Methods of treating tumors with anti-TIGIT antibodies

Abstract

The present disclosure relates to methods of treating cancer or manufacturing a medicament for treating cancer by using a medicament formulation or medicament comprising an anti-TIGIT monoclonal antibody suitable for co-administration or co-formulation with an anti-PD-L1 monoclonal antibody. The present disclosure also relates to articles of manufacture comprising a single dose of an anti-TIGIT monoclonal antibody, or both an anti-TIGIT monoclonal antibody and an anti-PD-L1 monoclonal antibody, and methods of treating cancer using such articles of manufacture and the formulations contained therein.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 493,691, filed March 31, 2023, and U.S. Provisional Application No. 63 / 494,982, filed April 7, 2023, the contents of each of which are incorporated herein by reference in their entirety. Technical Field

[0003] This disclosure relates to the field of treating tumors with anti-TIGIT monoclonal antibodies as a monotherapy or in combination with anti-PD-L1 monoclonal antibodies.

[0004] sequence list

[0005] This disclosure includes a sequence list that has been submitted electronically in XML format and is incorporated herein by reference in its entirety. The XML copy was created on March 29, 2024, named 000218-0072-WO1_SL.xml, and is 26,376 bytes in size. Background Technology

[0006] Cancer is a leading cause of death worldwide, with approximately 9,958,130 cancer deaths globally in 2020. In North America, the estimated number of new cases was 2,556,860 (1,372,000 in men and 1,184,860 in women), and the number of cancer deaths was 699,274. Similar estimates for Central and Eastern Europe in 2020 showed 1,314,193 new cases (657,259 in men and 656,934 in women) and 695,828 cancer deaths (Global Cancer Observatory, December 2020). For most malignancies, current therapies have insufficient impact on improving quality of life, slowing disease progression, prolonging survival, or curing patients.

[0007] Immunotherapy has become an established strategy for treating cancer and improving the prognosis of many patients with multiple cancers. Furthermore, combinations of immunotherapies have proven to be more effective in treating cancer. In fact, the FDA has granted Breakthrough Therapy Designation to the combination of tiragolumab and atezolizumab for first-line treatment of non-small cell lung cancer. Immunotherapy is typically administered to the patient over several hours. Patients receiving combination therapy receive two separate infusions, requiring participation for longer periods (if the therapy is administered on the same day) or more frequently (if the therapy is administered on different days). There is a need in the field for therapies, including combination therapies, that can be administered at a rate faster than intravenous infusion (e.g., via subcutaneous injection). Summary of the Invention

[0008] In one aspect, this disclosure provides a method of treating cancer in a subject with this need, the method comprising subcutaneously administering to the subject a dose of about 1,000 mg of an anti-TIGIT monoclonal antibody; wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6.

[0009] In another aspect, this disclosure provides the use of approximately 1,000 mg of an anti-TIGIT monoclonal antibody in the manufacture of a medicament for treating cancer in a subject with such need; wherein the medicament is formulated for subcutaneous administration, and wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6.

[0010] In another aspect, this disclosure provides an anti-TIGIT monoclonal antibody for treating cancer in a subject with this need, wherein the anti-TIGIT monoclonal antibody is a full-length antibody and is administered subcutaneously at a dose of about 1,000 mg, the full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6.

[0011] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is administered in the thigh or abdomen. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is administered in the thigh. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is administered in the abdomen. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is administered every three weeks (Q3W).

[0012] On the other hand, this disclosure provides a method for treating cancer in a subject with this need, comprising subcutaneously administering to the subject about 1,000 mg of an anti-TIGIT monoclonal antibody and administering to the subject about 1,875 mg to about 2,000 mg of an anti-PD-L1 monoclonal antibody; wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-L1 The monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, which comprises the amino acid sequence of SEQ ID NO: 10; HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 11; and HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 13; HVR-L2, which comprises the amino acid sequence of SEQ ID NO: 14; and HVR-L3, which comprises the amino acid sequence of SEQ ID NO: 15.

[0013] On the other hand, this disclosure provides the use of about 1,000 mg of an anti-TIGIT monoclonal antibody and about 1,875 mg to about 2,000 mg of an anti-PD-L1 monoclonal antibody in the manufacture of a medicament for treating cancer in a subject with such need; wherein the medicament is formulated for subcutaneous administration, and wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-L1 The monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, which comprises the amino acid sequence of SEQ ID NO: 10; HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 11; and HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 13; HVR-L2, which comprises the amino acid sequence of SEQ ID NO: 14; and HVR-L3, which comprises the amino acid sequence of SEQ ID NO: 15.

[0014] On the other hand, this disclosure provides an anti-TIGIT monoclonal antibody and an anti-PD-L1 monoclonal antibody for treating cancer in a subject with this need, wherein the anti-TIGIT monoclonal antibody is a full-length antibody and is administered subcutaneously at a dose of about 1,000 mg, the full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-L1 monoclonal antibody is a full-length antibody and is administered at a dose of about 1,875 mg to about 2,000 mg. For dosage administration, the full-length antibody comprises: a heavy chain variable region comprising: HVR-H1, which comprises the amino acid sequence of SEQ ID NO: 10; HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 11; and HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 13; HVR-L2, which comprises the amino acid sequence of SEQ ID NO: 14; and HVR-L3, which comprises the amino acid sequence of SEQ ID NO: 15.

[0015] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered simultaneously. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are co-formulated. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 24 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed during administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered sequentially.

[0016] In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is administered intravenously. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is administered subcutaneously.

[0017] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is administered every three weeks (Q3W).

[0018] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, ureteral carcinoma, urethral carcinoma, colorectal cancer, colon cancer, rectal cancer, kidney cancer, sarcoma, ovarian cancer, breast cancer, cervical cancer, fallopian tube cancer, endometrial cancer, uterine cancer, pancreatic cancer, gastric cancer, bladder cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer, thyroid cancer, sarcoma, prostate cancer, penile cancer, glioblastoma, thymic carcinoma, esophageal cancer, nasopharyngeal carcinoma, mesothelioma, liver cancer, biliary tract cancer, HPV-positive cancer, leukemia, lymphoma, brain cancer, neuroendocrine carcinoma, myeloma, mycosis fungoides, Merkel cell carcinoma, hematologic malignancies, mismatch repair deficient (dMMR) cancer, and microsatellite instability-high (MSI-H) cancer.

[0019] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: bladder cancer, muscle-invasive bladder cancer, urothelial carcinoma, ureteral cancer, urethral cancer, ureteral urothelial carcinoma, urethral urothelial carcinoma, renal cancer, renal pelvis cancer, renal cell carcinoma, clear cell renal carcinoma, rectal cancer, colon cancer, colorectal cancer, sarcoma, osteosarcoma, leiomyosarcoma, pleomorphic sarcoma, myxofibrosarcoma, liposarcoma, chondrosarcoma, lung cancer, non-small cell lung cancer, fallopian tube cancer, peritoneal cancer, esophageal cancer, esophageal squamous cell carcinoma, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, ovarian cancer, cervical cancer, cervical adenosquamous carcinoma, breast cancer, triple-negative breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, luminal B-type breast cancer, lymphoma, T-cell lymphoma, B-cell lymphoma. Cellular lymphoma, nasal lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, penile cancer, prostate cancer, castration-resistant prostate cancer, endometrial cancer, uterine cancer, myeloma, multiple myeloma, head and neck cancer, prostate cancer, melanoma, cutaneous melanoma, Merkel cell carcinoma, pancreatic cancer, hepatocellular carcinoma, gastric cancer, gastroesophageal junction adenocarcinoma, glioblastoma, glioblastoma multiforme, mycosis fungoides, HPV-positive cancer, HPV-associated cervical cancer, HPV-associated anal squamous cell carcinoma, HPV-associated penile squamous cell carcinoma, HPV-associated vulvar squamous cell carcinoma, vulvar cancer, vaginal cancer, anal cancer, oropharyngeal cancer, oropharyngeal squamous cell carcinoma, leukemia, acute myeloid leukemia, bone cancer, solitary osteoplasty, squamous cell carcinoma, cutaneous squamous cell carcinoma, thyroid cancer, microsatellite stable / mismatch repair intact (MSS / pMMR) Metastatic colorectal cancer, mismatch repair deficient (dMMR) cancer, microsatellite instability-high (MSI-H) cancer, nasal extranodal NK / T-cell lymphoma, neuroendocrine carcinoma, biliary tract cancer, bile duct cancer, and intrahepatic bile duct cancer.

[0020] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma, non-small cell lung cancer, breast cancer, triple-negative breast cancer, hepatocellular carcinoma, melanoma, Hodgkin lymphoma, head and neck cancer, colorectal cancer, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, squamous cell carcinoma of the skin, basal cell carcinoma, bladder cancer, endometrial cancer, esophageal cancer, malignant pleural mesothelioma, cancer with high tumor mutation burden (TMB), cancer with mismatch repair deficient (dMMR), and cancer with high microsatellite instability (MSI-H).

[0021] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, bronchial cancer, breast cancer, triple-negative breast cancer, estrogen receptor-positive breast cancer, HER2-positive breast cancer, lobular metastatic breast cancer, ductal breast cancer, cervical cancer, fallopian tube cancer, fallopian tube serous adenocarcinoma, ovarian cancer, ovarian endometrioid tumor, ovarian serous adenocarcinoma, ovarian seromucous carcinoma, uterine cancer, endometrial cancer, skin cancer, melanoma, cutaneous melanoma, Merkel cell carcinoma, head and neck cancer, head and neck squamous cell carcinoma, hematologic malignancies, leukemia, myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, thyroid cancer, thyroid gland cancer, thymic cancer, neuroendocrine carcinoma, pheochromocytoma, glioma, glioblastoma multiforme, paraganglioma, lymphoma, B-cell lymphoma, Hodgkin lymphoma, B... Non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, pancreatic cancer, pancreatic ductal adenocarcinoma, rectal cancer, colon cancer, colorectal cancer, urinary tract cancer, urogenital cancer, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, sarcoma, chondrosarcoma, clear cell sarcoma, liposarcoma, myxoid / round cell liposarcoma, synovial sarcoma, alveolar soft tissue sarcoma, glial sarcoma, uterine carcinosarcoma, kidney cancer, non-clear cell kidney cancer, renal cell carcinoma, bladder cancer, urothelial carcinoma, muscular invasive bladder cancer, non-muscular invasive bladder cancer, HER2-positive bladder cancer, gallbladder cancer, gastric cancer, esophageal cancer, esophageal squamous cell carcinoma, gastrointestinal cancer, gastroesophageal cancer, gastroesophageal junction cancer, HER2 Positive gastric cancer, primary peritoneal cancer, squamous cell carcinoma of the skin, prostate cancer, prostate adenocarcinoma, castration-resistant prostate cancer, urogenital cancer, ureteral urothelial carcinoma, renal pelvis urothelial carcinoma, urethral urothelial carcinoma, appendix cancer, penile cancer, anal canal cancer, hepatocellular carcinoma, hepatobiliary duct cancer, unresectable liver and intrahepatic bile duct cancer, bile duct cancer, intrahepatic bile duct cancer, extrahepatic bile duct cancer, HPV-related cancers, HPV-related anal squamous cell carcinoma, HPV-related cervical squamous cell carcinoma, HPV-related penile squamous cell carcinoma, HPV-related vulvar squamous cell carcinoma, nasopharyngeal carcinoma, nasopharyngeal carcinoma, laryngeal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, oral squamous cell carcinoma, and mycosis fungoides.

[0022] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: urothelial carcinoma, non-small cell lung cancer (NSCLC), breast cancer, triple-negative breast cancer, hepatocellular carcinoma, and melanoma. In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: multiple myeloma, cervical cancer, esophageal cancer, esophageal squamous cell carcinoma, lung cancer, non-small cell lung cancer, glioblastoma, endometrial cancer, ovarian cancer, squamous cell carcinoma, and head and neck cancer. In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: cervical cancer, head and neck squamous cell carcinoma, head and neck cancer, non-small cell lung cancer, non-squamous non-small cell lung cancer, esophageal squamous cell carcinoma, esophageal cancer, breast cancer, triple-negative breast cancer, gastric cancer, gastroesophageal junction adenocarcinoma, multiple myeloma, non-Hodgkin's lymphoma, B-cell lymphoma, liver cancer, bladder cancer, urothelial carcinoma, pancreatic cancer, and pancreatic adenocarcinoma. In some embodiments of any of the foregoing aspects, the cancer is a solid tumor. In some embodiments of any of the foregoing aspects, the cancer is a blood cancer.

[0023] In some embodiments of any of the foregoing aspects, the heavy chain variable region of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments of any of the foregoing aspects, the light chain variable region of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments of any of the foregoing aspects, the heavy chain variable region of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 16, and the light chain variable region of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is an IgG antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is an IgG1 or IgG4 antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody or the anti-TIGIT monoclonal antibody is a human antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody or the anti-TIGIT monoclonal antibody is a humanized antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is selected from the group consisting of atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, and MDX-1105.

[0024] In some embodiments of any of the foregoing aspects, the heavy chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8. In some embodiments of any of the foregoing aspects, the light chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments of any of the foregoing aspects, the heavy chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8, and the light chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 25. In some embodiments of any of the foregoing aspects, the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 25, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is an IgG antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is an IgG1 or IgG4 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a human antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a humanized antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody inhibits or blocks the interaction between CD226 and TIGIT. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is tisrelinumab.

[0025] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is in a liquid pharmaceutical composition comprising 160 mg / mL tirelinumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are in a liquid pharmaceutical formulation comprising 40 mg / mL tirelinumab, 80 mg / mL atezolizumab, and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.8.

[0026] In another aspect, this disclosure provides an article comprising a formulation containing 1,000 mg of tislelizumab.

[0027] In some embodiments of any of the foregoing aspects, the formulation further comprises 1,875 mg or 2,000 mg of atezolizumab. In some embodiments, the formulation further comprises 1,875 mg of atezolizumab. In other embodiments, the formulation further comprises 2,000 mg of atezolizumab. In some embodiments, the formulation further comprises hyaluronidase.

[0028] In another aspect, this disclosure provides an article comprising a formulation comprising 1,000 mg of tislelizumab and 1,875 mg or 2,000 mg of atezolizumab. In some embodiments of the foregoing aspects, the formulation comprises 1,875 mg of atezolizumab. In other embodiments, the formulation comprises 2,000 mg of atezolizumab. In some embodiments of the foregoing aspects, the formulation further comprises hyaluronidase.

[0029] In some embodiments of any of the foregoing aspects, the concentration of hyaluronidase is 2000 U / mL. In some embodiments of any of the foregoing aspects, the hyaluronidase is recombinant human hyaluronidase. In some embodiments of any of the foregoing aspects, the recombinant hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

[0030] In some embodiments of any of the foregoing aspects, the article is a vial. In some embodiments of any of the foregoing aspects, the vial is a single-dose vial. In some embodiments of any of the foregoing aspects, the vial is sealed with a chlorobutyl elastomer stopper.

[0031] In some embodiments of any of the foregoing aspects, the article of manufacture is a pre-filled syringe. In some embodiments of any of the foregoing aspects, the article of manufacture is an injection pump.

[0032] In some embodiments of any of the foregoing aspects, the article is a subcutaneous application device. In some embodiments of any of the foregoing aspects, the subcutaneous application device is selected from the group consisting of: syringes, infusion pumps, injection devices, infusion pumps, injection pens, needle-free devices, autoinjectors, and subcutaneous patch delivery systems.

[0033] In another aspect, this disclosure provides an article of manufacture comprising a subcutaneous administration device, wherein the subcutaneous administration device contains and delivers a fixed dose of 1,000 mg of tislelizumab to a patient. In some embodiments of this aspect, the subcutaneous administration device further contains and delivers a fixed dose of 1,875 mg or 2,000 mg of atezolizumab to the patient. In one embodiment, the subcutaneous administration device further contains and delivers a fixed dose of 1,875 mg of atezolizumab to the patient. In another embodiment, the subcutaneous administration device further contains and delivers a fixed dose of 2,000 mg of atezolizumab to the patient. In some embodiments of this aspect, the subcutaneous administration device further contains and delivers hyaluronidase to the patient. In one embodiment, the hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

[0034] In some embodiments of the foregoing aspects, the subcutaneous application device is selected from the group consisting of: syringes, infusion pumps, injection devices, infusion pumps, injection pens, needle-free devices, autoinjectors, and subcutaneous patch delivery systems. In one embodiment, the subcutaneous application device is a syringe. In another embodiment, the subcutaneous application device is an infusion pump.

