCD73, soluble CD73; PD LLOQ, lower limit of quantitation (see Example 3). [Figure 10][Figures 10A-10C] Olecuramab reduced CD73 on peripheral T cells and tumor CD73 surface expression as measured by mean fluorescence intensity (MFI) (Figure 10A) and percent CD73+ CD4 and CD8 cells in peripheral blood (Figure 10B); and in peripheral T cells (Figure 10C) across all doses after administration of olecuramab. SSC; side scatter (see Example 3). [Figure 11] [Figures 11A-11C] Figure 11A shows the percentage change in CD73-stained tumor cells with 2+ or 3+ intensity by immunohistochemistry 20 days after administration of olecullab at 10, 20, or 40 mg / kg in subjects with pancreatic or colorectal cancer (CRC). Figure 11B shows CD73 staining of tumors before and after treatment with olecullab. Figure 11C shows the change in CD73-stained tumor cells with 2+ or 3+ staining intensity and the change in CD8 TILs 20 days after administration of olecullab at 10, 20, or 40 mg / kg relative to baseline (see Example 3). [Figure 12] Figure 1 shows that oleclumab inhibited CD73 enzymatic activity in the tumor microenvironment. Staining indicates a decrease in free adenosine (see Example 3). [Figure 13]

[0023] Figure 1 shows the mean PK profiles from oleculab monotherapy studies. Pooled PK data (N=116) across indications and monotherapy and combination with durvalumab (see Example 3). [Figure 14] [Figures 14A-14B] Olecuramab demonstrated evidence of PD activity. Figure 14A shows the percentage change in tumors. Figure 14B shows the change in CD8 TILs (see Example 3). [Figure 15] 1 shows a dose expansion phase for oleculab in combination with durvalumab (see Example 4). [Figure 16]

[0023] Figure 1 shows the clinical activity of olecurumab in combination with durvalumab in MSS-CRC. >600 days of ongoing treatment (see Example 4). [Figure 17]

[0023] Figure 1 shows the clinical activity of oleculab in combination with durvalumab in pancreatic cancer (see Example 4). [Figure 18]

[0023] Figure 1 shows the clinical activity of olecurumab in combination with durvalumab in EGFRm NSCLC (see Example 4). [Figure 19] FIG. 1 shows a study flow diagram of the dose escalation phase for durvalumab and oleculab in combination with chemotherapy (for subjects with 1L metastatic PDAC, gemcitabine + nab-paclitaxel [Cohort A]; for subjects with 2L metastatic PDAC, mFOLFOX [Cohort B]) (see Example 5). [Figure 20] Dose-escalation phase treatment regimens for durvalumab and oleclumab in combination with chemotherapy are shown (for subjects with 1L metastatic PDAC, gemcitabine + nab-paclitaxel [Cohort A]; for subjects with 2L metastatic PDAC, mFOLFOX [Cohort B]) (see Example 5). [Figure 21]

[0023] Figure 1 shows a study flow diagram of the dose expansion phase for oleculab in combination with durvalumab and chemotherapy (see Example 5). [Figure 22] FIG. 1 shows the dose-expansion phase treatment regimen for durvalumab and oleclumab in combination with chemotherapy (gemcitabine + nab-paclitaxel [Cohort A] for subjects with 1L metastatic PDAC) (see Example 5). [Figure 23]

[0033] Figure 1 shows the dose expansion phase treatment regimen for oleclumab in combination with durvalumab and chemotherapy mFOLFOX [Cohort B] for subjects with 2L metastatic PDAC (see Example 5). [Figure 24][Figures 24A-24D] Treatment regimens for patients with first-line stage IV non-small cell lung cancer (NSCLC) are shown. Figure 24A shows the durvalumab monotherapy administration schedule. Figure 24B shows the durvalumab + oleculab administration schedule. Figure 24C shows the durvalumab + chemotherapy administration schedule. Figure 24D shows the durvalumab + chemotherapy + oleculab administration schedule (see Example 6). [Figure 25] [Figures 25A-25B] Treatment regimens for locally advanced, unresectable, stage III non-small cell lung cancer (NSCLC). Figure 25A shows the durvalumab monotherapy administration schedule. D = durvalumab; a = Subject receives durvalumab 1500 mg intravenously (IV) every four weeks (Q4W) (day 1 of each cycle). Figure 25B shows the durvalumab + oleculab administration schedule. D = durvalumab; O = oleculab; a = Subject receives 1500 mg intravenously (IV) every four weeks (Q4W) (day 1 of each cycle) and oleculab 3000 mg IV every two weeks (Q2W) (days 1 and 15) for cycles 1 and 2, then Q4W (starting on cycle 3, day 1 (D1)). On days when durvalumab and olecurumab are administered, olecurumab is administered first (see Example 7). [Figure 26] [Figures 26A-26C] Treatment regimens for resectable early-stage non-small cell lung cancer (NSCLC). Figure 26A shows treatment over the study period. Figure 26B shows the durvalumab monotherapy dosing schedule: subjects receive 1500 mg of durvalumab intravenously (IV) every two weeks (Q4W) (Week 1, Day 1). W = weeks; D = days; Du = durvalumab. Figure 26C shows the durvalumab + olecurumab dosing schedule: subjects receive 1500 mg of durvalumab IV Q4W (Week 1, Day 1) and 3000 mg of olecurumab IV every two weeks (Q2W) (Week 1, Day 1 and Week 3, Day 1). W = weeks; D = days; Du = durvalumab; O = olecurumab (see Example 8). [Figure 27]

[0039] Figure 1 shows treatment regimens for metastatic microsatellite-stable colorectal cancer. DLT = dose-limiting toxicity; FOLFOX = folinic acid (leucovorin), 5-fluorouracil, oxaliplatin. Subjects in Control 1 receive FOLFOX + bevacizumab. Additionally, subjects in Arms S1 and E1 receive durvalumab 1500 mg intravenously (IV) every four weeks (Q4W) (day 1 of every 14-day cycle) and olecullab 3000 mg IV every two weeks (Q2W) x 4 doses (starting on cycle 1, day 1), then Q4W (starting on cycle 5, day 1). On days when durvalumab and olecullab are administered, olecullab is administered first (see Example 9). [Figure 28]

[0039] Figure 1 shows a treatment regimen for high-risk metastatic microsatellite-stable colorectal cancer. mFOLFOX6 = folinic acid (leucovorin), 5-fluorouracil, oxaliplatin. Subjects in the control arm receive mFOLFOX6. Subjects in arm E1-COC receive mFOLFOX6 + durvalumab 1500 mg intravenously (IV) every four weeks (Q4W). Subjects in arm E2 receive mFOLFOX6 + durvalumab 1500 mg IV Q4W and oleculamab 300 mg IV every two weeks (Q2W) for four doses, then Q4W starting from cycle 5 (week 9, day 1). On days when durvalumab and oleculamab are administered, oleculamab is administered first (see Example 10). [Figure 29] [Figures 29A-29I] Figures 29A-29H show individual tumor growth (CT26) after treatment with a combination of anti-CD73, anti-PD-L1, 5FU, and OHP. Figure 29I shows Kaplan-Meier (survival curves) of BALB / c mice bearing CT26 tumors after treatment with a combination of anti-CD73, anti-PD-L1, 5FU, and OHP (see Example 11). [Figure 30] Figure 1 shows the expansion of IFNγ+ CD8+, CD4+ and NKp46+ lymphocytes in the tumor microenvironment (TME) of BALB / c mice bearing CT26 tumors after treatment with a combination of anti-CD73, anti-PD-L1, 5FU and OHP (see Example 11). [Figure 31] [Figures 31A-31I] Figures 31A-31H show individual tumor growth (CT26) after treatment with a combination of anti-CD73, anti-PD-L1, and docetaxel. Figure 31I shows Kaplan-Meier (survival curves) of BALB / c mice bearing CT26 tumors after treatment with a combination of anti-CD73, anti-PD-L1, and docetaxel (see Example 11). [Figure 32] [Figures 32A-32H] Individual tumor growth profiles of C57BL / 6 mice bearing MCA205 tumors after treatment with a combination of anti-CD73, anti-PD-L1, 5FU, and OHP (see Example 11). DETAILED DESCRIPTION OF THE INVENTION

[0054] The present disclosure relates to monoclonal antibodies directed against CD73, such as oleclumab or an antigen-binding fragment thereof, and the use of such antibodies or antigen-binding fragments in the treatment of tumors. The present disclosure also relates to a method of treating tumors, comprising administering to a patient in need thereof an anti-CD73 antibody, such as oleclumab or an antigen-binding fragment thereof, in combination with a monoclonal antibody directed against PD-L1, such as durvalumab or an antigen-binding fragment thereof. The present disclosure also relates to a method of treating tumors, comprising administering to a patient in need thereof an anti-CD73 antibody, such as oleclumab or an antigen-binding fragment thereof, in combination with chemotherapy, and in combination with an anti-PD-L1 antibody, such as durvalumab.

[0055] As used in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings: Unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.

[0056] As used herein, the term "antibody" refers to a protein capable of recognizing, and in particular binding to, an antigen. A normal or conventional mammalian antibody comprises a tetramer, which is typically composed of two identical pairs of polypeptide chains, each pair consisting of one "light" chain (typically having a molecular weight of about 25 kDa) and one "heavy" chain (typically having a molecular weight of about 50-70 kDa). As used herein, the terms "heavy chain" and "light chain" refer to any immunoglobulin polypeptide having sufficient variable domain sequence to confer specificity for a target antigen. The amino-terminal portion of each light chain and each heavy chain typically contains a variable domain of about 100-110 or more amino acids that is typically responsible for antigen recognition. The carboxyl-terminal portion of each chain typically defines a constant domain responsible for effector function. Thus, in naturally occurring antibodies, the full-length heavy chain immunoglobulin polypeptide comprises a variable domain (V H ) and three constant domains (C H1 , C H2 and C H3 ) and C H1 and C H2 Including the hinge region between the V H The domain is located at the amino terminus of the polypeptide and is C H3 The variable domain (V) is located at the carboxyl terminus of the full-length light chain immunoglobulin polypeptide. L ) and constant domain (C L ), including V L The domain is located at the amino terminus of the polypeptide and is C L The domain is at the carboxyl terminus.

[0057] Within full-length light and heavy chains, the variable and constant domains are typically connected by a "J" region of about 12 or more amino acids, with heavy chains also including a "D" region of about 10 more amino acids. The variable regions of each light / heavy chain pair typically form the antigen-binding site. The variable domains of naturally occurring antibodies typically exhibit relatively conserved framework regions (FR) of the same general structure connected by three hypervariable regions, also called complementarity-determining regions or CDRs. The CDRs from the two chains of each pair are typically aligned by the framework regions, which may enable them to bind to a specific epitope. From the amino terminus to the carboxyl terminus, the variable domains of both light and heavy chains typically include the domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0058] The term "antigen-binding fragment" refers to a portion of an intact antibody and / or the antigen-determining variable domain of an intact antibody. It is known that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments, linear antibodies, single-chain antibodies, diabodies, and multispecific antibodies (formed from antibody fragments).

[0059] As used herein, the term "patient" includes human subjects.

[0060] A "disorder" is any condition that would benefit from treatment with an antibody of the present disclosure. "Disorder" and "condition" are used interchangeably herein and include chronic and acute disorders or diseases, including pathological conditions that predispose a patient to the subject's disorder.

[0061] As used herein, the term "solid tumor" refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Examples of solid tumors include squamous cell carcinoma of the head and neck, cervical cancer, colorectal cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, and urothelial bladder cancer.

[0062] As used herein, the term "treatment" or "treating" refers to both therapeutic treatment and prophylactic or preventative measures. Subjects in need of treatment include patients with tumors and patients prone to having tumors or patients in whom tumors are to be prevented. In certain embodiments, the antibodies disclosed herein can be used to treat tumors, e.g., solid tumors. In certain embodiments, treating tumors includes inhibiting tumor growth, promoting tumor regression, or both inhibiting tumor growth and promoting tumor regression.

[0063] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a compound or composition capable of inducing a desired therapeutic effect when properly administered to a subject. One embodiment of the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one antibody of the present disclosure.

[0064] As used herein, the term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" refers to one or more formulation materials suitable for achieving or enhancing delivery of one or more antibodies of the present disclosure.

[0065] As used herein, the terms "olecuramab" and "MEDI9447" refer to a human immunoglobulin G1 lambda (IgG1λ) mAb that selectively binds to CD73 and inhibits the ectonucleotidase activity of CD73, as disclosed in U.S. Pat. No. 9,938,356 (which is incorporated herein by reference in its entirety). A triple mutation, L234F / L235E / P331S (according to the European Union numbering convention), is encoded within the heavy chain constant region to significantly attenuate IgG effector function. Olecuramab inhibits the catalysis of AMP to adenosine and organic phosphate by CD73. Extracellular adenosine, among other things, mediates the immunosuppressive effects of both MDSCs and Tregs.

[0066] In certain embodiments, oleclumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain. In certain embodiments, oleclumab comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 2. In other embodiments, oleclumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 3 to 5, and the light chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6 to 8.

[0067] In certain embodiments, a tumor in a human patient is treated by administering oleclumab or an antigen-binding fragment thereof to the patient.

[0068] The monotherapy dose of oleclumab or an antigen-binding fragment thereof to be administered to a patient will depend in part on the size (weight, body surface, or organ size) and condition (age and health) of the patient.

[0069] In certain embodiments, patients are administered one or more doses of oleculab or an antigen-binding fragment thereof as monotherapy or in combination therapy, and the dose of oleculab or an antigen-binding fragment thereof is between 750 mg and 3000 mg. In some embodiments, the dose of oleculab or an antigen-binding fragment thereof is 750 mg. In some embodiments, the dose of oleculab or an antigen-binding fragment thereof is 1500 mg. In some embodiments, the dose of oleculab or an antigen-binding fragment thereof is 2250 mg. In some embodiments, the dose of oleculab or an antigen-binding fragment thereof is 3000 mg.

[0070] In certain embodiments, patients are administered one or more doses of oleculab or an antigen-binding fragment thereof as monotherapy, where the dose is 5 mg / kg, 10 mg / kg, 20 mg / kg, or 40 mg / kg. In some embodiments, patients are administered one or more doses of oleculab or an antigen-binding fragment thereof as monotherapy, where the dose is about 40 mg / kg.

[0071] In certain embodiments, to a patient presenting with a tumor, oleclumab or an antigen-binding fragment thereof is administered only once or less frequently, while still providing benefit to the patient. In further embodiments, the patient is administered additional subsequent doses. Subsequent doses can be administered at various time intervals depending on the patient's age, weight, clinical evaluation, tumor burden, and / or other factors, including the judgment of the attending physician.

[0072] In certain embodiments, a bolus-loading dose of oleculab or an antigen-binding fragment thereof is administered to a patient presenting with a tumor. In certain embodiments, the patient will be administered a first dose of oleculab or an antigen-binding fragment thereof, followed by a second, lower dose of oleculab or an antigen-binding fragment thereof. The second, lower dose may be repeated every 14 to 28 days. In certain embodiments, the first dose of oleculab is 40 mg / kg and the second, lower dose of oleculab is 20 mg / kg.

[0073] In certain embodiments, olecullab or an antigen-binding fragment thereof is administered over a 2-week treatment period, a 4-week treatment period, a 6-week treatment period, an 8-week treatment period, a 12-week treatment period, a 24-week treatment period, or a treatment period of one year or more. In certain embodiments, olecullab or an antigen-binding fragment thereof is administered over a 3-week treatment period, a 6-week treatment period, a 9-week treatment period, a 12-week treatment period, a 24-week treatment period, or a treatment period of one year or more. In certain embodiments, olecullab or an antigen-binding fragment thereof is administered over a 2-month treatment period, a 4-month treatment period, or a treatment period of six months or more. In certain embodiments, olecullab or an antigen-binding fragment thereof is administered over a 1-year treatment period, a 2-year treatment period, or a treatment period of three years or more.

[0074] In certain embodiments, oleclumab or an antigen-binding fragment thereof is administered every week, every two weeks, every four weeks, every six weeks, every eight weeks, every ten weeks, or every twelve weeks.

[0075] In certain embodiments, administration of oleculab or an antigen-binding fragment thereof is repeated every 7 to 28 days. In other embodiments, administration of oleculab or an antigen-binding fragment thereof is repeated every 14 days. In further embodiments, administration of oleculab or an antigen-binding fragment thereof is repeated every 28 days.

[0076] In certain embodiments, administration of oleculab or an antigen-binding fragment thereof is repeated every 7 to 28 days (e.g., every 7 days, every 14 days, every 21 days, or every 28 days). In certain embodiments, oleculab or an antigen-binding fragment thereof is administered every 14 days for at least two doses (e.g., for two, three, or four doses), and then every 28 days. In certain embodiments, oleculab or an antigen-binding fragment thereof is administered every 21 days for at least two doses (e.g., for two, three, or four doses), and then every 28 days.

