Anti-CD73, anti-PD-L1 antibodies and chemotherapy for treatment of tumors

Abstract

The present invention relates to anti-CD73, anti-PD-L1 antibodies and chemotherapy for the treatment of tumors. The present disclosure relates to monoclonal antibodies directed against CD73, or antigen-binding fragments thereof, and the use of such antibodies, or antigen-binding fragments thereof, in the treatment of tumors. The disclosure also relates to methods for treating a tumor 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, against programmed death ligand 1 (PD-L1), also known as B7 homolog 1 (B7-H1). The disclosure also relates to methods for treating a tumor 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 chemotherapy.

Description

[0001] This application is a divisional application of Chinese patent application 202080039845.5, “Anti-CD73, anti-PD-L1 antibodies and chemotherapy for treating tumors,” filed on April 1, 2020.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. patent application serial number 62 / 828,177, filed April 2, 2019, which is incorporated herein by reference in its entirety. Technical Field

[0004] The present disclosure relates to monoclonal antibodies directed against cluster of differentiation [CD] 73 (CD73) or an antigen-binding fragment thereof, and the use of such antibodies or antigen-binding fragments thereof in the treatment of tumors. The present disclosure also relates to methods for treating tumors, comprising administering an anti-CD73 antibody or antigen-binding fragment thereof to a patient in need 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 for treating tumors, comprising administering an anti-CD73 antibody or antigen-binding fragment thereof to a patient in need thereof in combination with a PD-L1 antibody or antigen-binding fragment thereof and / or chemotherapy. Background Art

[0005] CD73, or ecto-5'-nucleotidase (5'-NT), is ubiquitously expressed in many tissues. This protein is anchored to the cell membrane via a glycosylphosphatidylinositol (GPI) bond, has exoenzymatic activity, and plays a role in signal transduction. The primary function of CD73 is to convert extracellular nucleotides (e.g., 5'-AMP), which are normally impermeable to cells, into their corresponding nucleotides (e.g., adenosine), which can readily enter most cells. The generation of adenosine by CD73 through dephosphorylation of AMP has been shown to regulate adenosine receptor engagement in many tissues, suggesting that adenosine plays a role in cytoprotection, cell growth, angiogenesis, and immunosuppression, and also plays a role in tumorigenesis.

[0006] CD73 expression 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 CD73 expression is associated with tumor invasion, metastasis, and reduced patient survival. CD73 creates an immunosuppressive environment, characterized by increased adenosine levels, which promotes cancer development and progression. Notably, CD73 expression is associated with a pro-metastatic phenotype in melanoma and breast cancer.

[0007] Programmed death ligand 1 (PD-L1), also known as B7H1, is a 40kDa transmembrane protein that serves as a major barrier to anti-cancer immunity. Binding of PD-L1 to the programmed death receptor (PD-1) inactivates T cells, protecting tumor cells and inhibiting detection by the immune system, thereby allowing cancer cells to proliferate unchecked. PD-L1 also binds to CD80, a co-stimulatory molecule. PD-L1 is naturally expressed by a variety of tumorigenic and activated immune cell types, including antigen-presenting cells, macrophages, monocytes, B cells, T cells, and non-hematopoietic cells. In addition, inflammatory cytokines induce PD-L1 expression; this includes interferon gamma (IFNγ). Activated T cells produce IFNγ, which is the most potent inducer of PD-L1. IFNγ, in turn, induces PD-L1 expression, promoting tumor protection, a mechanism known as adaptive immune resistance.

[0008] Immune checkpoint inhibitors hold great potential as cancer therapies. However, the clinical benefits of immune checkpoint inhibition are modest. One possible explanation is that tumors employ non-overlapping immunosuppressive mechanisms to promote immune evasion. Therefore, improved compositions and methods for reducing tumor-mediated immunosuppression are needed. Summary of the Invention

[0009] The present invention provides a method for treating a tumor in a human patient, comprising administering oleclumab or an antigen-binding fragment thereof to the patient. In certain embodiments, oleclumab or an antigen-binding fragment thereof is administered at a dose of 750-3000 mg. In certain embodiments, oleclumab or an antigen-binding fragment thereof is administered at a dose of 40 mg / kg.

[0010] The present disclosure also provides a method of treating a tumor in a human patient, comprising administering to the patient olerumab or an antigen-binding fragment thereof and durvalumab or an antigen-binding fragment thereof.

[0011] The present disclosure also provides a method of treating a tumor in a human patient, comprising administering olerumab or an antigen-binding fragment thereof and chemotherapy to the patient.

[0012] In some aspects, a method of treating a tumor in a human patient comprises administering olerumab or an antigen-binding fragment thereof to the patient.

[0013] In some aspects, a method of treating a tumor in a human patient comprises administering to the patient olerumab, or an antigen-binding fragment thereof, and durvalumab, or an antigen-binding fragment thereof.

[0014] In some aspects, a method of treating a tumor in a human patient comprises administering olerumab or an antigen-binding fragment thereof and chemotherapy to the patient. In some aspects, the method further comprises administering durvalumab or an antigen-binding fragment thereof.

[0015] In some aspects, olerumumab or its antigen-binding fragment is administered at a dose of 750 mg to 3000 mg. In some aspects, olerumumab or its antigen-binding fragment is administered at a dose of 750 mg. In some aspects, olerumumab or its antigen-binding fragment is administered at a dose of 1500 mg. In some aspects, olerumumab or its antigen-binding fragment is administered at a dose of 2250 mg. In some aspects, olerumumab or its antigen-binding fragment is administered at a dose of 3000 mg. In some aspects, olerumumab or its antigen-binding fragment is administered at a dose of 2250 mg followed by a dose of 3000 mg. In some aspects, olerumumab or its antigen-binding fragment is administered at a dose of 2250 mg for 4 doses followed by a dose of 3000 mg.

[0016] In some aspects, olerumumab or its antigen-binding fragment is administered every 14 to 28 days. In some aspects, olerumumab or its antigen-binding fragment is administered every 14 days. In some aspects, olerumumab or its antigen-binding fragment is administered every 28 days. In some aspects, olerumumab or its antigen-binding fragment is administered every 14 days for at least two doses, and then every 28 days. In some aspects, olerumumab or its antigen-binding fragment is administered every 14 days for four doses, and then every 28 days. In some aspects, olerumumab or its antigen-binding fragment is administered every 21 days. In some aspects, olerumumab or its antigen-binding fragment is administered every 21 days for at least two doses, and then every 28 days. In some aspects, olerumumab or its antigen-binding fragment is administered every 21 days for two to four doses, and then every 28 days. In some aspects, olerumumab or its antigen-binding fragment is administered every 21 days for two doses, and then every 28 days. In some aspects, olerumab or an antigen-binding fragment thereof is administered every 21 days for four doses, then every 28 days.

[0017] In some aspects, olerumab or an antigen-binding fragment thereof is administered at a dose of 2250 mg once every 21 days for two doses, followed by a dose of 3000 mg once every 28 days. In some aspects, olerumab or an antigen-binding fragment thereof is administered at a dose of 2250 mg once every 21 days for four doses, followed by a dose of 3000 mg once every 28 days.

[0018] In some aspects, olerumab or an antigen-binding fragment thereof is administered intravenously.

[0019] In some aspects, durvalumab or an antigen-binding fragment thereof is administered at a dose of 1500 mg.

[0020] In some aspects, durvalumab or an antigen-binding fragment thereof is administered every 21 days to every 28 days. In some aspects, durvalumab or an antigen-binding fragment thereof is administered every 28 days. In some aspects, durvalumab or an antigen-binding fragment thereof is administered every 21 days. In some aspects, durvalumab or an antigen-binding fragment thereof is administered every 21 days for at least two doses, then every 28 days. In some aspects, durvalumab or an antigen-binding fragment thereof is administered every 21 days for four doses, then every 28 days.

[0021] In some aspects, durvalumab or an antigen-binding fragment thereof is administered at a dose of 1500 mg every 21 days for four doses, followed by a dose of 1500 mg every 28 days.

[0022] In some aspects, durvalumab or an antigen-binding fragment thereof is administered intravenously.

[0023] In some aspects, the chemotherapy includes at least one of cisplatin, pemetrexed nab-paclitaxel, carboplatin, gemcitabine, cisplatin, oxaliplatin, leucovorin, 5-fluorouracil, and docetaxel.

[0024] In some aspects, the chemotherapy includes oxaliplatin, folinate, and 5-fluorouracil.

[0025] In some aspects, oxaliplatin is administered at 85 mg / m 2 In some aspects, oxaliplatin is administered every 2 weeks.

[0026] In some aspects, folinic acid is administered at 400 mg / m 2 In some aspects, folinate is administered every 2 weeks.

[0027] In some aspects, 5-fluorouracil is administered at 2400 mg / m 2 In some aspects, 5-fluorouracil is administered by continuous intravenous infusion over 46 to 48 hours. In some aspects, 5-fluorouracil is administered every 2 weeks over 46 to 48 hours.

[0028] In some aspects, chemotherapy includes 85 mg / m 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 2400 mg / m 2 5-Fluorouracil.

[0029] In some aspects, the method further comprises administering bevacizumab or its Fab. In some aspects, bevacizumab or its Fab is administered at a dosage of 5 mg / kg. In some aspects, bevacizumab or its Fab is administered every 2 weeks. In some aspects, bevacizumab or its Fab is administered intravenously.

[0030] In some aspects, 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.

[0031] In some aspects, nab-paclitaxel is administered at 100 mg / m 2 In some aspects, nab-paclitaxel is administered on days 1, 8, and 15 of a 21-day cycle.

[0032] In some aspects, gemcitabine is administered at 1000 mg / m 2 or 1250 mg / m 2 In some aspects, gemcitabine is administered on days 1 and 8 of a 21-day cycle.

[0033] In some aspects, pemetrexed is administered at 500 mg / m 2 In some aspects, pemetrexed is administered every three weeks.

[0034] In some aspects, carboplatin is administered at a dose of AUC 5 or 6. In some aspects, carboplatin is administered every three weeks.

[0035] In some aspects, cisplatin is administered at 75 mg / m 2 In some aspects, cisplatin is administered every three weeks.

[0036] In some aspects, chemotherapy comprises 1000 mg / m 2 Gemcitabine and 125 mg / m 2 Albumin-bound paclitaxel.

[0037] In some aspects, chemotherapy is administered every 7 to 28 days. In some aspects, chemotherapy is administered every 14 days.

[0038] In some aspects, administration of olerumab or an antigen-binding fragment thereof results in a partial response. In some aspects, administration of olerumab or an antigen-binding fragment thereof results in a complete response.

[0039] In some aspects, the tumor is a solid tumor. In some aspects, 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 aspects, pancreatic cancer is pancreatic ductal adenocarcinoma. In some aspects, the tumor is a resectable NSCLC tumor. In some aspects, the tumor is an early stage NSCLC tumor. In some aspects, the tumor is a stage IV NSCLC tumor. In some aspects, the colorectal cancer is a metastatic microsatellite stable tumor.

[0040] In some aspects, the tumor has high PD-L1 expression. The tumor with high PD-L1 expression can be a NSCLC tumor.

[0041] In some aspects, the tumor has low PD-L1 expression. The tumor with low PD-L1 expression can be a NSCLC tumor.

[0042] In some aspects, 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 a NSCLC tumor.

[0043] In some aspects, the patient has previously untreated metastatic pancreatic ductal adenocarcinoma. In some aspects, the patient has previously treated metastatic pancreatic ductal adenocarcinoma with a gemcitabine-based therapy.

[0044] In some aspects, the tumor has not received prior treatment in the setting of recurrence and / or metastasis. In some aspects, the patient has progressed on therapy containing anti-PD-1 or anti-PD-L1.

[0045] In some aspects, the tumor is first-line metastatic pancreatic ductal adenocarcinoma, wherein olerumab or an antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every 2 weeks for four doses and then every four weeks; and wherein the chemotherapy comprises 1000 mg / m 2 Gemcitabine and 125 mg / m 2 Nab-paclitaxel, with the chemotherapy administered on days 1, 8, and 15 of four 28-day cycles, then every 4 weeks.

[0046] In some aspects, the tumor is second-line metastatic pancreatic ductal adenocarcinoma, wherein olerumab or an antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every 2 weeks for four doses and then every four weeks; and wherein the chemotherapy comprises 85 mg / m 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 400 mg / m 2 5-FU followed by 2400 mg / m 25-FU, where the chemotherapy is administered on days 1 and 15 of four 28-day cycles, then every 4 weeks.

[0047] In some aspects, the method further comprises administering 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.

[0048] In some aspects, the tumor is first-line stage IV NSCLC with high PD-L1 expression, wherein the olerumab or antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every 2 weeks for two 14-day cycles and then every 4 weeks; and wherein the durvalumab or antigen-binding fragment thereof is administered at 1500 mg every 4 weeks.

[0049] In some aspects, the tumor is first-line stage IV NSCLC with low PD-L1 expression, wherein olerumab or an antigen-binding fragment thereof is administered (a) at 1500 mg every 3 weeks for four 21-day cycles, then every 4 weeks; or (b) at 2250 mg every 3 weeks for four 21-day cycles, then 3000 mg every 4 weeks; durvalumab or an antigen-binding fragment thereof is administered at 1500 mg every 3 weeks for four 21-day cycles, then every 4 weeks; and the chemotherapy comprises: (a) 100 mg / m2 on days 1, 8, and 15 of a 21-day cycle. 2 Albumin-bound paclitaxel for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles; (b) 1000 mg / m2 on days 1 and 8 of a 21-day cycle 2 or 1250 mg / m 2 Gemcitabine was continued for 4 cycles and was administered at 75 mg / m2 on day 1 of a 21-day cycle. 2 Cisplatin was continued for 4 cycles; (c) 1000 mg / m2 on days 1 and 8 of a 21-day cycle 2 or 1250 mg / m 2 Gemcitabine for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles; (d) 500 mg / m2 on day 1 of a 21-day cycle 2 Pemetrexed for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles, optionally with 500 mg / m² every 4 weeks as maintenance therapy after the 4 cycles 2 Pemetrexed; or (e) 500 mg / m2 on day 1 of a 21-day cycle 2 Pemetrexed was continued for 4 cycles and was administered at 75 mg / m2 on day 1 of a 21-day cycle. 2Cisplatin for 4 cycles, optionally with 500 mg / m² administered every 4 weeks as maintenance therapy after the 4 cycles 2 Pemetrexed.

[0050] In some aspects, the tumor is a locally advanced, unresectable Stage III NSCLC tumor, and wherein (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks, and (ii) 3000 mg of olerumab or an antigen-binding fragment thereof is administered every 2 weeks for 2 months, then every 4 weeks.

[0051] In some aspects, the tumor is a resectable, early-stage NSCLC tumor, and wherein (i) 1500 mg of durvalumab or an antigen-binding fragment thereof, and (ii) 3000 mg of olerumab or an antigen-binding fragment thereof, is administered every 2 weeks.

[0052] In some aspects, the tumor is a metastatic microsatellite stable colorectal cancer tumor, and wherein (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks; (ii) 3000 mg of olerulumab or an antigen-binding fragment thereof is administered every 2 weeks for four doses, then every 4 weeks; (iii) the chemotherapy comprises (a) 400 mg / m 2 every 2 weeks; 2 Folinic acid (b) 85 mg / m every 2 weeks 2 oxaliplatin; and (c) 2400 mg / m every 2 weeks 2 and (iv) 5 mg / kg of bevacizumab or an antigen-binding fragment thereof every 2 weeks.

[0053] In some aspects, the tumor is a microsatellite stable colorectal cancer tumor, and wherein (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks; (ii) 3000 mg of olerulumab or an antigen-binding fragment thereof is administered every 2 weeks for four or five doses, then every 4 weeks; and (iii) the chemotherapy comprises (a) 400 mg / m 2 every 2 weeks. 2 Folinic acid (b) 85 mg / m every 2 weeks 2 oxaliplatin on day 1; and (c) 400 mg / m 2 5-fluorouracil, then 2400 mg / m2 every 2 weeks 2 of 5-fluorouracil.

[0054] In some aspects, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0055] This application specifically involves the following technical solutions:

[0056] 1. A method of treating a tumor in a human patient, the method comprising administering olerumumab or an antigen-binding fragment thereof to the patient.

[0057] 2. A method of treating a tumor in a human patient, the method comprising administering to the patient olerumab or an antigen-binding fragment thereof and durvalumab or an antigen-binding fragment thereof.

[0058] 3. A method of treating a tumor in a human patient, the method comprising administering to the patient olerumab or an antigen-binding fragment thereof and chemotherapy.

[0059] 4. The method according to claim 3, further comprising administering durvalumab or an antigen-binding fragment thereof.