[0035] In some embodiments of any of the foregoing aspects, the product comprises about 3 mL to about 60 mL of full-length anti-TIGIT monoclonal antibody, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. In some embodiments of any of the foregoing aspects, the product comprises about 10 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. In some embodiments of any of the foregoing aspects, the product comprises about 7 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. In some embodiments of any of the foregoing aspects, the product comprises about 6.5 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. In some embodiments of any of the foregoing aspects, the product comprises about 21 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. Attached Figure Description

[0036] This patent or application document contains at least one color drawing. Upon request and payment of the necessary fees, the Patent Office will provide a published copy of this patent or application document with one or more color drawings.

[0037] Figure 1 illustrates a treatment regimen using a combination therapy comprising tirelinumab and atezolizumab. Figure 1 uses the following abbreviations: Atezolizumab; ECOG; IV; PD; PK; PS; Q3W; SC; TBD; Tira.

[0038] Figures 2A and 2B show two representative subjects from cohort 1A (who received a single subcutaneous dose of 880 mg tislelizumab in the abdomen (Figure 2A), followed by an intravenous dose of 600 mg tislelizumab), and two representative subjects from cohort 1B (who received a single subcutaneous dose of 880 mg tislelizumab in the thigh (Figure 2A)). Figure 2B )) Pharmacokinetic model fitted over time (days). Solid circle = direct observation; solid line = concentration predicted by a single model. Dashed line = model prediction. Detailed Implementation

[0039] conventional

[0040] Unless otherwise indicated, the methods disclosed herein, as well as the preparation and use of the compositions, are performed using conventional techniques in molecular biology, biochemistry, chromatin structure and analysis, computational chemistry, cell culture, recombinant DNA, and related fields within the scope of the art. These techniques are well described in the literature. See, for example, Current Protocols in Molecular Biology or Current Protocols in Immunology, John Wiley & Sons, New York, NY (2009); Ausubel et al., Short Protocols in Molecular Biology, 5th edition, Wiley & Sons, 2002; Sambrook and Russell, Molecular Cloning: A Laboratory Manual (4th edition, 2012); and other references.

[0041] The term "this article" refers to the entire publication.

[0042] It should be understood that, unless expressly denied or improper, any embodiment described herein, including those described under different aspects and different parts of this disclosure (including embodiments described only in examples), may be combined with one or more other embodiments disclosed herein. The combination of embodiments is not limited to those specific combinations claimed via the appended (including multiple appended) claims.

[0043] Any publications, patents, and published patent applications mentioned in this disclosure are specifically incorporated herein by reference. In case of any ambiguity, this specification (including its specific definitions) shall prevail.

[0044] Throughout the specification, the word “comprise” or variations such as “comprises” or “comprising”, which are synonyms of “including,” “containing,” or “characterized by,” are inclusive or open-ended and do not exclude additional unlisted elements or method steps.

[0045] Throughout this specification, where a composition is described as having, including, or comprising (or variations thereof) specific components, it is contemplated that the composition may also consist substantially of or be composed of the listed components. Similarly, where a method or process is described as having, including, or comprising specific process steps, the process may also consist substantially of or be composed of the stated process steps. Furthermore, it should be understood that, unless otherwise stated or explicitly indicated by the context, the order of steps or the sequence of certain actions is not important, as long as the compositions and methods described herein remain operable. Additionally, two or more steps or actions may be performed simultaneously.

[0046] The term "composed of" excludes any elements, steps, or ingredients not specifically listed.

[0047] The term “consistent essentially of” limits the scope of this disclosure to specific materials or steps, and those materials or steps that do not substantially affect the basic and novel features of this disclosure.

[0048] Any instance following the term "for example" is not intended to be exhaustive or restrictive.

[0049] The articles “a,” “one,” and “the” used in this article can refer to one or more (i.e., at least one) of the grammatical objects of the article. For example, “an element” means one element or more elements.

[0050] As used herein, the term "about" in the context of the methods employed in this disclosure refers to numerical variations that may occur, for example, through typical measurements and liquid handling procedures used to prepare isolated peptide or pharmaceutical compositions in the real world; through negligence or errors in these procedures; through variations in the manufacture, origin, or purity of the ingredients used to prepare the composition or perform the method, without materially affecting the chemical or physical properties of the compositions or methods of this disclosure. Such variations may be within 5% of a given value or range. The term "about" also covers amounts that vary due to different equilibrium conditions resulting from a particular initial mixture. Whether or not modified by the term "about," the paragraph includes equivalents of that amount. References to "about" values ​​or parameters herein include (and describe) examples relating to that value or parameter itself. For example, a description relating to "about X" includes the description of "X," and numerical ranges include numbers defining the range.

[0051] As used herein, the term “or” should be understood to mean “and / or” unless the context clearly indicates otherwise.

[0052] Although the numerical ranges and parameters described in this disclosure are approximate, the numerical values ​​described in specific instances are reported as precisely as possible. However, any numerical value inherently contains some error, which necessarily arises from the standard deviation found in their respective test measurements. Furthermore, the enumeration of numerical values ​​is not limited to the specifically listed values, but also includes numbers that a skilled person would typically round to in the context of significant figures. Moreover, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, the range “1 to 10” should be considered to include any and all subranges between (and including) the minimum value of 1 and the maximum value of 10; that is, all subranges begin with a minimum value of 1 or greater, such as 1 to 6.1, and end with a maximum value of 10 or less, such as 5.5 to 10. The disclosure of a range should also be considered as a disclosure of the endpoints of that range.

[0053] This document describes exemplary methods and materials, although similar or equivalent methods and materials may also be used in the practice or testing of this disclosure. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0054] definition

[0055] As used herein, “administering / administration of” a substance, compound, agent, or composition to a subject means that the substance, compound, agent, or composition comes into contact with the subject or the subject’s cells, tissues, organs, or body fluids. Such administration may be performed using one of a variety of methods known to those skilled in the art. For example, the substance, compound, agent, or composition may be administered parenterally, such as by injection. In some embodiments, the substance, compound, agent, or composition may be administered subcutaneously. In some embodiments, the substance, compound, agent, or composition may be administered intravenously. Administration may also be performed, for example, once, multiple times, and / or over one or more extended time periods. In some embodiments, administration includes both direct administration (including self-administration) and indirect administration (including the act of prescribing a drug). For example, as used herein, a physician who instructs a subject to self-administer a drug or has a drug administered by another person and / or prescribes a drug for a subject is administering a drug to the subject.

[0056] As used herein, the term “antibody” or “Ab” is used in the broadest sense and specifically covers monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, and multispecific antibodies (e.g., bispecific antibodies) and antibody fragments, provided they exhibit the desired biological activity. An “isolated” antibody is an antibody that has been identified and isolated and / or recovered from components of its native environment. Contaminant components of its native environment are materials that could interfere with the antibody’s research, diagnostic, or therapeutic use and may include enzymes, hormones, and other proteins or non-protein solutes. In some embodiments, the antibody is purified to (1) greater than 95% of its weight (e.g., determined by the Lowry method), and in some embodiments, greater than 99% by weight; (2) to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence (e.g., using a rotary cup sequencer); or (3) homogenized (by SDS-PAGE under reducing or non-reducing conditions, using, for example, Coomassie blue or silver staining). Isolated antibodies include in situ antibodies from recombinant cells, as at least one component of the antibody’s native environment is not present. However, typically, isolated antibodies are prepared through at least one purification step.

[0057] The terms “anti-TIGIT antibody,” “anti-TIGIT monoclonal antibody,” and “antibody that specifically binds to TIGIT” are used interchangeably herein and refer to an antibody capable of binding to TIGIT with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent targeting TIGIT. In some embodiments, such as those measured by radioimmunoassay (RIA), the binding of an anti-TIGIT antibody to unrelated non-TIGIT proteins is less than about 10% of the binding to TIGIT. In some embodiments, the antibody binding to TIGIT has a molecular weight of ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 μM). -8 M or smaller, such as 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 The dissociation constant (Kd) of M). In some embodiments, the anti-TIGIT antibody binds to conserved TIGIT epitopes in TIGIT from different species or to epitopes on TIGIT that allow cross-species reactions (such as epitopes containing amino acid residues Ser78, Ser80, and Lys82).

[0058] The terms “anti-PD-L1 antibody,” “anti-PD-L1 monoclonal antibody,” and “antibody that specifically binds to PD-L1” are used interchangeably herein and refer to an antibody capable of binding to PD-L1 with sufficient affinity so that the antibody can be used as a diagnostic and / or therapeutic agent targeting PD-L1. In some embodiments, such as those measured by radioimmunoassay (RIA), the binding of an anti-PD-L1 antibody to unrelated non-PD-L1 proteins is less than about 10% of the binding of the antibody to PD-L1. In some embodiments, the antibody binding to PD-L1 has a molecular weight of ≤ 1 μM, ≤ 100 nM, ≤ 10 nM, ≤ 1 nM, ≤ 0.1 nM, ≤ 0.01 nM, or ≤ 0.001 nM (e.g., 10 μM). -8 M or smaller, such as 10 -8 M to 10 -13 M, for example, 10 -9 M to 10 -13 The dissociation constant (Kd) of M). In some embodiments, the anti-PD-L1 antibody binds to conserved PD-L1 epitopes from different species or to epitopes on PD-L1 that allow cross-species reactions.

[0059] As used herein, the term "atelizumab" refers to an anti-PD-L1 monoclonal antagonist antibody having an International Nonproprietary Name (INN) 112 (WHO Drug Information, Vol. 28, No. 4, 2014, p. 488) or CAS Registry No. 1380723-44-3.

[0060] As used in this article, the term "cancer" refers to a disease caused by the uncontrolled division of abnormal cells in a part of the body. Cancer can be locally advanced or metastatic. In some cases, cancer is locally advanced. In some cases, cancer is metastatic. In some cases, cancer is recurrent. In some cases, cancer may be unresectable (e.g., unresectable locally advanced or metastatic cancer).

[0061] As used herein, the term "chimeric" antibody refers to an antibody in which a portion of the heavy chain and / or light chain is derived from a specific source or species, while the remainder of the heavy chain and / or light chain is derived from a different source or species.

[0062] The terms “full-length antibody,” “intact antibody,” and “whole antibody” are used interchangeably herein and refer to antibodies that are substantially in their complete form, rather than antibody fragments. Specifically, intact antibodies include those having heavy and light chains including an Fc region. The constant domain may be a native sequence constant domain (e.g., a human native sequence constant domain) or a variant of its amino acid sequence. It is known in the art that during antibody expression, a carboxypeptidase cleaves the C-terminus of the antibody. Such cleaved antibodies are considered substantially in their intact form and are therefore considered full-length antibodies despite the removal of one or more C-terminal amino acid residues. In some cases, intact antibodies may have one or more effector functions. In some embodiments, intact antibodies retain all effector functions. Optionally, one or more effector functions of an antibody may have been modified or eliminated.

[0063] As used herein, the term "effective function" refers to a biochemical event resulting from the interaction of the antibody Fc region with an Fc receptor or another effector molecule, such as an Fc receptor-like (FcRL) molecule, complement component C1q, and protein 21 containing a three-motif (TRIM21)). Effector functions include, but are not limited to, antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and complement-dependent cell-mediated cytotoxicity (CDC). As used herein, the term "ADCC" or "antibody-dependent cell-mediated cytotoxicity" refers to a cell-mediated reaction in which a nonspecific cytotoxic cell expressing FcγR recognizes a bound antibody on a target cell and subsequently causes lysis of the target cell. ADCC is associated with binding to FcγRIIIa; increased binding to FcγRIIIa leads to increased ADCC activity. As used herein, the term “ADCP” or “antibody-dependent cell-mediated phagocytosis” refers to a cell-mediated reaction in which nonspecific cytotoxic cells expressing FcγR recognize binding antibodies on target cells and subsequently cause phagocytosis of the target cells. As used herein, the term “CDC” or “complement-dependent cell cytotoxicity” refers to an effector function that leads to activation of the classical complement pathway, triggered by the binding of antibodies to antigens on target cells, activating a cascade of reactions in the blood containing the complement-associated proteome.

[0064] As used herein, the term "human antibody" refers to an antibody having an amino acid sequence corresponding to an antibody produced by humans and / or made using any technique known in the art for manufacturing human antibodies. "Human antibody" specifically excludes humanized antibodies containing non-human antigen-binding residues. Human antibodies can be produced using a variety of techniques known in the art, including phage display libraries, mouse fusion tumors, transgenic animals (e.g., mice), and single B cell techniques. See, for example, Lu et al., J. Biomed. Sci., 27:1 (2020); Hoogenboom and Winter, J. Mol. Biol., 227:381 (1991); Marks et al., J. Mol. Biol., 222:581 (1991), each of which is incorporated herein by reference in its entirety. The methods described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(l):86-95 (1991) can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel, New Insights in Pharmacology (Curr. Opin. Pharmacol.), 5: 368-74 (2001). Human antibodies can be prepared by administering an antigen to a transgenic animal that has been modified to produce human antibodies in response to antigen challenge, for example, by immunizing xenogeneic mice (see, for example, U.S. Patent Nos. 6,075,181 and 6,150,584 relating to XENOMOUSE™ technology). Other transgenic animals used for the production of human antibodies are also known in the art, including, for example, HuMAb mice, UntiMAb mice, Transchromo mice, VelocImmune mice, OmniRat, OmniMouse, Harbour mice, Kymouse, MeMo mice, and AlivaMab mice. See, for example, Brüggemann et al., Arch. Immunol. Ther. Exp. (Warsz.) 2015, Vol. 63, No. 2: 101-108. Additional techniques are also known in the art. See also, for example, Li et al., Proceedings of the National Academy of Sciences (Proc. Natl. Acad. Sci. USA), 103:3557-3562 (2006) on human antibodies produced by human B-cell hybridoma technology.

[0065] As used herein, a “humanized” antibody refers to a chimeric antibody containing both human and non-human antibody sequences. Typically, a humanized antibody contains a minimal sequence derived from a non-human immunoglobulin. For example, a humanized antibody may include a human immunoglobulin (receptor antibody) in which residues from the hypervariable region of the receptor are replaced by residues from the hypervariable region of a non-human species (donor antibody) (such as mouse, rat, rabbit, or non-human primate) that have the desired specificity, affinity, and capability. In some cases, certain frame region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, a humanized antibody may contain residues not present in the receptor antibody or donor antibody. These modifications are intended to further enhance antibody performance. Generally, a humanized antibody will substantially contain at least one variable domain, typically two, of all of these, where all or substantially all hypervariable loops correspond to hypervariable loops of the non-human immunoglobulin, and all or substantially all FRs are FRs of the human immunoglobulin sequence. A humanized antibody will also optionally contain at least a portion of the immunoglobulin constant region (Fc), which is typically the constant region of the human immunoglobulin. For further details, see Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1: 105-115 (1998); Harris, Biochem. Soc. Transactions 23: 1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994).

[0066] As used herein, the term "hyaluronidase" refers to an enzyme that catalyzes the degradation of hyaluronic acid (also known as hyaluronic acid). Hyaluronidase transiently hydrolyzes hyaluronic acid, a component of the subcutaneous matrix, and reduces the viscosity of the subcutaneous extracellular matrix to improve the delivery of subcutaneously administered drugs in systemic circulation. In some embodiments, the hyaluronidase is recombinant human hyaluronidase. In some embodiments, recombinant human hyaluronidase is administered subcutaneously.

[0067] As used herein, the terms “hypervariant region,” “HVR,” or “HV” refer to regions of antibody variable domains that are hypervariable in sequence and / or form structurally defined loops. Typically, antibodies contain six HVRs: three in VH (H1, H2, H3) and three in VL (L1, L2, L3). In natural antibodies, H3 and L3 exhibit the greatest diversity among the six HVRs, with H3, in particular, considered to play a unique role in conferring fine specificity to antibodies. See, for example, Xu et al., Immunity 13:37–45 (2000); Johnson and Wu, Methods in Molecular Biology 248:1–25 (Lo, ed., Human Press, Totowa, NJ, 2003). For example, in the absence of light chains, natural camelid antibodies consisting only of heavy chains are functional and stable. See, for example, Hamers-Casterman et al., Nature 363:446-448 (1993); Sheriff et al., Nature Struct. Biol. 3:733-736 (1996).