[0077] Also provided herein are methods of treating solid tumors in a human patient, comprising administering 40 mg / kg of oleculab or an antigen-binding fragment thereof to the patient. Also provided herein are methods of treating solid tumors in a human patient, comprising administering 750 to 3000 mg (e.g., 750, 1500, 2250, or 3000 mg) of oleculab or an antigen-binding fragment thereof to the patient.

[0078] In other embodiments, oleclumab or an antigen-binding fragment thereof can be administered in combination therapy with durvalumab or an antigen-binding fragment thereof.

[0079] As used herein, the term "durvalumab" refers to an antibody that selectively binds to PD-L1 and blocks PD-L1 from binding to the PD-1 receptor and the CD80 receptor, as disclosed in U.S. Patent No. 9,493,565, which is incorporated herein by reference in its entirety. The fragment crystallizable (Fc) domain of durvalumab contains a triple mutation within the constant domain of the IgG1 heavy chain, which reduces binding to complement components C1q and Fcγ receptors, which are responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC).

[0080] In certain embodiments, durvalumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain. In certain embodiments, durvalumab comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 9 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 10. In other embodiments, durvalumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 11-13, and the light chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 14-16.

[0081] In certain embodiments, to patients presenting with tumors, oleclumab or an antigen-binding fragment thereof is administered only once or less frequently in combination with durvalumab or an antigen-binding fragment thereof, while still providing benefit to the patient. In further embodiments, the patient is administered additional subsequent doses. The subsequent doses can be administered at various time intervals depending on the patient's age, weight, clinical evaluation, tumor burden, and / or other factors, including the judgment of the treating physician.

[0082] In certain embodiments, olecullab or an antigen-binding fragment thereof administered in combination therapy with durvalumab or an antigen-binding fragment thereof is administered over a 2-week treatment period, a 4-week treatment period, a 6-week treatment period, a 6-week treatment period, a 8-week treatment period, a 12-week treatment period, a 24-week treatment period, or a treatment period of one year or more. In certain embodiments, olecullab or an antigen-binding fragment thereof is administered over a 3-week treatment period, a 6-week treatment period, a 9-week treatment period, a 12-week treatment period, a 24-week treatment period, or a treatment period of one year or more. In certain embodiments, olecullab or an antigen-binding fragment thereof is administered over a 2-month treatment period, a 4-month treatment period, or a treatment period of six months or more.

[0083] In certain embodiments, oleculab or an antigen-binding fragment thereof administered in combination therapy with durvalumab or an antigen-binding fragment thereof is administered every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 10 weeks, or every 12 weeks. In certain embodiments, oleculab or an antigen-binding fragment thereof in combination therapy with durvalumab or an antigen-binding fragment thereof is administered over a 1-year treatment period, over a 2-year treatment period, or over a 3-year or greater treatment period.

[0084] In certain embodiments, administration of olecullab or an antigen-binding fragment thereof in combination therapy with durvalumab or an antigen-binding fragment thereof is repeated every 14 to 28 days. In other embodiments, administration of olecullab or an antigen-binding fragment thereof is repeated every 14 days. In other embodiments, administration of olecullab or an antigen-binding fragment thereof is repeated every 21 days. In a further embodiment, administration of olecullab or an antigen-binding fragment thereof is repeated every 28 days. In a further embodiment, administration of olecullab or an antigen-binding fragment thereof is every 14 days for at least two doses (e.g., for two, three, or four doses) and then every 28 days. In a further embodiment, administration of olecullab or an antigen-binding fragment thereof is every 21 days for at least two doses (e.g., for two, three, or four doses) and then every 28 days.

[0085] In certain embodiments, durvalumab is administered approximately as frequently as oleculab. In certain embodiments, administration of durvalumab is repeated every 14 to 28 days. In other embodiments, administration of durvalumab is repeated every 14 days. In other embodiments, administration of durvalumab is repeated every 21 days. In further embodiments, administration of durvalumab is repeated every 28 days. In further embodiments, administration of durvalumab is repeated every 21 days for at least two doses (e.g., for two doses, three doses, or four doses), and then every 28 days.

[0086] The combination therapy dose of oleculab or an antigen-binding fragment thereof with durvalumab will vary depending in part on the patient's size (weight, body surface, or organ size) and condition (age and health). In certain embodiments, a patient is administered one or more doses of oleculab or an antigen-binding fragment thereof in combination therapy, where the dose is 5 mg / kg, 10 mg / kg, 20 mg / kg, or 40 mg / kg. In certain embodiments, a patient is administered one or more doses of oleculab or an antigen-binding fragment thereof in combination therapy, where the dose is 750 mg, 1500 mg, 2250 mg, or 3000 mg.

[0087] The combination therapy dose of durvalumab with oleculab will vary depending in part on the size (weight, body surface, or organ size) and condition (age and health) of the patient. In certain embodiments, the patient is administered one or more doses of durvalumab or an antigen-binding fragment thereof in combination therapy, where the dose is 3 mg / kg, 10 mg / kg, or 20 mg / kg. In certain embodiments, the patient is administered one or more doses of durvalumab or an antigen-binding fragment thereof in combination therapy, where the dose of durvalumab or an antigen-binding fragment thereof is 1500 mg.

[0088] In certain embodiments, a bolus-loading dose of oleclumab or antigen-binding fragment and / or durvalumab or antigen-binding fragment thereof is administered to a patient presenting with a tumor. In certain embodiments, the patient will be administered a first dose of oleclumab or antigen-binding fragment and / or durvalumab or antigen-binding fragment, followed by a second, lower dose of oleclumab or antigen-binding fragment and / or durvalumab or antigen-binding fragment thereof.

[0089] In certain embodiments, patients are administered 2 mg / kg of oleculab or an antigen-binding fragment thereof every two weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every two weeks. In certain embodiments, patients are administered 5 mg / kg of oleculab or an antigen-binding fragment thereof every two weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every two weeks. In certain embodiments, patients are administered 10 mg / kg of oleculab or an antigen-binding fragment thereof every two weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every two weeks. In certain embodiments, patients are administered 20 mg / kg of oleculab or an antigen-binding fragment thereof every two weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every two weeks. In certain embodiments, patients are administered 40 mg / kg of oleculab or an antigen-binding fragment thereof every two weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every two weeks.

[0090] In certain embodiments, patients are administered 2 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every 2 weeks. In certain embodiments, patients are administered 5 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every 2 weeks. In certain embodiments, patients are administered 10 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every 2 weeks. In certain embodiments, patients are administered 20 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every 2 weeks. In certain embodiments, patients are administered 40 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 10 mg / kg of durvalumab or an antigen-binding fragment thereof every 2 weeks.

[0091] In certain embodiments, patients are administered 2 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 20 mg / kg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In certain embodiments, patients are administered 5 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 20 mg / kg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In certain embodiments, patients are administered 10 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 20 mg / kg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In certain embodiments, patients are administered 20 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 20 mg / kg of durvalumab or an antigen-binding fragment thereof every 4 weeks. In certain embodiments, patients are administered 40 mg / kg of oleculab or an antigen-binding fragment thereof every 4 weeks and 20 mg / kg of durvalumab or an antigen-binding fragment thereof every 4 weeks.

[0092] In certain embodiments, patients receive 1500 mg or 3000 mg of oleculab or an antigen-binding fragment thereof every 2 weeks and then every 4 weeks for two 28-day cycle doses, and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.

[0093] In a specific embodiment, a patient receives 3000 mg of oleculab or an antigen-binding fragment thereof every two weeks and 1500 mg of durvalumab or an antigen-binding fragment thereof.

[0094] In a specific embodiment, patients receive 3000 mg of oleculab or an antigen-binding fragment thereof every 2 weeks for 2 months and every 4 weeks thereafter, and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.

[0095] In other embodiments, oleclumab or an antigen-binding fragment thereof can be administered in combination therapy with chemotherapy.

[0096] In certain embodiments, to patients presenting with tumors, oleclumab or an antigen-binding fragment thereof is administered only once or less frequently in combination with chemotherapy, while still providing benefit to the patient. In further embodiments, the patient is administered additional subsequent doses. Subsequent doses can be administered at various time intervals depending on other factors, including the patient's age, weight, clinical evaluation, tumor burden, and / or the judgment of the attending physician.

[0097] In certain embodiments, oleclumab or an antigen-binding fragment thereof in combination with chemotherapy is administered over a 2-week treatment period, a 3-week treatment period, a 4-week treatment period, a 6-week treatment period, a 8-week treatment period, a 12-week treatment period, a 24-week treatment period, or a treatment period of one year or more. In certain embodiments, oleclumab or an antigen-binding fragment thereof is administered over a 3-week treatment period, a 6-week treatment period, a 9-week treatment period, a 12-week treatment period, a 24-week treatment period, or a treatment period of one year or more. In certain embodiments, oleclumab or an antigen-binding fragment thereof is administered over a 2-month treatment period, a 4-month treatment period, or a 6-month or more treatment period. In certain embodiments, oleclumab or an antigen-binding fragment thereof in combination with chemotherapy is administered over a 1-year treatment period, a 2-year treatment period, or a 3-year or more treatment period.

[0098] In certain embodiments, oleclumab or an antigen-binding fragment thereof in combination with chemotherapy is administered every 2 weeks, every 3 weeks, every 4 weeks, every 6 weeks, every 8 weeks, every 10 weeks, or every 12 weeks.

[0099] In certain embodiments, administration of oleclumab or an antigen-binding fragment thereof in combination with chemotherapy is repeated every 14 to 28 days. In other embodiments, administration of oleclumab or an antigen-binding fragment thereof is repeated every 14 days. In other embodiments, administration of oleclumab or an antigen-binding fragment thereof is repeated every 21 days. In a further embodiment, administration of oleclumab or an antigen-binding fragment thereof is repeated every 28 days. In a further embodiment, administration of oleclumab or an antigen-binding fragment thereof is every 14 days for at least two doses (e.g., for two, three, or four doses) and then every 28 days. In a further embodiment, administration of oleclumab or an antigen-binding fragment thereof is every 21 days for at least two doses (e.g., for two, three, or four doses) and then every 28 days.

[0100] The combination chemotherapy dose of oleculab or an antigen-binding fragment thereof will vary depending in part on the patient's size (weight, body surface, or organ size) and condition (age and health). In certain embodiments, a patient is administered one or more doses of oleculab or an antigen-binding fragment thereof in combination with chemotherapy, wherein the dose of oleculab or an antigen-binding fragment thereof is 750 mg, 1500 mg, or 3000 mg. In certain embodiments, a patient is administered one or more doses of oleculab or an antigen-binding fragment thereof in combination with chemotherapy, wherein the dose of oleculab or an antigen-binding fragment thereof is 2250 mg.

[0101] In certain embodiments, the chemotherapy includes at least one of cisplatin, pemetrexed, nab-paclitaxel, carboplatin, gemcitabine, cisplatin, oxaliplatin, leucovorin, 5-fluorouracil, and docetaxel. In certain embodiments, the chemotherapy includes a combination of at least two of cisplatin, pemetrexed, nab-paclitaxel, carboplatin, gemcitabine, cisplatin, oxaliplatin, leucovorin, 5-fluorouracil, and docetaxel. In certain embodiments, the chemotherapy includes oxaliplatin, leucovorin, and 5-fluorouracil. In certain embodiments, the chemotherapy includes nab-paclitaxel and carboplatin. In certain embodiments, the chemotherapy includes gemcitabine and cisplatin. In certain embodiments, the chemotherapy includes gemcitabine and carboplatin. In certain embodiments, the chemotherapy includes pemetrexed and carboplatin. In certain embodiments, the chemotherapy comprises pemetrexed and cisplatin.

[0102] In certain embodiments, the chemotherapy comprises at least one of gemcitabine, nab-paclitaxel, oxaliplatin, leucovorin, and 5-fluorouracil.

[0103] The combination chemotherapy dose with olecurab will vary depending in part on the size (weight, body surface, or organ size) and condition (age and health) of the patient. Olecurab can be used in combination with chemotherapy utilizing any chemotherapy regimen known in the art. In certain embodiments, patients receive 1000 mg / m 2 Gemcitabine at a dose of 125 mg / m 2 In certain embodiments, patients receive one or more doses of nab-paclitaxel at a dose of 85 mg / m 2 oxaliplatin at a dose of 400 mg / m², leucovorin at a dose of 400 mg / m² 2 and 5-fluorouracil at a dose of 2400 mg / m 2 One or more doses of

[0104] In certain embodiments, patients receive 85 mg / m 2 In certain embodiments, patients receive one or more doses of oxaliplatin at a dose of 400 mg / m 2 In certain embodiments, patients receive one or more doses of leucovorin at a dose of 2400 mg / m 2 In certain embodiments, patients receive one or more doses of 5-fluorouracil (5-FU) at a dose of 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 2400 mg / m 2 Patients will receive one or more doses of 5-fluorouracil.

[0105] In certain embodiments, patients receive 100 mg / m 2 In certain embodiments, patients receive one or more doses of 1000 or 1250 mg / m of nab-paclitaxel. 2 In certain embodiments, patients receive one or more doses of gemcitabine at a dose of 500 mg / m 2 In certain embodiments, patients are administered one or more doses of pemetrexed at an AUC of 5 or 6. In certain embodiments, patients are administered one or more doses of carboplatin at an AUC of 75 mg / m 2 Patients will receive one or more doses of cisplatin.

[0106] In certain embodiments, chemotherapy is administered approximately as frequently as oleclumab. In certain embodiments, chemotherapy administration is repeated every 7-28 days. In other embodiments, chemotherapy administration is repeated every 7 days. In other embodiments, chemotherapy administration is repeated every 14 days. In other embodiments, chemotherapy administration is repeated every 21 days. In further embodiments, chemotherapy administration is repeated every 28 days. In other embodiments, chemotherapy administration is repeated on days 1 and 8 of a 21-day cycle.

[0107] In other embodiments, oleclumab or an antigen-binding fragment thereof can be administered in combination therapy with chemotherapy and durvalumab or an antigen-binding fragment thereof.

[0108] In certain embodiments of the combination therapy comprising oleculamab, durvalumab, and chemotherapy, durvalumab is administered approximately as frequently as oleculamab. In certain embodiments, oleculamab is administered approximately twice as frequently as durvalumab. In certain embodiments, administration of durvalumab is repeated every 14 to 28 days. In other embodiments, administration of durvalumab is repeated every 14 days. In further embodiments, administration of durvalumab is repeated every 21 days. In further embodiments, administration of durvalumab is repeated every 28 days. In further embodiments, administration of durvalumab is repeated every 21 days for at least two doses (e.g., for two doses, three doses, or four doses), and then every 28 days.

[0109] The combination therapy dose of durvalumab or an antigen-binding fragment thereof with oleclumab or an antigen-binding fragment thereof and chemotherapy will depend in part on the size (weight, body surface, or organ size) and condition (age and health) of the patient. In certain embodiments, the patient is administered one or more doses of durvalumab or an antigen-binding fragment thereof as combination therapy, and the dose of durvalumab or an antigen-binding fragment thereof is 1500 mg.

[0110] In certain embodiments, patients receive 750 mg of oleculab or an antigen-binding fragment thereof every 2 weeks for four doses, and then every 4 weeks, 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks, and 1000 mg / m 2 of gemcitabine and 125 mg / m 2of nab-paclitaxel on days 1, 8, and 15, and every four weeks thereafter. In a specific embodiment, patients receive 1500 mg of oleculab or an antigen-binding fragment thereof every two weeks for four doses, and then every four weeks, 1500 mg of durvalumab or an antigen-binding fragment thereof every four weeks, and 1000 mg / m 2 of gemcitabine and 125 mg / m 2 of nab-paclitaxel on days 1, 8, and 15, and every four weeks thereafter. In a specific embodiment, patients receive 3000 mg of oleculab or an antigen-binding fragment thereof every two weeks for four doses, and then every four weeks, 1500 mg of durvalumab or an antigen-binding fragment thereof every four weeks, and 1000 mg / m 2 of gemcitabine and 125 mg / m 2 of nab-paclitaxel will be administered on days 1, 8, and 15, and every 4 weeks thereafter.

[0111] In certain embodiments, patients receive 750 mg of oleculab or an antigen-binding fragment thereof every 2 weeks for four doses, and then every 4 weeks, 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks, and 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 2400 mg / m 2 of 5-fluorouracil on days 1 and 15, and every four weeks thereafter. In a specific embodiment, patients receive 1500 mg of oleculab or an antigen-binding fragment thereof every two weeks for four doses, and then every four weeks, 1500 mg of durvalumab or an antigen-binding fragment thereof every four weeks, and 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 2400 mg / m 2of 5-fluorouracil on days 1 and 15, and every four weeks thereafter. In a specific embodiment, patients receive 3000 mg of oleculab or an antigen-binding fragment thereof every two weeks for four doses, and then every four weeks, 1500 mg of durvalumab or an antigen-binding fragment thereof every four weeks, and 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 2400 mg / m 2 of 5-fluorouracil is administered on days 1 and 15, and every 4 weeks thereafter.