[0060] 5. The method of any one of claims 1-4, wherein the olerumab or an antigen-binding fragment thereof is administered at a dose of 750 mg to 3000 mg.

[0061] 6. The method of claim 5, wherein the olerumab or antigen-binding fragment thereof is administered at a dose of 750 mg.

[0062] 7. The method of claim 5, wherein the olerumab or an antigen-binding fragment thereof is administered at a dose of 1500 mg.

[0063] 8. The method of claim 5, wherein the olerumab or an antigen-binding fragment thereof is administered at a dose of 2250 mg.

[0064] 9. The method of claim 5, wherein the olerumab or an antigen-binding fragment thereof is administered at a dose of 3000 mg.

[0065] 10. The method of claim 5, wherein the olerumab or antigen-binding fragment thereof is administered at a dose of 2250 mg followed by a dose of 3000 mg.

[0066] 11. The method of claim 10, wherein the olerumab or antigen-binding fragment thereof is administered at a dose of 2250 mg for 4 doses followed by a dose of 3000 mg.

[0067] 12. The method of any one of claims 1-11, wherein the olerumab or antigen-binding fragment thereof is administered every 14 to 28 days.

[0068] 13. The method of any one of regimens 1-11, wherein the olerumab or an antigen-binding fragment thereof is administered every 14 days.

[0069] 14. The method of any one of regimens 1-11, wherein the olerumab or an antigen-binding fragment thereof is administered every 28 days.

[0070] 15. The method of any one of regimens 1-11, wherein the olerumab or antigen-binding fragment thereof is administered every 14 days for at least two doses and then every 28 days.

[0071] 16. The method of any one of regimens 1-11, wherein the olerumab or antigen-binding fragment thereof is administered every 14 days for four doses and then every 28 days.

[0072] 17. The method of any one of regimens 1-11, wherein the olerumab or an antigen-binding fragment thereof is administered every 21 days.

[0073] 18. The method of any one of regimens 1-11, wherein the olerumab or antigen-binding fragment thereof is administered every 21 days for at least two doses and then every 28 days.

[0074] 19. The method of any one of regimens 1-11, wherein the olerumab or antigen-binding fragment thereof is administered every 21 days for two to four doses and then every 28 days.

[0075] 20. The method of claim 13, wherein the olerumab or antigen-binding fragment thereof is administered every 21 days for two doses and then once every 28 days.

[0076] 21. The method of claim 13, wherein the olerumab or antigen-binding fragment thereof is administered once every 21 days for four doses and then once every 28 days.

[0077] 22. The method of any one of claims 1-5, wherein the olerumab or 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.

[0078] 23. The method of any one of Schemes 1-5, wherein the olerumab 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.

[0079] 24. The method of any one of claims 1-23, wherein the olerumab or antigen-binding fragment thereof is administered intravenously.

[0080] 25. The method of any one of options 2 and 4-24, wherein the durvalumab or an antigen-binding fragment thereof is administered at a dose of 1500 mg.

[0081] 26. The method of any one of 2 and 4-25, wherein the durvalumab or an antigen-binding fragment thereof is administered every 21 to every 28 days.

[0082] 27. The method of any one of Schemes 2 and 4-26, wherein the durvalumab or an antigen-binding fragment thereof is administered every 28 days.

[0083] 28. The method of any one of options 2 and 4-26, wherein the durvalumab or an antigen-binding fragment thereof is administered every 21 days.

[0084] 29. The method of any one of Schemes 2 and 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.

[0085] 30. The method of any one of Schemes 2 and 4-26, wherein the durvalumab or antigen-binding fragment thereof is administered every 21 days for four doses and then every 28 days.

[0086] 31. The method of any one of Schemes 2 and 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.

[0087] 32. The method of any one of claims 1-31, wherein the durvalumab or an antigen-binding fragment thereof is administered intravenously.

[0088] 33. The method of any one of schemes 3-32, wherein the chemotherapy comprises at least one of cisplatin, pemetrexed, albumin-bound paclitaxel, carboplatin, gemcitabine, cisplatin, oxaliplatin, folinate, 5-fluorouracil, and docetaxel.

[0089] 34. The method of claim 33, wherein the chemotherapy comprises oxaliplatin, folinate, and 5-fluorouracil.

[0090] 35. The method according to scheme 33 or 34, wherein the oxaliplatin is administered at 85 mg / m 2 Dosage administration.

[0091] 36. The method according to any one of schemes 33-35, wherein the oxaliplatin is administered every 2 weeks.

[0092] 37. The method according to any one of schemes 33-36, wherein the calcium folinate is administered at 400 mg / m 2 Dosage administration.

[0093] 38. The method of any one of schemes 33-38, wherein the calcium folinate is administered every 2 weeks.

[0094] 39. The method according to any one of schemes 33-38, wherein the 5-fluorouracil is administered at 2400 mg / m 2 Dosage administration.

[0095] 40. The method of any one of claims 33-39, wherein the 5-fluorouracil is administered by continuous intravenous infusion for 46 to 48 hours.

[0096] 41. The method of any one of schemes 33-40, wherein the 5-fluorouracil is administered for 46 to 48 hours every 2 weeks.

[0097] 42. The method according to any one of regimens 33-41, wherein the chemotherapy comprises 85 mg / m 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 2400 mg / m 2 5-Fluorouracil.

[0098] 43. The method of any one of schemes 34-42, further comprising administering bevacizumab or an antigen-binding fragment thereof.

[0099] 44. The method of claim 43, wherein bevacizumab or an antigen-binding fragment thereof is administered at a dose of 5 mg / kg.

[0100] 45. The method of claim 43 or 44, wherein bevacizumab or an antigen-binding fragment thereof is administered every 2 weeks.

[0101] 46. ​​The method of any one of schemes 43-45, wherein bevacizumab or an antigen-binding fragment thereof is administered intravenously.

[0102] 47. 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.

[0103] 48. The method according to claim 33 or 47, wherein the albumin-bound paclitaxel is administered at a dose of 100 mg / m 2 Dosage administration.

[0104] 49. The method of any one of regimens 33, 47, or 48, wherein the nab-paclitaxel is administered on days 1, 8, and 15 of a 21-day cycle.

[0105] 50. The method according to claim 33 or 47, wherein the gemcitabine is administered at 1000 mg / m 2 or 1250 mg / m 2 Dosage administration.

[0106] 51. The method of any one of Regimens 33, 47, or 50, wherein the gemcitabine is administered on Days 1 and 8 of a 21-day cycle.

[0107] 52. The method according to claim 33 or 47, wherein the pemetrexed is administered at 500 mg / m 2 Dosage administration.

[0108] 53. The method of any one of schemes 33, 47 and 52, wherein the pemetrexed is administered every three weeks.

[0109] 54. The method of any one of Schemes 33 and 47-53, wherein the carboplatin is administered at a dose of AUC 5 or 6.

[0110] 55. The method according to any one of schemes 33 and 47-55, wherein the carboplatin is administered every three weeks.

[0111] 56. The method according to any one of schemes 33, 47 and 50-53, wherein the cisplatin is administered at 75 mg / m 2 Dosage administration.

[0112] 57. The method of any one of Schemes 33, 47, 50-53, and 56, wherein the cisplatin is administered every three weeks.

[0113] 58. The method of claim 33, wherein the chemotherapy comprises 1000 mg / m 2 Gemcitabine and 125 mg / m 2 Albumin-bound paclitaxel.

[0114] 59. The method of any one of Schemes 3-58, wherein the chemotherapy is administered every 7 to 28 days.

[0115] 60. The method of claim 59, wherein the chemotherapy is administered every 14 days.

[0116] 61. The method of any one of Schemes 1 and 5-24, wherein administration of olerumab or an antigen-binding fragment thereof results in a partial response.

[0117] 62. The method of any one of Schemes 1 and 5-24, wherein administration of olerumab or an antigen-binding fragment thereof results in a complete response.

[0118] 63. The method of any one of claims 1-62, wherein the tumor is a solid tumor.

[0119] 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.

[0120] 65. The method of claim 64, wherein the pancreatic cancer is pancreatic ductal adenocarcinoma.

[0121] 66. The method of claim 64, wherein the tumor is a resectable NSCLC tumor.

[0122] 67. The method of claim 64 or 66, wherein the tumor is an early-stage NSCLC tumor.

[0123] 68. The method of claim 64, wherein the tumor is a stage IV NSCLC tumor.

[0124] 69. The method of claim 64, wherein the colorectal cancer is metastatic microsatellite stable.

[0125] 70. The method of any one of schemes 1-64, wherein the tumor has high PD-L1 expression, optionally wherein the tumor is a NSCLC tumor.

[0126] 71. The method of any one of schemes 1-64, wherein the tumor has low PD-L1 expression, optionally wherein the tumor is a NSCLC tumor.

[0127] 72. A method according to any one of schemes 1-64, wherein the tumor lacks an activating epidermal growth factor receptor (EGFR) mutation and / or anaplastic lymphoma kinase (ALK) fusion, optionally wherein the tumor is a NSCLC tumor.

[0128] 73. The method of any one of claims 1-64, wherein the patient has previously untreated metastatic pancreatic ductal adenocarcinoma.

[0129] 74. The method of any one of claims 1-64, wherein the patient has metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy.

[0130] 75. The method of any one of schemes 1-74, wherein the tumor has not received previous treatment in the case of recurrence and / or metastasis.

[0131] 76. The method of any one of schemes 1-74, wherein the patient has progressed on therapy containing anti-PD-1 or anti-PD-L1.

[0132] 77. The method of any one of Schemes 3, 24, and 32, wherein the tumor is first-line metastatic pancreatic ductal adenocarcinoma, wherein olerumab or an antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every 2 weeks for four doses and then every four weeks; and wherein the chemotherapy comprises 1000 mg / m 2 Gemcitabine and 125 mg / m 2 Nab-paclitaxel, with the chemotherapy administered on days 1, 8, and 15 of four 28-day cycles, then every 4 weeks.

[0133] 78. The method of any one of Schemes 3, 24, and 32, wherein the tumor is second-line metastatic pancreatic ductal adenocarcinoma, wherein olerumab or an antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every 2 weeks for four doses and then every four weeks; and wherein the chemotherapy comprises 85 mg / m 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 400 mg / m 2 5-FU followed by 2400 mg / m 2 5-FU, where the chemotherapy is administered on days 1 and 15 of four 28-day cycles, then every 4 weeks.

[0134] 79. The method of claim 77 or 78, further comprising administering 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.

[0135] 80. The method of any one of Regimens 2, 24, and 32, wherein the tumor is first-line stage IV NSCLC with high PD-L1 expression, wherein the olerumab or antigen-binding fragment thereof is administered at 1500 mg or 3000 mg every 2 weeks for two 28-day cycles and then every 4 weeks; and wherein the durvalumab or antigen-binding fragment thereof is administered at 1500 mg every 4 weeks.

[0136] 81. The method of any one of schemes 4, 24, and 32, wherein the tumor is first-line stage IV NSCLC with low PD-L1 expression, wherein

[0137] (i) administering olerumab or an antigen-binding fragment thereof (a) at 1500 mg every 3 weeks for four 21-day cycles, then every 4 weeks; or (b) at 2250 mg every 3 weeks for four 21-day cycles, then 3000 mg every 4 weeks;

[0138] (ii) administering durvalumab or an antigen-binding fragment thereof at 1500 mg every 3 weeks for four 21-day cycles, then every 4 weeks; and

[0139] (iii) The chemotherapy comprises: (a) 100 mg / m2 on days 1, 8, and 15 of a 21-day cycle 2 Albumin-bound paclitaxel for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles; (b) 1000 mg / m2 on days 1 and 8 of a 21-day cycle 2 or 1250 mg / m 2 Gemcitabine was continued for 4 cycles and was administered at 75 mg / m2 on day 1 of a 21-day cycle. 2 Cisplatin was continued for 4 cycles; (c) 1000 mg / m2 on days 1 and 8 of a 21-day cycle 2 or 1250 mg / m 2 Gemcitabine for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles; (d) 500 mg / m2 on day 1 of a 21-day cycle 2 Pemetrexed for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles, optionally with 500 mg / m² every 4 weeks as maintenance therapy after the 4 cycles 2 Pemetrexed; or (e) 500 mg / m2 on day 1 of a 21-day cycle 2 Pemetrexed was continued for 4 cycles and was administered at 75 mg / m2 on day 1 of a 21-day cycle. 2 Cisplatin for 4 cycles, optionally with 500 mg / m² administered every 4 weeks as maintenance therapy after the 4 cycles 2 Pemetrexed.

[0140] 82. The method of any one of Regimens 2, 24, and 32, wherein the tumor is a locally advanced, unresectable Stage III NSCLC tumor, and wherein (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks, and (ii) 3000 mg of olerumab or an antigen-binding fragment thereof is administered every 2 weeks for 2 months, then every 4 weeks.

[0141] 83. The method of any one of regimens 2, 24, and 32, wherein the tumor is a resectable, early-stage NSCLC tumor, and wherein (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered, and (ii) 3000 mg of olerumab or an antigen-binding fragment thereof is administered every 2 weeks.

[0142] 84. The method of any one of schemes 4, 24, 32, and 46, wherein the tumor is a metastatic microsatellite stable colorectal cancer tumor, and wherein (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks; (ii) 3000 mg of olerulumab or an antigen-binding fragment thereof is administered every 2 weeks for four doses, then every 4 weeks; (iii) the chemotherapy comprises (a) 400 mg / m 2 every 2 weeks 2 Folinic acid (b) 85 mg / m every 2 weeks 2 oxaliplatin; and (c) 2400 mg / m every 2 weeks 2 and (iv) 5 mg / kg of bevacizumab or an antigen-binding fragment thereof every 2 weeks.

[0143] 85. The method of any one of schemes 4, 24, and 32, wherein the tumor is a microsatellite stable colorectal cancer tumor, and wherein (i) 1500 mg of durvalumab or an antigen-binding fragment thereof is administered every 4 weeks; (ii) 3000 mg of olerumumab or an antigen-binding fragment thereof is administered every 2 weeks for five doses, then every 4 weeks; and (iii) the chemotherapy comprises (a) 400 mg / m 2 every 2 weeks 2 Folinic acid (b) 85 mg / m every 2 weeks 2 oxaliplatin on day 1; and (c) 400 mg / m 2 5-fluorouracil, then 2400 mg / m2 every 2 weeks 2 of 5-fluorouracil.

[0144] 86. The method of any one of schemes 1-85, wherein the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. BRIEF DESCRIPTION OF THE DRAWINGS

[0145] Figure 1 is a graph showing the concentration of free sCD73 in cynomolgus monkeys after administration of olerumab at doses of 0 mg / kg (Group 1), 1 mg / kg (Group 2), 10 mg / kg (Group 3), or 107.8 mg / kg (Group 4). (See Example 2.)

[0146] Figure 2A and 2B Olerumab administration was shown not to enhance keyhole limpet hemocyanin T-dependent antibody response (KLH TDAR) in a dose-dependent manner. Figure 2A Shown are the mean anti-KLH IgM titers after KLH immunization in monkeys administered olerumab at doses of 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg, and Figure 2BShown are mean anti-KLH IgG titers following KLH immunization in monkeys administered olerumab at doses of 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg. (See Example 2.)

[0147] Figure 3A and 3B showed that administration of olerumab did not increase ex vivo IFN-γ or IL-2 production after KLH stimulation of peripheral blood mononuclear cells. Figure 3A shows mean KLH-specific IFN-γ production after KLH immunization in monkeys administered olerumab at doses of 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg, and Figure 3B KLH-specific IL-2 production following KLH immunization in monkeys administered olerumab at doses of 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg was shown. (See Example 2.)

[0148] Figure 4 qPCR detection of lymphocryptovirus (LCV) in most samples obtained from monkeys following administration of olerumab at doses of 0 mg / kg, 1 mg / kg, 10 mg / kg, or 107.8 mg / kg was shown. (See Example 2.)

[0149] Figure 5 Model assumptions for the pharmacokinetic / pharmacodynamic model used to predict human therapeutic doses of olelumab are shown. A two-compartment model with linear and target-mediated drug disposition clearance was used to adequately describe the serum concentration profile of MEDI9447. This model was used to describe monkey pharmacokinetic data, and the resulting parameter similarities and differences were then scaled to humans to predict doses using simulations. (See Example 2.)

[0150] Figure 6A and 6B The pharmacokinetic model and human dose prediction for cynomolgus monkeys are shown. Figure 6A )pass( Figure 5 ) fully describes all three different dose levels. After allometric scaling of the pharmacokinetic parameters of the model, the human serum concentration curves ( Figure 6B A serum exposure target of 52 μg / mL was determined from tumor suppression data in syngeneic mice, and simulations indicated that dosing equal to or higher than 15 mg / kg every two weeks (Q2W) would achieve and maintain sufficient exposure throughout the dosing period to be expected to produce therapeutic effects. (See Example 2.)