[0068] Many descriptions of HVR are used in the art and are covered herein. The Kabat complementarity-determining region (CDR) is based on sequence variability and is one of the most commonly used definitions (Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, MD. (1991)). Conversely, Chothia refers to the location of a structural loop (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)). AbM HVR represents a compromise between Kabat HVR and Chothia structural loops and is used by the AbM antibody modeling software from Oxford Molecular. "Contact" HVR is based on the analysis of available complex crystal structures. The IMGT numbering system was created by considering the high conservation of the V domain structure and integrating knowledge obtained from multiple sources: alignments of over 5000 sequences, literature data on frames (FRs) and complementarity-determining regions (CDRs), structural data from X-ray diffraction studies, and characterization of CDR hypervariable rings. The residues of each HVR in these HVRs are shown in Table 1 below.

[0069] Table 1.

[0070]

[0071] Unless otherwise stated, HVR is determined according to Kabat et al., as above. HVR may include the following “extended HVR”: residues 24 to 36 or 24 to 34 (L1), residues 46 to 56 or 50 to 56 (L2) and residues 89 to 97 or 89 to 96 (L3) in VL, and residues 26 to 35 (H1), residues 50 to 65 or 49 to 65 (H2) and residues 93 to 102, 94 to 102 or 95 to 102 (H3) in VH, each according to Kabat numbering.

[0072] As used herein, the term "monoclonal antibody" refers to an antibody derived from a single clone of a population of cells or cell lines that produce substantially homogeneous antibodies; that is, the individual antibodies produced by the cells are identical, except possibly with small amounts of naturally occurring mutations. Monoclonal antibodies are highly specific and highly specific to a single antigen. Furthermore, unlike polyclonal antibody formulations, which typically comprise different antibodies targeting different determinants (epitopes), each monoclonal antibody targets a single determinant on the antigen. Monoclonal antibodies can be human antibodies, humanized antibodies, or chimeric antibodies.

[0073] The terms “subject” and “patient” are used interchangeably herein and refer to a person in need of treatment. Therefore, as used herein, the terms “subject” or “patient” mean a human patient or subject to whom the compositions of this disclosure may be administered. In some embodiments, the subject requires treatment for cancer.

[0074] As used herein, the term "effective amount" refers to the minimum amount of a substance, compound, agent, or composition (such as an antibody) required to achieve a measurable improvement in a particular condition. Therapeutic effective amounts as used herein may vary depending on factors such as the patient's disease state, age, sex, and weight, and the ability of the substance, compound, agent, or composition (such as an antibody) to elicit the desired response in an individual. Appropriate amounts and dosing regimens can be determined using techniques conventional in the art. Therapeutic effective amounts are also the amount at which any toxic or adverse effects of the treatment are exceeded by the beneficial effects of the treatment. Beneficial or desired outcomes include clinical results such as: reduction of one or more symptoms caused by the disease, improvement of the patient's quality of life, reduction of the dosage of another drug required to treat the disease, and enhancement of the effects of other drugs (such as through targeting, delaying disease progression, and / or prolonging survival). In the context of cancer or tumors, a therapeutically effective amount of a drug may have the following effects: reduce the number of cancer cells; reduce tumor size; inhibit (i.e., to some extent slow down or ideally terminate) the infiltration of cancer cells into surrounding organs; inhibit (i.e., to some extent slow down or ideally terminate) tumor metastasis; inhibit tumor growth to some extent; and alleviate one or more of the symptoms associated with the disease and / or maintain remission to some extent. A therapeutically effective amount may be administered once or multiple times. For the purposes of this disclosure, a therapeutically effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve therapeutic treatment. A drug, compound, or pharmaceutical composition may or may not achieve a therapeutically effective amount when combined with another drug, compound, or pharmaceutical composition, as understood in a clinical context. Therefore, a “therapeuticly effective amount” may be considered in the context of administering one or more therapeutic agents, and a single therapeutically effective amount may be considered if the desired result can be obtained or achieved when combined with one or more other agents.

[0075] As used herein, the term "tisrelimumab" refers to the anti-TIGIT monoclonal antagonist antibody described in the following literature: WHO Drug Information (International Nonproprietary Names for Medicinal Substances), Proposed INN: List 117, Volume 31, Issue 2, published on June 9, 2017 (see page 343). In some embodiments, tisrelimumab has CAS Registry Number 1918185-84-8.

[0076] As used herein, the term "treatment" (and its variations, such as "treat" or "treating") refers to a clinical intervention aimed at altering the natural course of a treated individual or cell in a clinicopathological process. Ideal treatment outcomes include slowing disease progression, alleviating or reducing disease states, preventing cancer recurrence, preventing metastasis, and mitigating or improving prognosis. For example, an individual with cancer is considered successfully "treated" if one or more symptoms associated with cancer are reduced or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), reducing cancer-related symptoms, improving the quality of life of a person with cancer, reducing the dosage of other medications required to treat cancer, and / or prolonging the individual's survival.

[0077] As used herein, the term "variable region" or "variable domain" refers to a domain of the antibody heavy or light chain involved in antibody-antigen binding. The variable domains (VH and VL, respectively) of the heavy and light chains of natural antibodies typically have similar structures, with each domain containing four conserved frame regions (FRs) and three hypervariable regions (HVRs). (See, for example, Kindt et al., Kuby Immunology, 6th ed., WH Freeman and Co., p. 91 (2007)). While VH domains are typically paired with VL domains, a single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies binding to a specific antigen can be isolated using either the VH or VL domains of the antibody binding to that antigen to screen libraries of complementary VL or VH domains. See, for example, Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0078] Overview

[0079] This disclosure relates to methods of treating cancer with a full-length anti-TIGIT monoclonal antibody as a monotherapy or in combination with a full-length anti-PD-L1 antibody, and articles thereof for use in such methods.

[0080] Methods of treating cancer

[0081] In one aspect, this disclosure provides a method for treating cancer in a subject with this need, the method comprising administering an anti-TIGIT monoclonal antibody to the subject.

[0082] In some embodiments, the method includes administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody to a subject. In some embodiments, the method includes administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of about 1,875 mg or about 2,000 mg of anti-PD-L1 monoclonal antibody subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of about 1,875 mg or about 2,000 mg of anti-PD-L1 monoclonal antibody subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of about 1,875 mg of anti-PD-L1 monoclonal antibody to a subject. In some embodiments, the method includes subcutaneously administering to a subject a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and about 1,875 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the method includes subcutaneously administering to a subject a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and about 2,000 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the method includes subcutaneously administering to a subject a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and about 2,000 mg of anti-PD-L1 monoclonal antibody.

[0083] In some embodiments, the method includes administering a fixed dose of anti-TIGIT monoclonal antibody to a subject at a dose of 1,000 mg. In some embodiments, the method includes subcutaneously administering a fixed dose of anti-TIGIT monoclonal antibody to a subject. In some embodiments, the method includes administering a fixed dose of anti-TIGIT monoclonal antibody at a dose of 1,000 mg and a fixed dose of anti-PD-L1 monoclonal antibody at a dose of 1,875 mg or 2,000 mg to a subject. In some embodiments, the method includes subcutaneously administering a fixed dose of anti-TIGIT monoclonal antibody at a dose of 1,000 mg and a fixed dose of anti-PD-L1 monoclonal antibody at a dose of 1,875 mg or 2,000 mg to a subject. In some embodiments, the method includes administering a fixed dose of anti-TIGIT monoclonal antibody at a dose of 1,000 mg and a fixed dose of anti-PD-L1 monoclonal antibody at a dose of 1,875 mg to a subject. In some embodiments, the method includes subcutaneously administering a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 1,875 mg of anti-PD-L1 monoclonal antibody to a subject. In some embodiments, the method includes subcutaneously administering a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 2,000 mg of anti-PD-L1 monoclonal antibody to a subject. In some embodiments, the method includes subcutaneously administering a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 2,000 mg of anti-PD-L1 monoclonal antibody to a subject.

[0084] In another aspect, this disclosure provides the use of an anti-TIGIT monoclonal antibody in the manufacture of a medicament for treating cancer.

[0085] In some embodiments, the drug is formulated for administration of a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is formulated for administration of a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody.

[0086] In some embodiments, the drug is formulated for administration of a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is formulated for administration of a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody.

[0087] In another aspect, this disclosure provides the use of an anti-TIGIT monoclonal antibody and an anti-PD-L1 antibody in the manufacture of a medicament for the treatment of cancer.

[0088] In some embodiments, the drug is configured for administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of about 1,875 mg or about 2,000 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured for administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of about 1,875 mg or about 2,000 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the drug is configured for administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of about 1,875 mg of anti-PD-L1 monoclonal antibody to a subject. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured for administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of about 1,875 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the drug is configured to administer to a subject a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and about 2,000 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured to administer a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and about 2,000 mg of anti-PD-L1 monoclonal antibody.

[0089] In some embodiments, the drug is configured for administering a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 1,875 mg or 2,000 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured for administering a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 1,875 mg or 2,000 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the drug is configured for administering a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 1,875 mg of anti-PD-L1 monoclonal antibody to a subject. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured for administering a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 1,875 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the drug is configured to administer a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 2,000 mg of anti-PD-L1 monoclonal antibody to a subject. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured to administer a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 2,000 mg of anti-PD-L1 monoclonal antibody.

[0090] On the other hand, this disclosure provides an anti-TIGIT monoclonal antibody for the treatment of cancer.

[0091] In some embodiments, the anti-TIGIT monoclonal antibody is administered at a fixed dose of about 1,000 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously at a fixed dose of about 1,000 mg.

[0092] In some embodiments, the anti-TIGIT monoclonal antibody is administered at a fixed dose of 1,000 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously at a fixed dose of 1,000 mg.

[0093] On the other hand, this disclosure provides anti-TIGIT monoclonal antibodies and anti-PD-L1 antibodies for the treatment of cancer.

[0094] In some embodiments, the anti-TIGIT monoclonal antibody is administered at a fixed dose of about 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered at a fixed dose of about 1,875 mg or about 2,000 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously at a fixed dose of about 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered subcutaneously at a fixed dose of about 1,875 mg or about 2,000 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered at a fixed dose of about 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered at a fixed dose of about 1,875 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously at a fixed dose of about 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered subcutaneously at a fixed dose of about 1,875 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered at a fixed dose of about 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered at a fixed dose of about 2,000 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously at a fixed dose of about 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered subcutaneously at a fixed dose of about 2,000 mg.

[0095] In some embodiments, the anti-TIGIT monoclonal antibody is administered at a fixed dose of 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered at a fixed dose of 1,875 mg or 2,000 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously at a fixed dose of 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered subcutaneously at a fixed dose of 1,875 mg or 2,000 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered at a fixed dose of 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered at a fixed dose of 1,875 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously at a fixed dose of 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered subcutaneously at a fixed dose of 1,875 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered at a fixed dose of 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered at a fixed dose of 2,000 mg. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously at a fixed dose of 1,000 mg, and the anti-PD-L1 monoclonal antibody is administered subcutaneously at a fixed dose of 2,000 mg.

[0096] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: a heavy chain variable region (VH) comprising: HVR-H1 containing the amino acid sequence of SEQ ID NO: 1; HVR-H2 containing the amino acid sequence of SEQ ID NO: 2; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 3; and a light chain variable region (VL) comprising: HVR-L1 containing the amino acid sequence of SEQ ID NO: 4; HVR-L2 containing the amino acid sequence of SEQ ID NO: 5; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 6. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: VH, which comprises HVR-H1, HVR-H2 and HVR-H3 of tirelinumab; and VL, which comprises HVR-L1, HVR-L2 and HVR-L3 of tirelinumab.

[0097] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: VL, which comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 7; and VL, which comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises VH of tislelizumab. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises VL of tislelizumab. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises both VH and VL of tislelizumab.

[0098] In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments of any of the foregoing aspects, the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 24, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 25, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises the heavy chain of tislelizumab. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises the light chain of tislelizumab. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises the heavy and light chains of tislelizumab. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is tislelizumab. Tirelizumab is described in WHO Drug Information (International Nonproprietary Name for Medicinal Substances), proposed INN: Listing 117, Volume 31, Issue 2, published on June 9, 2017 (see page 343). In some embodiments of any of the foregoing aspects, tislelizumab has CAS Registry Number 1918185-84-8.

[0099] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is an IgG antibody. The anti-TIGIT monoclonal antibody may be an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is an IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a wild-type IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises a human IgG1 Fc region containing one or more amino acid modifications. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is an IgG4 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a wild-type IgG4 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises a human IgG4 Fc region containing one or more amino acid modifications. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is an antagonist antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody may have one or more effector functions. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody retains all effector functions. Optionally, one or more effector functions of the anti-TIGIT monoclonal antibody may have been modified or eliminated.

[0100] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a human antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a humanized antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a full-length antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a full-length IgG antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a full-length human IgG1 antibody. The anti-TIGIT monoclonal antibody may be an antibody fragment.

[0101] In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises: a heavy chain variable region (VH) comprising: HVR-H1 containing the amino acid sequence of SEQ ID NO: 10; HVR-H2 containing the amino acid sequence of SEQ ID NO: 11; and HVR-H3 containing the amino acid sequence of SEQ ID NO: 12; and a light chain variable region (VL) comprising: HVR-L1 containing the amino acid sequence of SEQ ID NO: 13; HVR-L2 containing the amino acid sequence of SEQ ID NO: 14; and HVR-L3 containing the amino acid sequence of SEQ ID NO: 15. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises: VH, which comprises atezolizumab HVR-H1, HVR-H2 and HVR-H3; and VL, which comprises atezolizumab HVR-L1, HVR-L2 and HVR-L3.

[0102] In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 16. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises: a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 16; and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 17. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises the VH of atezolizumab. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises the VL of atezolizumab. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises both the VH and VL of atezolizumab.

[0103] In some embodiments of any of the foregoing aspects, the heavy chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments of any of the foregoing aspects, the light chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 21; and the light chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 22; and the light chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises the heavy chain of atezolizumab. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises the light chain of atezolizumab. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises both the heavy and light chains of atezolizumab. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is atezolizumab.

[0104] In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is an IgG antibody. The anti-PD-L1 monoclonal antibody may be an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, or an IgG4 antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is an IgG1 or IgG4 antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is an IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is an IgG4 antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is an antagonist antibody. In some cases, the anti-PD-L1 monoclonal antibody may have one or more effector functions. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody retains all effector functions. Optionally, one or more effector functions of the anti-PD-L1 monoclonal antibody may have been modified or eliminated.

[0105] In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is a human antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is a humanized antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is a full-length antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is a full-length IgG antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is a full-length IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is a full-length human IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is a full-length humanized IgG1 antibody. The anti-PD-L1 monoclonal antibody may be an antibody fragment. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is atezolizumab, marketed as TECENTRIQ®. Atezolizumab is described in WHO Drug Information (International Nonproprietary Name for Medicinal Substances), proposed INN: List 112, Volume 28, Issue 4, 2014 (see page 488). In some embodiments of any of the foregoing aspects, atezolizumab has CAS Registry No. 1380723-44-3.

[0106] In some embodiments, the method includes administering a fixed dose of about 1,000 mg of tislelizumab to a subject. In some embodiments, the method includes administering a fixed dose of about 1,000 mg of tislelizumab subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of about 1,000 mg of tislelizumab and a fixed dose of about 1,875 mg or 2,000 mg of atezolizumab subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of about 1,000 mg of tislelizumab and a fixed dose of about 1,875 mg or 2,000 mg of atezolizumab subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of about 1,000 mg of tislelizumab and a fixed dose of about 1,875 mg of atezolizumab to a subject. In some embodiments, the method includes subcutaneously administering to a subject a fixed dose of about 1,000 mg of tislelizumab and about 2,000 mg of atezolizumab. In some embodiments, the method includes administering to a subject a fixed dose of about 1,000 mg of tislelizumab and about 2,000 mg of atezolizumab. In some embodiments, the method includes subcutaneously administering to a subject a fixed dose of about 1,000 mg of tislelizumab and about 2,000 mg of atezolizumab.