[0112] In certain embodiments, patients receive 1500 mg or 3000 mg of oleculab or an antigen-binding fragment thereof every two weeks for four doses, and then every four weeks, and 1000 mg / m 2 of gemcitabine and 125 mg / m 2 Patients will receive chemotherapy containing 100 mg of nab-paclitaxel. The chemotherapy may be administered on days 1, 8, and 15 of four 28-day cycles, and every four weeks thereafter. Patients will also receive 1500 mg of durvalumab or an antigen-binding fragment thereof every four weeks.

[0113] In certain embodiments, patients receive 1500 mg or 3000 mg of oleculab or an antigen-binding fragment thereof every two weeks for four doses, and every four weeks thereafter, and 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 400 mg / m 2 of 5-FU followed by 2400 mg / m 2 Patients will receive chemotherapy containing 5-FU. The chemotherapy may be administered on days 1 and 15 of four 28-day cycles, and every four weeks thereafter. 1500 mg of durvalumab or an antigen-binding fragment thereof may be administered every four weeks.

[0114] In certain embodiments, patients are receiving (i) oleculab or an antigen-binding fragment thereof at (a) 1500 mg every 3 weeks for four 21-day cycles, and then every 4 weeks; or (b) 2250 mg every 3 weeks for four 21-day cycles, and then 3000 mg every 4 weeks; (ii) durvalumab or an antigen-binding fragment thereof at 1500 mg every 3 weeks for four 21-day cycles, and then every 4 weeks; and (iii)(a) 100 mg / m 2 on days 1, 8, and 15 of a 21-day cycle for four cycles and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for four cycles; (b) 1000 mg / m 2 or 1250 mg / m 2 of gemcitabine on days 1 and 8 of a 21-day cycle for four cycles, and 75 mg / m 2 of cisplatin on day 1 of a 21-day cycle for four cycles; (c) 1000 mg / m 2 or 1250 mg / m 2 gemcitabine at 500 mg / m on days 1 and 8 of a 21-day cycle for four cycles and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for four cycles; (d) 500 mg / m 2 on day 1 of every 21-day cycle for four cycles and carboplatin at 5 or 6 AUC on day 1 of every 21-day cycle for four cycles; or (e) 500 mg / m 2 of pemetrexed on day 1 of a 21-day cycle for four cycles and 75 mg / m 2 of cisplatin on day 1 of a 21-day cycle for four cycles. Pemetrexed may also be administered at a dose of, for example, 500 mg / m 2 It can be administered every 4 weeks as maintenance therapy in

[0115] In certain embodiments, patients receive (i) 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks; (ii) 3000 mg of oleculab or an antigen-binding fragment thereof every 2 weeks for 5 doses and then every 4 weeks; and (iii)(a) 400 mg / m every 2 weeks 2 of folinic acid, (b) 85 mg / m every 2 weeks 2 of oxaliplatin; and (c) 400 mg / m on day 1. 2 of 5-fluorouracil and then 2400 mg / m2 of 5-fluorouracil every 2 weeks.

[0116] In other embodiments, bevacizumab or an antigen-binding fragment thereof can be administered in combination therapy with oleclumab or an antigen-binding fragment thereof and chemotherapy (e.g., chemotherapy including oxaliplatin, leucovorin, and 5-fluorouracil).

[0117] As used herein, the term "bevacizumab" refers to an antibody that selectively binds to vascular endothelial growth factor (VEGF), as disclosed in U.S. Pat. Nos. 6,884,879 and 7,169,901, which are incorporated herein by reference in their entireties.

[0118] In certain embodiments, bevacizumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain. In certain embodiments, bevacizumab comprises a light chain variable domain comprising the amino acid sequence of SEQ ID NO: 17 and a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO: 18. In other embodiments, durvalumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain, wherein the heavy chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 19-21, and the light chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 22-24.

[0119] In certain embodiments, patients are administered one or more doses of 5 mg / kg bevacizumab or an antigen-binding fragment thereof. The bevacizumab or an antigen-binding fragment thereof can be administered, for example, every two weeks. The bevacizumab or an antigen-binding fragment thereof can be administered, for example, intravenously.

[0120] In certain embodiments, patients receive (i) 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks; (ii) 3000 mg of oleculab or an antigen-binding fragment thereof every 2 weeks for four doses and then every 4 weeks; or (iii)(a) 400 mg / m every 2 weeks. 2 of folinic acid, (b) 85 mg / m every 2 weeks 2 of oxaliplatin; and (c) 2400 mg / m every 2 weeks 2 of 5-fluorouracil-containing chemotherapy; and (iv) 5 mg / kg of bevacizumab or an antigen-binding fragment thereof every two weeks.

[0121] In certain embodiments, the patient to be treated has a solid tumor that is breast cancer, ovarian cancer, head and neck cancer, prostate cancer, bladder cancer, colorectal cancer, non-small cell lung cancer (NSCLC), glioblastoma, renal cell carcinoma, or pancreatic cancer.

[0122] In certain embodiments, the patient to be treated has a solid tumor, such as colorectal cancer, non-small cell lung cancer, or pancreatic cancer. In certain embodiments, the cancer has pancreatic ductal adenocarcinoma. In certain embodiments, the patient has previously untreated metastatic pancreatic ductal adenocarcinoma. In certain embodiments, the patient has previously treated metastatic pancreatic ductal adenocarcinoma with gemcitabine-based therapy.

[0123] In certain embodiments, the patient has a resectable NSCLC tumor, an early stage NSCLC tumor, or a stage IV NSCLC tumor.

[0124] In certain embodiments, the patient has metastatic colorectal cancer.

[0125] In certain embodiments, the patient has a tumor with high or low PD-L1 expression. The tumor with high or low PD-L1 expression may be NSCLC.

[0126] In certain embodiments, the patient has a tumor that lacks an activating epidermal growth factor receptor (EGFR) mutation and / or an anaplastic lymphoma kinase (ALK) fusion. The tumor may be an NSCLC tumor.

[0127] In certain embodiments, the patient has a previously untreated tumor in the recurrent and / or metastatic setting.

[0128] The antibodies of the present disclosure can be selected for parenteral administration. For example, the antibodies of the present disclosure can be administered by intravenous infusion or subcutaneous injection. In certain embodiments, the administration is intravenous infusion.

[0129] Response Evaluation Criteria in Solid Tumors (RECIST) refers to a published set of rules that define when a cancer patient improves, stays the same, or gets worse during treatment. The types of response a patient can have are complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD).

[0130] The methods provided herein can be used for tumor disease control (DC), which can be a complete response (CR), partial response (PR), or stable disease (SD).

[0131] A "complete response" (CR) refers to the disappearance of all lesions, measurable or not, and the absence of new lesions. Confirmation of complete response can be obtained using repeated serial assessments for 4 weeks or more from the date of first documentation. New non-measurable lesions preclude a CR.

[0132] A "partial response" (PR) refers to a reduction in tumor burden of ≥ 50% relative to baseline, confirmation of which can be obtained using serial repeat assessments for at least 4 weeks from the date of first documentation.

[0133] "Progression" (PD) refers to an increase in tumor burden of ≥ 25% relative to the lowest recorded point (nadir). Confirmation can be obtained by serial repeat assessments for at least 4 weeks from the date of first documentation. New non-measurable lesions do not define PD.

[0134] "Stable disease" (SD) refers to not meeting the criteria for CR, PR, or PD.

[0135] Without intending to limit the disclosure, several embodiments of the present disclosure are described below for purposes of illustration.

[0136] In one embodiment (A1) of the methods provided herein, the method of treating a tumor in a human patient comprises administering oleclumab or an antigen-binding fragment thereof to the patient.

[0137] In one embodiment (A2) of A1, oleculab or an antigen-binding fragment thereof is administered at a dose of 2 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg or 40 mg / kg.

[0138] In another embodiment (A3) of A1, oleclumab or an antigen-binding fragment thereof is administered at a dose of 40 mg / kg.

[0139] In one embodiment (A4) of any one of A1 to A3, oleclumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

[0140] In one embodiment (A5) of A4, oleculab or an antigen-binding fragment thereof is administered every 14 days.

[0141] In one embodiment (A6) of A4, oleclumab or an antigen-binding fragment thereof is administered every 28 days.

[0142] In one embodiment (A7) of any one of A1 to A6, administration of oleclumab or an antigen-binding fragment thereof results in a partial response.

[0143] In another embodiment (A8) of any one of A1-A6, administration of oleclumab or an antigen-binding fragment thereof results in a complete response.

[0144] In another embodiment (A9) of any one of A1 to A6, the tumor is a solid tumor.

[0145] In one embodiment (A10) of A9, the solid tumor is colorectal cancer, non-small cell lung cancer or pancreatic cancer.

[0146] In one embodiment (A11) of any one of A1-A10, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0147] In one embodiment (A12) of the methods provided herein, the method of treating a solid tumor in a human patient comprises administering 40 mg / kg of oleculab or an antigen-binding fragment thereof to the patient.

[0148] In one embodiment (A13) of the methods provided herein, the method of treating a tumor in a human patient comprises administering to the patient olecurumab or an antigen-binding fragment thereof and durvalumab or an antigen-binding fragment thereof.

[0149] In one embodiment (A14) of A13, oleculab or an antigen-binding fragment thereof is administered at a dose of 2 mg / kg, 5 mg / kg, 10 mg / kg, 20 mg / kg or 40 mg / kg.

[0150] In one embodiment (A15) of A13 or A14, durvalumab or an antigen-binding fragment thereof is administered at a dose of 3 mg / kg, 10 mg / kg or 20 mg / kg.

[0151] In one embodiment (A16) of any one of A13 to A15, oleclumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

[0152] In one embodiment (A17) of any one of A13 to A16, durvalumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

[0153] In one embodiment (A18) of any one of A13 to A17, the tumor is a solid tumor.

[0154] In one embodiment (A19) of A18, the solid tumor is colorectal cancer, non-small cell lung cancer, or pancreatic cancer.

[0155] In one embodiment (A20) of any one of A13 to A19, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0156] In one embodiment (A21) of the methods provided herein, the method of treating a tumor in a human patient comprises administering oleclumab or an antigen-binding fragment thereof and chemotherapy to the patient.

[0157] In one embodiment (A22) of A21, oleclumab or an antigen-binding fragment thereof is administered in a dose of 750 mg, 1500 mg or 3000 mg.

[0158] In one embodiment (A23) of A21 or A22, oleclumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

[0159] In one embodiment (A24) of any one of A21 to A23, the method further comprises administering durvalumab or an antigen-binding fragment thereof.

[0160] In one embodiment (A25) of A24, durvalumab or an antigen-binding fragment thereof is administered in a dose of 1500 mg.

[0161] In one embodiment (A26) of A24 or A25, durvalumab or an antigen-binding fragment thereof is administered every 28 days.

[0162] In one embodiment (A27) of any one of A21 to A26, the chemotherapy includes at least one of gemcitabine, nab-paclitaxel, oxaliplatin, leucovorin, and 5-fluorouracil.

[0163] In one embodiment (A28) of A27, the chemotherapy is 1000 mg / m 2 of gemcitabine and 125 mg / m 2 Contains nab-paclitaxel.

[0164] In another embodiment (A29) of A27, the chemotherapy is 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 2400 mg / m 2 Contains 5-fluorouracil.

[0165] In one embodiment (A30) of any one of A21 to A29, the chemotherapy is administered every 7 to 28 days.

[0166] In one embodiment (A31) of any one of A29 to A30, 5-fluorouracil is administered by continuous intravenous infusion for 46 to 48 hours.

[0167] In one embodiment (A32) of A28, the patient has previously untreated metastatic pancreatic ductal adenocarcinoma.