[0151] Figure 7A and 7B . Figure 7A Study flow chart showing the dose-escalation phase of the olerumab monotherapy arms (pancreatic cancer and microsatellite-stable colorectal cancer (MSS-CRC)). Figure 7B Study flow chart showing the dose expansion and dose escalation portion of a study of olerumab (MEDI9447) and durvalumab administered as combination therapy to human patients with advanced solid tumors (pancreatic cancer and MSS-CRC). (See Example 3.)

[0152] Figure 8 Dosing schedules for the screening, treatment, and follow-up phases of a study of olerumumab (MEDI9447) administered as monotherapy and olerumumab (MEDI9447) / durvalumab combination therapy to human patients are shown. (See Example 3.)

[0153] Figure 9A and 9B Indicated as monotherapy ( Figure 9A ) or in combination with durvalumab ( Figure 9B ) Amount of free soluble CD73 observed after administration of olelumab. sCD73, soluble CD73; PD LLOQ, lower limit of quantification. (See Example 3.)

[0154] Figures 10A-10C Olerumab was shown to reduce CD73 surface expression on peripheral T cells and tumor CD73, as measured by mean fluorescence intensity (MFI) ( Figure 10A ) and CD73 + CD4 and CD8 cell percentages; ( Figure 10B ) in peripheral blood at all doses after olerumab administration; and in peripheral T cells ( Figure 10C ) measured. SSC; side scatter. (See Example 3.)

[0155] Figures 11A-11C . Figure 11A Shown are changes in the percentage of tumor cells staining for CD73 at an intensity of 2+ or 3+ by immunohistochemistry in subjects with pancreatic or colorectal cancer (CRC) 20 days after administration of olerumab at 10, 20, or 40 mg / kg. Figure 11B Shown are CD73 staining of tumors before and after treatment with olerumab. Figure 11C Shown are changes in CD73-stained tumor cells at 2+ or 3+ staining intensity and changes in CD8 TILs relative to baseline 20 days after administration of olelumab at 10, 20, or 40 mg / kg. (See Example 3.)

[0156] Figure 12Olerumab was shown to inhibit CD73 enzyme activity in the tumor microenvironment. Staining revealed a decrease in free adenosine. (See Example 3.)

[0157] Figure 13 Shown are the mean PK profiles from the olerumab monotherapy studies. Pooled PK data across indications and monotherapy and in combination with durvalumab (N=116).

[0158] (See Example 3.)

[0159] Figure 14A and 14B showed that olerumab demonstrated evidence of PD effect. Figure 14A Changes in tumor percentage are shown. Figure 14B Shows changes in CD8 TIL. (See Example 3.)

[0160] Figure 15 A dose expansion phase of olerumab in combination with durvalumab is shown. (See Example 4.)

[0161] Figure 16 Clinical activity of olelumab in combination with durvalumab was demonstrated in MSS-CRC. Treatment was sustained for >600 days. (See Example 4.)

[0162] Figure 17 Clinical activity of olerumab in combination with durvalumab was demonstrated in pancreatic cancer. (See Example 4.)

[0163] Figure 18 Clinical activity of olelumab in combination with durvalumab was demonstrated in EGFRm NSCLC. (See Example 4.)

[0164] Figure 19 Study flow chart showing the dose-escalation phase of olelumab in combination with durvalumab and chemotherapy (gemcitabine plus nab-paclitaxel for subjects with 1L metastatic PDAC [Cohort A]; mFOLFOX for subjects with 2L metastatic PDAC [Cohort B]).

[0165] (See Example 5.)

[0166] Figure 20 The dose-escalation phase of olelumab is shown in combination with durvalumab and chemotherapy (gemcitabine + nab-paclitaxel for subjects with 1L metastatic PDAC [Cohort A]; mFOLFOX for subjects with 2L metastatic PDAC [Cohort B]). (See Example 5.)

[0167] Figure 21Flowchart showing the dose expansion phase of the study of olerumab in combination with durvalumab and chemotherapy. (See Example 5.)

[0168] Figure 22 The dose expansion phase of olelumab is shown in combination with durvalumab and chemotherapy (gemcitabine + nab-paclitaxel for subjects with 1L metastatic PDAC [Cohort A]). (See Example 5.)

[0169] Figure 23 The dose expansion phase of olelumab is shown in combination with durvalumab and chemotherapy mFOLFOX (2L metastatic PDAC subjects [Cohort B]). (See Example 5.)

[0170] Figures 24A-24D Shows treatment options for patients with first-line stage IV non-small cell lung cancer (NSCLC). Figure 24A Durvalumab monotherapy dosing schedule is shown. Figure 24B Durvalumab + olerumab dosing schedule is shown. Figure 24C Durvalumab + chemotherapy dosing schedule is shown. Figure 24D The durvalumab + chemotherapy + olerulumab dosing regimen is shown. (See Example 6.)

[0171] Figures 25A-25B Shows treatment options for locally advanced, unresectable stage III non-small cell lung cancer (NSCLC). Figure 25A Durvalumab monotherapy dosing schedule is shown. D = Durvalumab; a = Subjects received durvalumab 1500 mg intravenously (IV) every 4 weeks (Q4W) on Day 1 of each cycle. Figure 25B Durvalumab + olerumab dosing schedule shown. D = durvalumab; O = olerumab; a = Subjects received 1500 mg intravenously (IV) on Day 1 of each cycle (Q4W) and olerumab 3000 mg IV every 2 weeks (Q2W) (Days 1 and 15) in Cycles 1 and 2, then Q4W starting on Day 1 (D1) of Cycle 3. On days where durvalumab and olerumab were administered, olerumab was administered first. (See Example 7.)

[0172] Figures 26A-26C Shown are treatment options for resectable early-stage non-small cell lung cancer (NSCLC). Figure 26A Treatment during the duration of the study is shown. Figure 26B Durvalumab monotherapy dosing schedule is shown: subjects received 1500 mg of durvalumab intravenously (IV) every 2 weeks (Q4W) on Day 1 of Week 1. W = Week; D = Day; Du = durvalumab. Figure 26CDurvalumab + olerumab dosing schedule shown: Subjects received 1500 mg of durvalumab IV on Day 1 of Week 1 Q4W and 3000 mg of olerumab IV on Day 1 of Week 1 and Day 1 of Week 3 every 2 weeks (Q2W). W = week; D = day; Du = durvalumab; O = olerumab. (See Example 8.)

[0173] Figure 27 Treatment regimens for patients with metastatic microsatellite-stable colorectal cancer. DLT = dose-limiting toxicity; FOLFOX = folinic acid (leucovorin), 5-fluorouracil, oxaliplatin. Subjects in control 1 received FOLFOX plus bevacizumab. Subjects in arms S1 and E1 also received 1500 mg of durvalumab intravenously (IV) every 4 weeks (Q4W) on Day 1 of every 14-day cycle and 3000 mg of olerumumab IV x 4 doses every 2 weeks (Q2W) starting on Day 1 of Cycle 1, then Q4W starting on Day 1 of Cycle 5. On days when durvalumab and olerumumab were administered, olerumumab was administered first. (See Example 9.)

[0174] Figure 28 Treatment regimens for patients with high-risk metastatic microsatellite-stable colorectal cancer. mFOLFOX6 = folinic acid (leucovorin), 5-fluorouracil, oxaliplatin. Subjects in the control arm received mFOLFOX6. Subjects in Arm E1-COC received mFOLFOX6 plus 1500 mg of durvalumab intravenously (IV) every 4 weeks (Q4W). Subjects in Arm E2 received mFOLFOX6 plus 1500 mg of durvalumab IV Q4W and 300 mg of olerumumab IV every 2 weeks (Q2W) for four doses, then Q4W starting in Cycle 5 (Week 9, Day 1). On days when durvalumab and olerumumab were administered, olerumumab was administered first. (See Example 10.)

[0175] Figures 29A-29I . Figures 29A-29H Shown is individual tumor growth (CT26) after treatment with a combination of anti-CD73, anti-PD-L1, 5FU, and OHP. Figure 29I Shown are Kaplan-Meier (survival curves) of CT26 tumor-bearing BALB / c mice after treatment with a combination of anti-CD73, anti-PD-L1, 5FU, and OHP. (See Example 11.)

[0176] Figure 30The results show an increase in IFNγ+CD8+, CD4+, and NKp46+ lymphocytes in the tumor microenvironment (TME) of CT26 tumor-bearing BALB / c mice after treatment with a combination of anti-CD73, anti-PD-L1, 5FU, and OHP. (See Example 11.)

[0177] Figures 31A-31I . Figures 31A-31H Shown is individual tumor growth (CT26) after treatment with the combination of anti-CD73, anti-PD-L1, and docetaxel. Figure 31I Shown are Kaplan-Meier (survival curves) of CT26 tumor-bearing BALB / c mice after treatment with a combination of anti-CD73, anti-PD-L1, and docetaxel. (See Example 11.)

[0178] Figures 32A-32H Shown are individual tumor growth profiles of MCA205 tumor-bearing C57BL / 6 mice following treatment with a combination of anti-CD73, anti-PD-L1, 5FU, and OHP. (See Example 11.) DETAILED DESCRIPTION

[0179] The present disclosure relates to monoclonal antibodies against CD73 (such as olerumumab) or its antigen-binding fragments, and the use of such antibodies or their antigen-binding fragments in the treatment of tumors. The present disclosure also relates to a method for treating tumors, which comprises administering an anti-CD73 antibody (such as olerumumab) or its antigen-binding fragment in combination with a monoclonal antibody against PD-L1 (such as durvalumab) or its antigen-binding fragment to a patient in need thereof. The present disclosure also relates to a method for treating tumors, which comprises administering an anti-CD73 antibody (such as olerumumab) or its antigen-binding fragment to a patient in need thereof in combination with an anti-PD-L1 antibody (such as durvalumab) and in combination with chemotherapy.

[0180] As used in accordance with this disclosure, unless otherwise indicated, the following terms 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.

[0181] As used herein, the term "antibody" refers to a protein that can recognize and specifically bind to an antigen. Ordinary or conventional mammalian antibodies comprise tetramers, which are typically composed of two pairs of identical 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 to the target antigen. The amino terminal portion of each light and heavy chain typically includes a variable domain of about 100 to 110 or more amino acids that are typically responsible for antigen recognition. The carboxyl terminal portion of each chain typically defines the constant domains that are responsible for effector function. Thus, in naturally occurring antibodies, a full-length heavy chain immunoglobulin polypeptide includes variable domains (V H ) and three constant domains (C H1 、C H2 and C H3 ) and C H1 and C H2 The hinge region between the V H The domain is located at the amino terminus of the polypeptide and the C H3 The variable domain is located at the carboxyl terminus, and the full-length light chain immunoglobulin polypeptide includes the variable domain (V L ) and constant domain (C L ), where V L The domain is located at the amino terminus of the polypeptide and the C L The domain is located at the carboxyl terminus.

[0182] In full-length light and heavy chains, the variable domains and constant domains are generally connected by a "J" region of about 12 or more amino acids, and the heavy chain also includes a "D" region of about 10 or more amino acids. The variable region of each light / heavy chain pair generally forms an antigen binding site. The variable domains of naturally occurring antibodies generally exhibit the same general structure of a relatively conservative framework region (FR) connected by three hypervariable regions (also referred to as complementary determining regions or CDRs). The CDRs from each pair of two chains are generally aligned by the framework region, which allows for binding to a specific epitope. From amino-terminal to carboxyl-terminal, light and heavy chain variable domains generally comprise domains FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4.

[0183] The term "antigen-binding fragment" refers to a portion of an intact antibody and / or refers to the antigen-determining variable domains 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.

[0184] As used herein, the term "patient" includes human subjects.

[0185] A "disorder" is any condition that would benefit from treatment with the disclosed antibodies. "Disorder" and "condition" are used interchangeably herein and include chronic and acute disorders or diseases, including those pathological conditions that predispose a patient to the disorder in question.

[0186] As used herein, the term "solid tumor" refers to an abnormal mass of tissue that typically does not contain cysts or fluid areas. Examples of solid tumors include head and neck squamous cell carcinoma, cervical cancer, colorectal cancer, non-small cell lung cancer, pancreatic cancer, prostate cancer, and bladder urothelial carcinoma.

[0187] As used herein, the term "treatment" or "treat" refers to both therapeutic treatment and prophylactic or preventative measures. Patients in need of treatment include those with tumors, those susceptible to tumors, or those to be prevented from developing tumors. In specific embodiments, the antibodies disclosed herein can be used to treat tumors, such as solid tumors. In specific embodiments, treatment of tumors includes inhibiting tumor growth, promoting tumor reduction, or both.

[0188] As used herein, the term "pharmaceutical composition" or "therapeutic composition" refers to a compound or composition capable of inducing a desired therapeutic effect when appropriately administered to a patient. 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.

[0189] As used herein, the term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier" refers to one or more formulation materials suitable for achieving or enhancing the delivery of one or more antibodies of the disclosure.

[0190] As used herein, the terms "olerumab" and "MEDI9447" refer to a human immunoglobulin G1λ (IgG1λ) mAb that selectively binds and inhibits the ectonucleotidase activity of CD73, as disclosed in U.S. Patent No. 9,938,356, which is incorporated herein by reference in its entirety. The triple mutation L234F / L235E / P331S (according to the EU numbering convention) encoded in the heavy chain constant region significantly reduces IgG effector function. olerumab inhibits AMP catalysis of adenosine and organophosphates by CD73. Extracellular adenosine mediates the immunosuppressive effects of MDSCs and Tregs, among others.

[0191] In certain embodiments, olerumab or an antigen-binding fragment thereof comprises a heavy chain variable domain and a light chain variable domain. In certain embodiments, olerumab 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, olerumab 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: 3-5, and wherein the light chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 6-8.

[0192] In certain embodiments, a tumor is treated in a human patient by administering olerumab or an antigen-binding fragment thereof to the patient.

[0193] The monotherapy dose of olerumab or an antigen-binding fragment thereof to be administered to a patient will vary depending, in part, on the patient's size (weight, body surface or organ size) and condition (age and general health).

[0194] In certain embodiments, one or more doses of olerumab or an antigen-binding fragment thereof are administered to a patient as monotherapy or in combination therapy, wherein the dose of olerumab or an antigen-binding fragment thereof is 750 mg to 3000 mg. In some embodiments, the dose of olerumab or an antigen-binding fragment thereof is 750 mg. In some embodiments, the dose of olerumab or an antigen-binding fragment thereof is 1500 mg. In some embodiments, the dose of olerumab or an antigen-binding fragment thereof is 2250 mg. In some embodiments, the dose of olerumab or an antigen-binding fragment thereof is 3000 mg.

[0195] In certain embodiments, one or more doses of olerumab, or an antigen-binding fragment thereof, are administered to a patient as monotherapy, wherein the dose is 5 mg / kg, 10 mg / kg, 20 mg / kg, or 40 mg / kg. In some embodiments, one or more doses of olerumab, or an antigen-binding fragment thereof, are administered to a patient as monotherapy, wherein the dose is 40 mg / kg.

[0196] In certain embodiments, olerumab or an antigen-binding fragment thereof is administered only once or infrequently to a patient with a tumor while still providing benefit to the patient. In other embodiments, additional subsequent doses are administered to the patient. Subsequent doses may be administered at varying intervals depending on the patient's age, weight, clinical assessment, tumor burden, and / or other factors, including the discretion of the attending physician.

[0197] In certain embodiments, a bolus loading dose of olerumumab or an antigen-binding fragment thereof is administered to a patient presenting with a tumor. In certain embodiments, a first dose of olerumumab or an antigen-binding fragment thereof is administered to the patient, followed by a second, lower dose of olerumumab 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 olerumumab is 40 mg / kg and the second, lower dose of olerumumab is 20 mg / kg.

[0198] In specific embodiments, orelumab or an antigen-binding fragment thereof is administered within a two-week treatment period, within a four-week treatment period, within a six-week treatment period, within an eight-week treatment period, within a twelve-week treatment period, within a twenty-four-week treatment period, or within a treatment period of one year or longer. In specific embodiments, orelumab or an antigen-binding fragment thereof is administered within a three-week treatment period, within a six-week treatment period, within a nine-week treatment period, within a twelve-week treatment period, within a twenty-four-week treatment period, or within a treatment period of one year or longer. In specific embodiments, orelumab or an antigen-binding fragment thereof is administered within a two-month treatment period, within a four-month treatment period, or within a six-month treatment period or longer. In specific embodiments, orelumab or an antigen-binding fragment thereof is administered within a one-year treatment period, within a two-year treatment period, or within a three-year treatment period or longer.