[0107] In some embodiments, the method includes administering a fixed dose of 1,000 mg of tislelizumab to a subject. In some embodiments, the method includes administering a fixed dose of 1,000 mg of tislelizumab subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 1,875 mg or 2,000 mg of atezolizumab subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 1,875 mg or 2,000 mg of atezolizumab subcutaneously to a subject. In some embodiments, the method includes administering a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 1,875 mg of atezolizumab to a subject. In some embodiments, the method includes administering a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 1,875 mg of atezolizumab subcutaneously to a subject. In some embodiments, the method includes administering a subject a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 2,000 mg of atezolizumab. In some embodiments, the method includes administering a subject subcutaneously a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 2,000 mg of atezolizumab.

[0108] In some embodiments, the drug is formulated for administration of a fixed dose of about 1,000 mg of tislelizumab. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is formulated for administration of a fixed dose of about 1,000 mg of tislelizumab. In some embodiments, the drug is formulated for administration of a fixed dose of about 1,000 mg of tislelizumab and a fixed dose of about 1,875 mg or about 2,000 mg of atezolizumab. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is formulated for administration of a fixed dose of about 1,000 mg of tislelizumab and a fixed dose of about 1,875 mg or about 2,000 mg of atezolizumab. In some embodiments, the drug is formulated for administration of a fixed dose of about 1,000 mg of tislelizumab and a fixed dose of about 1,875 mg of atezolizumab to a subject. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured for administering a fixed dose of about 1,000 mg of tislelizumab and a fixed dose of about 1,875 mg of atezolizumab. In some embodiments, the drug is formulated for administering a fixed dose of about 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of about 2,000 mg of atezolizumab to a subject. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured for administering a fixed dose of about 1,000 mg of tislelizumab and a fixed dose of about 2,000 mg of atezolizumab.

[0109] In some embodiments, the drug is formulated for administration of a fixed dose of 1,000 mg of tislelizumab. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is formulated for administration of a fixed dose of 1,000 mg of tislelizumab. In some embodiments, the drug is formulated for administration of a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 1,875 mg or 2,000 mg of atezolizumab. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is formulated for administration of a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 1,875 mg or 2,000 mg of atezolizumab. In some embodiments, the drug is formulated for administration of a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 1,875 mg of atezolizumab to a subject. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured for administration of a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 1,875 mg of atezolizumab. In some embodiments, the drug is formulated for administration of a fixed dose of 1,000 mg of anti-TIGIT monoclonal antibody and a fixed dose of 2,000 mg of atezolizumab to a subject. In some embodiments, the drug is formulated for subcutaneous administration to a subject and is configured for administration of a fixed dose of 1,000 mg of tislelizumab and a fixed dose of 2,000 mg of atezolizumab.

[0110] In some embodiments, tislelizumab is administered at a fixed dose of about 1,000 mg. In some embodiments, tislelizumab is administered subcutaneously at a fixed dose of about 1,000 mg. In some embodiments, tislelizumab is administered at a fixed dose of about 1,000 mg, and atezolizumab is administered at a fixed dose of about 1,875 mg or about 2,000 mg. In some embodiments, tislelizumab is administered subcutaneously at a fixed dose of about 1,000 mg, and atezolizumab is administered subcutaneously at a fixed dose of about 1,875 mg or about 2,000 mg. In some embodiments, tislelizumab is administered at a fixed dose of about 1,000 mg, and atezolizumab is administered at a fixed dose of about 1,875 mg. In some embodiments, tislelizumab is administered subcutaneously at a fixed dose of about 1,000 mg, and atezolizumab is administered subcutaneously at a fixed dose of about 1,875 mg. In some embodiments, tislelizumab is administered at a fixed dose of about 1,000 mg, and atezolizumab is administered at a fixed dose of about 2,000 mg. In some embodiments, tislelizumab is administered subcutaneously at a fixed dose of about 1,000 mg, and atezolizumab is administered subcutaneously at a fixed dose of about 2,000 mg.

[0111] In some embodiments, tislelizumab is administered at a fixed dose of 1,000 mg. In some embodiments, tislelizumab is administered subcutaneously at a fixed dose of 1,000 mg. In some embodiments, tislelizumab is administered at a fixed dose of 1,000 mg, and atezolizumab is administered at a fixed dose of 1,875 mg or 2,000 mg. In some embodiments, tislelizumab is administered subcutaneously at a fixed dose of 1,000 mg, and atezolizumab is administered subcutaneously at a fixed dose of 1,875 mg or 2,000 mg. In some embodiments, tislelizumab is administered at a fixed dose of 1,000 mg, and atezolizumab is administered at a fixed dose of 1,875 mg. In some embodiments, tislelizumab is administered subcutaneously at a fixed dose of 1,000 mg, and atezolizumab is administered subcutaneously at a fixed dose of 1,875 mg. In some embodiments, tislelizumab is administered at a fixed dose of 1,000 mg, and atezolizumab is administered at a fixed dose of 2,000 mg. In some embodiments, tislelizumab is administered subcutaneously at a fixed dose of about 1,000 mg, and atezolizumab is administered subcutaneously at a fixed dose of about 2,000 mg.

[0112] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody may be administered parenterally. In some embodiments, the anti-TIGIT monoclonal antibody is administered by injection. In some embodiments, the anti-TIGIT monoclonal antibody is administered intravenously or subcutaneously. In some embodiments, the anti-TIGIT monoclonal antibody is administered intravenously. In some embodiments, the anti-TIGIT monoclonal antibody is administered subcutaneously.

[0113] In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody may be administered parenterally. In some embodiments, the anti-PD-L1 monoclonal antibody is administered by injection. In some embodiments, the anti-PD-L1 monoclonal antibody is administered intravenously or subcutaneously. In some embodiments, the anti-PD-L1 monoclonal antibody is administered intravenously. In some embodiments, the anti-PD-L1 monoclonal antibody is administered subcutaneously.

[0114] In some embodiments, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are co-mixed. In some embodiments, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are co-formulated.

[0115] In some embodiments of any of the foregoing aspects, the subject is a human. In some embodiments of any of the foregoing aspects, the subject has not received prior checkpoint inhibitor treatment (i.e., is CPI-naïve). In some embodiments of any of the foregoing aspects, the subject has not received prior treatment with an anti-PD-L1 monoclonal antibody, an anti-PD-1 antibody, an anti-CTL1-4 antibody, or an anti-TIGIT monoclonal antibody. In some embodiments of any of the foregoing aspects, the subject has not received prior treatment with an anti-PD-L1 monoclonal antibody. In some embodiments of any of the foregoing aspects, the subject has not received prior treatment with an anti-PD-1 antibody. In some embodiments of any of the foregoing aspects, the subject has not received prior treatment with an anti-CTL1-4 antibody. In some embodiments of any of the foregoing aspects, the subject has not received prior treatment with an anti-TIGIT monoclonal antibody. In some embodiments of any of the foregoing aspects, the subject has not received cancer immunotherapy (CIT) treatment (i.e., is CIT-naïve).

[0116] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, ureteral cancer, urethral cancer, colorectal cancer, colon cancer, rectal cancer, kidney cancer, sarcoma, ovarian cancer, breast cancer, cervical cancer, fallopian tube cancer, endometrial cancer, uterine cancer, pancreatic cancer, gastric cancer, bladder cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer, thyroid cancer, sarcoma, prostate cancer, penile cancer, glioblastoma, thymic carcinoma, esophageal cancer, nasopharyngeal carcinoma, mesothelioma, liver cancer, biliary tract cancer, HPV-positive cancer, leukemia, lymphoma, brain cancer, neuroendocrine carcinoma, myeloma, mycosis fungoides, Merkel cell carcinoma, hematologic malignancies, mismatch repair deficient (dMMR) cancer, and microsatellite instability-high (MSI-H) cancer. In some embodiments of any of the foregoing aspects, the cancer is lung cancer. In some embodiments of any of the foregoing aspects, the cancer is non-small cell lung cancer. In some embodiments of any of the foregoing aspects, the cancer is renal cell carcinoma. In some embodiments of any of the foregoing aspects, the cancer is urothelial carcinoma. In some embodiments of any of the foregoing aspects, the cancer is ureteral cancer. In some embodiments of any of the foregoing aspects, the cancer is colorectal cancer. In some embodiments of any of the foregoing aspects, the cancer is colon cancer. In some embodiments of any of the foregoing aspects, the cancer is rectal cancer. In some embodiments of any of the foregoing aspects, the cancer is kidney cancer. In some embodiments of any of the foregoing aspects, the cancer is sarcoma. In some embodiments of any of the foregoing aspects, the cancer is ovarian cancer. In some embodiments of any of the foregoing aspects, the cancer is breast cancer. In some embodiments of any of the foregoing aspects, the cancer is cervical cancer. In some embodiments of any of the foregoing aspects, the cancer is fallopian tube cancer. In some embodiments of any of the foregoing aspects, the cancer is endometrial cancer. In some embodiments of any of the foregoing aspects, the cancer is uterine cancer. In some embodiments of any of the foregoing aspects, the cancer is pancreatic cancer. In some embodiments of any of the foregoing aspects, the cancer is stomach cancer. In some embodiments of any of the foregoing aspects, the cancer is bladder cancer. In some embodiments of any of the foregoing aspects, the cancer is esophageal cancer. In some embodiments of any of the foregoing aspects, the cancer is mesothelioma. In some embodiments of any of the foregoing aspects, the cancer is melanoma. In some embodiments of any of the foregoing aspects, the cancer is head and neck cancer. In some embodiments of any of the foregoing aspects, the cancer is thyroid cancer. In some embodiments of any of the foregoing aspects, the cancer is sarcoma. In some embodiments of any of the foregoing aspects, the cancer is prostate cancer. In some embodiments of any of the foregoing aspects, the cancer is penile cancer. In some embodiments of any of the foregoing aspects, the cancer is glioblastoma. In some embodiments of any of the foregoing aspects, the cancer is thymic carcinoma. In some embodiments of any of the foregoing aspects, the cancer is esophageal cancer. In some embodiments of any of the foregoing aspects, the cancer is nasopharyngeal carcinoma.In some embodiments of any of the foregoing aspects, the cancer is mesothelioma. In some embodiments of any of the foregoing aspects, the cancer is liver cancer. In some embodiments of any of the foregoing aspects, the cancer is biliary tract cancer. In some embodiments of any of the foregoing aspects, the cancer is HPV-positive cancer. In some embodiments of any of the foregoing aspects, the cancer is leukemia. In some embodiments of any of the foregoing aspects, the cancer is lymphoma. In some embodiments of any of the foregoing aspects, the cancer is brain cancer. In some embodiments of any of the foregoing aspects, the cancer is neuroendocrine carcinoma. In some embodiments of any of the foregoing aspects, the cancer is myeloma. In some embodiments of any of the foregoing aspects, the cancer is mycosis fungoides. In some embodiments of any of the foregoing aspects, the cancer is Merkel cell carcinoma. In some embodiments of any of the foregoing aspects, the cancer is a hematologic malignancy. In some embodiments of any of the foregoing aspects, the cancer is mismatch repair deficient (dMMR) cancer. In some embodiments of any of the foregoing aspects, the cancer is high microsatellite instability (MSI-H) cancer.

[0117] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: bladder cancer, muscular invasive bladder cancer, urothelial carcinoma, ureteral cancer, urethral cancer, ureteral urothelial carcinoma, urethral urothelial carcinoma, renal cancer, renal pelvis cancer, renal cell carcinoma, clear cell renal carcinoma, rectal cancer, colon cancer, colorectal cancer, sarcoma, osteosarcoma, leiomyosarcoma, pleomorphic sarcoma, myxofibrosarcoma, liposarcoma, chondrosarcoma, lung cancer, non-small cell lung cancer, fallopian tube cancer, peritoneal cancer, esophageal cancer, esophageal squamous cell carcinoma, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, ovarian cancer, cervical cancer, cervical adenosquamous carcinoma, breast cancer, triple-negative breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, luminal B-type breast cancer, lymphoma, T-cell lymphoma, B-cell lymphoma. Cellular lymphoma, nasal lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, penile cancer, prostate cancer, castration-resistant prostate cancer, endometrial cancer, uterine cancer, myeloma, multiple myeloma, head and neck cancer, prostate cancer, melanoma, cutaneous melanoma, Merkel cell carcinoma, pancreatic cancer, hepatocellular carcinoma, gastric cancer, gastroesophageal junction adenocarcinoma, glioblastoma, glioblastoma multiforme, mycosis fungoides, HPV-positive cancer, HPV-associated cervical cancer, HPV-associated anal squamous cell carcinoma, HPV-associated penile squamous cell carcinoma, HPV-associated vulvar squamous cell carcinoma, vulvar cancer, vaginal cancer, anal cancer, oropharyngeal cancer, oropharyngeal squamous cell carcinoma, leukemia, acute myeloid leukemia, bone cancer, solitary osteoplasty, squamous cell carcinoma, cutaneous squamous cell carcinoma, thyroid cancer, microsatellite stable / mismatch repair intact (MSS / pMMR) Metastatic colorectal cancer, mismatch repair deficient (dMMR) cancer, microsatellite instability-high (MSI-H) cancer, nasal extranodal NK / T-cell lymphoma, neuroendocrine carcinoma, biliary tract cancer, bile duct cancer, and intrahepatic bile duct cancer.

[0118] In some embodiments of any of the foregoing aspects, the breast cancer is triple-negative breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, or luminal type B breast cancer.

[0119] In some embodiments of any of the foregoing aspects, the lymphoma is a T-cell lymphoma, a B-cell lymphoma, a nasal lymphoma, a non-Hodgkin lymphoma, or a follicular lymphoma.

[0120] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma, non-small cell lung cancer, breast cancer, triple-negative breast cancer, hepatocellular carcinoma, melanoma, Hodgkin lymphoma, head and neck cancer, colorectal cancer, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, squamous cell carcinoma of the skin, basal cell carcinoma, bladder cancer, endometrial cancer, esophageal cancer, malignant pleural mesothelioma, cancer with high tumor mutation burden (TMB), cancer with mismatch repair deficient (dMMR), and cancer with high microsatellite instability (MSI-H).

[0121] In any of the embodiments described above, the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, bronchial cancer, breast cancer, triple-negative breast cancer, estrogen receptor-positive breast cancer, HER2-positive breast cancer, lobular metastatic breast cancer, ductal breast cancer, cervical cancer, fallopian tube cancer, fallopian tube serous adenocarcinoma, ovarian cancer, ovarian endometrioid tumor, ovarian serous adenocarcinoma, ovarian seromucous carcinoma, uterine cancer, endometrial cancer, skin cancer, melanoma, cutaneous melanoma, Merkel cell carcinoma, head and neck cancer, head and neck squamous cell carcinoma, hematologic malignancies, leukemia, myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, thyroid cancer, thyroid gland cancer, thymic cancer, neuroendocrine carcinoma, pheochromocytoma, glioma, glioblastoma multiforme, paraganglioma, lymphoma, B-cell lymphoma, Hodgkin lymphoma, B... Non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, pancreatic cancer, pancreatic ductal adenocarcinoma, rectal cancer, colon cancer, colorectal cancer, urinary tract cancer, urogenital cancer, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, sarcoma, chondrosarcoma, clear cell sarcoma, liposarcoma, myxoid / round cell liposarcoma, synovial sarcoma, alveolar soft tissue sarcoma, glial sarcoma, uterine carcinosarcoma, kidney cancer, non-clear cell kidney cancer, renal cell carcinoma, bladder cancer, urothelial carcinoma, muscular invasive bladder cancer, non-muscular invasive bladder cancer, HER2-positive bladder cancer, gallbladder cancer, gastric cancer, esophageal cancer, esophageal squamous cell carcinoma, gastrointestinal cancer, gastroesophageal cancer, gastroesophageal junction cancer, HER2 Positive gastric cancer, primary peritoneal cancer, squamous cell carcinoma of the skin, prostate cancer, prostate adenocarcinoma, castration-resistant prostate cancer, urogenital cancer, ureteral urothelial carcinoma, renal pelvis urothelial carcinoma, urethral urothelial carcinoma, appendix cancer, penile cancer, anal canal cancer, hepatocellular carcinoma, hepatobiliary duct cancer, unresectable liver and intrahepatic bile duct cancer, bile duct cancer, intrahepatic bile duct cancer, extrahepatic bile duct cancer, HPV-related cancers, HPV-related anal squamous cell carcinoma, HPV-related cervical squamous cell carcinoma, HPV-related penile squamous cell carcinoma, HPV-related vulvar squamous cell carcinoma, nasopharyngeal carcinoma, nasopharyngeal carcinoma, laryngeal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, oral squamous cell carcinoma, and mycosis fungoides.