[0168] In one embodiment (A33) of A29, the patient has metastatic pancreatic ductal adenocarcinoma that has been previously treated with gemcitabine-based therapy. Embodiments of the present disclosure are further described in the following sections: [Section 1] 1. A method of treating a tumor in a human patient, comprising administering oleclumab or an antigen-binding fragment thereof to said patient. [Section 2] 1. A method of treating a tumor in a human patient, comprising administering to the patient oleclumab or an antigen-binding fragment thereof and durvalumab or an antigen-binding fragment thereof. [Section 3] 1. A method of treating a tumor in a human patient, comprising administering to said patient oleclumab or an antigen-binding fragment thereof and chemotherapy. [Section 4] The method according to item 3, further comprising administering durvalumab or an antigen-binding fragment thereof. [Section 5] 5. The method according to any one of items 1 to 4, wherein the oleclumab or antigen-binding fragment thereof is administered at a dose of 750 mg to 3000 mg. [Section 6] Item 6. The method according to item 5, wherein the oleclumab or antigen-binding fragment thereof is administered in a dose of 750 mg. [Section 7] Item 6. The method according to item 5, wherein the oleclumab or antigen-binding fragment thereof is administered at a dose of 1500 mg. [Section 8] The method according to item 5, wherein the oleclumab or antigen-binding fragment thereof is administered at a dose of 2250 mg. [Section 9] Item 6. The method according to item 5, wherein the oleclumab or antigen-binding fragment thereof is administered at a dose of 3000 mg. [Section 10] 6. The method according to claim 5, wherein the oleclumab or antigen-binding fragment thereof is administered in a dose of 2250 mg, and then in a dose of 3000 mg. [Section 11] 11. The method according to claim 10, wherein the oleclumab or antigen-binding fragment thereof is administered at a dose of 2250 mg for four doses, and then at a dose of 3000 mg. [Section 12] 12. The method according to any one of items 1 to 11, wherein oleclumab or an antigen-binding fragment thereof is administered every 14 to 28 days. [Section 13] 12. The method according to any one of items 1 to 11, wherein oleclumab or an antigen-binding fragment thereof is administered every 14 days. [Section 14] 12. The method according to any one of items 1 to 11, wherein oleclumab or an antigen-binding fragment thereof is administered every 28 days. [Section 15] 12. The method according to any one of items 1 to 11, wherein the oleclumab or antigen-binding fragment thereof is administered every 14 days for at least two doses, and then every 28 days. [Section 16] 12. The method according to any one of items 1 to 11, wherein the oleclumab or antigen-binding fragment thereof is administered every 14 days for four doses, and then every 28 days. [Section 17] 12. The method according to any one of items 1 to 11, wherein the oleclumab or antigen-binding fragment thereof is administered every 21 days. [Section 18] 12. The method according to any one of items 1 to 11, wherein the oleclumab or antigen-binding fragment thereof is administered every 21 days for at least two doses, and then every 28 days. [Section 19] 12. The method according to any one of items 1 to 11, wherein the oleclumab or antigen-binding fragment thereof is administered every 21 days for 2 to 4 doses, and then every 28 days. [Section 20] Item 14. The method according to item 13, wherein the oleclumab or antigen-binding fragment thereof is administered every 21 days for two doses, and then once every 28 days. [Section 21] Item 14. The method according to item 13, wherein the oleclumab or antigen-binding fragment thereof is administered once every 21 days for four doses, and then once every 28 days. [Section 22] 6. The method according to any one of items 1 to 5, wherein the oleclumab or antigen-binding fragment thereof is administered once at a dose of 2250 mg every 21 days, and then once at a dose of 3000 mg every 28 days for two doses. [Section 23] 6. The method according to any one of items 1 to 5, wherein the oleclumab or antigen-binding fragment thereof is administered once every 21 days at a dose of 2250 mg, and then once every 28 days at a dose of 3000 mg for four doses. [Section 24] 24. The method according to any one of items 1 to 23, wherein the oleclumab or antigen-binding fragment thereof is administered intravenously. [Section 25] 25. The method according to any one of items 2 or 4 to 24, wherein the durvalumab or antigen-binding fragment thereof is administered at a dose of 1500 mg. [Section 26] 26. The method according to any one of items 2 and 4 to 25, wherein the durvalumab or an antigen-binding fragment thereof is administered every 21 to 28 days. [Section 27] 27. The method according to any one of items 2 or 4 to 26, wherein the durvalumab or an antigen-binding fragment thereof is administered every 28 days. [Section 28] 27. The method according to any one of items 2 or 4 to 26, wherein the durvalumab or an antigen-binding fragment thereof is administered every 21 days. [Section 29] 27. The method according to any one of items 2 or 4 to 26, wherein the durvalumab or antigen-binding fragment thereof is administered every 21 days for at least two doses, and then every 28 days. [Section 30] 27. The method according to any one of items 2 or 4 to 26, wherein the durvalumab or antigen-binding fragment thereof is administered every 21 days for four doses and then every 28 days. [Section 31] 27. The method of any one of items 2 or 4 to 26, wherein the durvalumab or antigen-binding fragment thereof is administered at a dose of 1500 mg every 21 days for four doses, and then at a dose of 1500 mg every 28 days. [Section 32] 32. The method according to any one of items 1 to 31, wherein the durvalumab or an antigen-binding fragment thereof is administered intravenously. [Section 33] 33. The method according to any one of items 3 to 32, wherein the chemotherapy comprises at least one of cisplatin, pemetrexed, nab-paclitaxel, carboplatin, gemcitabine, cisplatin, oxaliplatin, leucovorin, 5-fluorouracil, and docetaxel. [Section 34] Item 34. The method according to item 33, wherein the chemotherapy comprises oxaliplatin, leucovorin, and 5-fluorouracil. [Section 35] The oxaliplatin is 85 mg / m 2 35. The method according to item 33 or 34, wherein the dose is [Section 36] 36. The method according to any one of items 33 to 35, wherein the oxaliplatin is administered every two weeks. [Section 37] The leucovorin is 400 mg / m 2 37. The method according to any one of items 33 to 36, wherein the compound is administered at a dose of [Section 38] 39. The method according to any one of items 33 to 38, wherein the leucovorin is administered every two weeks. [Section 39] The 5-fluorouracil is 2400 mg / m 2 39. The method according to any one of items 33 to 38, wherein the compound is administered at a dose of [Section 40] 40. The method according to any one of items 33 to 39, wherein the 5-fluorouracil is administered by continuous intravenous infusion for 46 to 48 hours. [Section 41] 41. The method according to any one of items 33 to 40, wherein the 5-fluorouracil is administered over 46 to 48 hours every two weeks. [Section 42] The chemotherapy is 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 2400 mg / m 2 42. The method according to any one of items 33 to 41, comprising 5-fluorouracil. [Section 43] 43. The method according to any one of items 34 to 42, further comprising administering bevacizumab or an antigen-binding fragment thereof. [Section 44] 44. The method according to item 43, wherein bevacizumab or an antigen-binding fragment thereof is administered at a dose of 5 mg / kg. [Section 45] 45. The method according to item 43 or 44, wherein bevacizumab or an antigen-binding fragment thereof is administered every two weeks. [Section 46] 46. ​​The method according to any one of items 43 to 45, wherein bevacizumab or an antigen-binding fragment thereof is administered intravenously. [Section 47] 34. The method according to claim 33, wherein the chemotherapy comprises (a) nab-paclitaxel and carboplatin; (b) gemcitabine and cisplatin; (c) gemcitabine and carboplatin; (d) pemetrexed and carboplatin; and (e) pemetrexed and cisplatin. [Section 48] The nab-paclitaxel was administered at 100 mg / m 2 48. The method according to item 33 or 47, wherein the dose is [Section 49] 49. The method of any one of paragraphs 33, 47 or 48, wherein the nab-paclitaxel is administered on days 1, 8 and 15 of a 21-day cycle. [Section 50] The gemcitabine is 1000 mg / m 2 or 1250 mg / m 2 48. The method according to item 33 or 47, wherein the dose is [Section 51] 51. The method of any one of clauses 33, 47 or 50, wherein the gemcitabine is administered on days 1 and 8 of a 21-day cycle. [Section 52] The pemetrexed is administered at a dose of 500 mg / m 2 48. The method according to item 33 or 47, wherein the dose is [Section 53] 53. The method of any one of paragraphs 33, 47, or 52, wherein the pemetrexed is administered every three weeks. [Section 54] 54. The method according to any one of items 33 and 47 to 53, wherein the carboplatin is administered at a dose of AUC5 or 6. [Section 55] 56. The method according to any one of items 33 and 47 to 55, wherein the carboplatin is administered every three weeks. [Section 56] The cisplatin is 75 mg / m 2 54. The method according to any one of items 33, 47, and 50 to 53, wherein the compound is administered at a dose of [Section 57] Item 57. The method according to any one of items 33, 47, 50 to 53, and 56, wherein the cisplatin is administered every three weeks. [Section 58] The chemotherapy is 1000 mg / m 2 of gemcitabine and 125 mg / m 2 34. The method according to claim 33, comprising administering nab-paclitaxel of the formula: [Section 59] 59. The method according to any one of items 3 to 58, wherein the chemotherapy is administered every 7 to 28 days. [Section 60] 60. The method of claim 59, wherein the chemotherapy is administered every 14 days. [Section 61] 25. The method of any one of items 1 or 5 to 24, wherein the administration of oleclumab or an antigen-binding fragment thereof results in a partial response. [Section 62] 25. The method of any one of items 1 or 5 to 24, wherein the administration of oleclumab or an antigen-binding fragment thereof results in a complete response. [Section 63] Item 63. The method according to any one of items 1 to 62, wherein the tumor is a solid tumor. [Section 64] Item 64. The method according to item 63, wherein the solid tumor is breast cancer, ovarian cancer, head and neck cancer, prostate cancer, bladder cancer, colorectal cancer, non-small cell lung cancer (NSCLC), glioblastoma, renal cell carcinoma, or pancreatic cancer. [Section 65] Item 65. The method according to item 64, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma. [Section 66] 65. The method according to paragraph 64, wherein the tumor is a resectable NSCLC tumor. [Section 67] 67. The method according to paragraph 64 or 66, wherein the tumor is an early stage NSCLC tumor. [Section 68] 65. The method according to paragraph 64, wherein the tumor is a stage IV NSCLC tumor. [Section 69] 65. The method of claim 64, wherein the colorectal cancer is metastatic and microsatellite stable. [Section 70] 65. The method according to any one of items 1 to 64, wherein the tumor has high PD-L1 expression, and optionally the tumor is an NSCLC tumor. [Section 71] 65. The method of any one of paragraphs 1 to 64, wherein the tumor has low PD-L1 expression, and optionally the tumor is an NSCLC tumor. [Section 72] 65. The method of any one of items 1 to 64, wherein the tumor lacks an activating epidermal growth factor receptor (EGFR) mutation and / or an anaplastic lymphoma kinase (ALK) fusion, and optionally, the tumor is an NSCLC tumor. [Section 73] 65. The method according to any one of paragraphs 1 to 64, wherein the patient has previously untreated metastatic pancreatic ductal adenocarcinoma. [Section 74] 65. The method of any one of paragraphs 1 to 64, wherein the patient has metastatic pancreatic ductal adenocarcinoma that has been previously treated with gemcitabine-based therapy. [Section 75] 75. The method according to any one of paragraphs 1 to 74, wherein the tumor has not received previous treatment in the recurrent and / or metastatic setting. [Section 76] 75. The method according to any one of items 1 to 74 above, wherein the patient is undergoing an anti-PD-1 or anti-PD-L1 containing therapy. [Section 77] The tumor is first-line metastatic pancreatic ductal adenocarcinoma, the oleclumab or antigen-binding fragment thereof is administered at 1500 mg or 3000 mg for four doses every two weeks and then every four weeks, and the chemotherapy is administered at 1000 mg / m 2 of gemcitabine and 125 mg / m 2 33. The method of any one of paragraphs 3, 24 or 32, comprising nab-paclitaxel of the formula: [Section 78] The tumor is second-line metastatic pancreatic ductal adenocarcinoma, the oleclumab or antigen-binding fragment thereof is administered at 1500 mg or 3000 mg for four doses every two weeks and then every four weeks, and the chemotherapy is administered at 85 mg / m 2 of oxaliplatin, 400 mg / m 2 of leucovorin and 400 mg / m 2 of 5-FU followed by 2400 mg / m 2 33. The method of any one of paragraphs 3, 24 or 32, comprising 5-FU of the formula (I) above, wherein the chemotherapy is administered on days 1 and 15 of four 28-day cycles and every four weeks thereafter. [Section 79] 79. The method of claim 77 or 78, further comprising administering 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks. [Section 80] 33. The method of any one of clauses 2, 24, or 32, wherein the tumor is high first-line stage IV NSCLC with high PD-L1 expression, and the oleclumab or antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every 2 weeks and then every 4 weeks for two 28-day cycles, and the durvalumab or antigen-binding fragment thereof is administered at 1500 mg every 4 weeks. [Section 81] the tumor is first-line stage IV NSCLC with low PD-L1 expression; (i) the oleclumab or antigen-binding fragment thereof is administered (a) at 1500 mg every 3 weeks for four 21-day cycles, and then every 4 weeks; or (b) at 2250 mg every 3 weeks for four 21-day cycles, and then at 3000 mg every 4 weeks; (ii) the durvalumab or antigen-binding fragment thereof is administered at 1500 mg every 3 weeks and every 4 weeks thereafter for four 21-day cycles; and (iii) The chemotherapy consists of: (a) 100 mg / m on days 1, 8, and 15 of a 21-day cycle for four cycles; 2 of nab-paclitaxel and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for four cycles; (b) 1000 mg / m on days 1 and 8 of a 21-day cycle for four cycles. 2 or 1250 mg / m 2 of gemcitabine and 75 mg / m on day 1 of a 21-day cycle for 4 cycles 2 (c) cisplatin at 1000 mg / m on days 1 and 8 of a 21-day cycle for four cycles 2 or 1250 mg / m 2 gemcitabine and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for four cycles; (d) 500 mg / m on day 1 of a 21-day cycle for four cycles 2 of pemetrexed and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for 4 cycles, optionally at 500 mg / m2 pemetrexed administered every 4 weeks as maintenance therapy after four cycles, pemetrexed and carboplatin; or (e) 500 mg / m on day 1 of a 21-day cycle for four cycles. 2 pemetrexed at 75 mg / m on day 1 of a 21-day cycle for four cycles 2 cisplatin, optionally at 500 mg / m 2 33. The method of any one of paragraphs 4, 24, or 32, comprising pemetrexed and cisplatin, wherein pemetrexed is administered every four weeks as maintenance therapy after four cycles. [Section 82] 33. The method of any one of clauses 2, 24, or 32, wherein the tumor is a locally advanced unresectable stage III NSCLC tumor, and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks, and (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every 2 weeks for 2 months and then every 4 weeks. [Section 83] 33. The method of any one of clauses 2, 24, or 32, wherein the tumor is a resectable early-stage NSCLC tumor, and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered, and (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every two weeks. [Section 84] The tumor is a metastatic microsatellite-stable colorectal cancer tumor, and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every four weeks; (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every two weeks for four doses and then every four weeks; (iii) the chemotherapy is: (a) 400 mg / m every two weeks 2 of folinic acid, (b) 85 mg / m every 2 weeks 2 of oxaliplatin; and (c) 2400 mg / m every 2 weeks 250. The method of any one of clauses 4, 24, 32 or 46, wherein (iv) 5 mg / kg of 5-fluorouracil is administered every two weeks. [Section 85] The tumor is a microsatellite-stable colorectal cancer tumor, and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every four weeks; (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every two weeks for five doses and then every four weeks; and (iii) the chemotherapy is: (a) 400 mg / m every two weeks 2 folinic acid; (b) 85 mg / m every 2 weeks 2 of oxaliplatin; and (c) 400 mg / m on day 1. 2 of 5-fluorouracil and then 2400 mg / m every 2 weeks 2 33. The method according to any one of items 4, 24 or 32, comprising 5-fluorouracil. [Section 86] 86. The method according to any one of the above paragraphs 1 to 85, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. [Example]

[0169] The following examples illustrate specific embodiments of the present disclosure and various uses thereof. They are provided for illustrative purposes only and should not be construed as limiting the scope of the invention in any way.

[0170] Example 1. Evaluation of Olecurab Toxicity in Mouse and Monkey Species Mice and cynomolgus monkeys were selected as pharmacologically relevant species for the evaluation of oleculab toxicity. This evaluation was based on a combination of factors: (i) the moderate to high protein sequence identity between mouse and cynomolgus monkey CD73 and human CD73 (86% and 98%, respectively); (ii) the similar binding affinity of oleculab for mouse, cynomolgus monkey, and human CD73; and (iii) the similar potency of oleculab against cell-based mouse, monkey, and human recombinant CD73 enzyme activity in in vitro assays. In addition, in cynomolgus monkeys, a single IV dose of ≥ 1 mg / kg oleculab (the lowest dose tested) suppressed soluble CD73 in serum, and dose was associated with the duration of suppression. Systemic and local toxicity of olecullab was evaluated in Good Laboratory Practice (GLP) toxicity studies in CD-1 mice (5-week, repeated intravenous [IV] bolus doses, once every 4 days, for a total of 9 doses) at 0 mg / kg, 100 mg / kg, or 200 mg / kg, and in cynomolgus monkeys (5-week, repeated IV 30-minute infusion doses, once weekly, for a total of 5 doses) at 0 mg / kg, 30.5 mg / kg, 103.7 mg / kg, or 300.7 mg / kg. No olecullab-related adverse effects were noted in CD-1 mice at doses up to 200 mg / kg or in cynomolgus monkeys at doses up to 300.7 mg / kg. Safety pharmacology endpoints (electrocardiogram [ECG], blood pressure, and behavioral tests) were also free of olecullab-related effects (assessed as part of the 5-week cynomolgus monkey study). Therefore, the no-observed-adverse-effect level (NOAEL) was 200 mg / kg / dose (the highest dose tested; maximum observed concentration [C max ], 6,200μg / mL; area under the concentration-time curve [AUC] 0~96hr , 229,000 μg·hr / mL)) and 300.7 mg / kg / dose in cynomolgus monkeys (highest dose tested; C max , 11,000 μg / mL; AUC 0~168.5hr In a GLP human tissue cross-reactivity assessment, oleculab staining was observed in multiple cell types across the human tissue panel examined.

[0171] The ability of olecullab (alone or in combination with durvalumab) to induce cytokine release was evaluated in human in vitro assays using blood or peripheral blood mononuclear cells from healthy donors. Olecullab, presented in solution or immobilized on plastic wells by dry coating, did not induce cytokine release, alone or in combination with durvalumab.

[0172] Example 2: Single-dose pharmacokinetic / pharmacodynamic cynomolgus monkey study Five male cynomolgus monkeys were administered a single IV bolus dose of oleclumab at doses of 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg. Serum was collected 0.08, 0.5, 2, 8, and 24 hours after administration and 2, 3, 5, 7, 10, 14, 21, 28, and 35 days after administration, prior to the first dose.

[0173] To detect free sCD73, plates were coated overnight with 0.5 μg / mL anti-CD73 antibody, and then 50 μL of monkey serum was added to the plate. The plate was incubated for 15 min ± 1 min, washed, and anti-CD73-HRP was added. Free sCD73 was suppressed in all dose groups. However, the suppression of free sCD73 was dose-dependent (Figure 1).

[0174] To assess immune modulation, foreign antigen (KLH) responses were measured. First, monkeys were immunized with adjuvant-free KLH on day 1 to assess foreign antigen (KLH) responses. KLH T cell-dependent antibody responses (TDAR) were elicited on days 7, 8, 11, 15, 22, 29, and 36. Ex vivo KLH stimulation of PBMC IFN-γ and IL-2 ELISPOT assays was assessed on days 1, 4, 8, 7, 15, and 22. Olecurumab did not enhance responses to foreign antigen (KLH). Anti-KLH IgM and IgG antibody responses were detectable but did not show a dose-dependent increase with olecurumab treatment (Figures 2A and 2B). T cell responses to ex vivo KLH stimulation were detectable but were unchanged by olecurumab treatment (Figures 3A and 3B).

[0175] Endogenous pathogen responses were also investigated by endogenous pathogen confirmation. Endogenous pathogen antibodies were measured using chemiluminescent ELISA on days 1, 8, 14, 15, and 29, and endogenous pathogen T cell IFN-γ ELISPOT was measured on days 14 and 29. LCV (the monkey homolog of EBV) was detectable at low levels in most cynomolgus monkeys (Figure 4). IgG titers against EBV gp125 and CMV gB were detectable and were not altered by olecuramab treatment. T cell responses against EBV BZLF1 and inactivated human CMV were detectable and were not consistently altered by olecuramab treatment.

[0176] Example 3: Olecurumab as Monotherapy and in Combination with Durvalumab in the Treatment of Solid Tumors The study was a first-in-human (FTIH), Phase 1, multicenter, open-label, dose-escalation and dose-expansion study of oleculab administered as a single agent or in combination with durvalumab in adult subjects with selected advanced solid tumors to evaluate safety, tolerability, PK, immunogenicity, pharmacodynamics, and preliminary antitumor activity. The study flow diagram for dose escalation and dose expansion for this portion of the study is described in Figures 7A and 7B. The following abbreviations and legends are used to describe the study flow diagram: DLT = dose-limiting toxicity; MSS-CRC = microsatellite-stable CRC.