[0199] In specific embodiments, olerumab 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.

[0200] In certain embodiments, olerumumab or an antigen-binding fragment thereof is administered repeatedly every 7 to 28 days. In other embodiments, olerumumab or an antigen-binding fragment thereof is administered repeatedly every 14 days. In yet other embodiments, olerumumab or an antigen-binding fragment thereof is administered repeatedly every 28 days.

[0201] In certain embodiments, olerumab or an antigen-binding fragment thereof is administered repeatedly every 7 to 28 days (e.g., every 7 days, every 14 days, every 21 days, or every 28 days). In certain embodiments, olerumab or an antigen-binding fragment thereof is administered once every 14 days for at least two doses (e.g., two, three, or four doses), followed by administration every 28 days. In certain embodiments, olerumab or an antigen-binding fragment thereof is administered once every 21 days for at least two doses (e.g., two, three, or four doses), followed by administration every 28 days.

[0202] Also provided herein are methods for treating solid tumors in human patients, comprising administering 40 mg / kg of olerumumab or an antigen-binding fragment thereof to the patient. Also provided herein are methods for treating solid tumors in human patients, comprising administering 750-3000 mg (e.g., 750, 1500, 2250, or 3000 mg) of olerumumab or an antigen-binding fragment thereof to the patient.

[0203] In other embodiments, olerumab or an antigen-binding fragment thereof can be administered in combination therapy with durvalumab or an antigen-binding fragment thereof.

[0204] As used herein, the term "durvalumab" refers to an antibody that selectively binds to PD-L1 and blocks the binding of PD-L1 to PD-1 and CD80 receptors, 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 in the constant domain of the IgG1 heavy chain that reduces binding to complement component C1q and Fcγ receptors, which are responsible for mediating antibody-dependent cell-mediated cytotoxicity (ADCC).

[0205] 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 wherein the light chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 14-16.

[0206] In certain embodiments, olerumab or an antigen-binding fragment thereof is administered only once or infrequently to a patient with a tumor in combination with durvalumab or an antigen-binding fragment thereof, while still providing benefit to the patient. In other embodiments, additional subsequent doses are administered to the patient. Subsequent doses may be administered at varying time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and / or other factors, including the discretion of the attending physician.

[0207] In specific embodiments, olerumab or an antigen-binding fragment thereof is administered in combination therapy with durvalumab or an antigen-binding fragment thereof within a two-week treatment period, within a four-week treatment period, within a six-week treatment period, within an eight-week treatment period, within a twelve-week treatment period, within a twenty-four-week treatment period, or within a treatment period of one year or longer. In specific embodiments, olerumab or an antigen-binding fragment thereof is administered within a three-week treatment period, within a six-week treatment period, within a nine-week treatment period, within a twelve-week treatment period, within a twenty-four-week treatment period, or within a treatment period of one year or longer. In specific embodiments, olerumab or an antigen-binding fragment thereof is administered within a two-month treatment period, within a four-month treatment period, or within a six-month treatment period or longer.

[0208] In specific embodiments, oreluzumab or an antigen-binding fragment thereof is administered in combination therapy with durvalumab or an antigen-binding fragment thereof every two weeks, every three weeks, every four weeks, every six weeks, every eight weeks, every ten weeks, or every twelve weeks. In specific embodiments, oreluzumab or an antigen-binding fragment thereof is administered in combination therapy with durvalumab or an antigen-binding fragment thereof for a one-year treatment period, a two-year treatment period, or a three-year or longer treatment period.

[0209] In specific embodiments, olerumumab or its antigen-binding fragment is administered repeatedly every 14 to 28 days in combination therapy with durvalumab or its antigen-binding fragment. In other embodiments, olerumumab or its antigen-binding fragment is administered repeatedly every 14 days. In other embodiments, olerumumab or its antigen-binding fragment is administered repeatedly every 21 days. In further embodiments, olerumumab or its antigen-binding fragment is administered repeatedly every 28 days. In further embodiments, olerumumab or its antigen-binding fragment is administered every 14 days for at least two doses (e.g., two, three, or four doses) and then every 28 days. In further embodiments, olerumumab or its antigen-binding fragment is administered every 21 days for at least two doses (e.g., two, three, or four doses) and then every 28 days.

[0210] In certain embodiments, durvalumab is administered at a frequency comparable to that of olerumumab. In certain embodiments, durvalumab is administered repeatedly every 14 to 28 days. In other embodiments, durvalumab is administered repeatedly every 14 days. In other embodiments, durvalumab is administered repeatedly every 21 days. In further embodiments, durvalumab is administered repeatedly every 28 days. In further embodiments, durvalumab is administered repeatedly every 21 days for at least two doses (e.g., two doses, three doses, or four doses), and then every 28 days.

[0211] The dosage of the combination therapy of olerumumab or its antigen-binding fragment and durvalumab will vary in part depending on the patient's body size (weight, body surface or organ size) and condition (age and overall health). In specific embodiments, one or more doses of olerumumab or its antigen-binding fragment are administered to the patient as a combination therapy, wherein the dose is 5 mg / kg, 10 mg / kg, 20 mg / kg or 40 mg / kg. In specific embodiments, one or more doses of olerumumab or its antigen-binding fragment are administered to the patient as a combination therapy, wherein the dose of olerumumab or its antigen-binding fragment is 750 mg, 1500 mg, 2250 mg or 3000 mg.

[0212] The dosage of durvalumab in combination therapy with olerumumab will vary in part based on the patient's size (weight, body surface or organ size) and condition (age and overall health). In specific embodiments, one or more doses of durvalumab or an antigen-binding fragment thereof are administered to a patient as a combination therapy, wherein the dose is 3 mg / kg, 10 mg / kg, or 20 mg / kg. In specific embodiments, one or more doses of durvalumab or an antigen-binding fragment thereof are administered to a patient as a combination therapy, wherein the dose is 1500 mg.

[0213] In certain embodiments, a bolus loading dose of olerumab, or an antigen-binding fragment thereof, and / or durvalumab, or an antigen-binding fragment thereof, is administered to a patient presenting with a tumor. In certain embodiments, a first dose of olerumab, or an antigen-binding fragment thereof, and / or durvalumab, or an antigen-binding fragment thereof, is administered to the patient, followed by a second, lower dose of olerumab, or an antigen-binding fragment thereof, and / or durvalumab, or an antigen-binding fragment thereof.

[0214] In specific embodiments, the patient is administered 2 mg / kg of olerumumab, or an antigen-binding fragment thereof, every two weeks, and 10 mg / kg of durvalumab, or an antigen-binding fragment thereof, is administered to the patient every two weeks. In specific embodiments, the patient is administered 5 mg / kg of olerumumab, or an antigen-binding fragment thereof, every two weeks, and 10 mg / kg of durvalumab, or an antigen-binding fragment thereof, is administered to the patient every two weeks. In specific embodiments, the patient is administered 10 mg / kg of olerumumab, or an antigen-binding fragment thereof, every two weeks, and 10 mg / kg of durvalumab, or an antigen-binding fragment thereof, is administered to the patient every two weeks. In specific embodiments, the patient is administered 20 mg / kg of olerumumab, or an antigen-binding fragment thereof, every two weeks, and 10 mg / kg of durvalumab, or an antigen-binding fragment thereof, is administered to the patient every two weeks. In specific embodiments, the patient is administered 40 mg / kg of olerumumab, or an antigen-binding fragment thereof, every two weeks, and 10 mg / kg of durvalumab, or an antigen-binding fragment thereof, is administered to the patient.

[0215] In certain embodiments, 2 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 10 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every two weeks. In certain embodiments, 5 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 10 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every two weeks. In certain embodiments, 10 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 10 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every two weeks. In certain embodiments, 20 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 10 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every two weeks. In certain embodiments, 40 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 10 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every two weeks.

[0216] In certain embodiments, 2 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 20 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every four weeks. In certain embodiments, 5 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 20 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every four weeks. In certain embodiments, 10 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 20 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every four weeks. In certain embodiments, 20 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 20 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every four weeks. In certain embodiments, 40 mg / kg of olerumab or an antigen-binding fragment thereof is administered to the patient every four weeks, and 20 mg / kg of durvalumab or an antigen-binding fragment thereof is administered to the patient every four weeks.

[0217] In specific embodiments, patients are administered 1500 mg or 3000 mg of olerumab, or an antigen-binding fragment thereof, every 2 weeks for two 28-day cycle doses, then every 4 weeks; and 1500 mg of durvalumab, or an antigen-binding fragment thereof, is administered every 4 weeks.

[0218] In specific embodiments, the patient is administered 3000 mg of olerumab or an antigen-binding fragment thereof every 2 weeks and 1500 mg of durvalumab or an antigen-binding fragment thereof.

[0219] In specific embodiments, the patient is administered 3000 mg of olerumab or an antigen-binding fragment thereof every 2 weeks for two months, then every 4 weeks, and 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks.

[0220] In other embodiments, olerumab or an antigen-binding fragment thereof can be administered in combination therapy with chemotherapy.

[0221] In certain embodiments, olerumab or an antigen-binding fragment thereof is administered only once or infrequently to a patient with a tumor in combination with chemotherapy while still providing benefit to the patient. In further embodiments, additional subsequent doses are administered to the patient. Subsequent doses may be administered at varying time intervals depending on the patient's age, weight, clinical assessment, tumor burden, and / or other factors, including the discretion of the attending physician.

[0222] In specific embodiments, olerumumab or an antigen-binding fragment thereof is administered in combination with chemotherapy over a two-week treatment period, a three-week treatment period, a four-week treatment period, a six-week treatment period, an eight-week treatment period, a twelve-week treatment period, a twenty-four-week treatment period, or a treatment period of one year or longer. In specific embodiments, olerumumab or an antigen-binding fragment thereof is administered over a three-week treatment period, a six-week treatment period, a nine-week treatment period, a twelve-week treatment period, a twenty-four-week treatment period, or a treatment period of one year or longer. In specific embodiments, olerumumab or an antigen-binding fragment thereof is administered over a two-month treatment period, a four-month treatment period, or a six-month treatment period or longer. In specific embodiments, olerumumab or an antigen-binding fragment thereof is administered over a one-year treatment period, a two-year treatment period, or a three-year treatment period or longer.

[0223] In specific embodiments, olerumab or an antigen-binding fragment thereof is administered every two weeks, every three weeks, every four weeks, every six weeks, every eight weeks, every ten weeks, or every twelve weeks in combination with chemotherapy.

[0224] In certain embodiments, in combination with chemotherapy, olerumumab or its antigen-binding fragment is administered repeatedly every 14 to 28 days. In other embodiments, olerumumab or its antigen-binding fragment is administered repeatedly every 14 days. In other embodiments, olerumumab or its antigen-binding fragment is administered repeatedly every 21 days. In further embodiments, olerumumab or its antigen-binding fragment is administered repeatedly every 28 days. In further embodiments, olerumumab or its antigen-binding fragment is administered every 14 days for at least two doses (e.g., two, three, or four doses) and then every 28 days. In further embodiments, olerumumab or its antigen-binding fragment is administered every 21 days for at least two doses (e.g., two, three, or four doses) and then every 28 days.

[0225] The dosage of the combination therapy of olerumumab or its antigen-binding fragment and chemotherapy will vary in part according to the patient's body size (weight, body surface or organ size) and condition (age and overall health). In specific embodiments, in combination with chemotherapy, one or more doses of olerumumab or its antigen-binding fragment are administered to the patient, wherein the dose of olerumumab or its antigen-binding fragment is 750 mg, 1500 mg or 3000 mg. In specific embodiments, in combination with chemotherapy, one or more doses of olerumumab or its antigen-binding fragment are administered to the patient, wherein the dose of olerumumab or its antigen-binding fragment is 2250 mg.

[0226] In certain embodiments, the chemotherapy comprises at least one of cisplatin, pemetrexed, nab-paclitaxel, carboplatin, gemcitabine, cisplatin, oxaliplatin, leucovorin, 5-fluorouracil, and docetaxel. In certain embodiments, the chemotherapy comprises 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 comprises oxaliplatin, leucovorin, and 5-fluorouracil. In certain embodiments, the chemotherapy comprises nab-paclitaxel and carboplatin. In certain embodiments, the chemotherapy comprises gemcitabine and cisplatin. In certain embodiments, the chemotherapy comprises gemcitabine and carboplatin. In certain embodiments, the chemotherapy comprises pemetrexed and carboplatin. In certain embodiments, the chemotherapy comprises pemetrexed and cisplatin.

[0227] In certain embodiments, the chemotherapy comprises at least one of gemcitabine, nab-paclitaxel, oxaliplatin, folinate, and 5-fluorouracil.

[0228] The dosage of chemotherapy combined with olerumumab will vary in part based on the patient's size (weight, body surface or organ size) and condition (age and overall health). Olerumumab can be used in combination with chemotherapy using any chemotherapy regimen known in the art. In a specific embodiment, the dosage of one or more doses administered to a patient is 1000 mg / m 2 Gemcitabine and a dose of 125 mg / m 2 In a specific embodiment, the patient is administered one or more doses of 85 mg / m 2 Oxaliplatin at a dose of 400 mg / m 2 Calcium folinate and a dose of 2400 mg / m 2 of 5-fluorouracil.

[0229] In certain embodiments, the patient is administered one or more doses of 85 mg / m 2 In certain embodiments, the patient is administered one or more doses of 400 mg / m 2 In certain embodiments, the patient is administered one or more doses of 2400 mg / m 2 In certain embodiments, one or more doses of 85 mg / m 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 2400mg / m 2 of 5-fluorouracil.

[0230] In certain embodiments, one or more doses of 100 mg / m 2 In certain embodiments, the patient is administered one or more doses of 1000 or 1250 mg / m 2 In certain embodiments, the patient is administered one or more doses of 500 mg / m 2 In certain embodiments, one or more doses of pemetrexed at AUC 5 or 6 of carboplatin are administered to the patient. In certain embodiments, one or more doses of 75 mg / m 2 of cisplatin.

[0231] In certain embodiments, chemotherapy is administered at a frequency comparable to that of olerulumab. In certain embodiments, chemotherapy is administered every 7 to 28 days. In other embodiments, chemotherapy is administered every 7 days. In other embodiments, chemotherapy is administered every 14 days. In other embodiments, chemotherapy is administered every 21 days. In other embodiments, chemotherapy is administered every 28 days. In other embodiments, chemotherapy is administered on days 1 and 8 of a 21-day cycle.

[0232] In other embodiments, olerumab or an antigen-binding fragment thereof can be administered in combination therapy with chemotherapy and durvalumab or an antigen-binding fragment thereof.

[0233] In certain embodiments, the combination therapy includes olerumumab, durvalumab, and chemotherapy, and durvalumab is administered about as frequently as olerumumab. In certain embodiments, olerumumab is administered about twice as frequently as durvalumab. In certain embodiments, durvalumab is administered repeatedly every 14 to 28 days. In other embodiments, durvalumab is administered repeatedly every 14 days. In further embodiments, durvalumab is administered repeatedly every 21 days. In further embodiments, durvalumab is administered repeatedly every 28 days. In further embodiments, durvalumab is administered repeatedly every 21 days for at least two doses (e.g., two doses, three doses, or four doses), and then every 28 days.

[0234] The dosage of the combination therapy of durvalumab or an antigen-binding fragment thereof with olerumab or an antigen-binding fragment thereof and chemotherapy will vary in part depending on the patient's size (weight, body surface or organ size) and condition (age and overall health). In a specific embodiment, one or more doses of durvalumab or an antigen-binding fragment thereof are administered to a patient as a combination therapy, wherein the dose of durvalumab or an antigen-binding fragment thereof is 1500 mg.

[0235] In certain embodiments, patients are administered 750 mg of olerumab 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 / m2 on days 1, 8, and 15. 2 Gemcitabine and 125 mg / m 2 In a specific embodiment, the patient is administered 1500 mg of olerulumab 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 / m2 on days 1, 8, and 15. 2 Gemcitabine and 125 mg / m 2 In a specific embodiment, the patient is administered 3000 mg of olerulumab 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 / m2 on days 1, 8, and 15. 2 Gemcitabine and 125 mg / m 2 Albumin-bound paclitaxel was then administered every 4 weeks.

[0236] In certain embodiments, patients are administered 750 mg of olerumab 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 / m2 on days 1 and 15. 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 2400 mg / m 2 In a specific embodiment, the patient is administered 1500 mg of olerumab 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 / m2 on days 1 and 15. 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 2400 mg / m 2 In certain embodiments, patients are administered 3000 mg of olerumab 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 / m2 on days 1 and 15. 2 Oxaliplatin, 400 mg / m 2Calcium folinate and 2400 mg / m 2 5-Fluorouracil is then administered every 4 weeks.