[0122] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: urothelial carcinoma, non-small cell lung cancer (NSCLC), breast cancer, triple-negative breast cancer, hepatocellular carcinoma, and melanoma.

[0123] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: multiple myeloma, cervical cancer, esophageal cancer, esophageal squamous cell carcinoma, lung cancer, non-small cell lung cancer, glioblastoma, endometrial cancer, ovarian cancer, squamous cell carcinoma, and head and neck cancer.

[0124] In some embodiments of any of the foregoing aspects, the cancer is selected from the group consisting of: cervical cancer, squamous cell carcinoma of the head and neck, head and neck cancer, non-small cell lung cancer, non-squamous non-small cell lung cancer, esophageal squamous cell carcinoma, esophageal cancer, breast cancer, triple-negative breast cancer, gastric cancer, gastroesophageal junction adenocarcinoma, multiple myeloma, non-Hodgkin lymphoma, B-cell lymphoma, liver cancer, bladder cancer, urothelial carcinoma, pancreatic cancer, and pancreatic adenocarcinoma.

[0125] In some embodiments of any of the foregoing aspects, the cancer is a solid tumor. In some embodiments of any of the foregoing aspects, the solid tumor is PD-L1 positive. In some embodiments of any of the foregoing aspects, the solid tumor is a histologically confirmed PD-L1 solid tumor. In some embodiments of any of the foregoing aspects, the solid tumor is locally advanced, recurrent, or metastatic.

[0126] In some embodiments of any of the foregoing aspects, the cancer is a blood cancer.

[0127] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered simultaneously. In some embodiments, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are co-formulated. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered individually.

[0128] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 24 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 23 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 22 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 21 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 20 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 19 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 18 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 17 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 16 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 15 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 14 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 13 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 12 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 11 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 10 hours or less prior to administration to the subject.In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 9 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 8 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 7 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 6 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 5 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 4 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 3 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 2 hours or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 1 hour or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 45 minutes or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 30 minutes or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 15 minutes or less prior to administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 10 minutes or less before administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 5 minutes or less before administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 4 minutes or less before administration to the subject.In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 3 minutes or less before administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 2 minutes or less before administration to the subject. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 1 minute or less before administration to the subject.

[0129] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed during administration to the subject.

[0130] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered parenterally. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered intravenously or subcutaneously. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered intravenously. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered subcutaneously.

[0131] In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is administered in a formulation comprising about 15 mM to about 25 mM histidine acetate, about 200 mM to about 280 mM sucrose, about 0.04% (w / v) to about 0.08% (w / v) polysorbate, about 5 mM to about 15 mM methionine, and a pH of about 5.3 to about 6.0. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is administered in a formulation comprising about 20 mM histidine acetate, about 240 mM sucrose, about 0.06% (w / v) polysorbate 20, about 10 mM methionine, and a pH of about 5.8. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is administered in a formulation comprising 15 mM to 25 mM histidine acetate, 200 mM to 280 mM sucrose, 0.04% (w / v) to 0.08% (w / v) polysorbate, 5 mM to 15 mM methionine, and a pH of 5.3 to 6.0. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is administered in a formulation comprising 20 mM histidine acetate, 240 mM sucrose, 0.06% (w / v) polysorbate, 10 mM methionine, and a pH of 5.8.

[0132] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is in a liquid pharmaceutical composition comprising 160 mg / mL tirelinumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5. In some embodiments, the pharmaceutical composition comprises 160 mg / mL tirelinumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5.

[0133] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody and anti-PD-L1 are contained in a liquid pharmaceutical formulation comprising 40 mg / ml tirelinumab, 80 mg / ml atezolizumab, and 2000 U / ml hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.8. In some embodiments, the pharmaceutical formulation comprises 40 mg / ml tirelinumab, 80 mg / ml atezolizumab, and 2000 U / ml hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.8.

[0134] The specific sequences of the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are provided in Table 2.

[0135] Table 2: Amino acid sequences.

[0136]

[0137] It is known in the art that during antibody expression and processing in cell cultures, C-terminal cleavage by carboxypeptidase occurs in the culture medium. In some cases, only the C-terminal lysine residues of the heavy chain are cleaved. In other cases, additional residues may be cleaved. The sequences provided herein are also intended to cover variants that occur due to the production process, such as those resulting from C-terminal cleavage.

[0138] It is also known in the art that the C-terminal cleavage process is imprecise, and additional C-terminal residues are cleaved. Therefore, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without two C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without three C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without four C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without five C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without six C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without seven C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without eight C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without nine C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without ten C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without eleven C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without twelve C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without thirteen C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without fourteen C-terminal residues is also contemplated. In some embodiments, for each sequence containing a C-terminal lysine disclosed herein, a corresponding sequence without fifteen C-terminal residues is also contemplated.

[0139] In some embodiments, anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody are co-mixed. In some embodiments, anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody are co-mixed subcutaneously. In some embodiments, anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody are co-mixed in the abdomen. In some embodiments, anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody are co-mixed subcutaneously in the abdomen. In some embodiments, anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody are co-mixed in the thigh. In some embodiments, anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody are co-mixed subcutaneously in the thigh. In some embodiments, administration of anti-PD-L1 monoclonal antibody is performed simultaneously with administration of anti-TIGIT monoclonal antibody. In some embodiments, anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody are co-formulated. In some embodiments, intravenous administration of anti-PD-L1 monoclonal antibody is performed after administration of anti-TIGIT monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is administered before the anti-TIGIT monoclonal antibody is administered. In some embodiments, the anti-PD-L1 monoclonal antibody is administered after the anti-TIGIT monoclonal antibody is administered.

[0140] In some embodiments, the anti-TIGIT monoclonal antibody is administered at a frequency selected from the group consisting of: Q1W, Q2W, Q3W, Q4W, Q5W, and Q6W. In some embodiments, the anti-TIGIT monoclonal antibody is administered at a frequency of Q3W in one or more cycles. In some embodiments, the anti-PD-L1 monoclonal antibody is administered at a frequency of Q3W in one or more cycles. In some embodiments, the anti-PD-L1 monoclonal antibody and the anti-TIGIT monoclonal antibody are administered independently at a frequency of Q3W in one or more cycles.

[0141] In some embodiments, 1,000 mg of anti-TIGIT monoclonal antibody is co-mixed or co-formulated with 1,875 mg or 2,000 mg of anti-PD-L1 monoclonal antibody. In some embodiments, 1,000 mg of anti-TIGIT monoclonal antibody is co-mixed with 2,000 mg of anti-PD-L1 monoclonal antibody. In some embodiments, 1,000 mg of anti-TIGIT monoclonal antibody is co-mixed with 1,875 mg of anti-PD-L1 monoclonal antibody. In some embodiments, the co-mixture is administered subcutaneously. In some embodiments, the co-mixture is administered subcutaneously in the thigh. In some embodiments, the co-mixture is administered subcutaneously in the abdomen. In some embodiments, 1,000 mg of anti-TIGIT monoclonal antibody is co-mixed with 2,000 mg of anti-PD-L1 monoclonal antibody and administered subcutaneously in the abdomen of a subject who requires this. In some embodiments, 1,000 mg of anti-TIGIT monoclonal antibody is mixed with 1,875 mg of anti-PD-L1 monoclonal antibody and administered subcutaneously to the thigh of the subject in need.

[0142] In some embodiments, after subcutaneous administration of the co-mixture, 1,200 mg of anti-PD-L1 monoclonal antibody and 600 mg of anti-TIGIT monoclonal antibody are administered intravenously at Q3W. In some embodiments, intravenous Q3W administration of 1,200 mg of anti-PD-L1 monoclonal antibody and 600 mg of anti-TIGIT monoclonal antibody begins at cycle 2 (i.e., after one cycle of subcutaneous administration of the co-mixture). In some embodiments, intravenous Q3W administration of 1,200 mg of anti-PD-L1 monoclonal antibody and 600 mg of anti-TIGIT monoclonal antibody begins at cycle 4 (i.e., after three cycles of subcutaneous administration of the co-mixture). In some embodiments, 1,200 mg of anti-PD-L1 monoclonal antibody and 600 mg of anti-TIGIT monoclonal antibody are administered intravenously separately at Q3W. In some embodiments, 2,000 mg of anti-PD-L1 monoclonal antibody and 1,000 mg of anti-TIGIT monoclonal antibody are administered Q3W, for example, as a co-formulation described herein. In some embodiments, 2,000 mg of anti-PD-L1 monoclonal antibody and 1,000 mg of anti-TIGIT monoclonal antibody are administered intravenously Q3W. In some embodiments, 2,000 mg of anti-PD-L1 monoclonal antibody and 1,000 mg of anti-TIGIT monoclonal antibody are administered intravenously alone Q3W.

[0143] In some embodiments, the liquid drug formulation of this disclosure is administered every three weeks (Q3W). In some embodiments, the liquid drug formulation of this disclosure is administered subcutaneously at a frequency of Q3W. In some embodiments, the liquid drug formulation of this disclosure is administered intravenously at a frequency of Q3W.

[0144] Products

[0145] In another aspect, this disclosure provides an article of manufacture comprising a formulation containing 1,000 mg of tislelizumab. In some embodiments, the article of manufacture comprises a formulation containing 1,000 mg of tislelizumab.

[0146] In some embodiments, the formulation further comprises 1,875 mg or 2,000 mg of atezolizumab. In some embodiments, the formulation further comprises 1,875 mg or 2,000 mg of atezolizumab. In some embodiments, the formulation further comprises 1,875 mg of atezolizumab. In some embodiments, the formulation further comprises 2,000 mg of atezolizumab. In some embodiments, the formulation further comprises 2,000 mg of atezolizumab.

[0147] In some embodiments, the formulation further comprises hyaluronidase. In some embodiments, the hyaluronidase is recombinant human hyaluronidase. In some embodiments, the hyaluronidase is human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20. In some embodiments, the concentration of hyaluronidase is from 500 U / mL to 2600 U / mL. In some embodiments, the concentration of hyaluronidase is from 1400 U / mL to 2600 U / mL. In some embodiments, the concentration of hyaluronidase is 2000 U / mL.

[0148] In some embodiments, the formulation comprises 160 mg / mL tirelinumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5. In some embodiments, it comprises 160 mg / mL tirelinumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5. In some embodiments, it comprises 160 mg / mL tirelinumab and 2000 U / mL rHuPH20 in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5.

[0149] In another aspect, this disclosure provides an article of manufacture comprising a formulation comprising 1,000 mg of tislelizumab and 1,875 mg or 2,000 mg of atezolizumab. In some embodiments, the formulation comprises 1,000 mg of tislelizumab and 1,875 mg or 2,000 mg of atezolizumab. In some embodiments, the formulation comprises 1,000 mg of tislelizumab and 1,875 mg or 2,000 mg of atezolizumab. In some embodiments, the formulation comprises 1,000 mg of tislelizumab and 1,875 mg or 2,000 mg of atezolizumab.

[0150] In some embodiments, the formulation comprises 1,875 mg of atezolizumab.

[0151] In some embodiments, the formulation comprises 2,000 mg of atezolizumab.

[0152] In some embodiments, the formulation further comprises hyaluronidase. In some embodiments, the concentration of hyaluronidase is 2000 U / mL. In some embodiments, the hyaluronidase is recombinant human hyaluronidase. In some embodiments, the recombinant hyaluronidase is human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

[0153] In some embodiments of any of the foregoing aspects, the article is a vial. In some embodiments of any of the foregoing aspects, the vial is a single-dose vial. In some embodiments of any of the foregoing aspects, the vial is a 10 cubic centimeter (“10-cc”) vial. In some embodiments of any of the foregoing aspects, the vial is a 15-cc vial. In some embodiments of any of the foregoing aspects, the vial is a 20-cc vial. In some embodiments of any of the foregoing aspects, the vial is a 25-cc vial. In some embodiments of any of the foregoing aspects, the vial is a 30-cc vial. In some embodiments of any of the foregoing aspects, the vial is a 35-cc vial. In some embodiments of any of the foregoing aspects, the vial is a 40-cc vial. In some embodiments of any of the foregoing aspects, the vial is a 45-cc vial. In some embodiments of any of the foregoing aspects, the vial is a 50-cc vial. In some embodiments of any of the foregoing aspects, the vial is a glass vial. In some embodiments of any of the foregoing aspects, the vial is a plastic vial.

[0154] In some embodiments of any of the foregoing aspects, the vial is sealed with a chlorobutyl elastomer stopper. In some embodiments of any of the foregoing aspects, the stopper is a D21-7S stopper. Without being bound by theory, the D21-7S stopper results in reduced particle formation in the liquid pharmaceutical formulation. In some embodiments of any of the foregoing aspects, the D21-7S stopper has a thinner stopper septum.

[0155] In some embodiments of any of the foregoing aspects, the article of manufacture is a pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 10-cc pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 15-cc pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 20-cc pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 25-cc pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 30-cc pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 35-cc pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 40-cc pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 45-cc pre-filled syringe. In some embodiments of any of the foregoing aspects, the pre-filled syringe is a 50-cc pre-filled syringe.

[0156] In some embodiments of any of the foregoing aspects, the article of manufacture is an infusion pump. In some embodiments of any of the foregoing aspects, the article of manufacture is a subcutaneous application device. In some embodiments of any of the foregoing aspects, the subcutaneous application device is selected from the group consisting of: syringes, infusion pumps, injection devices, infusion pumps, injection pens, needle-free devices, auto-injectors, and subcutaneous patch delivery systems. In some embodiments of any of the foregoing aspects, the subcutaneous application device is a syringe. In some embodiments of any of the foregoing aspects, the subcutaneous application device is an infusion pump. In some embodiments of any of the foregoing aspects, the subcutaneous application device is an injection device. In some embodiments of any of the foregoing aspects, the subcutaneous application device is an infusion pump. In some embodiments of any of the foregoing aspects, the subcutaneous application device is an injection pen. In some embodiments of any of the foregoing aspects, the subcutaneous application device is a needle-free device. In some embodiments of any of the foregoing aspects, the subcutaneous application device is an auto-injector. In some embodiments of any of the foregoing aspects, the subcutaneous application device is a subcutaneous patch delivery system.

[0157] In another aspect, this disclosure provides an article of manufacture comprising a subcutaneous administration device that contains and delivers a fixed dose of 1,000 mg of tislelizumab to a patient. In some embodiments, the subcutaneous administration device contains and delivers a fixed dose of 1,000 mg of tislelizumab to a patient.

[0158] In some embodiments, the subcutaneous administration device further contains and delivers a fixed dose of 1,875 mg or 2,000 mg of atezolizumab to the patient. In some embodiments, the subcutaneous administration device further contains and delivers a fixed dose of 1,875 mg or 2,000 mg of atezolizumab to the patient. In some embodiments, the subcutaneous administration device further contains and delivers a fixed dose of 1875 mg of atezolizumab to the patient. In some embodiments, the subcutaneous administration device further contains and delivers a fixed dose of 1875 mg of atezolizumab to the patient. In some embodiments, the subcutaneous administration device further contains and delivers a fixed dose of 2,000 mg of atezolizumab to the patient. In some embodiments, the subcutaneous administration device further contains and delivers a fixed dose of 2,000 mg of atezolizumab to the patient.