[0177] Safety was assessed by the presence of adverse events (AEs), serious adverse events (SAEs), DLTs, and changes from baseline in laboratory parameters, vital signs, and electrocardiogram results. Endpoints for assessing antitumor activity included objective response (OR), disease control (DC), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RECIST v1.1 was used to evaluate tumor response. Pharmacokinetic parameters included, but were not limited to, maximum observed concentration, area under the concentration-time curve, clearance, and terminal half-life. Endpoints for assessing the immunogenicity of oleclumab and durvalumab included the number and percentage of subjects who developed detectable anti-drug antibodies, and endpoints for assessing pharmacodynamic activity included evaluation of target expression (e.g., CD73, PD-L1) in tumor biopsy specimens.

[0178] 1. Target For the dose escalation arm, the study population included subjects ≥ 18 years of age with histologically or cytologically confirmed colorectal adenocarcinoma (CRC) or pancreatic adenocarcinoma. Subjects with CRC or pancreatic adenocarcinoma had to have received and progressed on standard therapy, or had failed or been intolerant to standard therapy.

[0179] In the dose-escalation phase, subjects with CRC or pancreatic adenocarcinoma had not received more than five prior therapies. Subjects with CRC enrolled in the dose-expansion phase had received at least two regimens containing a fluoropyrimidine (e.g., 5-FU or capecitabine), oxaliplatin, and irinotecan (unless contraindicated), but had received no more than four prior systemic therapies in the metastatic setting and could not have defective DNA mismatch repair. Subjects with KRAS mutations (e.g., exon 2, codon 12, or 13) were allowed.

[0180] Subjects with pancreatic adenocarcinoma enrolled in the dose expansion phase had to have received no more than one prior systemic therapy in the metastatic setting. The first 20 subjects with CRC and pancreatic adenocarcinoma in the expansion phase must have positive CD73 expression by IHC in at least 10% of tumor cells with weak, moderate, or strong staining; or a combination of such staining.

[0181] All subjects were required to have at least one lesion measurable using RECIST guidelines, an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and adequate organ function. Adequate organ function was defined as follows: absolute neutrophil count ≥ 1,500 / mm 3 ;Platelet count ≧75,000 / mm 3prothrombin time-international normalized ratio and partial thromboplastin time ≦1.5×ULN; hemoglobin ≧9.0 g / dL; creatinine clearance or 24-hour urine CrCl>50 mL / min (calculated by the Cockcroft-Gault formula); total bilirubin ≦1.5×ULN (except in subjects with documented or suspected Gilbert's disease) (for these subjects, bilirubin must be ≦3×ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≦2.5×upper limit of normal (ULN) (AST / ALT may be up to 5×ULN in the presence of liver metastases but may not be associated with concomitant hyperbilirubin); potassium, sodium, magnesium, and calcium (corrected for serum albumin) ≦grade 1 or within the normal institutional range; and albumin ≧3.0 g / dL.

[0182] Subjects were excluded from participation in the study if they received a TNFRSF agonist prior to treatment, received a regimen containing a CTLA-4, PD-L1, or PD-1 antagonist for subjects with CRC or pancreatic adenocarcinoma prior to treatment, required the use of additional immunosuppression other than corticosteroids for management of an AE, experienced a recurrence of an AE when rechallenged and currently required a maintenance dose of >10 mg prednisone per day or equivalent, received any conventional or investigational anticancer therapy within 28 days prior to the first dose of oleclumab within 14 days of the first dose of oleclumab, or received any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for the treatment of cancer.

[0183] 2. Dose escalation phase The dose escalation phase of the study consisted of two arms: (i) escalating dose levels of olecullab monotherapy, and (ii) escalating dose levels of olecullab in combination with a single dose level of durvalumab (both administered in subjects with advanced CRC or pancreatic adenocarcinoma).

[0184] In the olecullab monotherapy dose-escalation arm, consecutive cohorts of 3 to 6 subjects each received one of four dose levels of olecullab (5, 10, 20, or 40 mg / kg) via IV infusion Q2W unless the maximum tolerated dose (MTD) was reached before completion of all dose-escalation cohorts (Figure 8). In the olecullab / durvalumab combination therapy dose-escalation arm, consecutive cohorts of 3 to 6 subjects each received one of four dose levels of olecullab (5, 10, 20, or 40 mg / kg) and a single dose level of 10 mg / kg durvalumab via IV infusion Q2W unless the MTD was reached before completion of all dose-escalation cohorts (Figure 8). If the MTD of olecullab was exceeded at the 5 mg / kg dose level in the monotherapy or combination therapy arms, a lower dose level of 2 mg / kg olecullab was explored within that arm.

[0185] The oleclumab dose selection was based on nonclinical data and clinical safety margins based on the nonclinical safety data previously described for mice and monkeys. A pharmacologically driven starting dose level of 5 mg / kg oleclumab was predicted to achieve 98%-91% CD73 saturation (peak and trough, respectively) during the first dosing interval. At the starting dose level of 5 mg / kg, cynomolgus monkey toxicity studies demonstrated a 19-fold (human equivalent dose [HED]-based), 73-fold (Cmax-based), and 70-fold (AUC-based) safety margin. The dose escalation scheme in this study was designed to achieve higher and more sustained inhibition of the CD73 target while maintaining an adequate safety margin. At the highest dose of 40 mg / kg, cynomolgus monkey toxicity studies provided a 2-fold (HED-based), 8-fold (Cmax-based), and 8-fold (AUC-based) safety margin.

[0186] The dose level and treatment schedule for durvalumab (10 mg / kg Q2W) was based on the safe dose established in a Phase 1 / 2 study to evaluate the safety, tolerability, and PK of durvalumab in subjects with advanced solid tumors.

[0187] The initial proposed olecullab and durvalumab combination dose level utilized a durvalumab dose level (10 mg / kg IV Q2W) that has been shown to have an acceptable safety profile along with an olecullab dose level (5 mg / kg IV Q2W), which was not expected to result in maximal inhibition of CD73 throughout the dosing interval. If the MTD was exceeded before the proposed maximum combination dose of 40 mg / kg olecullab and 10 mg / kg durvalumab, combination dosing was further explored utilizing 3 mg / kg durvalumab.

[0188] The dose escalation phase was carried out in a 3+3 design. A minimum of three subjects were enrolled in each dose level cohort. Administration of the first dose of investigational drug was staggered by a minimum of 24 hours between the first and second subjects treated in each dose level cohort. If no dose-limiting toxicity (DLT) was observed in the first three subjects during the DLT evaluation period and all available safety data were reviewed by a study-specific dose escalation committee, dose escalation continued to the next higher dose cohort. If one of the three subjects in a dose level cohort experienced a DLT, the dose level cohort was expanded to a total of six subjects. If one or less of the six subjects in a dose level cohort experienced a DLT, dose escalation continued to the next higher dose level cohort. Six subjects were enrolled in the highest dose level cohort that did not exceed the MTD.

[0189] In the olecullab / durvalumab combination arm, if the MTD was exceeded at any olecullab dose level, additional cohorts of olecullab with 3 mg / kg durvalumab Q2W were explored. The first cohort of 3 to 6 subjects received olecullab at the same dose level and treatment schedule that exceeded the MTD, this time via IV infusion Q2W with 3 mg / kg durvalumab. If this provided without exceeding the MTD, rather than the highest monotherapy olecullab protocol-defined dose, each additional successive cohort of 3 to 6 subjects was enrolled following a Q2W or Q4W treatment schedule in combination with 3 mg / kg durvalumab Q2W, according to the olecullab dose level described above. Upon completion of the combination dose escalation, if the MTD was exceeded with 10 mg / kg durvalumab Q2W, an alternative treatment schedule of olecullab at the highest dose level that did not exceed the MTD on a Q2W or Q4W treatment schedule was explored in combination with 20 mg / kg durvalumab Q4W.

[0190] 3.Results Among 42 efficacy-evaluable patients in the dose-expansion phase receiving oleclumab 40 mg / kg plus durvalumab 10 mg / kg, the overall objective response rate (ORR; confirmed and unconfirmed) was 7.1% (95% confidence interval [CI]: 1.5% vs. 19.5%). The ORRs (confirmed and unconfirmed) in the MSS-CRC cohort (n=21) and pancreatic adenocarcinoma cohort (n=20) were 4.8% (95% CI: 0.1%, 23.8%) and 10.0% (95% CI: 1.2%, 31.7%), respectively. The overall disease control rate (DCR; 8 weeks) in the dose-expansion phase was 16.7% (95% CI: 7.0%, 31.4%). The DCR in the MSS-CRC and pancreatic adenocarcinoma cohorts was 14.3% (95% CI: 3.0%, 36.3%) and 20.0% (95% CI: 5.7%, 43.7%), respectively.

[0191] The following PK data are based on a total of 97 subjects after treatment with olecullab 5–40 mg / kg Q2W administered as monotherapy (n=40) or in combination with durvalumab 10 mg / kg Q2W (n=57). Olecullab appeared to exhibit nonlinear PK at the lowest dose of olecullab 5 mg / kg and linear PK at doses of olecullab 10 mg / kg and above in both the monotherapy and combination therapy cohorts. Serum exposure was similar when olecullab was administered alone or in combination with durvalumab. PK exposure (trough plasma concentration [Ctrough]) increased more than proportionally from olecullab 5 to 10 mg / kg and approximately dose-proportionally from olecullab 10 to 40 mg / kg. Accumulation of olecullab was observed after repeated dosing. The mean accumulation ratio was C max ranges from 1.15 to 1.46, and C trough The range of values ​​for the serotonin receptor agonist (SRI) and serotonin receptor agonist (SRI) ranged from 1.68 to 10.7.

[0192] Complete suppression of soluble free CD73 was observed after administration of oleculab as monotherapy or in combination therapy. Serum soluble free CD73 levels were always below the limit of detection (0.25 ng / mL) in the majority of subjects after the first dose of oleculab (Figure 9).

[0193] Olecurab reduced CD73 surface expression in peripheral T cells at all doses, as measured by mean fluorescence intensity (MFI) (FIG. 10A) and percent CD73+ CD4 and CD8 cells (FIG. 10B), without a concomitant reduction in total CD4 and CD8 cells (FIG. 10C).

[0194] Treatment with olecullab during dose escalation led to a reduction in CD73-stained tumor cells by IHC at the 40 mg / kg dose 20 days after treatment initiation (Figures 11A and 11B). Treatment with olecullab alone reduced tumor CD73 expression in 5 / 9 patients who expressed >5% 2+ / 3+ CD73 at baseline, while increasing CD8+ TILs in all 5 samples (Figure 11C). Olecullab also inhibited CD73 enzymatic activity in the tumor microenvironment (Figure 12).

[0195] Linear pharmacokinetics was observed at doses of ≥10 mg / kg of oleculab. Based on these results, serum concentrations greater than 40 μg / mL were predicted to saturate >99% of CD73, and the estimated effective half-life during the treatment period was determined to be approximately 13 days (Figure 13). ADAs were not detected. Oleculab also demonstrated evidence of PD activity (Figure 14). Reduction of CD73 with 40 mg / kg oleculab was associated with an expansion of CD8+ T cells in patients with baseline >5% 2+ / 3+ CD73. Based on safety analysis, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy, the recommended Phase 2 dose of oleculab 40 mg / kg Q2W was selected.

[0196] Example 4: Olecurumab Combination with Durvalumab; Dose Expansion Phase 1. Target A dose-expansion study of olecullab in combination with durvalumab was conducted in adult subjects to evaluate safety, tolerability, PK, immunogenicity, pharmacodynamics, and preliminary antitumor activity in adult subjects with selected advanced solid tumors. A study flow diagram for the combo dose-expansion is shown in Figure 15. The following abbreviations and legends are used to describe the study flow diagram: MAD = maximum administered dose; MTD = maximum tolerated dose; EGFRm = epidermal growth factor receptor mutant; NSCLC = non-small cell lung cancer.

[0197] Subjects with NSCLC enrolled in the dose expansion phase must have an EGFR mutation known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletion, L858R, L861Q) and must have received at least one, but no more than four, prior treatments (including investigational treatments) in the metastatic setting, and must have received an approved EGFR TKI that subsequently progressed clinically or radiologically or was intolerant.

[0198] Subjects were excluded from participation in the study if they received a TNFRSF agonist prior to treatment, had previous exposure to any investigational immunotherapy or received an EGFR TKI, received previous treatment with a CTLA-4, PD-L1 containing regimen, required the use of additional immunosuppression other than corticosteroids for management of an AE, experienced a recurrence of an AE when rechallenged and currently required a maintenance dose of >10 mg prednisone per day or equivalent, received any conventional or investigational anticancer therapy within 28 days prior to the first dose of oleclumab within 14 days of the first dose of oleclumab, or received any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for the treatment of cancer.

[0199] Once the MTD or MAD was established in the combination arm of the dose-escalation phase, dose expansion of the oleclumab / durvalumab combination was initiated. The combination dose-expansion phase included three tumor-specific cohorts: a) up to 100 subjects with previously treated MSS-CRC, b) up to 100 subjects with previously treated pancreatic adenocarcinoma, and c) up to 40 subjects with previously treated EGFRm NSCLC.

[0200] The selection of dose levels and treatment schedules was based on consideration of PK, safety, and comparative pharmacodynamic effects as a function of dose level and treatment schedule, with the constraint that dose levels not exceed the applicable MTD or MAD.

[0201] An interim analysis was performed when the first 20 subjects per MSS-CRC dose expansion cohort, pancreatic adenocarcinoma dose expansion cohort, and EGFRm NSCLC dose expansion cohort had been enrolled and followed for at least 16 weeks. A second interim analysis was performed after 40 subjects per MSS-CRC cohort and pancreatic adenocarcinoma cohort had been enrolled and followed for at least 16 weeks.

[0202] All subjects were periodically evaluated for antitumor activity. Antitumor activity was assessed using objective response (OR), disease control (DC), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RECIST v1.1 guidelines were used to evaluate tumor response. All subjects will be followed for survival until the end of the study.

[0203] 3.Results Among 42 efficacy-evaluable subjects in the oleclumab 40 mg / kg plus durvalumab 10 mg / kg dose-expansion phase, the overall objective response rate (ORR; confirmed and unconfirmed) was 7.1% (95% confidence interval [CI]: 1.5%: 19.5%). The confirmed ORR in the MSS-CRC cohort (n=41) and pancreatic adenocarcinoma cohort (n=41) was 2.4% (95% CI: 0.1%, 23.8%) and 7.3% (unconfirmed) and 4.9% (confirmed) (95% CI: 1.2%, 31.7%), respectively. See Figures 16 and 17. The overall disease control rate (DCR; 8 weeks) in the dose-expansion phase was 16.7% (95% CI: 7.0%, 31.4%). The DCR in the MSS-CRC and pancreatic adenocarcinoma cohorts was 14.3% (95% CI: 3.0%, 36.3%) and 20.0% (95% CI: 5.7%, 43.7%), respectively.

[0204] The confirmed ORR in EGFRm NSCLC (n=20) was 20% for all patients compared with 9.8% when durvalumab was administered as monotherapy (ATLANTIC trial; see Clinictrials.gov No. NCT02087423) (Figure 18).

[0205] Example 5: Olecurab treatment with or without durvalumab in combination with chemotherapy in subjects with metastatic pancreatic ductal adenocarcinoma This study is a Phase 1b / 2, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, preliminary antitumor activity, immunogenicity, and PK of olecullab with or without durvalumab in combination with chemotherapy administered to subjects with metastatic pancreatic ductal adenocarcinoma (PDAC). Subjects with previously untreated metastatic PDAC (1L metastatic PDAC) were enrolled in Cohort A. Subjects with metastatic PDAC previously treated with gemcitabine-based chemotherapy (no exposure to 5-FU, capecitabine, or oxaliplatin; 2L metastatic PDAC) were enrolled in Cohort B. The study consists of two parts: dose escalation (Part 1) and dose expansion (Part 2).

[0206] A maximum of approximately 204 subjects were enrolled in the study: up to 24 subjects in Part 1 (dose escalation) and up to 180 subjects in Part 2 (dose expansion). All subjects in both cohorts were treated until disease progression (criteria for treatment in the setting of progressive disease [PD] were not met), intolerable toxicity, subject withdrawal of consent, or another discontinuation criterion was encountered.

[0207] Safety was assessed by the presence of adverse events (AEs), serious adverse events (SAEs), DLTs, and changes from baseline in laboratory parameters, vital signs, and electrocardiogram results. Endpoints for evaluation of antitumor activity included objective response (OR), disease control (DC), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). RECIST v1.1 was used to evaluate tumor response. Pharmacokinetic parameters included, but were not limited to, maximum observed concentration (C max ), C max Time to reach (t max ), AUC, clearance, apparent volume of distribution (V d ) and terminal half-life (t 1 / 2 We also evaluated the occurrence of anti-drug antibodies (ADA) and their potential effects on safety, pharmacodynamics, PK, and antitumor activity.