[0237] In certain embodiments, patients are administered 1500 mg or 3000 mg of olerumab or an antigen-binding fragment thereof every 2 weeks for four doses and then every 4 weeks; and a regimen comprising 1000 mg / m 2 Gemcitabine and 125 mg / m 2 Chemotherapy with nab-paclitaxel. Chemotherapy is administered on days 1, 8, and 15 of four 28-day cycles, and then every 4 weeks. In addition, 1500 mg of durvalumab or an antigen-binding fragment thereof may be administered every 4 weeks.

[0238] In certain embodiments, patients are administered 1500 mg or 3000 mg of olerumab or an antigen-binding fragment thereof every 2 weeks for four doses and then every 4 weeks; and a regimen comprising 85 mg / m 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 400 mg / m 2 5-FU followed by 2400 mg / m 2 Chemotherapy with 5-FU. Chemotherapy is administered on days 1 and 15 of four 28-day cycles, then every 4 weeks. In addition, 1500 mg of durvalumab or an antigen-binding fragment thereof may be administered every 4 weeks.

[0239] In certain embodiments, the patient is administered (i) olerumab, or an antigen-binding fragment thereof, (a) at 1500 mg every 3 weeks for four 21-day cycles, then every 4 weeks; or (b) at 2250 mg every 3 weeks for four 21-day cycles, 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, then every 4 weeks; and (iii) chemotherapy comprising: (a) 100 mg / m 2 on days 1, 8, and 15 of a 21-day cycle; 2 Albumin-bound paclitaxel for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles; (b) 1000 mg / m2 on days 1 and 8 of a 21-day cycle 2 or 1250 mg / m 2 Gemcitabine was continued for 4 cycles and was administered at 75 mg / m2 on day 1 of a 21-day cycle. 2 Cisplatin was continued for 4 cycles; (c) 1000 mg / m2 on days 1 and 8 of a 21-day cycle 2 or 1250 mg / m2 Gemcitabine for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles; (d) 500 mg / m2 on day 1 of a 21-day cycle 2 Pemetrexed for 4 cycles and 5 or 6 AUC carboplatin on day 1 of a 21-day cycle for 4 cycles; or (e) 500 mg / m2 on day 1 of a 21-day cycle 2 Pemetrexed was continued for 4 cycles and was administered at 75 mg / m2 on day 1 of a 21-day cycle. 2 Cisplatin is continued for 4 cycles. Pemetrexed may be further administered as maintenance therapy, for example at 500 mg / m² every 4 weeks. 2 Application.

[0240] In certain embodiments, the patient is administered (i) 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks; (ii) 3000 mg of olerulumab or an antigen-binding fragment thereof every 2 weeks for five doses, then every 4 weeks; and (iii) chemotherapy comprising (a) 400 mg / m2 every 2 weeks. 2 Folinic acid (b) 85 mg / m every 2 weeks 2 oxaliplatin on day 1; and (c) 400 mg / m 2 of 5-fluorouracil, then 2400 mg / m2 of 5-fluorouracil every 2 weeks.

[0241] In other embodiments, bevacizumab or an antigen-binding fragment thereof can be administered in combination therapy with olelumab or an antigen-binding fragment thereof and chemotherapy (e.g., chemotherapy comprising oxaliplatin, leucovorin, and 5-fluorouracil).

[0242] As used herein, the term "bevacizumab" refers to an antibody that selectively binds to vascular endothelial growth factor (VEGF), as disclosed in US Pat. Nos. 6,884,879 and 7,169,901, which are incorporated herein by reference in their entireties.

[0243] 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 wherein the light chain variable domain comprises the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 22-24.

[0244] In certain embodiments, one or more doses of 5 mg / kg bevacizumab or an antigen-binding fragment thereof are administered to the patient. Bevacizumab or an antigen-binding fragment thereof can be administered, for example, every 2 weeks. Bevacizumab or an antigen-binding fragment thereof can be administered, for example, intravenously.

[0245] In certain embodiments, the patient is administered (i) 1500 mg of durvalumab or an antigen-binding fragment thereof every 4 weeks; (ii) 3000 mg of olerulumab or an antigen-binding fragment thereof every 2 weeks for four doses, then every 4 weeks; (iii) chemotherapy comprising (a) 400 mg / m2 every 2 weeks. 2 Folinic acid (b) 85 mg / m every 2 weeks 2 oxaliplatin; and (c) 2400 mg / m every 2 weeks 2 and (iv) 5 mg / kg of bevacizumab or an antigen-binding fragment thereof every 2 weeks.

[0246] In certain embodiments, the patient being 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.

[0247] In certain embodiments, the patient being treated has a solid tumor, such as colorectal cancer, non-small cell lung cancer, or pancreatic cancer. In certain embodiments, the patient has pancreatic ductal adenocarcinoma. In certain embodiments, the patient has previously untreated metastatic pancreatic ductal adenocarcinoma. In certain embodiments, the patient has previously been treated with a gemcitabine-based therapy for metastatic pancreatic ductal adenocarcinoma.

[0248] In certain embodiments, the patient has a resectable NSCLC tumor, an early-stage NSCLC tumor, or a stage IV NSCLC tumor.

[0249] In certain embodiments, the patient has metastatic colorectal cancer.

[0250] In certain embodiments, the patient has a tumor with high or low PD-L1 expression. The tumor with high or low PD-L1 expression can be NSCLC.

[0251] 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 a NSCLC tumor.

[0252] In certain embodiments, the patient has a tumor that has not received prior treatment in a recurrent and / or metastatic setting.

[0253] 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 by subcutaneous injection. In specific embodiments, administration is performed by intravenous infusion.

[0254] Response Evaluation Criteria in Solid Tumors (RECIST) refers to a set of published rules that define when a cancer patient improves, remains the same, or worsens during treatment. The types of responses a patient may have are complete response (CR), partial response (PR), progressive disease (PD), and stable disease (SD).

[0255] The methods provided herein can be used for disease control (DC) of tumors. Disease control can be complete response (CR), partial response (PR) or stable disease (SD).

[0256] A "complete response" (CR) is defined as the disappearance of all lesions (whether measurable or non-measurable) and the absence of new lesions. A complete response can be confirmed using repeated serial assessments at least four weeks from the first recorded date. New non-measurable lesions are excluded from CR.

[0257] A "partial response" (PR) is a ≥50% reduction in tumor burden relative to baseline. Confirmation can be obtained using serial repeat assessments for at least 4 weeks from the first recorded date.

[0258] "Progressive disease" (PD) refers to an increase in tumor burden of ≥25% relative to the recorded minimum value (nadir). Confirmation can be obtained by serial repeat assessments for at least 4 weeks from the first recorded date. New non-measurable lesions do not define PD.

[0259] “Stable disease” (SD) means that the criteria for CR, PR, or PD are not met.

[0260] Without limiting the present disclosure, various embodiments of the present disclosure are described below for illustrative purposes.

[0261] In one aspect (A1) of the methods provided herein, a method of treating a tumor in a human patient comprises administering olerumab or an antigen-binding fragment thereof to the patient.

[0262] In one aspect (A2) of A1, olerumab 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.

[0263] In another aspect (A3) of A1, olerumab or an antigen-binding fragment thereof is administered at a dose of 40 mg / kg.

[0264] In one aspect (A4) of any one of A1-A3, olerumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

[0265] In one aspect (A5) of A4, olerumab or an antigen-binding fragment thereof is administered every 14 days.

[0266] In another aspect (A6) of A4, olerumab or an antigen-binding fragment thereof is administered every 28 days.

[0267] In one aspect (A7) of any one of A1-A6, administration of olerumab or an antigen-binding fragment thereof results in a partial response.

[0268] In another aspect (A8) of any one of A1-A6, administration of olerumab or an antigen-binding fragment thereof results in a complete response.

[0269] In another aspect (A9) of any one of A1-A6, the tumor is a solid tumor.

[0270] In one aspect (A10) of A9, the solid tumor is colorectal cancer, non-small cell lung cancer, or pancreatic cancer.

[0271] In one aspect (A11) of any one of A1-A10, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0272] In one aspect (A12) of the methods provided herein, a method of treating a solid tumor in a human patient comprises administering 40 mg / kg of olerumab or an antigen-binding fragment thereof to the patient.

[0273] In one aspect (A13) of the methods provided herein, a method of treating a tumor in a human patient comprises administering to the patient olerumab, or an antigen-binding fragment thereof, and durvalumab, or an antigen-binding fragment thereof.

[0274] In one aspect (A14) of A13, olerumab 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.

[0275] In one aspect (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.

[0276] In one aspect (A16) of any one of A13-A15, olerumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

[0277] In one aspect (A17) of any one of A13-A16, durvalumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

[0278] In one aspect (A18) of any one of A13-A17, the tumor is a solid tumor.

[0279] In one aspect (A19) of A18, the solid tumor is colorectal cancer, non-small cell lung cancer, or pancreatic cancer.

[0280] In one aspect (A20) of any one of A13-A19, the patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0281] In one aspect (A21) of the methods provided herein, a method of treating a tumor in a human patient comprises administering to the patient olerumab or an antigen-binding fragment thereof and chemotherapy.

[0282] In one aspect (A22) of A21, olerumab or an antigen-binding fragment thereof is administered at a dose of 750 mg, 1500 mg or 3000 mg.

[0283] In one aspect (A23) of A21 or A22, olerumab or an antigen-binding fragment thereof is administered every 14 to 28 days.

[0284] In one aspect (A24) of any one of A21-A23, the method further comprises administering durvalumab or an antigen-binding fragment thereof.

[0285] In one aspect (A25) of A24, durvalumab or an antigen-binding fragment thereof is administered at a dose of 1500 mg.

[0286] In one aspect (A26) of A24 or A25, durvalumab or an antigen-binding fragment thereof is administered every 28 days.

[0287] In one aspect (A27) of any one of A21-A26, the chemotherapy comprises at least one of gemcitabine, nab-paclitaxel, oxaliplatin, folinate, and 5-fluorouracil.

[0288] In one aspect (A28) of A27, the chemotherapy comprises 1000 mg / m 2 Gemcitabine and 125 mg / m 2 Albumin-bound paclitaxel.

[0289] In another aspect (A29) of A27, chemotherapy comprises 85 mg / m 2 Oxaliplatin, 400 mg / m 2 Calcium folinate and 2400 mg / m 2 5-Fluorouracil.

[0290] In one aspect (A30) of any one of A21-A29, the chemotherapy is administered every 7 to 28 days.

[0291] In one aspect (A31) of any one of A29-A30, 5-fluorouracil is administered by continuous intravenous infusion over 46 to 48 hours.

[0292] In one aspect (A32) of A28, the patient has previously untreated metastatic pancreatic ductal adenocarcinoma.

[0293] In one aspect (A33) of A29, the patient has metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy.

[0294] Examples

[0295] The following examples illustrate specific embodiments of the present disclosure and various uses thereof. They are set forth for illustrative purposes only and should not be construed in any way as limiting the scope of the present invention.

[0296] Example 1: Toxicity evaluation of olelumab in mice and monkeys

[0297] Mice and cynomolgus monkeys were selected as pharmacologically relevant species to evaluate the toxicity of olerumumab. This assessment was based on a combination of factors: (i) moderate to high protein sequence identity between mouse and cynomolgus monkey CD73 and human CD73 (86% and 98%, respectively); (ii) similar binding affinity of olerumumab to mouse, cynomolgus monkey, and human CD73; and (iii) similar potency of olerumumab against mouse, monkey, and human recombinant CD73 enzymatic activity in cell-based in vitro assays. In addition, in cynomolgus monkeys, a single IV dose of ≥1 mg / kg of olerumumab (the lowest dose tested) inhibited soluble CD73 in serum with a dose-related duration of inhibition. The systemic and local toxicity of olerumab was evaluated in a Good Laboratory Practice (GLP) toxicity study in CD-1 mice at 0 mg / kg, 100 mg / kg, or 200 mg / kg (5 weeks, repeated intravenous [IV] bolus doses every 4 days for a total of 9 doses) and in cynomolgus monkeys at 0 mg / kg, 30.5 mg / kg, 103.7, or 300.7 mg / kg (5 weeks, repeated IV 30-minute infusion doses once weekly for a total of 5 doses). No adverse reactions related to olerumab were observed at doses up to 200 mg / kg in CD-1 mice or up to 300.7 mg / kg in cynomolgus monkeys. Safety pharmacology endpoints (electrocardiogram [ECG], blood pressure, and behavioral examinations) evaluated as part of the 5-week cynomolgus monkey study also did not show effects related to olerumab. Therefore, the 200 mg / kg / dose (the highest dose tested; maximum observed concentration [C max ], 6,200 μg / mL; area under the concentration-time curve [AUC] 0-96hr , 229,000 μg·hr / mL) and 300.7 mg / kg / dose in cynomolgus monkeys (the highest dose tested; C max , 11,000 μg / mL; AUC 0-168.5hr , 834,000 μg·hr / mL) is considered the no-observed-adverse-effect level (NOAEL). In the GLP human tissue cross-reactivity assessment, olerumab staining was observed in multiple cell types across the human tissue panel examined.

[0298] The ability of olerumab (alone or in combination with durvalumab) to induce cytokine release was evaluated in a human in vitro assay using blood or peripheral blood mononuclear cells from healthy donors. Olerumab, alone or in combination with durvalumab (in solution or immobilized on plastic wells by dry coating), did not induce cytokine release.

[0299] Example 2: Single-dose pharmacokinetic / pharmacodynamic study in cynomolgus monkeys

[0300] Five male cynomolgus monkeys were administered olerumab as a single IV bolus 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 before the first dose and 2, 3, 5, 7, 10, 14, 21, 28, and 35 days after the first dose.

[0301] To detect free sCD73, the plate was coated with 0.5ug / mL anti-CD73 antibody overnight, and then 50uL monkey serum was added to the plate. The plate was incubated for 15min±1min, washed, and anti-CD73-HRP was added. Free sCD73 was inhibited in all dose groups, but the inhibition of free sCD73 was dose-dependent ( Figure 1 ).

[0302] To determine immune modulation, exogenous antigen (KLH) responses were measured. KLH responses were measured by first immunizing monkeys with unadjuvanted exogenous antigen (KLH) on day 1. KLH T cell-dependent antibody responses (TDARs) were performed on days 7, 8, 11, 15, 22, 29, and 36. Ex vivo KLH stimulation of PBMC IFN-γ and IL-2 ELISPOTs was measured on days 1, 4, 8, 7, 15, and 22. Olezumab did not enhance the response to exogenous antigen (KLH). Anti-KLH IgM and IgG antibody responses were detectable, but did not show a dose-dependent increase with oleezumab treatment ( Figure 2A and 2B T cell responses to ex vivo KLH stimulation were detectable but did not change with olerumab treatment ( Figure 3A and 3B ).

[0303] Endogenous pathogen responses were also investigated by endogenous pathogen validation. 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. In most cynomolgus monkeys, LCV (the monkey homolog of EBV) was detected at low levels ( Figure 4 IgG titers to EBV gp125 and CMV gB were detected but did not change with olerumab treatment. T cell responses to EBVBZLF1 and inactivated human CMV were detected but did not change with olerumab treatment.

[0304] Example 3: Olerumab monotherapy and combination with durvalumab in the treatment of solid tumors

[0305] The study is a first-in-human (FTIH), Phase 1, multicenter, open-label, dose-escalation and dose-expansion study in which olerumab is administered as a single agent or in combination with durvalumab in adult subjects to evaluate the safety, tolerability, PK, immunogenicity, pharmacodynamics, and preliminary antitumor activity in adult subjects with selected advanced solid tumors. Figure 7A and 7B The study flow diagram for dose escalation and dose expansion used for this part of the study is shown in The following abbreviations and legends are used to describe the study flow diagram: DLT = dose-limiting toxicity; MSS-CRC = microsatellite stable CRC.

[0306] Safety was assessed by the occurrence of adverse events (AEs), serious adverse events (SAEs), DLTs, and changes from baseline in laboratory parameters, vital signs, and electrocardiogram results. Endpoints for the assessment of antitumor activity included objective response (OR), disease control (DC), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Tumor response was assessed using RECIST v1.1. Pharmacokinetic parameters included, but were not limited to, maximum observed concentration, area under the concentration-time curve, clearance, and terminal half-life. Endpoints for the assessment of immunogenicity of olelumab and durvalumab included the number and percentage of subjects who developed detectable anti-drug antibodies, while endpoints for the assessment of pharmacodynamic activity included assessment of target expression (e.g., CD73, PD-L1) in tumor biopsy specimens.