[0159] In some embodiments, the subcutaneous application device further contains and delivers hyaluronidase to the patient. In some embodiments, the concentration of hyaluronidase is 2000 U / mL. In some embodiments, the hyaluronidase is recombinant human hyaluronidase. In some embodiments, the hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

[0160] In some embodiments, the subcutaneous application device is selected from the group consisting of: syringes, infusion pumps, injection devices, infusion pumps, injection pens, needle-free devices, autoinjectors, and subcutaneous patch delivery systems. In some embodiments, the subcutaneous application device is a syringe. In some embodiments, the subcutaneous application device is an infusion pump. In some embodiments, the subcutaneous application device is selected from the group consisting of injection devices. In some embodiments, the subcutaneous application device is selected from the group consisting of infusion pumps. In some embodiments, the subcutaneous application device is selected from the group consisting of injection pens. In some embodiments, the subcutaneous application device is selected from the group consisting of needle-free devices. In some embodiments, the subcutaneous application device is selected from the group consisting of autoinjectors. In some embodiments, the subcutaneous application device is selected from the group consisting of subcutaneous patch delivery systems.

[0161] In some embodiments of any of the foregoing aspects, the product comprises about 3 mL to about 60 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. In some embodiments of any of the foregoing aspects, the product comprises about 10 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. In some embodiments of any of the foregoing aspects, the product comprises about 7 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. In some embodiments of any of the foregoing aspects, the product comprises about 6.5 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20. In some embodiments of any of the foregoing aspects, the product comprises about 21 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose, and polysorbate 20.

[0162] In some embodiments of any of the foregoing aspects, the product comprises about 3 mL to about 30 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 3 mL to about 25 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 3 mL to about 20 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 25 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 22 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 20 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 18 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 16 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 14 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 12 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 10 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL to about 8 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 5 mL to about 7 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 5 mL to about 8 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 5 mL to about 10 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 5 mL to about 21 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 5.5 mL to about 7.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 6 mL to about 8 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 6 mL to about 10 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 6 mL to about 12 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 8 mL to about 12 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 9 mL to about 11 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 15 mL to about 30 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 18 mL to about 30 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 18 mL to about 28 mL of the formulation.In some embodiments of any of the foregoing aspects, the article comprises about 18 mL to about 26 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 18 mL to about 24 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 19 mL to about 23 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 20 mL to about 22 mL of the formulation.

[0163] In some embodiments of any of the foregoing aspects, the product comprises about 3 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 3.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 4.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 5.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 6 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 6.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 7 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 7.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 8 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 8.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 9 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 9.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 10 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 10.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 11 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 11.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 12 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 12.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 12.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 13 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 13.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 14 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 14.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 15 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 15.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 16 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 16.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 17 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 17.5 mL of the formulation.In some embodiments of any of the foregoing aspects, the product comprises about 18 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 18.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 19 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 19.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 20 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 21 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 22 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 23 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 24 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 25 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 26 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises about 27 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 28 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 29 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises about 30 mL of the formulation.

[0164] In some embodiments of any of the foregoing aspects, the product comprises 3 mL to 30 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 3 mL to 25 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 3 mL to 20 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 25 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 22 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 20 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 18 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 16 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 14 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 12 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 10 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL to 8 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 5 mL to 7 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 5 mL to 8 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 5 mL to 10 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 5 mL to 21 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 5.5 mL to 7.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 6 mL to 8 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 6 mL to 10 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 6 mL to 12 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 8 mL to 12 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 9 mL to 11 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 15 mL to 30 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 18 mL to 30 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 18 mL to 28 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 18 mL to 26 mL of the formulation.In some embodiments of any of the foregoing aspects, the article comprises 18 mL to 24 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 19 mL to 23 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 20 mL to 22 mL of the formulation.

[0165] In some embodiments of any of the foregoing aspects, the product comprises 3 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 3.5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 4 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 4.5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 5.5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 6 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 6.5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 7 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 7.5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 8 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 8.5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 9 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 9.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 10 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 10.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 11 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 11.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 12 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 12.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 13 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 13.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 14 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 14.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the product comprises 15 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 15.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 16 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 16.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 17 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 17.5 mL of the formulation. In some embodiments of any of the foregoing aspects, the article comprises 18 mL of the formulation.In some embodiments of any of the foregoing aspects, the product comprises 18.5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 19 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 19.5 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 20 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 21 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 22 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 23 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 24 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 25 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 26 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 27 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 28 mL of the preparation. In some embodiments of any of the foregoing aspects, the product comprises 29 mL of the preparation. In some embodiments of any of the foregoing aspects, the article comprises 30 mL of the formulation.

[0166] In another aspect, this disclosure provides an article comprising a formulation suitable for subcutaneous injection, the formulation comprising: (a) 1000 mg of anti-TIGIT monoclonal antibody, (b) 1875 mg or 2000 mg of anti-PD-L1 monoclonal antibody, (c) 5 mM to 30 mM histidine buffer, (d) 180 mM to 320 mM sucrose, (e) 0.03% (w / v) to 0.08% (w / v) polysorbate 20, and (f) 500 U / mL to 2600 U / mL hyaluronidase at a pH of approximately 5.2 to 6.1; wherein the anti-TIGIT monoclonal antibody comprises: a heavy chain variable region comprising: HVR-H1, which comprises the amino acid sequence of SEQ ID NO: 1; and HVR-H2, which comprises SEQ ID NO: 2. The anti-PD-L1 monoclonal antibody comprises: an amino acid sequence of SEQ ID NO: 10; HVR-H2, containing the amino acid sequence of SEQ ID NO: 11; and HVR-H3, containing the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: HVR-L1, containing the amino acid sequence of SEQ ID NO: 13; HVR-L2, containing the amino acid sequence of SEQ ID NO: 14; and HVR-L3, containing the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-L1 monoclonal antibody comprises: a heavy chain variable region comprising: HVR-H1, containing the amino acid sequence of SEQ ID NO: 13; HVR-L2, containing the amino acid sequence of SEQ ID NO: 14; and HVR-L3, containing the amino acid sequence of SEQ ID NO: 15. The amino acid sequence of ID NO: 15. In some embodiments, the article comprises a formulation containing: (a) 1000 mg of anti-TIGIT monoclonal antibody, (b) 1875 mg or 2000 mg of anti-PD-L1 monoclonal antibody, (c) 15 mM to 25 mM histidine buffer, (d) 200 mM to 280 mM sucrose, (e) 0.04% (w / v) to 0.08% (w / v) polysorbate 20, (f) 1400 U / mL to 2600 U / mL hyaluronidase, and a pH of about 5.5 to 5.8.In some embodiments, the article comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) 1000 mg anti-TIGIT monoclonal antibody, (b) 1875 mg or 2000 mg anti-PD-L1 monoclonal antibody, (c) 15 mM to 25 mM histidine buffer, (d) 200 mM to 280 mM sucrose, (e) 0.04% (w / v) to 0.08% (w / v) polysorbate 20, (f) 1400 U / mL to 2600 U / mL hyaluronidase, and a pH of about 5.5 to 5.8. In some embodiments, the article comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) 1000 mg anti-TIGIT monoclonal antibody, (b) 1875 mg anti-PD-L1 monoclonal antibody, (c) 15 mM to 25 mM histidine buffer, (d) 200 mM to 280 mM sucrose, (e) 0.04% (w / v) to 0.08% (w / v) polysorbate 20, (f) 1400 U / mL to 2600 U / mL hyaluronidase, and a pH of approximately 5.5 to 5.8. In some embodiments, the article comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) 1000 mg anti-TIGIT monoclonal antibody, (b) 2000 mg anti-PD-L1 monoclonal antibody, (c) 15 mM to 25 mM histidine buffer, (d) 200 mM to 280 mM sucrose, (e) 0.04 % (w / v) to 0.08 % (w / v) polysorbate 20, (f) 1400 U / mL to 2600 U / mL hyaluronidase, and a pH of approximately 5.5 to 5.8.

[0167] In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 7. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 8. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: VL, which comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 7; and VL, which comprises the amino acid sequence of SEQ ID NO: 9. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 24. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments of any of the foregoing aspects, the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 24, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 25, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a full-length antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a full-length IgG antibody.In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a full-length IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a full-length human IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is a full-length humanized IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody retains one or more effector functions. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody retains all effector functions. In some embodiments of any of the foregoing aspects, one or more effector functions of the anti-TIGIT monoclonal antibody may have been modified or eliminated. In some embodiments of any of the foregoing aspects, the anti-TIGIT monoclonal antibody is tisrelimumab. Tirelimumab is described in WHO Drug Information (International Nonproprietary Name for Medicinal Substances), proposed INN: Listing 117, Volume 31, Issue 2, published on June 9, 2017 (see page 343). In some embodiments, tislelizumab has CAS Registry Number 1918185-84-8. The anti-TIGIT monoclonal antibody can be an antibody fragment.

[0168] In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 16. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody comprises: VH, which comprises the amino acid sequence of SEQ ID NO: 16; and VL, which comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 21. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody heavy chain comprises the amino acid sequence of SEQ ID NO: 22. In some embodiments of any of the foregoing aspects, the light chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 21; and the light chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments of any of the foregoing aspects, the heavy chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 22; and the light chain of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 23. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody is a full-length antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is a full-length IgG antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is a full-length IgG1 antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is a full-length human IgG1 antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is a full-length humanized IgG1 antibody. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody retains one or more effector functions. In some embodiments of any of the foregoing aspects, the anti-PD-L1 monoclonal antibody retains all effector functions. In some embodiments of any of the foregoing aspects, one or more effector functions of the anti-PD-L1 monoclonal antibody may have been modified or eliminated. The anti-PD-L1 monoclonal antibody may be an antibody fragment. In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab.In some embodiments, the anti-PD-L1 monoclonal antibody is atezolizumab, marketed as TECENTRIQ™. Atezolizumab is described in WHO Drug Information (International Nonproprietary Name for Medicinal Substances), proposed INN: List 112, Volume 28, Issue 4, 2014 (see page 488). In some embodiments, atezolizumab has CAS Registry Number 1380723-44-3.

[0169] In another aspect, this disclosure provides an article comprising a formulation suitable for subcutaneous injection, the formulation comprising: (a) about 1,000 mg tirelinumab, (b) about 1,875 mg or about 2,000 mg atezolizumab, (c) about 20 mM histidine acetate, (d) about 240 mM sucrose, (e) about 10 mM methionine, (f) about 0.06% (w / v) polysorbate 20, and (g) about 2,000 U / mL hyaluronidase at a pH of about 5.8. In some embodiments, the product comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) about 1,000 mg tirelinumab, (b) about 1,875 mg or about 2,000 mg atezolizumab, (c) about 20 mM histidine acetate, (d) about 240 mM sucrose, (e) about 10 mM methionine, (f) about 0.06% (w / v) polysorbate 20, and (g) about 2,000 U / mL hyaluronidase at a pH of about 5.8.

[0170] In some embodiments, the product comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) about 1,000 mg tirelinumab, (b) about 1,875 mg or about 2,000 mg atezolizumab, (c) about 20 mM histidine acetate, (d) about 240 mM sucrose, (e) about 10 mM methionine, (f) about 0.06% (w / v) polysorbate 20, and (g) about 2,000 U / mL hyaluronidase at a pH of about 5.8.

[0171] In some embodiments, the product comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) about 1,000 mg tirelinumab, (b) about 1,875 mg atezolizumab, (c) about 20 mM histidine acetate, (d) about 240 mM sucrose, (e) about 10 mM methionine, (f) about 0.06% (w / v) polysorbate 20, and (g) about 2,000 U / mL hyaluronidase at a pH of about 5.8.

[0172] In some embodiments, the product comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) about 1,000 mg tirelinumab, (b) about 2,000 mg atezolizumab, (c) about 20 mM histidine acetate, (d) about 240 mM sucrose, (e) about 10 mM methionine, (f) about 0.06% (w / v) polysorbate 20, and (g) about 2,000 U / mL hyaluronidase at a pH of about 5.8.

[0173] In some embodiments, the product comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) 1,000 mg tirelinumab, (b) 1875 mg or about 2000 mg atezolizumab, (c) 20 mM histidine acetate, (d) 240 mM sucrose, (e) 10 mM methionine, (f) 0.06% (w / v) polysorbate 20, and (g) 2000 U / mL hyaluronidase at pH 5.8.

[0174] In some embodiments, the product comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) 1,000 mg tirelinumab, (b) 1,875 mg atezolizumab, (c) 20 mM histidine acetate, (d) 240 mM sucrose, (e) 10 mM methionine, (f) 0.06% (w / v) polysorbate 20, and (g) 2000 U / mL hyaluronidase at pH 5.8.

[0175] In some embodiments, the product comprises a formulation suitable for subcutaneous injection, the formulation comprising: (a) 1,000 mg tirelinumab, (b) 2,000 mg atezolizumab, (c) 20 mM histidine acetate, (d) 240 mM sucrose, (e) 10 mM methionine, (f) 0.06% (w / v) polysorbate 20, and (g) 2,000 U / mL hyaluronidase at pH 5.8.

[0176] In some embodiments of any of the foregoing aspects, the article of manufacture includes a subcutaneous application device. In some embodiments, the subcutaneous application device is selected from the group consisting of: syringes, infusion pumps, injection devices, infusion pumps, injection pens, needle-free devices, autoinjectors, and subcutaneous patch delivery systems. In some embodiments, the subcutaneous application device is a syringe. In some embodiments, the subcutaneous application device is an infusion pump. In some embodiments, the subcutaneous application device is an injection pen. In some embodiments, the subcutaneous application device is a needle-free device. In some embodiments, the subcutaneous application device is an autoinjector. In some embodiments, the subcutaneous application device is a subcutaneous patch delivery system. In some embodiments, the subcutaneous application device is a pre-filled syringe.

[0177] In some embodiments of any of the foregoing aspects, the article of manufacture comprises a formulation of the present disclosure.

[0178] Drug formulation

[0179] In another aspect, this disclosure provides a liquid pharmaceutical formulation comprising 160 mg / mL tirelinumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5. In some embodiments, the formulation comprises 160 mg / mL tirelinumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5. In some embodiments, 160 mg / mL tirelinumab and 2000 U / mL rHuPH20 are contained in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5.

[0180] In another aspect, this disclosure provides a liquid pharmaceutical formulation comprising 40 mg / ml tirelinumab and 80 mg / ml atezolizumab, and 2000 U / ml hyaluronidase, in a mixture of 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, and pH 5.8. In some embodiments, the formulation comprises 40 mg / ml tirelinumab, 80 mg / ml atezolizumab, and 2000 U / ml hyaluronidase, in a mixture of 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, and pH 5.8.

[0181] In some embodiments, the formulation comprises 40 mg / ml tirelinumab, 80 mg / ml atezolizumab, and 2000 U / ml rHuPH20 in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.8.

[0182] Exemplary embodiments

[0183] Specific embodiments of this disclosure are described in the following numbered paragraphs:

[0184] 1. A method of treating cancer in a subject with this need, the method comprising subcutaneously administering to the subject a dose of about 1,000 mg of an anti-TIGIT monoclonal antibody; wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6.

[0185] 2. Use of approximately 1,000 mg of an anti-TIGIT monoclonal antibody in the manufacture of a medicament for treating cancer in a subject with such need; wherein the medicament is formulated for subcutaneous administration, and wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6.

[0186] 3. An anti-TIGIT monoclonal antibody for treating cancer in a subject with this need, wherein the anti-TIGIT monoclonal antibody is a full-length antibody and is administered subcutaneously at a dose of about 1,000 mg, the full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6.

[0187] 4. The method according to Example 1, the use according to Example 2, or the anti-TIGIT monoclonal antibody according to Example 3, wherein the anti-TIGIT monoclonal antibody is administered to the thigh or abdomen.

[0188] 5. The method according to Example 1 or 4, the use according to Example 2 or 4, or the anti-TIGIT monoclonal antibody according to Example 3 or 4, wherein the anti-TIGIT monoclonal antibody is administered every three weeks (Q3W).

[0189] 6. A method of treating cancer in a subject with this need, the method comprising subcutaneously administering to the subject about 1,000 mg of an anti-TIGIT monoclonal antibody and administering to the subject about 1,875 mg to about 2,000 mg of an anti-PD-L1 monoclonal antibody; wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-L1 The monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, which comprises the amino acid sequence of SEQ ID NO: 10; HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 11; and HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 13; HVR-L2, which comprises the amino acid sequence of SEQ ID NO: 14; and HVR-L3, which comprises the amino acid sequence of SEQ ID NO: 15.