[0208] 1. Target Subjects in this study included adult subjects ≥18 years of age with histologically or cytologically confirmed pancreatic adenocarcinoma. Subjects with previously untreated metastatic PDAC (1L metastatic PDAC) were enrolled in Cohort A. Subjects with metastatic PDAC previously treated with gemcitabine-based chemotherapy (no exposure to 5-FU, capecitabine, or oxaliplatin [if considered curative]; 2L metastatic PDAC) were enrolled in Cohort B.

[0209] All subjects were required to have at least one measurable lesion using RECIST guidelines, an Eastern Cooperative Oncology Group (ECOG) score of 0 or 1, and adequate organ function. Adequate organ function was defined as follows: absolute neutrophil count ≥ 1,500 μ / L; platelet count ≥ 100,000 μ / L; hemoglobin ≥ 9.0 g / dL; creatinine clearance > 40 mL / min; total bilirubin ≤ 1.5 × ULN (except for subjects with documented or suspected Gilbert's disease) (for these subjects, bilirubin must be ≤ 3 × ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × upper limit of normal (ULN) (AST / ALT can be up to 5 × ULN in the presence of liver metastases); and albumin ≥ 3.0 g / dL.

[0210] Subjects were excluded from participation in the study if they had received any conventional or investigational anti-cancer therapy within 21 days or palliative radiation therapy within 14 days prior to the first planned dose of study treatment or any previous immune-mediated treatment.

[0211] 2. Dose escalation phase During Part 1, dose escalation of olecullab was performed in combination with durvalumab and chemotherapy (gemcitabine plus nab-paclitaxel for subjects with 1L metastatic PDAC [Cohort A]; a modified regimen of leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX) for subjects with 2L metastatic PDAC [Cohort B]) to determine the maximum tolerated dose (MTD) or highest protocol-defined dose per regimen (see Figure 19). Up to 24 subjects were enrolled in Part 1 (dose escalation): 9-12 subjects with 1L metastatic PDAC were enrolled in Cohort A, and 9-12 subjects with 2L metastatic PDAC were enrolled in Cohort B and treated with escalating dose levels of olecullab.

[0212] Dose escalation began with the enrollment of at least three subjects (and a maximum of six subjects) at dose level 1 (1500 mg IV Q2W × 4, then Q4W). Subjects were monitored for DLTs. If no DLTs were observed in a cohort of three to six evaluable subjects, dose escalation to the next higher dose cohort was permitted after review of all available safety data. If one subject of three or more evaluable subjects within a dose level cohort experienced a DLT, that dose level cohort was expanded to a total of six subjects. If one or fewer of six subjects within a dose level cohort experienced a DLT, dose escalation continued to the next higher dose level cohort. If ≥ two subjects within a dose level cohort experienced a DLT, the MTD was exceeded and no further subjects were enrolled in that dose level cohort. If this occurred, the previous dose level cohort was evaluated for the MTD, and if not already expanded, a total of six subjects were treated at the previous dose level. If ≦1 of 6 subjects experienced a DLT at the previous dose level, that dose level was the MTD. If the MTD was exceeded at the starting dose level, a lower dose level of oleclumab 750 mg (dose level 1) could be evaluated.

[0213] During the dose escalation phase, patients received the following treatments, as shown in Figure 20 and outlined below: Cohort A: Olecurab at one of three dose levels (750 mg, 1500 mg, or 3000 mg) IV Q2W, then every four weeks (Q4W) for four doses; and Durvalumab 1500 mg IV Q4W, and Gemcitabine 1000mg / m2 IV and nab-paclitaxel 125mg / m2 IV on days 1, 8, and 15, then repeat on a Q4W schedule.

[0214] Cohort B: Olecurab at one of three dose levels (750 mg, 1500 mg, or 3000 mg) IV Q2W, then Q4W for four doses; and Durvalumab 1500 mg IV Q4W, and mFOLFOX on days 1 and 15, then repeat on a Q4W schedule: oxaliplatin 85 mg / m 2 IV: leucovorin 400 mg / m 2 IV 5-FU 400 mg / m 2 IV bolus followed by 5-FU 2400 mg / m 2 administered by continuous IV infusion over 46 to 48 hours.

[0215] [Table 1]

[0216] 3. Dose expansion phase If a recommended phase 2 dose (RP2D) for a cohort was identified, enrollment in Part 2 dose expansion proceeded, as outlined in Figure 21. During Part 2 (dose expansion), the RP2D of olecullab identified for each regimen in Part 1 was evaluated in combination with chemotherapy, with or without durvalumab. A maximum of 180 subjects were enrolled in Part 2, with 30 subjects per treatment arm. Patients were stratified according to tumor expression of CD73 by immunohistochemistry (IHC) and randomized to treatment arms. Subjects in Cohort A (1L metastatic PDAC) were randomized 1:1:1 to one of three treatment arms: gemcitabine and nab-paclitaxel (arm A1); olecullab + gemcitabine and nab-paclitaxel (arm A2); or olecullab + durvalumab + gemcitabine and nab-paclitaxel (arm A3). Subjects in Cohort B (2L metastatic PDAC) were randomized 1:1:1 to one of three treatment arms: mFOLFOX (arm B1); olecullab + mFOLFOX (arm B2); or olecullab + durvalumab + mFOLFOX (arm B3). There was no crossover between treatment arms.

[0217] Dose levels for oleculab in Part 1 (dose escalation) were determined. As shown in Figures 22 and 23 and outlined below, subjects in Cohorts A and B were randomized to receive the following treatments: Cohort A Arm A1 Gemcitabine 1000 mg / m on days 1, 8, and 15 2 IV and nab-paclitaxel 125 mg / m 2 IV, then repeated on a Q4W schedule Arm A2 Olecurab IV Q2W for 4 doses, then Q4W, and Gemcitabine 1000 mg / m on days 1, 8, and 15 2 IV and nab-paclitaxel 125 mg / m 2 IV, then repeated on a Q4W schedule Arm A3 Olecurab IV Q2W for 4 doses, then Q4W, and durvalumab 1500 mg IV Q4W, and Gemcitabine 1000 mg / m on days 1, 8, and 15 2 IV and nab-paclitaxel 125 mg / m 2 IV, then repeated on a Q4W schedule.

[0218] Cohort B Arm B1 mFOLFOX on days 1 and 15, then repeat on a Q4W schedule: oxaliplatin 85 mg / m 2 IV: leucovorin 400 mg / m 2 IV 5-FU 400 mg / m 2 IV bolus followed by 5-FU 2400 mg / m 2 was administered by continuous IV infusion over 46 to 48 hours. Arm B2 Olecurab IV Q2W for 4 doses, then Q4W, and mFOLFOX on days 1 and 15, then repeat on a Q4W schedule: oxaliplatin 85 mg / m 2 IV: leucovorin 400 mg / m 2 IV 5-FU 400 mg / m 2 IV bolus followed by 5-FU 2400 mg / m 2 administered by continuous IV infusion over 46-48 hours Arm B3 Olecurab IV Q2W for 4 doses, then Q4W, and durvalumab 1500 mg IV Q4W, and mFOLFOX on days 1 and 15, then repeat on a Q4W schedule: oxaliplatin 85 mg / m 2 IV: leucovorin 400 mg / m 2 IV 5-FU 400 mg / m 2 IV bolus followed by 5-FU 2400 mg / m 2 administered by continuous IV infusion over 46 to 48 hours.

[0219] Example 6: Olecurab and durvalumab treatment with or without chemotherapy in subjects with first-line stage IV non-small cell lung cancer (NSCLC) A phase 1b, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of oleculab and durvalumab, with or without chemotherapy, in subjects with first-line stage IV non-small cell lung cancer (NSCLC). Subjects with high PD-L1 (i.e., PD-L1 TC≧50%) and low PD-L1 (i.e., PD-L1 TC≦50%) were treated.

[0220] 1. Target Subjects in this study include adult subjects aged ≥ 18 years with histologically or cytologically documented stage IV NSCLC whose tumors lack activating epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions and are not amenable to curative surgery or radiation. Subjects must have not received prior chemotherapy or any other systemic therapy for stage IV NSCLC. All subjects must have a World Health Organization (WHO) / Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 at the time of enrollment and treatment assignment. Subjects must have no prior exposure to immune-mediated therapies, including but not limited to therapeutic anti-cancer vaccines.

[0221] Subjects were excluded from participation in the study if they had received any previous chemotherapy or any other systemic therapy for stage IV NSCLC; if they were receiving any concurrent chemotherapy, biological therapy, or hormonal therapy for the treatment of their cancer; or if they had received or were receiving any immunosuppressive medication within 28 days prior to the first dose of this study, other than (i) intranasal, inhaled, or topical steroids or local steroid injections; (ii) systemic corticosteroids at physiological doses not exceeding 10 mg / day of prednisone or its equivalent; and (iii) steroids as premedication for hypersensitivity reactions. Subjects were also excluded if they had received radiation therapy unless it was (i) definitive radiation administered at least 12 months before the date of progression to stage IV disease, (ii) palliative radiation to the brain with relevant criteria for stable or absent disease symptoms at least 4 weeks before the first study treatment dose, or (iii) palliative radiation to painful bone lesions (which must occupy less than 30% of the bone marrow) at least 2 weeks before the first study treatment dose.

[0222] 2. Treatment At least 30 patients were enrolled in each treatment arm as shown in Table 2 and illustrated in Figures 24A-24D. Patients with high PD-L1 (i.e., PD-L1 expression on ≥50% of tumor cells) were enrolled in Cohort A, and patients with low PD-L1 (i.e., PD-L1 expression on <50% of tumor cells) were enrolled in Cohort B.

[0223] [Table 2]

[0224] Chemotherapy will be selected from the following: (a) nab-paclitaxel + carboplatin (squamous and non-squamous patients); (b) gemcitabine + cisplatin (squamous patients only); (c) gemcitabine + carboplatin (squamous patients only); (d) pemetrexed + carboplatin (non-squamous patients only), and (e) pemetrexed + cisplatin (non-squamous patients only). Non-squamous patients who received carboplatin / cisplatin + pemetrexed and progressed after four cycles of carboplatin / cisplatin + pemetrexed will receive pemetrexed maintenance therapy unless contraindicated. For Arm B1, pemetrexed maintenance therapy may be administered every three weeks (q3w) or every four weeks (q4w). For Arm B3, pemetrexed maintenance therapy may be administered q4w.

[0225] Olecurumab, durvalumab, and chemotherapy were administered according to the schedule in Table 3.

[0226] [Table 3]

[0227] If the initial dose level in arms A3 and / or B3 was tolerated, a new treatment arm was initiated with a higher dose of olecurab, as shown in Table 4.

[0228] [Table 4]

[0229] Treatment continues until clinical or radiological progression occurs. In the chemotherapy-containing arm, chemotherapy is administered for 4 cycles or until progressive disease (PD) is observed, whichever occurs sooner (i.e., 4 cycles unless PD occurs before completion of planned therapy).

[0230] 3.Results Adverse events, physical examinations, laboratory findings, and vital signs will be assessed from all arms to demonstrate the safety of olecurumab and durvalumab with or without chemotherapy.

[0231] Eight patients received durvalumab and olecurumab in Cohort A3, and six patients received them in the Cohort B3 safety run-in for the durvalumab + chemotherapy + olecurumab arm. Safety was assessed and the dose was well tolerated. The Study Level Safety Review Board agreed to escalate Cohort B3 from the 1500 mg olecurumab dose to the 3000 mg dose because no DLTs were reported.

[0232] Overall response rate (ORR), progression-free survival, and date of objective response were evaluated in all arms and demonstrated that the combination of olecurumab and durvalumab is effective for the treatment of first-line stage IV non-small cell lung cancer (NSCLC) in patients with high PD-L1, and that the combination of olecurumab, durvalumab, and chemotherapy is effective for the treatment of first-line stage IV NSCLC in patients with low PD-L1.

[0233] Example 7: Olecurumab and durvalumab treatment in subjects with locally advanced unresectable stage III non-small cell lung cancer A phase 2, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of oleculab and durvalumab in subjects with locally advanced, unresectable stage III non-small cell lung cancer (NSCLC).

[0234] 1. Target Subjects in this study included adult subjects at least 18 years of age (weight at least 35 kg) with locally advanced, unresectable stage III NSCLC who had not progressed after definitive concurrent chemoradiotherapy (cCRT). Definitive radiotherapy refers to a total dose of 1.8 Gy per fraction or ≥ 60 Gy in bioequivalent doses. Concurrent chemotherapy refers to a platinum-based doublet. The final chemotherapy dose must be completed before or concurrent with the final radiation dose.

[0235] All subjects were required to have at least one previously irradiated tumor lesion measurable by RECIST v. 1.1, a life expectancy of at least 12 weeks, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0236] Subjects were excluded from participation in the study if they had mixed small cell and non-small cell lung cancer histology. Subjects were also excluded from the study for use of immunosuppressive medications within 14 days prior to the first dose of study drug, other than (i) intranasal, inhaled, or topical steroids or local steroid injections; (ii) systemic corticosteroids at physiological doses not exceeding 10 mg / day of prednisone or its equivalent; and (iii) steroids as premedication for hypersensitivity reactions. Subjects were also excluded for any previous exposure to anti-PD-1, anti-PD-L1, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibodies for the treatment of NSCLC.

[0237] 2. Treatment Patients began study treatment within 42 days of the cCRT bacteriological session. Up to 60 subjects per treatment arm were randomized equally to the durvalumab control and experimental arms. Patients in the control arm received 1500 mg of durvalumab intravenously every 4 weeks (Q4W) for 12 months. See Figure 25A. Patients in the experimental arm received (i) 1500 mg of durvalumab intravenously every 4 weeks (Q4W) for 12 months, plus (ii) 3000 mg of oleculab intravenously every 2 weeks (Q2W) for 2 months, followed by Q4W for 10 months (starting on cycle 3, day 1). See Figure 25B.

[0238] Subjects were treated for a maximum of 12 months unless there was disease progression, unacceptable toxicity, or another reason for termination of treatment (eg, subject resolution or noncompliance).

[0239] 3.Results The combination of olecullab and durvalumab will be demonstrated to be safe by evaluating adverse events, laboratory findings, electrocardiogram results, and vital signs.The combination of olecullab and durvalumab will be demonstrated to be more effective than durvalumab alone in the treatment of stage III NSCLC by evaluating objective response (OR) by RECIST v.1.1, duration of response (DoR), disease control (DC), progression-free survival (PFS) at 12 months, PFS by RECIST v.1.1, and overall survival (OS).

[0240] Example 8: Olecurab and durvalumab treatment in subjects with resectable early-stage non-small cell lung cancer A phase 2, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of oleculab and durvalumab in subjects with resectable early-stage non-small cell lung cancer (NSCLC).

[0241] 1. Target Subjects in this study were: (a) NSCLC (8 of the American Joint Committee on Cancer staging system) with stage I (>2 cm) to IIIA (for subjects with N2 disease, only subjects with one single nodal station ≤3 cm were eligible); th (b) Adult subjects at least 18 years of age (weighing at least 35 kg) with cytologically and / or histologically documented NSCLC considered amenable to complete surgical resection were included. Subjects had not received any other therapy (chemotherapy, biological therapy, or radiation therapy) for this condition. All subjects had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0242] Subjects were excluded from the study if they had mixed small cell and non-small cell lung cancer histology. Subjects were also excluded from the study as a result of participation in another interventional clinical study within 90 days prior to enrollment. Subjects were also excluded from the study for use of immunosuppressive medication within 14 days prior to the first dose of study drug, other than (i) intranasal, inhaled, or topical steroids or topical steroid injections; (ii) systemic corticosteroids at physiological doses not exceeding 12 mg / day of prednisone or its equivalent; and (iii) steroids as premedication for hypersensitivity reactions.

[0243] A maximum of 40 subjects were enrolled per treatment arm.

[0244] 2. Treatment Treatment over the duration of the study is shown in Figure 26A. Subjects were treated with durvalumab monotherapy or the combination of durvalumab and oleculab for up to 28 days. Treatment was discontinued in the event of disease progression, unacceptable toxicity, or another reason (e.g., subject resolution or noncompliance). Subjects receiving durvalumab monotherapy received 1500 mg of durvalumab intravenously Q4W (Week 1, Day 1) (Figure 26B). Subjects receiving combination therapy received 1500 mg of durvalumab intravenously Q4W (Week 1, Day 1) plus 3000 mg of oleculab intravenously Q2W (Week 1, Day 1 and Week 3, Day 1) (Figure 26C).

[0245] The 28-day treatment period was followed by surgical resection. Surgical resection occurred within 14 days of the treatment period. After surgical resection, subjects were followed until day 105. If a subject received adjuvant chemotherapy or radiation therapy before day 105, the subject was removed from the study and the end of study visit was scheduled before the start of adjuvant therapy.