[0307] 1. Subjects

[0308] For the dose-escalation arm, the subject population included subjects aged ≥18 years with histologically or cytologically confirmed colorectal adenocarcinoma (CRC) or pancreatic adenocarcinoma. Subjects with CRC or pancreatic adenocarcinoma must have progressed on standard therapy, be refractory to standard therapy, or be intolerant to standard therapy.

[0309] In the dose-escalation phase, subjects with CRC or pancreatic adenocarcinoma must have received no more than five prior lines of therapy. Subjects with CRC enrolled in the dose-expansion phase must have received at least two regimens including a fluoropyrimidine [e.g., 5-FU or capecitabine], oxaliplatin, and irinotecan (unless contraindicated), but in the metastatic setting, no more than four prior lines of systemic therapy and must not have defective DNA mismatch repair. Subjects with KRAS mutations (e.g., exon 2, codon 12, or 13) are also enrolled.

[0310] Pancreatic adenocarcinoma subjects enrolled in the dose expansion phase must have received one but no more than two prior lines of systemic therapy in the metastatic setting. The first twenty subjects with CRC and pancreatic adenocarcinoma in the expansion phase must have positive CD73 expression (determined by IHC) on at least 10% of tumor cells, with staining as weak, moderate, or strong; or a combination of such staining.

[0311] All subjects were required to have at least one lesion with a score of 0 or 1 using the RECIST guidelines (Eastern Cooperative Oncology Group (ECOG)) and adequate organ function, defined as an absolute neutrophil count ≥1,500 / mm 3 Platelet count ≥75,000 / mm 3 ; prothrombin 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, as determined by the Cockcroft-Gault formula; 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 as high as 5×ULN in the presence of liver metastases but must not be associated with elevated bilirubin); potassium, sodium, magnesium, and calcium (corrected for serum albumin) ≤grade 1 or within institutional ranges of normal; and albumin ≥3.0 g / dL.

[0312] Subjects were excluded from study participation if they had received prior treatment with a TNFRSF agonist, had received prior treatment with a regimen containing a CTLA-4, PD-L1, or PD-1 antagonist (for subjects with CRC or pancreatic adenocarcinoma), required additional immunosuppression other than corticosteroids to manage AEs, had recurrence of AEs if rechallenged, and currently required a maintenance dose of >10 mg prednisone or equivalent daily, had received any conventional or investigational anticancer therapy within 28 days prior to the first dose of olerumab, within 14 days of the first dose of olerumab, or had received any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment.

[0313] 2. Dose escalation phase

[0314] The dose-escalation phase of the study included two arms: (i) escalating dose levels of olerumab monotherapy and (ii) escalating dose levels of olerumab in combination with a single dose level of durvalumab, both administered in subjects with advanced CRC or pancreatic adenocarcinoma.

[0315] In the olerumab monotherapy dose-escalation arm, sequential cohorts of 3 to 6 subjects each received 1 of 4 dose levels of olerumab (5, 10, 20, or 40 mg / kg) by IV infusion every 2 weeks unless the maximum tolerated dose (MTD) was reached before all dose-escalation cohorts were completed. Figure 8 In the olerumab / durvalumab combination therapy dose-escalation arm, consecutive cohorts of 3 to 6 subjects each received one of four dose levels of olerumab (5, 10, 20, or 40 mg / kg) and a single dose level of 10 mg / kg of durvalumab, administered by IV infusion every 2 weeks, unless the MTD was reached before all dose-escalation cohorts were completed. Figure 8 If the MTD of olerumab is exceeded at the 5 mg / kg dose level in either the monotherapy or combination therapy arm, a lower dose level of olerumab of 2 mg / kg will be explored in that arm.

[0316] The dose selection of olerumab was based on nonclinical data and a clinical safety range based on nonclinical safety data, as described above for mice and monkeys. The pharmacologically driven starting dose level of 5 mg / kg olerumab is expected to have 98% to 91% CD73 saturation (peak and trough values, respectively) in the first dosing interval. At the starting dose level of 5 mg / kg, the cynomolgus monkey toxicity study provided a safety margin of 19-fold (based on the human equivalent dose [HED]), 73-fold (based on Cmax), and 70-fold (based on AUC). The dose escalation scheme in this study is designed to achieve higher and more sustained CD73 target inhibition while maintaining an adequate safety margin. At the highest dose of 40 mg / kg, the cynomolgus monkey toxicity study provided a safety margin of 2-fold (based on HED), 8-fold (based on Cmax), and 8-fold (based on AUC).

[0317] The dose level and treatment schedule of durvalumab (10 mg / kg Q2W) were based on the safety dose established in a Phase 1 / 2 study to evaluate the safety, tolerability, and PK of durvalumab in subjects with advanced solid tumors.

[0318] The proposed initial olerumab and durvalumab combination dose level utilized the durvalumab dose level (10 mg / kg IV every 2 weeks) that demonstrated an acceptable safety profile, while the olerumab dose level (5 mg / kg IV every 2 weeks) was not expected to provide maximal CD73 inhibition across the dosing interval. If the MTD was exceeded before the maximum proposed combination dose (40 mg / kg olerumab and 10 mg / kg durvalumab), the combination dose was further explored using 3 mg / kg durvalumab.

[0319] The dose escalation phase was performed on a 3+3 design. At least three subjects were enrolled in each dose level cohort, with the first dose of the study product staggered by at least 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 3 subjects during the DLT assessment and all available safety data were reviewed by the study-specific dose escalation committee, dose escalation would continue to the next higher dose cohort. If 1 of the 3 subjects in a dose level cohort experienced a DLT, that dose level cohort would be expanded to a total of 6 subjects. If no more than 1 of the 6 subjects in a dose level cohort experienced a DLT, dose escalation would continue to the next higher dose level cohort. 6 subjects were enrolled in the highest dose level cohort that did not exceed the MTD.

[0320] In the olerumab / durvalumab combination arm, if the MTD was exceeded at any olerumab dose level, additional cohorts of olerumab with 3 mg / kg durvalumab administered Q2W were explored. The first cohort of 3 to 6 subjects received olerumab at the same dose level and regimen that exceeded the MTD, but now received 3 mg / kg durvalumab via IV infusion Q2W. If the MTD was not exceeded, and provided this was not the highest monotherapy olerumab regimen-defined dose, additional sequential cohorts of 3 to 6 subjects were enrolled, each following a Q2W or Q4W regimen in combination with 3 mg / kg durvalumab administered Q2W, based on the olerumab dose level described above. After combination dose escalation was completed, if the MTD was not exceeded at 10 mg / kg durvalumab administered Q2W, an alternative treatment regimen of olerumab at the highest dose level that did not exceed the MTD on the Q2W or Q4W regimen in combination with 20 mg / kg durvalumab administered Q4W was explored.

[0321] 3. Results

[0322] Among the 42 efficacy-evaluable subjects in the dose-expansion phase of olerumab 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%, 19.5%). The ORR (confirmed and unconfirmed) in the MSS-CRC (n=21) and pancreatic adenocarcinoma (n=20) cohorts was 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.

[0323] The following PK data are based on a total of 97 subjects treated with olerumab 5 to 40 mg / kg Q2W as monotherapy (n=40) or in combination with durvalumab 10 mg / kg Q2W (n=57). In both the monotherapy and combination therapy cohorts, nonlinear PK appeared to be exhibited at the lowest dose of 5 mg / kg of olerumab and linear PK was exhibited at 10 mg / kg and higher doses of olerumab. Serum exposure was similar when olerumab was administered alone or in combination with durvalumab. PK exposure (plasma trough concentration [Ctrough]) increased in a more than proportional manner from olerumab 5 to 10 mg / kg and in an approximately dose-proportional manner from olerumab 10 to 40 mg / kg. Accumulation of olerumab was observed after repeated dosing; C max The average accumulation ratio of C trough The average accumulation ratios ranged from 1.68 to 10.7.

[0324] Complete inhibition of free soluble CD73 was observed after administration of olerumab as monotherapy or in combination with durvalumab. Free serum soluble CD73 levels were below the limit of detection (0.25 ng / mL) in most subjects at all times after the first dose of olerumab (Figure 9).

[0325] Olerumab reduced the surface expression of CD73, as measured by mean fluorescence intensity (MFI) ( Figure 10A ) and the percentage of CD73+CD4 and CD8 cells in peripheral T cells ( Figure 10B ), there was no simultaneous reduction in total CD4 and CD8 cell counts at all doses ( Figure 10C ).

[0326] Dose-escalating treatment with olerulumab at 40 mg / kg 20 days after treatment initiation resulted in a decrease in CD73-stained tumor cells as determined by IHC ( Figure 11A and 11B Treatment with olelumab alone reduced tumor CD73 expression in 5 / 9 patients expressing >5% 2+ / 3+ CD73 at baseline, while increasing CD8+ TILs in all 5 samples ( Figure 11C Olerumab also inhibits CD73 enzyme activity in the tumor microenvironment ( Figure 12 ).

[0327] Linear PK was observed at doses ≥10 mg / kg of olerulumab. Based on these results, serum concentrations above 40 μg / mL are expected to saturate >99% CD73, and the estimated effective half-life for the duration of dosing was determined to be approximately 13 days ( Figure 13 ). No ADA was detected. Olerumab also demonstrated evidence of a PD effect (Figure 14). CD73 was reduced at 40 mg / kg of olerumab and was associated with an increase in CD8+ T cells in patients with >5% 2+ / 3+ CD73 at baseline. Based on safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy analyses, the recommended Phase 2 dose of olerumab of 40 mg / kg Q2W was selected.

[0328] Example 4: Olerumab in combination with durvalumab; dose expansion phase

[0329] 1. Subjects

[0330] A dose expansion study of olerumab in combination with durvalumab was conducted in adult subjects to evaluate safety, tolerability, PK, immunogenicity, pharmacodynamics, and preliminary anti-tumor activity in adult subjects with selected advanced solid tumors. The flow chart of the combination dose expansion study 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.

[0331] NSCLC subjects enrolled in the dose expansion phase must have EGFR mutations known to be associated with EGFR TKI sensitivity (including G719X, exon 19 deletions, L858R, L861Q) and, in the metastatic setting, must have received at least one but no more than four prior lines of therapy (including investigational therapy) and must have received an approved EGFR TKI followed by clinical or radiographic progression or intolerance.

[0332] Subjects were excluded from study participation if they had received prior treatment with a TNFRSF agonist, had prior exposure to any investigational immunotherapy or received an EGFR TKI, had received prior therapy containing a CTLA-4, PD-L1 regimen, required additional immunosuppression other than corticosteroids to manage AEs, had recurrence of AEs if rechallenged, and currently required a maintenance dose of >10 mg prednisone or equivalent daily, had received any conventional or investigational anticancer therapy within 28 days prior to the first dose of olerumab or within 14 days of the first dose of olerumab, or had received any concurrent chemotherapy, immunotherapy, or biologic or hormonal therapy for cancer treatment.

[0333] Once the MTD or MAD was established in the combination arm of the dose-escalation phase, dose expansion of the olerumab / durvalumab combination therapy began. The dose-expansion phase included the following 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.

[0334] The selection of dose levels and treatment regimens is based on considerations of PK, safety, and comparative pharmacodynamic effects as a function of dose level and treatment regimen, with the constraint that the dose level will not exceed the applicable MTD or MAD.

[0335] For each of the MSS-CRC, pancreatic adenocarcinoma, and EGFRmNSCLC dose-expansion cohorts, an interim analysis was conducted when the first 20 subjects were enrolled and followed for at least 16 weeks. For each of the MSS-CRC and pancreatic adenocarcinoma cohorts, a second interim analysis was conducted after 40 subjects were enrolled and followed for at least 16 weeks.

[0336] All subjects were regularly assessed 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). Tumor response was assessed using RECIST v1.1 guidelines. All subjects were followed for survival until the end of the study.

[0337] 3. Results

[0338] Among the 42 efficacy-evaluable subjects in the dose-expansion phase of olerumab 40 mg / kg + durvalumab 10 mg / kg, the overall objective response rate (ORR; confirmed and unconfirmed) was 7.1% (95% confidence interval [CI]: 1.5%, 19.5%). Confirmed ORRs in the MSS-CRC (n=41) and pancreatic adenocarcinoma (n=41) cohorts were 2.4% (95% CI: 0.1%, 23.8%) and 7.3% (unconfirmed) and 4.9% (confirmed) (95% CI: 1.2%, 31.7%), respectively. Figure 16 and 17 The overall disease control rate (DCR; 8 weeks) during the dose-expansion phase was 16.7% (95% CI: 7.0%, 31.4%). The DCRs in the MSS-CRC and pancreatic adenocarcinoma cohorts were 14.3% (95% CI: 3.0%, 36.3%) and 20.0% (95% CI: 5.7%, 43.7%), respectively.

[0339] The confirmed ORR in all patients with EGFRm NSCLC (n=20) was 20%, compared to 9.8% when durvalumab was administered as monotherapy (see ATLANTIC trial; Clinictrials.gov No. NCT02087423) ( Figure 18 Example 5: Olerumab with or without durvalumab in combination with chemotherapy in subjects with metastatic pancreatic ductal adenocarcinoma

[0340] 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 olerumab, with or without durvalumab, in combination with chemotherapy in 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 who had previously been treated with gemcitabine-based chemotherapy (not exposed to 5-FU, capecitabine, or oxaliplatin; 2L metastatic PDAC) were enrolled in Cohort B. The study consisted of two parts: dose escalation (Part 1) and dose expansion (Part 2).

[0341] The study enrolled up to approximately 204 subjects: 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 (without meeting standard of care in the setting of progressive disease [PD]), unacceptable toxicity, withdrawal of consent, or other discontinuation criteria.

[0342] Safety was assessed by the occurrence of adverse events (AEs), serious adverse events (SAEs), DLTs, and changes from baseline in laboratory parameters, vital signs, and electrocardiograms. Endpoints for evaluating antitumor activity included objective response (OR), disease control (DC), duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Tumor response was assessed using RECIST v1.1. Pharmacokinetic parameters included, but were not limited to, maximum observed concentration (C max ), reach C max Time (t max ), AUC, clearance, apparent volume of distribution (V d ) and terminal half-life (t 1 / 2 The development of antidrug antibodies (ADAs) and their potential impact on safety, pharmacodynamics, PK, and antitumor activity were also evaluated.

[0343] 1. Subjects

[0344] This study included adult subjects aged 18 years or older with histologically or cytologically confirmed pancreatic adenocarcinoma. Subjects with previously untreated metastatic PDAC (1L metastatic PDAC) were included in Cohort A. Subjects with metastatic PDAC previously treated with gemcitabine-based chemotherapy (without exposure to 5-FU, capecitabine, or oxaliplatin [if considered a line of treatment]; 2L metastatic PDAC) were included in Cohort B.

[0345] All subjects were required to have at least one lesion with a score of 0 or 1, measurable using the RECIST guidelines (Eastern Cooperative Oncology Group (ECOG)), and adequate organ function, defined as: 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 whom bilirubin must be ≤3×ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5× upper limit of normal (ULN) (AST / ALT can be as high as 5×ULN in the presence of liver metastases); and albumin ≥3.0 g / dL.

[0346] Subjects were excluded from study participation if they had received any conventional or investigational anticancer therapy within 21 days before the prescheduled first dose of study treatment, palliative radiotherapy within 14 days, or any previous immune-mediated therapy.

[0347] 2. Dose escalation phase

[0348] During Part 1, dose expansion of olerulumab 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 (see Table 1) of each regimen. Figure 19 Part 1 (dose escalation) enrolled up to 24 subjects: 9-12 subjects with 1L metastatic PDAC in Cohort A and 9-12 subjects with 2L metastatic PDAC in Cohort B were treated with escalating doses of olelumab.

[0349] Dose escalation begins with enrollment of at least 3 subjects (and a maximum of 6 subjects) at dose level 1 (1500 mg IV Q2W x 4 then Q4W). Subjects are monitored for DLTs. If no DLT is observed in a cohort of 3 to 6 evaluable subjects, dose escalation to the next higher dose cohort is permitted after review of all available safety data. If 1 subject in a dose level cohort of 3 or more evaluable subjects experiences a DLT, that dose level cohort will be expanded to a total of 6 subjects. If no more than 1 of 6 subjects in a dose level cohort experiences a DLT, dose escalation will continue to the next higher dose level cohort. If ≥ 2 subjects in a dose level cohort experience a DLT, the MTD is exceeded and no additional subjects are enrolled in that dose level cohort. If this occurs, the MTD is assessed for the previous dose level cohort, and if not already expanded, a total of 6 subjects are treated at the previous dose level. If ≤ 1 of 6 subjects experiences a DLT at the previous dose level, that dose level is the MTD. If the MTD is exceeded at the starting dose level, a lower dose level of olerumab 750 mg (dose level -1) can be evaluated.