[0190] 7. Use of about 1,000 mg of an anti-TIGIT monoclonal antibody and about 1,875 mg to about 2,000 mg of an anti-PD-L1 monoclonal antibody in the manufacture of a medicament for treating cancer in a subject with such need; wherein the medicament is formulated for subcutaneous administration, and wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-L1 The monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, which comprises the amino acid sequence of SEQ ID NO: 10; HVR-H2, which comprises the amino acid sequence of SEQ ID NO: 11; and HVR-H3, which comprises the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: HVR-L1, which comprises the amino acid sequence of SEQ ID NO: 13; HVR-L2, which comprises the amino acid sequence of SEQ ID NO: 14; and HVR-L3, which comprises the amino acid sequence of SEQ ID NO: 15.

[0191] 8. An anti-TIGIT monoclonal antibody and an anti-PD-L1 monoclonal antibody for treating cancer in a subject with this need, wherein the anti-TIGIT monoclonal antibody is a full-length antibody and is administered subcutaneously at a dose of about 1,000 mg, the full-length antibody comprising: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 1; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 2; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 4; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 5; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-L1 monoclonal antibody is a full-length antibody and is administered at a dose of about 1,875 mg to about 2,000 mg. For dosage administration, the full-length antibody comprises: a heavy chain variable region comprising: HVR-H1, comprising the amino acid sequence of SEQ ID NO: 10; HVR-H2, comprising the amino acid sequence of SEQ ID NO: 11; and HVR-H3, comprising the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: HVR-L1, comprising the amino acid sequence of SEQ ID NO: 13; HVR-L2, comprising the amino acid sequence of SEQ ID NO: 14; and HVR-L3, comprising the amino acid sequence of SEQ ID NO: 15.

[0192] 9. The anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to Example 6, the use according to Example 7, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to Example 8, wherein the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered simultaneously.

[0193] 10. The method according to Example 6 or 9, the use according to Example 7 or 9, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to Example 8 or 9, wherein the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are co-formulated.

[0194] 11. The method according to Example 6 or 9, the use according to Example 7 or 9, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to Example 8 or 9, wherein the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed 24 hours or less before administration to the subject.

[0195] 12. The method, use, or anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to Example 11, wherein the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are mixed during administration to the subject.

[0196] 13. The method according to Example 6, the use according to Example 7, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to Example 8, wherein the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are administered sequentially.

[0197] 14. The method according to any one of Examples 6 and 9 to 13, the use according to any one of Examples 7 and 9 to 13, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 13, wherein the anti-PD-L1 monoclonal antibody is administered intravenously.

[0198] 15. The method according to any one of Examples 6 and 9 to 13, the use according to any one of Examples 7 and 9 to 13, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 13, wherein the anti-PD-L1 monoclonal antibody is administered subcutaneously.

[0199] 16. The method according to any one of Examples 6 and 9 to 15, the use according to any one of Examples 7 and 9 to 15, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 15, wherein the anti-TIGIT monoclonal antibody is administered every three weeks (Q3W).

[0200] 17. The method according to any one of Examples 1, 4 to 6, and 9 to 16; the use according to any one of Examples 2, 4, 5, 7, and 9 to 16; the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5; or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 16, wherein the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, ureteral cancer, urethral cancer, colorectal cancer, colon cancer, rectal cancer, kidney cancer, sarcoma, ovarian cancer, breast cancer, cervical cancer, fallopian tube cancer, endometrial cancer, uterine cancer, pancreatic cancer, gastric cancer, bladder cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer, thyroid cancer, sarcoma, prostate cancer, penile cancer, glioblastoma, thymic cancer, esophageal cancer, nasopharyngeal carcinoma, mesothelioma, liver cancer, biliary tract cancer, HPV. Positive cancers include leukemia, lymphoma, brain cancer, neuroendocrine carcinoma, myeloma, mycosis fungoides, Merkel cell carcinoma, hematologic malignancies, mismatch repair deficient (dMMR) cancers, and microsatellite instability-high (MSI-H) cancers.

[0201] 18. The method according to any one of Examples 1, 4 to 6 and 9 to 16, the use according to any one of Examples 2, 4, 5, 7 and 9 to 16, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-L1 according to any one of Examples 8 to 16. Monoclonal antibodies, wherein the cancer is selected from the group consisting of: bladder cancer, muscle-invasive bladder cancer, urothelial carcinoma, ureteral cancer, urethral cancer, ureteral urothelial carcinoma, urethral urothelial carcinoma, renal cancer, renal pelvis cancer, renal cell carcinoma, clear cell renal carcinoma, rectal cancer, colon cancer, colorectal cancer, sarcoma, osteosarcoma, leiomyosarcoma, pleomorphic sarcoma, myxofibrosarcoma, liposarcoma, chondrosarcoma, lung cancer, non-small cell lung cancer, fallopian tube cancer, peritoneal cancer, esophageal cancer, esophageal squamous cell carcinoma, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, ovarian cancer, cervical cancer, cervical adenosquamous carcinoma, breast cancer, triple-negative breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, luminal B-type breast cancer, lymphoma, T-cell lymphoma, B-cell lymphoma. Cellular lymphoma, nasal lymphoma, non-Hodgkin's lymphoma, follicular lymphoma, penile cancer, prostate cancer, castration-resistant prostate cancer, endometrial cancer, uterine cancer, myeloma, multiple myeloma, head and neck cancer, prostate cancer, melanoma, cutaneous melanoma, Merkel cell carcinoma, pancreatic cancer, hepatocellular carcinoma, gastric cancer, gastroesophageal junction adenocarcinoma, glioblastoma, glioblastoma multiforme, mycosis fungoides, HPV-positive cancer, HPV-associated cervical cancer, HPV-associated anal squamous cell carcinoma, HPV-associated penile squamous cell carcinoma, HPV-associated vulvar squamous cell carcinoma, vulvar cancer, vaginal cancer, anal cancer, oropharyngeal cancer, oropharyngeal squamous cell carcinoma, leukemia, acute myeloid leukemia, bone cancer, solitary osteoplasty, squamous cell carcinoma, cutaneous squamous cell carcinoma, thyroid cancer, microsatellite stable / mismatch repair intact (MSS / pMMR) Metastatic colorectal cancer, mismatch repair deficient (dMMR) cancer, microsatellite instability-high (MSI-H) cancer, nasal extranodal NK / T-cell lymphoma, neuroendocrine carcinoma, biliary tract cancer, bile duct cancer, and intrahepatic bile duct cancer.

[0202] 19. The method according to any one of Examples 1, 4 to 6 and 9 to 16, the use according to any one of Examples 2, 4, 5, 7 and 9 to 16, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 16, wherein the cancer is selected from the group consisting of: Merkel cell carcinoma, urothelial carcinoma, renal cell carcinoma, non-small cell lung cancer, breast cancer, triple-negative breast cancer, hepatocellular carcinoma, melanoma, Hodgkin lymphoma, head and neck cancer, colorectal cancer, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, squamous cell carcinoma of the skin, basal cell carcinoma, bladder cancer, endometrial cancer, esophageal cancer, malignant pleural mesothelioma, cancer with high tumor mutation burden (TMB), cancer with mismatch repair deficient (dMMR), and cancer with high microsatellite instability (MSI-H).

[0203] 20. The method according to any one of Examples 1, 4 to 6, and 9 to 16; the use according to any one of Examples 2, 4, 5, 7, and 9 to 16; the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5; or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 16, wherein the cancer is selected from the group consisting of: lung cancer, non-small cell lung cancer, bronchial carcinoma, breast cancer, triple-negative breast cancer, estrogen receptor-positive breast cancer, HER2... Positive breast cancer, lobular metastatic breast cancer, ductal breast cancer, cervical cancer, fallopian tube cancer, fallopian tube serous adenocarcinoma, ovarian cancer, ovarian endometrioid tumor, ovarian serous adenocarcinoma, ovarian seromucous carcinoma, uterine cancer, endometrial cancer, skin cancer, melanoma, cutaneous melanoma, Merkel cell carcinoma, head and neck cancer, head and neck squamous cell carcinoma, hematologic malignancies, leukemia, myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, thyroid cancer, thyroid gland cancer, thymic carcinoma, neuroendocrine carcinoma, pheochromocytoma, glioma, glioblastoma multiforme, paraganglioma, lymphoma, B-cell lymphoma, Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma. Cellular lymphoma, follicular lymphoma, marginal zone lymphoma, pancreatic cancer, pancreatic ductal adenocarcinoma, rectal cancer, colon cancer, colorectal cancer, urinary tract cancer, genitourinary system cancer, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, sarcoma, chondrosarcoma, clear cell sarcoma, liposarcoma, myxoid / round cell liposarcoma, synovial sarcoma, alveolar soft tissue sarcoma, glial sarcoma, uterine carcinosarcoma, kidney cancer, non-clear cell kidney cancer, renal cell carcinoma, bladder cancer, urothelial carcinoma, muscularly invasive bladder cancer, non-muscularly invasive bladder cancer, HER2-positive bladder cancer, gallbladder cancer, gastric cancer, esophageal cancer, esophageal squamous cell carcinoma, gastrointestinal cancer, gastroesophageal cancer, gastroesophageal junction cancer, HER2 Positive gastric cancer, primary peritoneal cancer, squamous cell carcinoma of the skin, prostate cancer, prostate adenocarcinoma, castration-resistant prostate cancer, urogenital cancer, ureteral urothelial carcinoma, renal pelvis urothelial carcinoma, urethral urothelial carcinoma, appendix cancer, penile cancer, anal canal cancer, hepatocellular carcinoma, hepatobiliary duct cancer, unresectable liver and intrahepatic bile duct cancer, bile duct cancer, intrahepatic bile duct cancer, extrahepatic bile duct cancer, HPV-related cancers, HPV-related anal squamous cell carcinoma, HPV-related cervical squamous cell carcinoma, HPV-related penile squamous cell carcinoma, HPV-related vulvar squamous cell carcinoma, nasopharyngeal carcinoma, nasopharyngeal carcinoma, laryngeal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, oral squamous cell carcinoma, and mycosis fungoides.

[0204] 21. The method according to any one of Examples 1, 4 to 6 and 9 to 16, the use according to any one of Examples 2, 4, 5, 7 and 9 to 16, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 16, wherein the cancer is selected from the group consisting of: urothelial carcinoma, non-small cell lung cancer (NSCLC), breast cancer, triple-negative breast cancer, hepatocellular carcinoma, and melanoma.

[0205] 22. The method according to any one of Examples 1, 4 to 6 and 9 to 16, the use according to any one of Examples 2, 4, 5, 7 and 9 to 16, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 16, wherein the cancer is selected from the group consisting of: multiple myeloma, cervical cancer, esophageal cancer, esophageal squamous cell carcinoma, lung cancer, non-small cell lung cancer, glioblastoma, endometrial cancer, ovarian cancer, squamous cell carcinoma, and head and neck cancer.

[0206] 23. The method according to any one of Examples 1, 4 to 6 and 9 to 16, the use according to any one of Examples 2, 4, 5, 7 and 9 to 16, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 16, wherein the cancer is selected from the group consisting of: cervical cancer, head and neck squamous cell carcinoma, head and neck cancer, non-small cell lung cancer, non-squamous non-small cell lung cancer, esophageal squamous cell carcinoma, esophageal cancer, breast cancer, triple-negative breast cancer, gastric cancer, gastroesophageal junction adenocarcinoma, multiple myeloma, non-Hodgkin lymphoma, B-cell lymphoma, liver cancer, bladder cancer, urothelial carcinoma, pancreatic cancer, and pancreatic adenocarcinoma.

[0207] 24. The method according to any one of Examples 1, 4 to 6 and 9 to 16, the use according to any one of Examples 2, 4, 5, 7 and 9 to 16, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 16, wherein the cancer is a solid tumor.

[0208] 25. The method according to any one of Examples 1, 4 to 6 and 9 to 16, the use according to any one of Examples 2, 4, 5, 7 and 9 to 16, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 16, wherein the cancer is a blood cancer.

[0209] 26. The method according to any one of Examples 6 and 9 to 25, the use according to any one of Examples 7 and 9 to 25, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 25, wherein the heavy chain variable region of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 16.

[0210] 27. The method according to any one of Examples 6 and 9 to 26, the use according to any one of Examples 7 and 9 to 26, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 26, wherein the light chain variable region of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 17.

[0211] 28. The method according to any one of Examples 6 and 9 to 27, the use according to any one of Examples 7 and 9 to 27, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 27, wherein the heavy chain variable region of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 16, and the light chain variable region of the anti-PD-L1 monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 17.

[0212] 29. The method according to any one of Examples 6 and 9 to 28, the use according to any one of Examples 7 and 9 to 28, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 28, wherein the anti-PD-L1 monoclonal antibody is an IgG antibody.

[0213] 30. The method, use, or anti-TIGIT monoclonal antibody and anti-PD-L1 antibody according to Example 29, wherein the anti-PD-L1 monoclonal antibody is an IgG1 or IgG4 antibody.

[0214] 31. The method according to any one of Examples 6 and 9 to 30, the use according to any one of Examples 7 and 9 to 30, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 30, wherein the anti-PD-L1 monoclonal antibody or the anti-TIGIT monoclonal antibody is a human antibody.

[0215] 32. The method according to any one of Examples 6 and 9 to 30, the use according to any one of Examples 7 and 9 to 30, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 30, wherein the anti-PD-L1 monoclonal antibody or the anti-TIGIT monoclonal antibody is a humanized antibody.

[0216] 33. The method according to any one of Examples 6 and 9 to 30, the use according to any one of Examples 7 and 9 to 30, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 30, wherein the anti-PD-L1 monoclonal antibody is selected from the group consisting of atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, and MDX-1105.

[0217] 34. The method according to any one of Examples 1, 4 to 6 and 9 to 33, the use according to any one of Examples 2, 4, 5, 7 and 9 to 33, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5 and 17 to 25, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 33, wherein the heavy chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8.

[0218] 35. The method according to any one of Examples 1, 4 to 6 and 9 to 34, the use according to any one of Examples 2, 4, 5, 7 and 9 to 34, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 34, wherein the light chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 9.

[0219] 36. The method according to any one of Examples 1, 4 to 6 and 9 to 35, the use according to any one of Examples 2, 4, 5, 7 and 9 to 35, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 35, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 35, wherein the heavy chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8, and the light chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 9.

[0220] 37. The method according to any one of Examples 1, 4 to 6 and 9 to 36, the use according to any one of Examples 2, 4, 5, 7 and 9 to 36, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 36, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 36, wherein the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24.

[0221] 38. The method according to any one of Examples 1, 4 to 6 and 9 to 37, the use according to any one of Examples 2, 4, 5, 7 and 9 to 37, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 37, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 37, wherein the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 25.

[0222] 39. The method according to any one of Examples 1, 4 to 6 and 9 to 38, the use according to any one of Examples 2, 4, 5, 7 and 9 to 38, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 38, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 38, wherein the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20.

[0223] 40. The method according to any one of Examples 1, 4 to 6 and 9 to 39, the use according to any one of Examples 2, 4, 5, 7 and 9 to 39, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 39, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 39, wherein the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20.

[0224] 41. The method according to any one of Examples 1, 4 to 6 and 9 to 39, the use according to any one of Examples 2, 4, 5, 7 and 9 to 39, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 39, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 39, wherein the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 25, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 20.

[0225] 42. The method according to any one of Examples 1, 4 to 6 and 9 to 41, the use according to any one of Examples 2, 4, 5, 7 and 9 to 41, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 41, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 41, wherein the anti-TIGIT monoclonal antibody is an IgG antibody.

[0226] 43. The method, use, or anti-TIGIT monoclonal antibody or anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to Example 42, wherein the anti-TIGIT monoclonal antibody is an IgG1 or IgG4 antibody.

[0227] 44. The method according to any one of Examples 1, 4 to 6 and 9 to 43, the use according to any one of Examples 2, 4, 5, 7 and 9 to 43, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 43, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 43, wherein the anti-TIGIT monoclonal antibody is a human antibody.

[0228] 45. The method according to any one of Examples 1, 4 to 6 and 9 to 43, the use according to any one of Examples 2, 4, 5, 7 and 9 to 43, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 43, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 43, wherein the anti-TIGIT monoclonal antibody is a humanized antibody.