[0246] 3.Results Pathological changes (e.g., major pathological response (MPR)) will be evaluated to demonstrate that the combination of olecullab and durvalumab leads to pathological responses in resected tumor specimens from patients with early-stage NSCLC cancer. Additionally, MPR, pathological complete response (pCR), and best complete response (BOR) and ORR by RECIST v 1.1 will be evaluated to demonstrate that the combination of olecullab and durvalumab has anti-tumor activity in resectable early-stage NSCLC. Adverse events, laboratory findings, and vital signs will be evaluated to demonstrate that the combination of olecullab and durvalumab is safe.

[0247] Example 9: Olecurab and durvalumab in combination with chemotherapy and bevacizumab treatment in subjects with metastatic microsatellite-stable colorectal cancer A phase 1b / 2, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of oleclumab and durvalumab in combination with chemotherapy and bevacizumab as first-line (1L) therapy in subjects with metastatic microsatellite-stable colorectal cancer (MSS-CRC). The study included two parts: Part 1 was a phase 1b safety study, and Part 2 was a phase 2 efficacy and safety study.

[0248] 1. Target Subjects in this study included adult subjects at least 18 years of age (weight at least 35 kg) with metastatic MSS-CRC who had not received previous systemic treatment in the recurrent / metastatic setting (subjects treated with previous adjuvant chemotherapy or radiochemotherapy were accepted as long as progression was within 6 months of completing the adjuvant regimen). All subjects had histological documentation of advanced or metastatic CRC and confirmed tumor location from mutation testing and disease assessment documented during screening. Subjects must not have defective DNA mismatch repair (MSI) as documented by testing. Subjects had at least one lesion measurable by RECIST v1.1 (previously irradiated lesions could be considered target lesions if the lesion was clearly defined, measurable by RECIST, and had clearly progressed during or after the most recent therapy). All subjects had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0249] Subjects were excluded from the study as a result of any concurrent chemotherapy, investigational drug, biological therapy, or hormone therapy for cancer treatment (concurrent use of hormone therapy for non-cancer-related conditions (e.g., hormone replacement therapy) was acceptable). Subjects were also excluded from the study for radiotherapy treatment to more than 30% of the bone marrow or with a large radiation field within 4 weeks prior to the first scheduled dose of study treatment. Subjects were also excluded for having previously received any immune-mediated therapy or anti-angiogenesis. Subjects were also excluded from the study for use of immunosuppressive medication within 14 days prior to the first dose of study drug, other than (i) intranasal, inhaled, or topical steroids or topical steroid injections, and (ii) steroids as premedication for hypersensitivity reactions.

[0250] A minimum of 6 subjects were enrolled in Part 1, and a maximum of 50 subjects per treatment arm were enrolled in Part 2.

[0251] 2. Treatment After a screening period of up to 28 days, subjects were assigned to a study arm (Part 1) or randomized (Part 2). In both study parts, treatment was administered until disease progression or any discontinuation criteria were met (e.g., consent withdrawal, unacceptable toxicity, non-compliance, confirmed progression, etc.).

[0252] Part 1 did not include dose escalation. The first group of 3 subjects was enrolled in the Part 1 arm and evaluated for safety. Decision-making in Part 1 was based on rules adapted from the modified Toxicity Probability Interval-2 (mTPI-2) algorithm (Guo et al., Contemp Clin Trials 58:23-33 (2017)) using a simple beta-binomial Bayesian model. If the decision rule was "stay" for the first 3 subjects, an additional group of 2 to 4 subjects was enrolled at the same dose level; if the decision rule was "de-escalate," an additional group of 3 subjects was enrolled at a lower dose of oleclumab while maintaining the standard dose of FOLFOX, bevacizumab, and durvalumab. If the decision rule was "complete," the current dose was selected for Part 2 of the study.

[0253] In part 2, randomization was initially distributed evenly across all arms (1:1:1) and stratified based on primary tumor location (right vs. left). After randomization of 50 subjects to the control arm, subjects continued to be enrolled in the control arm, but the allocation ratio to the different arms could be adjusted.

[0254] Treatment groups are shown in Table 5 and treatment schedules are shown in FIG.

[0255] [Table 5]

[0256] Folinic acid (leucovorin) + 5-fluorouracil + oxaliplatin (FOLFOX) + bevacizumab was administered as outlined in the protocol according to the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines. Specifically, 400 mg / m 2 of folinic acid administered intravenously every 2 weeks (Q2W) (day 1 of every 14-day cycle); 85 mg / m 2 of oxaliplatin was administered by intravenous infusion Q2W (day 1 of every 14-day cycle); and 2400 mg / m 2 5-fluorouracil was administered by continuous intravenous infusion over 46–48 hours Q2W (days 1–2 of every 14-day cycle). 5-fluorouracil was administered only as an infusion without a bolus. Also, 5 mg / kg bevacizumab was administered by intravenous infusion Q2W (day 1 of every 14-day cycle).

[0257] In arms S1 and E1, 1500 mg of durvalumab was administered intravenously every 4 weeks (Q4W) and 3000 mg of oleculab was administered intravenously every 2 weeks (Q2W) for four doses, then Q4W (starting on cycle 5, day 1).

[0258] 3.Results Objective response by RECIST v.1.1 is assessed to demonstrate that the combination of oleclumab and durvalumab with FOLFOX plus bevacizumab has superior antitumor activity compared with FOLFOX plus bevacizumab in subjects with 1L MSS-CRC. Also, best complete response (BOR), duration of response (DoR), disease control (DC), 12-month progression-free survival (PFS-12), and progression-free survival (PFS) and overall survival (OS) assessed by RECIST v 1.1 are assessed to demonstrate that the combination of oleclumab and durvalumab with FOLFOX plus bevacizumab has superior antitumor activity compared with FOLFOX plus bevacizumab in subjects with 1L MSS-CRC. Adverse events, dose-limiting toxicities (DLTs), laboratory findings, and vital signs are assessed to demonstrate that the combination of oleclumab and durvalumab with FOLFOX plus bevacizumab is safe.

[0259] Example 10: Olecurumab and durvalumab in combination with adjuvant chemotherapy treatment in subjects with high-risk metastatic microsatellite-stable colorectal cancer A phase 2, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of oleculab and durvalumab in combination with adjuvant chemotherapy in subjects with high-risk metastatic microsatellite-stable colorectal cancer (MSS-CRC).

[0260] 1. Target Subjects in this study included adult subjects at least 18 years old (weight at least 35 kg) who had undergone definitive surgical resection for stage II or III MSS-CRC, were eligible for 6 months of mFOLFOX6 adjuvant therapy within 8 weeks after surgery, and had confirmed positive postoperative circulating tumor DNA (ctDNA). All subjects were required to have stage II high-risk disease: any T4 or T3 lesion with one of the following characteristics: high grade (3), clinical presentation with bowel obstruction and perforation, histological evidence of vascular invasion, lymphatic invasion, and paraneural invasion (≤12 lymph nodes examined). Subjects must not have received previous systemic chemotherapy, immunotherapy, or radiation therapy for the treatment of colorectal cancer (CRC) and must not have defective DNA mismatch repair (MSI). Subjects had surgical resections with negative surgical margins (R0; defined as >1 mm clearance). All subjects had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0261] Subjects were excluded from the study if there was evidence of metastatic disease (including the presence of tumor cells in ascites or peritoneal carcinomatosis resected "en bloc"). Subjects were also excluded for concurrent chemotherapy, investigational drugs, biological therapy, or hormonal therapy for cancer treatment. Subjects were also excluded from the study for use of immunosuppressive medications within 14 days prior to the first dose of study drug, other than (i) intranasal, inhaled, or topical steroids or topical steroid injections, and (ii) steroids as premedication for hypersensitivity reactions.

[0262] 2. Treatment Subjects were randomized to one of the study arms. Approximately 40 subjects were enrolled per treatment arm. Randomization was strategized by American Joint Committee on Cancer stage of the primary tumor (stage II vs. stage III). Study arms and treatments are summarized in Table 6, and dosing regimens are shown in Figure 28.

[0263] [Table 6]

[0264] In all arms, mFOLFOX6 was administered every 2 weeks (Q2W) as outlined in the protocol according to the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines. Specifically, oxaliplatin was administered at 85 mg / m 2 At a dose of 2.0m 2 Folinic acid (leucovorin) was administered by intravenous (IV) infusion (day 1 of every 14-day cycle) limited to a maximum body surface area (BSA) of 400 mg / m 2 Fluorouracil (5-FU) was administered by IV infusion (day 1 of every 14-day cycle) at a dose of 400 mg / m by IV bolus on day 1. 2 , followed by 1,200 mg / m for 2 days 2 / day (total of 2,400 mg / m over 46–48 hours) 2 Durvalumab was administered at a dose of 1500 mg IV every 4 weeks (Q4W) and oleculab was administered at a dose of 3000 mg IV Q2W for four doses, then Q4W (starting in cycle 5).

[0265] Subjects were treated for a maximum of 6 months or until relapse, unacceptable toxicity, withdrawal of consent, etc. Subjects could be followed for a maximum of 5 years from randomization.

[0266] 3.Results We demonstrate that the combination of oleclumab and durvalumab with mFOLFOX6 has superior antitumor activity compared with mFOLFOX6 in subjects with high-risk stage II or stage III MSS-CRC by evaluating circulating tumor DNA (ctDNA) clearance at 6 months. ctDNA clearance was defined as a change in ctDNA status from baseline ctDNA positive to ctDNA negative post-randomization, and comparisons between groups were performed at a significance level of 0.2 (two-sided) using the Cochran-Mantel-Haenszel test stratified by disease stage. Furthermore, we compare disease-free survival (DFS), 12-month DFS (DFS-12), and overall survival (OS), demonstrating that the combination of oleclumab and durvalumab with mFOLFOX6 has superior antitumor activity compared with FOLFOX in subjects with high-risk stage II or stage III MSS-CRC.

[0267] Adverse events, laboratory findings, and vital signs will be evaluated to demonstrate that the combination of oleculab and durvalumab with mFOLFOX6 is safe.

[0268] Example 11: Anti-CD73 and anti-PD-L1 in combination with chemotherapy in colorectal and fibrosarcoma models Assays were performed in mouse colorectal and fibrosarcoma models to demonstrate the efficacy of anti-CD73 and anti-PD-L1 antibodies in combination with chemotherapy.

[0269] 1. Materials and Methods animal In vivo studies were performed using 8-week-old BALB / cAnNCtr mice (Charles River UK) or C57BL / 6. Animals were housed in AstraZeneca vivariums with free access to food and water and cared for daily by trained personnel. Mice were handled in accordance with the Home Office Animals Scientific Procedures Act, 1986, UK.

[0270] In vivo efficacy assay Animals were implanted subcutaneously with mouse syngeneic tumor lines, 0.5e6 CT26 (colorectal mice) or 0.5e6 MCA205 (50% Matrigel) (fibrosarcoma mice), depending on the mouse strain. Tumor progression was monitored by caliper measurements three times per week. Animals were treated (as monotherapy or in various combinations) with anti-CD73 mouse IgG1 (in-house, AstraZeneca), 10 mg / kg, twice weekly for four doses starting on day 3; anti-PD-L1 mouse IgG1 D265A (in-house, AstraZeneca), 10 mg / kg, twice weekly for a maximum total of six doses starting on day 10 (when combined with OHP and 5FU) or day 4 (when combined with docetaxel) (see figure legends for specific experimental information); 5-fluorouracil (Fresenius Kabi) and oxaliplatin (Accord), single doses of 50 mg / kg and 6 mg / kg on day 9 (and in some experiments, day 10); and docetaxel (Sanofi), 10 mg / kg, once weekly for two doses starting on day 4. The two antibodies, plus 5FU and OHP, were administered intraperitoneally, while docetaxel was administered intravenously. When tumor size reached 15 mm in diameter, the animals were humanely sacrificed.

[0271] In vivo pharmacodynamic assays Animals were subcutaneously implanted with 0.5e6 CT26 mouse colorectal carcinoma cells. Tumor progression was monitored by caliper measurement three times per week. Starting on day 3, animals were treated with anti-CD73 mouse IgG1 (in-house, AstraZeneca) at 10 mg / kg twice weekly for four doses; starting on day 10, anti-PD-L1 mouse IgG1 D265A (in-house, AstraZeneca) at 10 mg / kg twice weekly for two doses; and on day 10, 5-fluorouracil (Fresenius Kabi) and oxaliplatin (Accord) at a single dose of 50 mg / kg and 6 mg / kg, respectively (as monotherapy or in various combinations). All drugs were administered intraperitoneally. Animals were humanely sacrificed 15 days after implantation, and tumors were used for downstream analysis.

[0272] Tissue Processing and Flow Cytometry Tumors were digested using an enzyme cocktail of 1 mg / ml collagenase IV, 20 units / mL DNase I, and 20 units / mL hyaluronidase I (all from Sigma). Single cell suspensions were then stained with a live / dead dye (see Table 7 below) and treated with Fc block (anti-mouse CD16 / CD32 eBioScience cat#14-0161-86). Cells were then stained for surface markers (see table and below for reagent list), fixed, and permeabilized using the eBioScience Foxp3 / Transcription Factor Staining Kit (00-5523-00). Cells were then stained for intracellular markers (see Table 7 below). Samples were acquired on a BD Symphony flow cytometer and analyzed using FlowJo software version 10. Data were plotted using GraphPad Prizm software.

[0273] [Table 7]

[0274] 2.Results Anti-CD73 + anti-PD-L1 + 5FU + OHP in the CT26 (colorectal) model To analyze the efficacy of anti-CD73 and anti-PD-L1 antibodies in combination with 5FU and OHP in the CT26 model, animals were implanted subcutaneously (sc) with 0.5e6 CT26 and treated intraperitoneally (ip) with anti-mouse antibodies twice weekly (anti-CD73 starting on day 3 post-implantation for four doses and anti-PD-L1 on day 10 for six doses). 5-fluorouracil (5FU) and oxaliplatin (OHP) were administered ip on day 9. Animals were humanely sacrificed when tumor diameter approached 15 mm. Animals sacrificed early due to well-being issues such as tumor symptoms were excluded from the analysis. For survival calculations, animals sacrificed due to tumor symptoms before tumor diameter reached 15 mm were considered to have tumor volumes of 500 mm. 3 If the mean value was greater than 1, the analysis was continued. The results are shown in Figures 29A-29I.

[0275] In further analysis of activity in the CT26 model, animals were implanted sc with 0.5e6 CT26 and treated ip twice weekly with anti-mouse antibodies (anti-CD73 starting on day 3 post-implant, 4 doses and anti-PD-L1 on day 10, 2 doses). 5FU and OHP were administered ip on day 9. Figure 30 shows data from whole tumor digests (samples collected on day 15 post-implant) analyzed by flow cytometry without ex vivo restimulation (intracellular staining).

[0276] Anti-CD73 + anti-PD-L1 + docetaxel in the CT26 (colorectal) model To analyze the efficacy of anti-CD73 and anti-PD-L1 antibodies in combination with docetaxel in the CT26 model, animals were implanted sc with 0.5e6 CT26 and treated i.p. twice weekly with anti-mouse antibodies (anti-CD73 starting on day 3 post-implant, 4 doses, and anti-PD-L1 on day 4, 4 doses). Docetaxel was administered i.v. once weekly (starting on day 4, 2 doses). Animals were humanely sacrificed when tumor diameter approached 15 mm. Animals sacrificed early due to well-being issues such as tumor symptoms were excluded from analysis. For survival calculations, animals sacrificed due to tumor symptoms before tumor diameter reached 15 mm were considered to be 500 mm in tumor volume. 3 If the mean value exceeded 100%, the analysis was continued. The results are shown in Figures 31A to 31I.

[0277] Anti-CD73 + anti-PD-L1 + 5FU + OHP in the MCA205 (fibrosarcoma) model To analyze efficacy in the MCA205 model, animals were implanted sc with 0.5e6 MCA205 (50% Matrigel) and treated with anti-mouse antibodies ip twice weekly (anti-CD73 starting on day 3 post-implant, 4 doses and anti-PD-L1 on day 10, 5 doses). 5FU and OHP were administered ip on day 9. The results are shown in Figures 32A-H.

[0278] 3. Conclusion In mice implanted with CT26 tumors, the combination of anti-PD-L1 + anti-CD73 + 5FU + OHP resulted in a complete response in 6 of 12 mice (50%) compared with a maximum of 2 of 12 mice (approximately 17%) in the anti-PD-L1 + 5FU + OHP combination group, and the combination of anti-PD-L1 + anti-CD73 + docetaxel resulted in a complete response in 7 of 12 mice (58%) compared with a maximum of 3 of 12 mice (25%) in the anti-PD-L1 + docetaxel combination group.