[0350] like Figure 20 As shown and summarized below, during the dose escalation phase, patients received the following treatments: Queue A:

[0351] olerumab IV at one of three dose levels (750 mg, 1500 mg, or 3000 mg) administered Q2W for 4 doses, then every 4 weeks (Q4W); and

[0352] Administer durvalumab 1500 mg IV every 4 weeks, and

[0353] Gemcitabine 1000 mg / m² IV and nab-paclitaxel 125 mg / m² IV on days 1, 8, and 15, then repeated every 4 weeks Queue B:

[0354] olerumab IV at one of three dose levels (750 mg, 1500 mg, or 3000 mg) administered Q2W for 4 doses, then Q4W; and

[0355] Administer durvalumab 1500 mg IV every 4 weeks, and

[0356] Administer mFOLFOX on days 1 and 15 and then repeat on a Q4W schedule: oxaliplatin 85 mg / m 2 IV; leucovorin 400 mg / m 2 IV; IV bolus of 5-FU 400 mg / m 2 , followed by 5-FU 2400 mg / m by continuous IV infusion over 46 to 48 hours 2 .

[0357] Table 1: Olerumab dose levels evaluated in Part 1 (dose escalation)

[0358]

[0359] 3. Dose expansion phase

[0360] Once the recommended phase 2 dose (RP2D) for the cohort is determined, the process for inclusion in the part 2 dose expansion is as follows Figure 21 Overview. During Part 2 (dose expansion), the RP2D of olerumab, determined for each regimen in Part 1, was assessed with or without durvalumab in combination with chemotherapy. Part 2 enrolled up to 180 subjects, with 30 subjects in each 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); olerumab + gemcitabine and nab-paclitaxel (Arm A2); or olerumab + durvalumab + gemcitabine and nab-paclitaxel (Arm A3). Participants in Cohort B (2L metastatic PDAC) were randomly assigned in a 1:1:1 ratio to one of three treatment arms: mFOLFOX (Arm B1); olerumab plus mFOLFOX (Arm B2); or olerumab plus durvalumab plus mFOLFOX (Arm B3). There was no crossover between treatment arms.

[0361] The dose levels of olelumab were determined during Part 1 (dose escalation). Figure 22 and 23 As shown and summarized below, subjects in Cohorts A and B were randomly assigned to receive the following treatments:

[0362] Queue A

[0363] Arm A1

[0364] o Gemcitabine 1000 mg / m on days 1, 8, and 15 2 IV and nab-paclitaxel 125 mg / m 2 IV, then repeat on a Q4W schedule

[0365] Arm A2

[0366] o Olerumab IV administered Q2W for 4 doses, then Q4W, and

[0367] o Gemcitabine 1000 mg / m on days 1, 8, and 15 2 IV and nab-paclitaxel 125 mg / m 2 IV, then repeat on a Q4W schedule

[0368] Arm A3

[0369] o Olerumab IV administered Q2W for 4 doses, then Q4W, and

[0370] o Administer durvalumab 1500 mg IV every 4 weeks, and

[0371] o Gemcitabine 1000 mg / m on days 1, 8, and 15 2 IV and nab-paclitaxel 125 mg / m 2 IV, then repeat on a Q4W schedule Queue B

[0372] Arm B1

[0373] o Administer mFOLFOX on days 1 and 15 and then repeat on a Q4W schedule: oxaliplatin 85 mg / m 2 IV; leucovorin 400 mg / m 2 IV; IV bolus of 5-FU 400 mg / m 2 , followed by 5-FU 2400 mg / m by continuous IV infusion over 46 to 48 hours 2 .

[0374] Arm B2

[0375] o Olerumab IV administered Q2W for 4 doses, then Q4W, and

[0376] o Administer mFOLFOX on days 1 and 15 and then repeat on a Q4W schedule: oxaliplatin 85 mg / m 2 IV; leucovorin 400 mg / m 2 IV; IV bolus of 5-FU 400 mg / m 2 , followed by 5-FU 2400 mg / m by continuous IV infusion over 46 to 48 hours 2 .

[0377] Arm B3

[0378] o Olerumab IV administered Q2W for 4 doses, then Q4W, and

[0379] o Administer durvalumab 1500 mg IV every 4 weeks, and

[0380] o Administer mFOLFOX on days 1 and 15 and then repeat on a Q4W schedule: oxaliplatin 85 mg / m 2 IV; leucovorin 400 mg / m 2 IV; IV bolus of 5-FU 400 mg / m 2 , followed by 5-FU 2400 mg / m by continuous IV infusion over 46 to 48 hours 2 .

[0381] Example 6: Treatment of subjects with first-line stage IV non-small cell lung cancer (NSCLC) with olerumab and durvalumab with or without chemotherapy

[0382] A Phase 1b, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of olerumab and durvalumab with or without chemotherapy in first-line stage IV non-small cell lung cancer (NSCLC) subjects. Subjects with high PD-L1 (i.e., PD-L1 TC ≥ 50%) and low PD-L1 (i.e., PD-L1 TC < 50%) were treated.

[0383] 1. Subjects

[0384] The study included adult subjects aged ≥18 years with histologically or cytologically documented stage IV NSCLC who were ineligible for curative surgery or radiation therapy and whose tumors lacked activating epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions. Subjects had not previously received chemotherapy or any other systemic treatment for stage IV NSCLC. At enrollment and treatment assignment, all subjects had to have a World Health Organization (WHO) / Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Subjects had no prior exposure to immune-mediated therapies, including therapeutic anticancer vaccines.

[0385] Subjects were excluded from study participation if they had previously received chemotherapy or any other systemic therapy for stage IV NSCLC; if they were receiving any concurrent chemotherapy, biological therapy, or hormonal therapy for cancer treatment; or if they had received or were receiving any immunosuppressive medication within 28 days prior to the first dose of the study, except for (i) intranasal, inhaled, or topical steroids, or local steroid injections, (ii) systemic corticosteroids in physiologic doses not exceeding 10 mg / day of prednisone or its equivalent, and (iii) steroids used as premedication for hypersensitivity reactions. Subjects were also excluded if they had received radiation therapy, unless they had (i) received definitive radiation therapy at least 12 months before disease progression to stage IV, (ii) received palliative radiation therapy to the brain at least 4 weeks before the first dose of study treatment, with the relevant criteria being stable or asymptomatic, or (iii) received palliative radiation therapy to painful bone lesions (which must occupy less than 30% of the bone marrow) at least 2 weeks before the first dose of study treatment.

[0386] 2. Treatment

[0387] Each treatment arm included at least 30 patients, as provided in Table 2 and as Figures 24A-24D Patients with high PD-L1 (ie, PD-L1 expression ≥50% on tumor cells) were included in cohort A, whereas patients with low PD-L1 (ie, PD-L1 expression <50% on tumor cells) were included in cohort B.

[0388] Table 2: Olerumab + Durvalumab ± Chemotherapy Treatment Groups

[0389] queue arm treat A A1 Durvalumab A A3 Durvalumab + olelumab B B1 Durvalumab + chemotherapy B B3 Durvalumab + chemotherapy + olerulumab

[0390] Chemotherapy was selected from the group consisting of: (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 progressed after four cycles of carboplatin / cisplatin + pemetrexed received pemetrexed maintenance therapy unless contraindicated. For Arm B1, pemetrexed maintenance therapy could be given every three weeks (q3w) or every four weeks (q4w). For Arm B3, pemetrexed maintenance therapy could be given every 4w.

[0391] Olerumab, durvalumab, and chemotherapy were administered according to the schedule in Table 3 .

[0392] Table 3: Olerutumab + Durvalumab ± Chemotherapy Administration Schedule

[0393]

[0394]

[0395] a If body weight drops to ≤30 kg, administer a weight-based dose of 20 mg / kg.

[0396] If the initial dose levels of arms A3 and / or B3 were tolerated, a new treatment arm was initiated with a higher dose of olerumab, as shown in Table 4.

[0397] Table 4: Olerumab escalation

[0398]

[0399] Treatment continued until clinical or radiographic progression occurred. In the chemotherapy-included arm, chemotherapy was administered for 4 cycles or until progressive disease (PD) was observed, whichever occurred sooner (i.e., 4 cycles unless PD occurred before completion of planned therapy).

[0400] 3. Results

[0401] Adverse events, physical examinations, laboratory test results, and vital signs were assessed in all arms to demonstrate that olerumab and durvalumab, with or without chemotherapy, were safe.

[0402] In Cohort A3, eight patients received durvalumab and olerumab, while six patients in Cohort B3 received durvalumab, chemotherapy, and olerumab as a safety run-in. Safety was assessed and the doses were well tolerated. Given the absence of reported DLTs, a study-level safety review meeting agreed to escalate Cohort B3 from 1500 mg of olerumab to 3000 mg.

[0403] Overall response rate (ORR), progression-free survival, and objective response date were evaluated across all arms to demonstrate that the combination of olerumab and durvalumab is effective as a first-line treatment for stage IV non-small cell lung cancer (NSCLC) in patients with high PD-L1 levels and that the combination of olerumab, durvalumab, and chemotherapy is effective as a first-line treatment for stage IV patients with low PD-L1 levels. Example 7: Olerumab and durvalumab in the treatment of subjects with locally advanced, unresectable stage III non-small cell lung cancer

[0404] A phase 2, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of olerumab and durvalumab in participants with locally advanced, unresectable stage III non-small cell lung cancer (NSCLC).

[0405] 1. Subjects

[0406] This study included adult patients at least 18 years of age (weighing at least 35 kg) with locally advanced, unresectable Stage III NSCLC who had not progressed after definitive concurrent chemoradiotherapy (cCRT). Definitive RT was defined as a total dose of ≥60 Gy, administered in fractions of 1.8 Gy or a biologically equivalent dose of 1.8 Gy. Concurrent chemotherapy was defined as a platinum-based doublet chemotherapy. The final chemotherapy must have been completed before or concurrently with the final radiation dose.

[0407] 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) score of 0 or 1.

[0408] Subjects were excluded from study participation if they had mixed small cell and non-small cell lung cancer histology. Subjects were excluded from the study if they had used immunosuppressive medications within 14 days prior to the first dose of study drug, with the exception of: (i) intranasal, inhaled, or topical steroids, or topical steroid injections, (ii) systemic corticosteroids in physiologic doses not exceeding 10 mg / day of prednisone or its equivalent, and (iii) steroids used as premedication for hypersensitivity reactions. Any subjects previously exposed to anti-PD-1, anti-PD-L1, or anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antibodies used for the treatment of NSCLC were also excluded.

[0409] 2. Treatment

[0410] Patients started study treatment within 42 days of the last cCRT. Up to 60 subjects were randomized to each treatment arm in equal proportions to the durvalumab control arm and the experimental arm. Patients in the control arm received 1500 mg of durvalumab intravenously every 4 weeks (Q4W) for 12 months. 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 olerulumab intravenously every 2 weeks (Q2W) for 2 months, then Q4W starting on day 1 of cycle 3 for 10 months. Figure 25B .

[0411] Subjects received treatment for up to 12 months unless disease progression, unacceptable toxicity, or other reasons for treatment discontinuation (e.g., subject decision or non-compliance).

[0412] 3. Results

[0413] Adverse events, laboratory test results, electrocardiogram results, and vital signs were evaluated to demonstrate that the combination of olerumab and durvalumab was safe. Objective response (OR) according to RECIST v.1.1, duration of response (DoR), disease control (DC), 12-month progression-free survival (PFS) according to RECIST v.1.1, PFS according to RECIST v.1.1, and overall survival (OS) were also evaluated to demonstrate that the combination of olerumab and durvalumab was more effective than durvalumab alone in the treatment of stage III NSCLC.

[0414] Example 8: Olerumab and durvalumab in the treatment of subjects with resectable early-stage non-small cell lung cancer

[0415] A phase 2, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of olerumab and durvalumab in participants with resectable early-stage non-small cell lung cancer (NSCLC).

[0416] 1. Subjects

[0417] The study included adult subjects at least 18 years of age (weighing at least 35 kg) with cytologically and / or histologically documented NSCLC (a) stage I (>2 cm) to stage IIIA (for subjects with N2 disease, only subjects with 1 single nodule measuring ≤3 cm were eligible) NSCLC according to the American Joint Committee on Cancer, 8th edition staging classification; and (b) considered suitable for complete surgical resection. For this condition, subjects had not received any other therapy (chemotherapy, biotherapy, or radiation therapy). All subjects had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0418] Subjects were excluded from study participation if they had mixed small cell and non-small cell lung cancer histology. Subjects were also excluded from the study due to participation in another interventional clinical study within 90 days prior to enrollment. Subjects were excluded from the study if they used immunosuppressive drugs within 14 days prior to the first dose of study drug, with the exception of: (i) intranasal, inhaled, or topical steroids, or local steroid injections, (ii) systemic corticosteroids in physiologic doses not exceeding 12 mg / day of prednisone or its equivalent, and (iii) steroids used as premedication for hypersensitivity reactions.

[0419] Up to 40 subjects will be enrolled in each treatment arm.

[0420] 2. Treatment

[0421] Treatment during the study duration Figure 26A As shown. Subjects received durvalumab monotherapy or the combination of durvalumab and olerulumab for up to 28 days. Treatment discontinuation due to disease progression, unacceptable toxicity, or other reasons (e.g., subject decision or non-compliance). Subjects receiving durvalumab monotherapy received 1500 mg durvalumab intravenously Q4W on Day 1 of Week 1. ( Figure 26B .) Subjects receiving combination therapy received 1500 mg durvalumab intravenously Q4W on Day 1 of Week 1, plus 3000 mg olerulumab intravenously Q2W on Day 1 of Week 1 and Day 1 of Week 3.

[0422] ( Figure 26C . )

[0423] Surgical resection was performed after a 28-day treatment period. Surgical resection was performed within 14 days of the treatment period. After surgical resection, subjects were followed up until Day 105. If a subject received adjuvant chemotherapy or radiotherapy before Day 105, the subject was removed from the study, and the end of study visit was pre-scheduled before the start of adjuvant therapy.

[0424] 3. Results

[0425] Pathological changes, such as major pathological response (MPR), were evaluated to demonstrate that the combination of olerumab and durvalumab resulted in a pathological response in resected tumor specimens from patients with early-stage NSCLC. MPR, pathological complete response (pCR), and best overall response (BOR), as well as ORR according to RECIST v 1.1, were also evaluated to demonstrate that the combination of olerumab and durvalumab had antitumor activity in resectable early-stage NSCLC. Adverse events, laboratory test results, and vital signs were assessed to demonstrate that the combination of olerumab and durvalumab was safe.

[0426] Example 9: Olerumab and durvalumab in combination with chemotherapy and bevacizumab in subjects with metastatic microsatellite-stable colorectal cancer

[0427] A Phase 1b / 2, open-label, multicenter study was conducted to evaluate the efficacy (anti-tumor activity) and safety of olerumab 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 consisted of two parts. Part 1 was a Phase 1b safety study, and Part 2 was a Phase 2 efficacy and safety study.

[0428] 1. Subjects

[0429] Subjects in this study included adult subjects at least 18 years of age (weighing at least 35 kg) with metastatic MSS-CRC who had not received prior systemic therapy in the recurrent and / or metastatic setting (subjects who had received prior adjuvant chemotherapy or chemoradiotherapy, as long as progression was not within 6 months of completing the adjuvant regimen). All subjects had documented histology of advanced or metastatic CRC and mutation testing documented during screening, with tumor location confirmed by disease assessment. Subjects must not have deficient 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 well-defined, measurable by RECIST, and had clear progression during or after the most recent treatment). All subjects had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0430] Subjects were excluded from the study due to treatment with any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer (concurrent hormonal therapy for non-cancer related conditions (e.g., hormone replacement therapy) was acceptable). Subjects who had received radiotherapy to more than 30% of the bone marrow or wide-field radiation within 4 weeks prior to the first scheduled dose of study treatment were also excluded. Subjects who had previously received any immune-mediated therapy or anti-angiogenic therapy were also excluded. Subjects were excluded from the study due to use of immunosuppressive drugs within 14 days prior to the first dose of study drug, with the exception of: (i) intranasal, inhaled, or topical steroids, or topical steroid injections and (ii) steroids as premedication for hypersensitivity reactions.

[0431] Part 1 enrolled at least 6 subjects, while Part 2 enrolled up to 50 subjects per treatment arm.

[0432] 2. Treatment

[0433] After a screening period of up to 28 days, subjects were assigned (Part 1) or randomized (Part 2) to a study arm. In both study parts, treatment was administered until disease progression or any discontinuation criteria (e.g., withdrawal of consent, unacceptable toxicity, non-compliance, confirmed progressive disease, etc.) were achieved.

[0434] Part 1 did not involve dose escalation. An initial group of 3 subjects was enrolled in Part 1 and safety was assessed. Decisions in Part 1 were based on rules adapted from the modified toxicity probability interval-2 (mTPI-2) algorithm (Guo et al., Contemp Clin Trials 58:23-33 (2017)), which uses a simple beta-binomial Bayesian model. If the decision rule was to "keep" the first 3 subjects, an additional group of 2-4 subjects was recruited at the same dose level; if the decision rule was to "downgrade," an additional group of 3 subjects was enrolled in a lower dose of olelumab while maintaining the standard dose of FOLFOX plus bevacizumab plus durvalumab. If the decision rule was to "complete," the current dose was selected for Part 2 of the study.

[0435] In Part 2, randomization was initially evenly distributed across all arms (1:1:1) and stratified based on the location of the primary tumor (right versus left). After 50 subjects were randomly assigned to the control arm, the control arm continued to recruit subjects, but the allocation ratio could be adjusted for different arms.

[0436] The treatment groups are provided in Table 5 and are Figure 27 Treatment options are provided in s.

[0437] Table 5: Olerumab + Durvalumab ± Chemotherapy Treatment Groups

[0438]

[0439] Folinic acid (calcium folinate) + 5-fluorouracil + oxaliplatin (FOLFOX) plus bevacizumab was administered according to the National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) guidelines. Specifically, 400 mg / m2 was administered intravenously every 2 weeks (Q2W) (on day 1 of each 14-day cycle). 2 Folinic acid: 85 mg / m² administered by IV infusion every 2 weeks (day 1 of each 14-day cycle) 2 Oxaliplatin; and 2400 mg / m² administered by continuous intravenous infusion over 46 to 48 hours Q2W (Days 1-2 of each 14-day cycle) 2 5-Fluorouracil was administered as an infusion only, with no bolus injection. In addition, bevacizumab was administered at 5 mg / kg via intravenous infusion every 2 weeks (Day 1 of each 14-day cycle).

[0440] In arms S1 and E1, durvalumab 1500 mg was administered intravenously every 4 weeks (Q4W), and olerumab 3000 mg was administered intravenously every 2 weeks (Q2W) for four doses and then Q4W starting on Cycle 5, Day 1.

[0441] 3. Results

[0442] Objective responses according to RECIST v 1.1 were assessed to demonstrate that the combination of olerumab and durvalumab, and FOLFOX plus bevacizumab, had superior antitumor activity compared to FOLFOX plus bevacizumab in subjects with 1L MSS-CRC. Best overall 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) according to RECIST v 1.1 were also assessed to demonstrate that the combination of olerumab and durvalumab, and FOLFOX plus bevacizumab, had superior antitumor activity compared to FOLFOX plus bevacizumab in subjects with 1L MSS-CRC. Adverse events, dose-limiting toxicities (DLTs), laboratory test results, and vital signs were assessed to demonstrate that the combination of olerumab and durvalumab, and FOLFOX plus bevacizumab, was safe.

[0443] Example 10: Olerumab and durvalumab in combination with adjuvant chemotherapy in subjects with high-risk metastatic microsatellite-stable colorectal cancer

[0444] A phase 2, open-label, multicenter study was conducted to evaluate the efficacy (antitumor activity) and safety of olerumab and durvalumab in combination with adjuvant chemotherapy in subjects with high-risk metastatic microsatellite-stable colorectal cancer (MSS-CRC).

[0445] 1. Subjects

[0446] Participants in this study (including adult subjects at least 18 years of age (weighing at least 35 kg) who underwent curative surgical resection of stage II or III MSS-CRC) were eligible to receive 6 months of adjuvant mFOLFOX6 therapy within 8 weeks of surgery and were confirmed to be circulating tumor DNA (ctDNA) positive after surgery. All subjects were required to have high-risk stage II: any T4 lesion or T3 lesion with any of the following features: high grade (3), clinical manifestations of intestinal obstruction and perforation, histological signs of vascular, lymphovascular and perineural invasion, and examination of ≤12 lymph nodes. Subjects must not have received previous systemic chemotherapy, immunotherapy or radiation therapy for colorectal cancer (CRC) and must not have deficient DNA mismatch repair (MSI). Subjects underwent surgical resection with negative margins (R0; defined as >1 mm gap). All subjects had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

[0447] Subjects were excluded from the study if they had evidence of metastatic disease (including the presence of tumor cells in ascites or en bloc resection of peritoneal cancer). Subjects were also excluded if their cancer was being treated with concurrent chemotherapy, investigational products, biologics, or hormonal therapy. Subjects were excluded from the study if they had used immunosuppressive drugs within 14 days before the first dose of study drug, with the exception of (i) intranasal, inhaled, or topical steroids, or topical steroid injections, and (ii) steroids used as premedication for hypersensitivity reactions.

[0448] 2. Treatment

[0449] Subjects were randomly assigned to one of the study arms. Approximately 40 subjects were enrolled in each treatment arm. Strategic randomization was performed according to the American Joint Committee on Cancer staging of primary tumors (stage II vs. stage III). The study arms and treatments are summarized in Table 6 and are shown in Table 6. Figure 28 Dosage regimens are provided in .

[0450] Table 6: Olerutumab + Durvalumab ± Chemotherapy Treatment Groups

[0451] arm treat comparison mFOLFOX6 E1-COC mFOLFOX6+durvalumab E2 mFOLFOX6+durvalumab+olelumab

[0452] COC = contribution of components; E = experimental; mFOLFOX6 = folinic acid (leucovorin), 5-fluorouracil, oxaliplatin

[0453] In all arms, mFOLFOX6 was administered every 2 weeks (Q2W) as outlined by the National Comprehensive Cancer Network and European Society of Medical Oncology guidelines. Specifically, oxaliplatin was administered at 85 mg / m 2 The dose was administered by intravenous (IV) infusion (Day 1 of each 14-day cycle) with a maximum body surface area (BSA) limit of 2.0 m 2 Folinic acid (calcium folinate) at 400 mg / m 2 The dose is administered by (IV) infusion on Day 1 of each 14-day cycle. 400 mg / m2 is administered by IV bolus on Day 1. 2 Fluorouracil (5-FU) was administered at a dose of 1,200 mg / m 2 / day for 2 days (total 2,400 mg / m2 over 46-48 hours) 2 ) IV infusion (Days 1-2 of each 14-day cycle). Durvalumab was administered IV at a dose of 1500 mg every 4 weeks (Q4W), and olerumumab was administered IV at a dose of 3000 mg Q2W for four doses and then Q4W starting in Cycle 5.

[0454] Subjects were treated for up to 6 months or until relapse, unacceptable toxicity, withdrawal of consent, etc. Subjects were followed up for up to 5 years from randomization.

[0455] 3. Results

[0456] The clearance of circulating tumor DNA (ctDNA) at 6 months was assessed to demonstrate that the combination of olerumab and durvalumab with mFOLFOX6 had superior antitumor activity compared to mFOLFOX6 in subjects with high-risk stage II or III MSS-CRC. CtDNA clearance was defined as the change in ctDNA status from ctDNA-positive at baseline to ctDNA-negative after randomization, and the groups were compared stratified by disease stage using the Cochran-Mantel-Haenszel test at a significance level of 0.2 (2-sided). Disease-free survival (DFS), DFS at 12 months (DFS-12), and overall survival (OS) were also compared to demonstrate that the combination of olerumab and durvalumab with mFOLFOX6 had superior antitumor activity compared to FOLFOX in subjects with high-risk stage II or III MSS-CRC.

[0457] Adverse events, laboratory test results, and vital signs were assessed to demonstrate that the combination of olerumab and durvalumab, along with mFOLFOX6, was safe.

[0458] Example 11: Combination of Anti-CD73 and Anti-PD-L1 with Chemotherapy in Colorectal and Fibrosarcoma Models

[0459] Assays were performed in murine colorectal and fibrosarcoma models to demonstrate the efficacy of anti-CD73 and anti-PD-L1 antibodies in combination with chemotherapy.

[0460] 1. Materials and Methods

[0461] animal

[0462] In vivo studies were performed using 8-week-old BALB / cAnNCtr mice (Charles River UK) or C57BL / 6 mice. Animals were housed in an AstraZeneca vivarium with free access to food and water and cared for daily by trained personnel. Mice were handled according to the UK Home Office Animal Scientific Procedures Act (1986).

[0463] In vivo efficacy assay

[0464] Animals were implanted subcutaneously with 0.5e6 CT26 (mouse colorectal) or 0.5e6 MCA205 (50% Matrigel) (mouse fibrosarcoma) of the murine syngeneic tumor line, depending on the mouse strain. Tumor progression was monitored three times per week by caliper measurements. Animals were treated as follows (as monotherapy or in various combinations): anti-CD73 mouse IgG1 (in-house, AstraZeneca) at 10 mg / kg twice a week for 4 doses starting on day 3; anti-PD-L1 mouse IgG1 D265A (in-house, AstraZeneca) at 10 mg / kg twice a week starting on day 10 (when combined with OHP and 5FU) or day 4 (when combined with docetaxel) for a total of 6 doses (see figure legends for information on specific experiments); 5-fluorouracil (Fresenius Kabi) and oxaliplatin (Accord) at single doses of 50 mg / kg and 6 mg / kg on day 9 (or day 10 in some experiments); docetaxel (Sanofi) at 10 mg / kg once a week for 2 doses starting on day 4. Both antibodies plus 5FU and OHP were administered intraperitoneally, while docetaxel was administered intravenously. Once tumor size reached 15 mm in diameter, animals were humanely sacrificed.

[0465] In vivo pharmacodynamics assay

[0466] Animals were implanted subcutaneously with 0.5e6 CT26 mouse colorectal cancer cells. Tumor progression was monitored 3 times a week by caliper measurement. The animals were treated as follows (as monotherapy or in different combinations): starting from day 3, 10 mg / kg, twice a week, 4 doses, anti-CD73 mouse IgG1 (in-house, AstraZeneca); anti-PD-L1 mouse IgG1 D265A (in-house, AstraZeneca), starting from day 10, 10 mg / kg, twice a week, 2 doses; 5-fluorouracil (Fresenius Kabi) and oxaliplatin (Accord), single doses, 50 mg / kg and 6 mg / kg on day 10. All drugs were administered intraperitoneally. On day 15 after implantation, the animals were humanely sacrificed and the tumors were used for downstream analysis.

[0467] Tissue processing and flow cytometry

[0468] The enzyme mixture of 1mg / mL collagenase IV, 20 units / mL DNA enzyme I and 20 units / mL hyaluronidase I (all from Sigma)) is used to digest tumor.Then use live / dead differentiation dye staining single cell suspension (see table 7 below), and process with Fc block (anti-mouse CD16 / CD32 eBioScience company classification number 14-0161-86). Subsequently, eBioScience Foxp3 / transcription factor staining kit (00-5523-00) is used to carry out surface marker staining (reagent list see table and below) and fix and permeabilize cell. Next, cell is carried out intracellular marker staining (see table 7 below). Sample is collected on BD Symphony flow cytometer, and analyzed using FlowJo software version 10. Data are drawn using GraphPad Prizm software.

[0469] Table 7: Reagents used for tissue processing and flow cytometry

[0470]

[0471] *The anti-CD73 antibody used in this panel was conjugated using the PE / R-phycoerythrin conjugation kit - Lightning-Link In-house production and conjugation (ab102918).

[0472] 2. Results

[0473] Anti-CD73+anti-PD-L1+5FU+OHP, CT26 (colorectal) model

[0474] 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 with 0.5e6 CT26-subcutaneously (sc) and treated with anti-mouse antibodies intraperitoneally (ip) twice a week (anti-CD73 starting on day 3 after implantation for 4 doses and anti-PD-L1 starting on day 10 for 6 doses). 5-Fluorouracil (5FU) and oxaliplatin (OHP) were administered ip on day 9. Once the tumor diameter approached 15 mm, the animals were humanely sacrificed. Animals that were sacrificed early due to welfare issues (e.g., tumor status) were excluded from the analysis. For survival calculations, if the tumor volume exceeded 500 mm 3 , animals sacrificed due to tumor status before the tumor reached 15 mm in diameter were retained in the analysis. Figures 29A-29I middle.

[0475] In further analysis of activity in the CT26 model, animals were implanted with 0.5e6 CT26 sc and treated ip twice weekly with anti-mouse antibodies (anti-CD73 starting on day 3 post-implantation for 4 doses and anti-PD-L1 starting on day 10 for 2 doses). 5FU and OHP were administered ip on day 9. Figure 30 Data are shown for whole tumor digests (samples collected at day 15 post-implantation) analyzed by flow cytometry without ex vivo restimulation (intracellular staining).

[0476] Anti-CD73 + anti-PD-L1 + docetaxel in the CT26 (colorectal) model

[0477] To analyze the efficacy of anti-CD73 and anti-PD-L1 antibodies in combination with docetaxel in the CT26 model, animals were implanted with 0.5e6 CT26 sc and treated with anti-mouse antibodies ip twice a week (anti-CD73 starting on day 3 after implantation for 4 doses and anti-PD-L1 starting on day 4 for 4 doses). Docetaxel was administered iv once a week (2 doses starting on day 4). Once the tumor diameter approached 15 mm, the animals were humanely sacrificed. Animals that were sacrificed early due to welfare issues (e.g., tumor status) were excluded from the analysis. For survival calculations, if the tumor volume exceeded 500 mm 3 , animals sacrificed due to tumor status before the tumor reached 15 mm in diameter were retained in the analysis. Figures 31A-31I middle.

[0478] Anti-CD73+anti-PD-L1+5FU+OHP, MCA205 (fibrosarcoma) model

[0479] To analyze the efficacy in the MCA205 model, animals were implanted with 0.5e6 MCA205 (50% Matrigel) sc and treated with anti-mouse antibodies ip twice a week (anti-CD73 starting on day 3 after implantation for 4 doses and anti-PD-L1 starting on day 10 for 5 doses). 5FU and OHP were administered ip on day 9. The results are shown in Figures 32A-32H middle.

[0480] 3. Conclusion

[0481] In mice implanted with CT26 tumors, the combination of anti-PD-L1 + anti-CD73 + 5FU + OHP resulted in 6 of 12 (50%) complete responses, while the anti-PD-L1 + 5FU + OHP combination group resulted in a maximum of 2 of 12 (about 17%) complete responses. In addition, the combination of anti-PD-L1 + anti-CD73 + docetaxel resulted in 7 of 12 (58%) complete responses, while the anti-PD-L1 + docetaxel combination group resulted in a maximum of 3 of 12 (about 25%) complete responses.

[0482] In samples from animals treated with the combination of anti-CD73, anti-PD-L1, 5FU, and OHP, the percentages of IFNγ+CD8+, CD4+, and NKp46+ lymphocytes in the tumor microenvironment (TME) increased.

[0483] In mice implanted with MCA205 tumors, the combination of anti-PD-L1+anti-CD73+5FU+OHP resulted in 8 of 13 (61%) complete responses, while the anti-PD-L1+5FU+OHP combination group resulted in 4 of 13 (30%) complete responses.

[0484] These data suggest that anti-CD73 antibodies enhance the efficacy of anti-PD-L1 plus chemotherapy (including, for example, 5FU+OHP and docetaxel) in multiple cancer types.

[0485] ***

[0486] Although the present invention has been described in terms of various embodiments, it should be understood that variations and modifications will occur to those skilled in the art. Therefore, the appended claims are intended to cover all such equivalent variations that fall within the scope of the invention. Furthermore, the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0487] Unless expressly indicated to the contrary, each embodiment described herein can be combined with any other one or more other embodiments. In particular, unless expressly indicated to the contrary, any feature or embodiment indicated as preferred or advantageous can be combined with any other one or more features or embodiments indicated as preferred or advantageous.

[0488] All references cited in this application are expressly incorporated herein by reference.

[0489] Table 8: Disclosed sequences

[0490]

[0491]

Claims

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

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

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

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

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

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

7. The method of claim 5, wherein the olerumab or an antigen-binding fragment thereof is administered at a dose of 1500 mg.

8. The method of claim 5, wherein the olerumab or an antigen-binding fragment thereof is administered at a dose of 2250 mg.

9. The method of claim 5, wherein the olerumab or an antigen-binding fragment thereof is administered at a dose of 3000 mg.

10. The method of claim 5, wherein the olerumab or an antigen-binding fragment thereof is administered at a dose of 2250 mg followed by a dose of 3000 mg.

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