[0279] The percentages of IFNγ+CD8+, CD4+, and NKp46+ lymphocytes were increased within the tumor microenvironment (TME) in samples from animals treated with the combination of anti-CD73, anti-PD-L1, 5FU, and OHP.

[0280] In mice implanted with MCA205 tumors, the combination of anti-PD-L1 + anti-CD73 + 5FU + OHP resulted in a complete response in 8 of 13 mice (61%) compared with 4 of 13 mice (30%) in the anti-PD-L1 + 5FU + OHP combination group.

[0281] These data indicate that anti-CD73 antibodies increase the efficacy of anti-PD-L1 plus chemotherapy (e.g., including 5FU+OHP and docetaxel) treatment in multiple cancer types.

[0282] While the present invention has been described with reference to various embodiments, it is understood that variations and modifications will occur to those skilled in the art. It is therefore intended by the appended claims to cover all such equivalent variations that are within the scope of the invention as claimed. Additionally, the section headings used herein are for organizational purposes only and should not be construed as limiting the subject matter described.

[0283] Each embodiment described herein may be combined with any other embodiment unless clearly stated to the contrary. In particular, any feature or embodiment indicated as being preferred or advantageous may be combined with any other feature or embodiment indicated as being preferred or advantageous unless clearly stated to the contrary.

[0284] All references cited in this application are expressly incorporated herein by reference.

[0285] [Table 8]

[0286] [Table 9]

Claims

1. 1. A method of treating a tumor in a human patient, comprising administering oleclumab or an antigen-binding fragment thereof to said patient.

2. 1. A method of treating a tumor in a human patient, comprising administering to the patient oleclumab or an antigen-binding fragment thereof and durvalumab or an antigen-binding fragment thereof.

3. 1. A method of treating a tumor in a human patient, comprising administering to said patient oleclumab or an antigen-binding fragment thereof and chemotherapy.

4. 4. The method of claim 3, further comprising administering durvalumab or an antigen-binding fragment thereof.

5. 5. The method of any one of claims 1 to 4, wherein the oleclumab or antigen-binding fragment thereof is administered in a dose of 750 mg to 3000 mg.

6. 6. The method of claim 5, wherein the oleclumab or antigen-binding fragment thereof is administered in a dose of 750 mg.

7. 6. The method of claim 5, wherein the oleclumab or antigen-binding fragment thereof is administered in a dose of 1500 mg.

8. 6. The method of claim 5, wherein the oleclumab or antigen-binding fragment thereof is administered in a dose of 2250 mg.

9. 6. The method of claim 5, wherein the oleclumab or antigen-binding fragment thereof is administered in a dose of 3000 mg.

10. 6. The method of claim 5, wherein the oleclumab or antigen-binding fragment thereof is administered in a dose of 2250 mg and thereafter in a dose of 3000 mg.

11. 11. The method of claim 10, wherein the oleclumab or antigen-binding fragment thereof is administered at a dose of 2250 mg for four doses and then at a dose of 3000 mg.

12. 12. The method of any one of claims 1 to 11, wherein oleclumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

13. 12. The method of any one of claims 1 to 11, wherein the oleclumab or antigen-binding fragment thereof is administered every 14 days.

14. 12. The method of any one of claims 1 to 11, wherein oleclumab or an antigen-binding fragment thereof is administered every 28 days.

15. 12. The method of any one of claims 1-11, wherein the oleclumab or antigen-binding fragment thereof is administered every 14 days for at least two doses, and then every 28 days.

16. 12. The method of any one of claims 1-11, wherein the oleclumab or antigen-binding fragment thereof is administered every 14 days for four doses and then every 28 days.

17. 12. The method of any one of claims 1 to 11, wherein the oleclumab or antigen-binding fragment thereof is administered every 21 days.

18. 12. The method of any one of claims 1-11, wherein the oleclumab or antigen-binding fragment thereof is administered every 21 days for at least two doses, and then every 28 days.

19. 12. The method of any one of claims 1-11, wherein the oleclumab or antigen-binding fragment thereof is administered every 21 days for 2-4 doses and then every 28 days.

20. 14. The method of claim 13, wherein the oleclumab or antigen-binding fragment thereof is administered every 21 days for two doses and then once every 28 days.

21. 14. The method of claim 13, wherein the oleclumab or antigen-binding fragment thereof is administered once every 21 days and then once every 28 days for four doses.

22. 6. The method of any one of claims 1-5, wherein the oleclumab or antigen-binding fragment thereof is administered once every 21 days at a dose of 2250 mg and then once every 28 days at a dose of 3000 mg for two doses.

23. 6. The method of any one of claims 1-5, wherein the oleclumab or antigen-binding fragment thereof is administered at a dose of 2250 mg once every 21 days for four doses, and then at a dose of 3000 mg once every 28 days.

24. 24. The method of any one of claims 1 to 23, wherein the oleclumab or antigen-binding fragment thereof is administered intravenously.

25. 25. The method of any one of claims 2 or 4-24, wherein the durvalumab or antigen-binding fragment thereof is administered at a dose of 1500 mg.

26. 26. The method of any one of claims 2 or 4-25, wherein the durvalumab or antigen-binding fragment thereof is administered every 21 days to every 28 days.

27. 27. The method of any one of claims 2 or 4-26, wherein the durvalumab or antigen-binding fragment thereof is administered every 28 days.

28. 27. The method of any one of claims 2 or 4 to 26, wherein the durvalumab or antigen-binding fragment thereof is administered every 21 days.

29. 27. The method of any one of claims 2 or 4-26, wherein the durvalumab or antigen-binding fragment thereof is administered every 21 days for at least two doses and then every 28 days.

30. 27. The method of any one of claims 2 or 4-26, wherein the durvalumab or antigen-binding fragment thereof is administered every 21 days for four doses and then every 28 days.

31. 27. The method of any one of claims 2 or 4-26, wherein the durvalumab or antigen-binding fragment thereof is administered at a dose of 1500 mg every 21 days for four doses, and then at a dose of 1500 mg every 28 days.

32. 32. The method of any one of claims 1 to 31, wherein the durvalumab or antigen-binding fragment thereof is administered intravenously.

33. 33. The method of any one of claims 3 to 32, wherein the chemotherapy comprises at least one of cisplatin, pemetrexed, nab-paclitaxel, carboplatin, gemcitabine, cisplatin, oxaliplatin, leucovorin, 5-fluorouracil, and docetaxel.

34. 34. The method of claim 33, wherein the chemotherapy comprises oxaliplatin, leucovorin, and 5-fluorouracil.

35. The oxaliplatin is 85 mg / m ２ 35. The method of claim 33 or 34, wherein the dose is

36. 36. The method of any one of claims 33 to 35, wherein the oxaliplatin is administered every two weeks.

37. The leucovorin is 400 mg / m ２ The method of any one of claims 33 to 36, wherein the compound is administered in a dose of

38. 39. The method of any one of claims 33-38, wherein the leucovorin is administered every two weeks.

39. The 5-fluorouracil is 2400 mg / m ２ The method of any one of claims 33 to 38, wherein the compound is administered in a dose of

40. 40. The method of any one of claims 33 to 39, wherein the 5-fluorouracil is administered by continuous intravenous infusion for 46 to 48 hours.

41. 41. The method of any one of claims 33 to 40, wherein the 5-fluorouracil is administered over a 46-48 hour period every two weeks.

42. The chemotherapy is 85 mg / m ２ of oxaliplatin, 400 mg / m ２ of leucovorin and 2400 mg / m ２ 42. The method of any one of claims 33 to 41, comprising 5-fluorouracil of

43. 43. The method of any one of claims 34 to 42, further comprising administering bevacizumab or an antigen-binding fragment thereof.

44. 44. The method of claim 43, wherein the bevacizumab or antigen-binding fragment thereof is administered at a dose of 5 mg / kg.

45. 45. The method of claim 43 or 44, wherein the bevacizumab or antigen-binding fragment thereof is administered every two weeks.

46. 46. ​​The method of any one of claims 43 to 45, wherein the bevacizumab or antigen-binding fragment thereof is administered intravenously.

47. 34. The method of claim 33, wherein the chemotherapy comprises: (a) nab-paclitaxel and carboplatin; (b) gemcitabine and cisplatin; (c) gemcitabine and carboplatin; (d) pemetrexed and carboplatin; and (e) pemetrexed and cisplatin.

48. The nab-paclitaxel was administered at 100 mg / m ２ 48. The method of claim 33 or 47, wherein the dose is

49. 49. The method of any one of claims 33, 47, or 48, wherein the nab-paclitaxel is administered on days 1, 8, and 15 of a 21-day cycle.

50. The gemcitabine is administered at a dose of 1000 mg / m ２ or 1250 mg / m ２ 48. The method of claim 33 or 47, wherein the dose is

51. 51. The method of any one of claims 33, 47, or 50, wherein the gemcitabine is administered on days 1 and 8 of a 21-day cycle.

52. The pemetrexed is administered at a dose of 500 mg / m ２ 48. The method of claim 33 or 47, wherein the dose is

53. 53. The method of any one of claims 33, 47, or 52, wherein the pemetrexed is administered every three weeks.

54. 54. The method of any one of claims 33 or 47-53, wherein the carboplatin is administered at a dose of AUC 5 or 6.

55. 56. The method of any one of claims 33 or 47-55, wherein the carboplatin is administered every three weeks.

56. The cisplatin is 75 mg / m ２ 54. The method of any one of claims 33, 47 or 50-53, wherein the compound is administered in a dose of

57. 57. The method of any one of claims 33, 47, 50-53, or 56, wherein the cisplatin is administered every three weeks.

58. The chemotherapy is 1000 mg / m ２ of gemcitabine and 125 mg / m ２ 34. The method of claim 33, comprising nab-paclitaxel of

59. 59. The method of any one of claims 3 to 58, wherein the chemotherapy is administered every 7 to 28 days.

60. 60. The method of claim 59, wherein the chemotherapy is administered every 14 days.

61. 25. The method of any one of claims 1 or 5-24, wherein said administration of oleclumab or an antigen-binding fragment thereof results in a partial response.

62. 25. The method of any one of claims 1 or 5-24, wherein said administration of oleclumab or an antigen-binding fragment thereof results in a complete response.

63. 63. The method of any one of claims 1 to 62, wherein the tumor is a solid tumor.

64. 64. The method of claim 63, wherein the solid tumor is breast cancer, ovarian cancer, head and neck cancer, prostate cancer, bladder cancer, colorectal cancer, non-small cell lung cancer (NSCLC), glioblastoma, renal cell carcinoma, or pancreatic cancer.

65. 65. The method of claim 64, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

66. 65. The method of claim 64, wherein the tumor is a resectable NSCLC tumor.

67. 67. The method of claim 64 or 66, wherein the tumor is an early stage NSCLC tumor.

68. 65. The method of claim 64, wherein the tumor is a stage IV NSCLC tumor.

69. 65. The method of claim 64, wherein the colorectal cancer is metastatic microsatellite stable.

70. 65. The method of any one of claims 1 to 64, wherein the tumor has high PD-L1 expression, and optionally the tumor is a NSCLC tumor.

71. 65. The method of any one of claims 1 to 64, wherein the tumor has low PD-L1 expression, and optionally the tumor is a NSCLC tumor.

72. 65. The method of any one of claims 1 to 64, wherein the tumor lacks an activating epidermal growth factor receptor (EGFR) mutation and / or an anaplastic lymphoma kinase (ALK) fusion, and optionally, the tumor is a NSCLC tumor.

73. 65. The method of any one of claims 1-64, wherein the patient has previously untreated metastatic pancreatic ductal adenocarcinoma.

74. 65. The method of any one of claims 1 to 64, wherein the patient has metastatic pancreatic ductal adenocarcinoma that has been previously treated with gemcitabine-based therapy.

75. 75. The method of any one of claims 1 to 74, wherein the tumor has not received previous treatment in the recurrent and / or metastatic setting.

76. 75. The method of any one of claims 1 to 74, wherein the patient is undergoing an anti-PD-1 or anti-PD-L1 containing therapy.

77. The tumor is first-line metastatic pancreatic ductal adenocarcinoma, the oleclumab or antigen-binding fragment thereof is administered at 1500 mg or 3000 mg for four doses every two weeks and then every four weeks, and the chemotherapy is administered at 1000 mg / m ２ of gemcitabine and 125 mg / m ２ nab-paclitaxel, wherein the chemotherapy is administered on days 1, 8, and 15 of four 28-day cycles and every four weeks thereafter.

78. The tumor is second-line metastatic pancreatic ductal adenocarcinoma, the oleclumab or antigen-binding fragment thereof is administered at 1500 mg or 3000 mg for four doses every two weeks and then every four weeks, and the chemotherapy is administered at 85 mg / m ２ of oxaliplatin, 400 mg / m ２ of leucovorin and 400 mg / m ２ of 5-FU followed by 2400 mg / m ２ 33. The method of any one of claims 3, 24 or 32, wherein the chemotherapy comprises 5-FU of 5-FU administered on days 1 and 15 of four 28 day cycles and every four weeks thereafter.

79. 79. The method of claim 77 or 78, further comprising administering 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.

80. 33. The method of any one of claims 2, 24 or 32, wherein the tumor is high first-line stage IV NSCLC with high PD-L1 expression, and the oleclumab or antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every two weeks and then every four weeks for two 28-day cycles, and the durvalumab or antigen-binding fragment thereof is administered at 1500 mg every four weeks.

81. the tumor is first-line stage IV NSCLC with low PD-L1 expression; (i) the oleclumab or antigen-binding fragment thereof is administered (a) at 1500 mg every three weeks for four 21-day cycles, and then every four weeks; or (b) at 2250 mg every three weeks for four 21-day cycles, and then at 3000 mg every four weeks; (ii) the durvalumab or antigen-binding fragment thereof is administered at 1500 mg every 3 weeks and every 4 weeks thereafter for four 21-day cycles; and (iii) the chemotherapy comprises (a) 100 mg / m on days 1, 8, and 15 of a 21-day cycle for four cycles; ２ of nab-paclitaxel and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for four cycles; (b) 1000 mg / m on days 1 and 8 of a 21-day cycle for four cycles; ２ or 1250 mg / m ２ of gemcitabine and 75 mg / m on day 1 of a 21-day cycle for four cycles ２ (c) cisplatin at 1000 mg / m on days 1 and 8 of a 21-day cycle for four cycles; ２ or 1250 mg / m ２ gemcitabine and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for four cycles; (d) 500 mg / m on day 1 of a 21-day cycle for four cycles; ２ of pemetrexed and carboplatin at 5 or 6 AUC on day 1 of a 21-day cycle for 4 cycles, optionally at 500 mg / m ２ pemetrexed and carboplatin administered every 4 weeks as maintenance therapy after 4 cycles; or (e) 500 mg / m on day 1 of a 21-day cycle for 4 cycles. ２ of pemetrexed and 75 mg / m on day 1 of a 21-day cycle for four cycles ２ cisplatin, optionally at 500 mg / m ２ 33. The method of any one of claims 4, 24, or 32, wherein the pemetrexed comprises pemetrexed and cisplatin administered every four weeks as maintenance therapy after four cycles.

82. 33. The method of any one of claims 2, 24, or 32, wherein the tumor is a locally advanced unresectable Stage III NSCLC tumor and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks, and (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every 2 weeks for 2 months and then every 4 weeks.

83. 33. The method of any one of claims 2, 24, or 32, wherein the tumor is a resectable early-stage NSCLC tumor and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered, and (ii) 3000 mg of oleculab or an antigen-binding fragment thereof is administered every two weeks.

84. The tumor is a metastatic microsatellite-stable colorectal cancer tumor, and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every four weeks; (ii) 3000 mg of olecurumab or an antigen-binding fragment thereof is administered every two weeks for four doses and then every four weeks; (iii) the chemotherapy is ２ of folinic acid, (b) 85 mg / m every 2 weeks ２ oxaliplatin; and (c) 2400 mg / m every 2 weeks ２ 5-fluorouracil; and (iv) 5 mg / kg bevacizumab or an antigen-binding fragment thereof is administered every two weeks.

85. The tumor is a microsatellite-stable colorectal cancer tumor, and (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every four weeks; (ii) 3000 mg of olecurumab or an antigen-binding fragment thereof is administered every two weeks for five doses and then every four weeks; and (iii) the chemotherapy is: (a) 400 mg / m every two weeks ２ folinic acid; (b) 85 mg / m every 2 weeks ２ of oxaliplatin on day 1; and (c) 400 mg / m on day 1. ２ of 5-fluorouracil and then 2400 mg / m every 2 weeks ２ 33. The method of any one of claims 4, 24 or 32, comprising 5-fluorouracil.

86. 86. The method of any one of claims 1-85, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

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