[0229] 46. ​​The method according to any one of Examples 1, 4 to 6 and 9 to 43, the use according to any one of Examples 2, 4, 5, 7 and 9 to 43, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 43, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 43, wherein the anti-TIGIT monoclonal antibody inhibits or blocks the interaction between CD226 and TIGIT.

[0230] 47. The method according to any one of Examples 1, 4 to 6 and 9 to 43, the use according to any one of Examples 2, 4, 5, 7 and 9 to 43, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 43, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 43, wherein the anti-TIGIT monoclonal antibody is tireliumab.

[0231] 48. The method according to any one of Examples 1, 4 to 6 and 9 to 47, the use according to any one of Examples 2, 4, 5, 7 and 9 to 47, the anti-TIGIT monoclonal antibody according to any one of Examples 3 to 5, 17 to 25 and 34 to 47, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 47, wherein the anti-TIGIT monoclonal antibody is in a liquid pharmaceutical composition comprising 160 mg / mL tirelinumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.5.

[0232] 49. The method according to any one of Examples 6 and 9 to 47, the use according to any one of Examples 7 and 9 to 47, or the anti-TIGIT monoclonal antibody and anti-PD-L1 monoclonal antibody according to any one of Examples 8 to 47, wherein the anti-TIGIT monoclonal antibody and the anti-PD-L1 monoclonal antibody are in a liquid pharmaceutical formulation comprising 40 mg / ml tirelinumab, 80 mg / ml atezolizumab, and 2000 U / ml hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.8.

[0233] 50. An article comprising a formulation containing 1,000 mg of tislelizumab.

[0234] 51. The product according to Example 50, wherein the formulation further comprises 1,875 mg or 2,000 mg of atezolizumab.

[0235] 52. The product according to Example 50, wherein the formulation further comprises 1,875 mg of atezolizumab.

[0236] 53. The product according to Example 50, wherein the formulation further comprises 2,000 mg of atezolizumab.

[0237] 54. The article according to any one of Examples 50 to 53, wherein the formulation further comprises hyaluronidase.

[0238] 55. An article comprising a compound containing 1,000 mg of tislelizumab and 1,875 mg or 2,000 mg of atezolizumab.

[0239] 56. The product according to Example 55, wherein the formulation comprises 1,875 mg of atezolizumab.

[0240] 57. The product according to Example 55, wherein the formulation comprises 2,000 mg of atezolizumab.

[0241] 58. The article according to any one of Examples 55 to 57, wherein the formulation further comprises hyaluronidase.

[0242] 59. The product according to Example 54 or 58, wherein the concentration of the hyaluronidase is 2000 U / mL.

[0243] 60. The product according to any one of Examples 54 and 58 to 59, wherein the hyaluronidase is recombinant human hyaluronidase.

[0244] 61. The article according to Example 60, wherein the recombinant hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

[0245] 62. The article according to any one of Examples 50 to 61, wherein the article is a vial.

[0246] 63. The article according to Example 62, wherein the vial is a single-dose vial.

[0247] 64. The article according to Example 62 or 63, wherein the vial is sealed with a chlorobutyl elastomer stopper.

[0248] 65. The article of any one of Examples 50 to 61, wherein the article is a pre-filled syringe.

[0249] 66. The article of any one of Examples 50 to 61, wherein the article is an injection pump.

[0250] 67. The article of any one of Examples 50 to 61, wherein the article is a subcutaneous application device.

[0251] 68. The article of manufacture according to Example 67, wherein the subcutaneous application device is selected from the group consisting of: syringes, injection pumps, injection devices, infusion pumps, injection pens, needle-free devices, auto-injectors, and subcutaneous patch delivery systems.

[0252] 69. An article of manufacture comprising a subcutaneous administration device, wherein the subcutaneous administration device contains and delivers a fixed dose of 1,000 mg tislelizumab to a patient.

[0253] 70. The article of manufacture according to Example 69, wherein the subcutaneous administration device further contains and delivers a fixed dose of atezolizumab of 1,875 mg or 2,000 mg to the patient.

[0254] 71. The article of manufacture according to Example 70, wherein the subcutaneous administration device further contains and delivers a fixed dose of atezolizumab of 1,875 mg to the patient.

[0255] 72. The article of manufacture according to Example 70, wherein the subcutaneous administration device further contains and delivers a fixed dose of 2,000 mg atezolizumab to the patient.

[0256] 73. The article of any one of Examples 69 to 72, wherein the subcutaneous application device further contains and delivers hyaluronidase to the patient.

[0257] 74. The article according to Example 73, wherein the hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

[0258] 75. The article of manufacture according to any one of Examples 69 to 74, wherein the subcutaneous application device is selected from the group consisting of: syringes, injection pumps, injection devices, infusion pumps, injection pens, needle-free devices, autoinjectors, and subcutaneous patch delivery systems.

[0259] 76. The article of any one of Examples 69 to 75, wherein the subcutaneous application device is a syringe.

[0260] 77. The article according to Examples 69 to 75, wherein the subcutaneous application device is an injection pump.

[0261] 78. The article according to any one of Examples 50 to 77, wherein the article comprises about 3 mL to about 60 mL of full-length anti-TIGIT monoclonal antibody, and one or more of hyaluronidase, histidine buffer, sucrose and polysorbate 20.

[0262] 79. The product according to Example 78, wherein the product comprises about 10 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose and polysorbate 20.

[0263] 80. The product according to Example 78, wherein the product comprises about 7 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose and polysorbate 20.

[0264] 81. The product according to Example 78, wherein the product comprises about 6.5 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose and polysorbate 20.

[0265] 82. The product according to Example 78, wherein the product comprises about 21 mL of tirelinumab, and one or more of hyaluronidase, histidine buffer, sucrose and polysorbate 20.

[0266] Example

[0267] Example 1. Open-label, multicenter dose-discovery study of tisrelimumab and atezolizumab

[0268] A two- to three-arm, open-label, multicenter dose-finding study to determine the dose of a combination of subcutaneous (SC) administration of the anti-TIGIT monoclonal antibody tirelinumab and subcutaneous administration of the anti-PD-L1 monoclonal antibody atezolizumab compared to sequential intravenous (IV) administration of atezolizumab followed by tirelinumab is being initiated and is being conducted in subjects with locally advanced or metastatic solid tumors. The study is based on pharmacokinetic (PK) analyses of serum tirelinumab and atezolizumab (i.e., Cp of serum tirelinumab and atezolizumab before administration of atezolizumab in cycle 1 (cycle 2 before dosing). 谷 ).

[0269] This study consists of the following three cohorts:

[0270] ● Cohort 1: Cycle 1: On day 1 of the first cycle (21 days): (1) 880 mg tislelizumab SC mixed with 2000 mg atezolizumab SC was administered in the abdomen, or (2) 880 mg tislelizumab SC mixed with 1875 mg atezolizumab SC was administered in the thigh. Cycle 2 onwards: Subjects will begin Cycle 2 with 1200 mg atezolizumab IV every 3 weeks (Q3W) (day 1 of each cycle), followed by 600 mg tislelizumab IV, until disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of informed consent.

[0271] ● Cohort 2: Cycles 1-3: Subjects will receive 1,000 mg tislelizumab SC mixed with 1,875 mg atezolizumab SC in the thigh every 3 weeks on day 1 of each cycle for 3 cycles (21 days per cycle). Cycle 4 onwards: Subjects will begin Cycle 4 with 1200 mg atezolizumab IV every 3 weeks (day 1 of each cycle), followed by 600 mg tislelizumab IV, until disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of informed consent.

[0272] ● Cohort 3: Cycles 1 to 3: Subjects will receive 1,000 mg tislelizumab SC mixed with 1,875 mg atezolizumab SC via abdominal infusion on day 1 of each cycle, Q3W, for 3 cycles (21 days per cycle). Cycle 4 onwards: Subjects will begin Cycle 4 with 1200 mg atezolizumab IV infusion on day 1 of each cycle, Q3W, followed by 600 mg tislelizumab IV, until disease progression, loss of clinical benefit, unacceptable toxicity, or withdrawal of informed consent.

[0273] Cohort 1 enrolled 30 eligible subjects (15 for abdominal injection (Cohort 1A) and 15 for thigh injection (Cohort 1B)), and Cohorts 2 and 3 will each enroll approximately 25 to 30 eligible subjects to achieve at least 15 evaluable subjects in each cohort, for a total of approximately 74 to 100 eligible subjects. Cohort 3 may not be initiated or may enroll fewer subjects if data from Cohort 2 is deemed sufficient. Based on the known PK morphologies of tisrelimumab IV and atezolizumab IV, the sample size will allow for estimation of PK parameters to enable phase III dose selection.

[0274] In cohort 1A, 15 subjects received a single subcutaneous dose of 880 mg tislelizumab followed by an intravenous dose of 600 mg tislelizumab. Pharmacokinetic model parameter estimates were then obtained. See Table 3. Data from two representative subjects in cohort 1A and two representative subjects in cohort 1B were used to generate time-fitted pharmacokinetic models. See Figures 2A and 2B, respectively.

[0275] Table 3. Estimated values ​​of parameters for the population pharmacokinetic model

[0276]

[0277] Two hundred population pharmacokinetic model-based simulated clinical trials were conducted using patient characteristics from 326 subjects. Table 4 below presents a summary statistical table of simulated serum tirelimumab concentrations after administration of the indicated regimens and doses to simulated subjects.

[0278] As shown in Table 4, statistical analysis of predicted pharmacokinetic patterns showed that subcutaneous administration of 1000 mg tislelizumab in Q3W was non-inferior to intravenous administration of 600 mg tislelizumab in Q3W, as indicated by the predicted cycle 1 AUC and Cmin values ​​when the abdomen or thigh was used as the administration site for the subcutaneous dose. Therefore, the 1000 mg subcutaneous dose would be as effective as the 600 mg tislelizumab IV dose in Q3W. Therefore, subcutaneous administration of 1000 mg tislelizumab was chosen as the dose for cohorts 2 and 3.

[0279] Table 4. Total Statistical Table of Serum Tirelimumab Concentrations

[0280]

[0281] Subjects who discontinued their study treatment early were defined as those who discontinued for reasons other than toxicity before completing two cycles in cohort 1 or four cycles in cohorts 2 and 3, and were replaced if they were deemed not evaluable.

[0282] All participants will be asked to report any symptoms and adverse events as soon as possible, especially within the first 72 hours after the first injection. The first two patients in each of the thigh and abdomen injection groups in Cohort 1 (participants in both thigh and abdomen injection groups may be recruited simultaneously) and the first two patients in each of Cohorts 2 and 3 (participants in Cohorts 2 and 3 may be recruited simultaneously) will be observed for 1 week before the next participant is administered. After the third participant in the thigh and abdomen groups in Cohorts 2 and 3, there will be no staggering in participant recruitment. Cohort review of all safety data will begin 7 days after the last participant in the respective cohort receives the second cycle of administration.

[0283] After the start of study treatment, all adverse events will be reported until 30 days after the last dose of study treatment or until the start of a new systemic anticancer therapy (whichever occurs first). Serious adverse events will continue to be reported until 90 days after the last dose of study treatment or until the start of a new systemic anticancer therapy (whichever occurs first). Furthermore, regardless of whether subsequent anticancer therapy has been started, adverse events of particular concern will continue to be reported until 90 days after the last dose of study treatment. After this period, any death or serious adverse event believed to be related to prior use of the study drug should be reported. Adverse events should be followed up until the event resolves to baseline or better, is assessed as stable, the subject is lost to follow-up, or the subject withdraws informed consent. All serious adverse events related to the study treatment or protocol-related procedures should be tracked to the extent possible until a final outcome can be reported.

[0284] Tumor assessment was performed every 6 weeks (Q6W) (± 7 days) during the first 48 weeks, and then every 9 weeks (Q9W) (± 7 days) thereafter, until radiographic disease progression (PD) or loss of clinical benefit occurred. Overall survival (OS) of participants will continue to be followed up until death, loss to follow-up, withdrawal from the study, or study termination, whichever occurs first.

[0285] Figure 1 provides an overview of the research design.

[0286] reason

[0287] This study will determine the dosage and site of administration by comparing the SC co-administration of tislelizumab and atezolizumab with their IV administration routes, and will assess safety, tolerability, and pharmacokinetics (PK). In previous studies, only the IV administration route was tested for both tislelizumab and atezolizumab. Bioavailability, safety, immunogenicity, and preliminary efficacy data for the SC administration of the tislelizumab and atezolizumab combination will facilitate further development of SC administration routes. In addition, the safety, PK, and immunogenicity of rHuPH20 will be assessed. The co-administration mixture with 2000 U / mL rHuPH20 will be derived from both atezolizumab SC and tislelizumab SC formulations.

[0288] Goals and End Points

[0289] This study was designed to evaluate the pharmacokinetics, safety, tolerability, and exploratory efficacy of various doses of tislelizumab and atezolizumab as a single SC injection (i.e., a co-mixture of tislelizumab and atezolizumab SC with rHuPH20) and sequentially administered tislelizumab and atezolizumab IV in subjects with locally advanced or metastatic solid tumors. Objectives and corresponding endpoints are described in Table 5 below.

[0290] Table 5. Goals and Endpoints

[0291]

[0292] In Cohort 1, participants underwent tumor assessment at baseline and again at Q6W (± 7 days) after Day 1 of Period 1 for 48 weeks. After completing the 48-week tumor assessment, tumor assessments were performed every 9 weeks (± 7 days) until progression of radiographic disease, withdrawal of informed consent, death, or study termination according to RECIST v1.1 (whichever occurs first). Participants who received treatment after experiencing progression of disease according to RECIST v1.1 would undergo tumor assessment at Q6W (± 2 weeks) after initial recording of progression, or more frequently if clinically indicated (regardless of study duration), until treatment cessation. Scans could be performed at any time if disease progression or loss of clinical benefit was suspected.

[0293] Response was assessed using RECIST v1.1 on the aforementioned imaging modalities (e.g., CT scans and MRI). Assessment of overall tumor response at all time points was based on RECIST v1.1. Results were reviewed prior to the next cycle of dosing. Treatment with tisrelimumab and atezolizumab was continued as long as the subject received clinical benefit without unacceptable toxicity or symptom worsening due to disease progression, after a comprehensive assessment of radiographic data, biopsy results, and clinical status. Study treatment was permitted to continue if the subject met all criteria for disease progression according to RECIST v1.1 and provided written consent.

[0294] Reaction assessment and biomarkers and biological samples

[0295] Objective response will be assessed according to RECIST v1.1 and determined by repeat assessments ≥ 4 weeks after initial recording to CR and PR.

[0296] The laboratory tests to be performed include:

[0297] 1. Serological tests: HIV serology, HBV serology (e.g., HBsAg, HBsAb, and total HBcAb); HBV DNA (for subjects who are negative for HBsAg and HBsAb but positive for total HBcAb); HCV serology (e.g., HCV antibody and (if HCV antibody is positive) HCV RNA); EBV serology (e.g., EBV viral capsid antigen (VCA) IgM; EBV VCA IgG or EBV nuclear antigen (EBNA) IgG; and EBV PCR).

[0298] 2. Hematology: White blood cell (WBC) count and differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes), red blood cell (RBC) count, hemoglobin, hematocrit, platelet count and differential count;

[0299] 3. Electrolyte tests (serum or plasma): bicarbonate or total carbon dioxide (if local standards of care are taken into account), sodium, magnesium, potassium, calcium, chloride, glucose, blood urea nitrogen (BUN) or urea, creatinine, total protein, albumin, phosphate, total bilirubin, ALP, ALT, AST and lactate dehydrogenase (LDH);

[0300] 4. Serum C-reactive protein (CRP)

[0301] 5. Urine analysis, including test strips (pH, specific gravity, glucose, protein, ketones, blood).

[0302] 6. Pregnancy testing: All women of childbearing potential will undergo a serum pregnancy test 14 days prior to the start of the study drug. During the study, a urine pregnancy test will be performed within 96 hours of administration on day 1 of each cycle and after the study treatment is discontinued;

[0303] 7. Coagulation (INR and aPTT) or prothrombin time (PTT); and

[0304] 8. Thyroid-stimulating hormone (TSH), free T3 (or total T3 at sites where free T3 testing was not performed), and free T4.

[0305] Samples used for the following laboratory tests will be sent for analysis:

[0306] 1. Serum and plasma samples were used for PK analysis (using validated assays for tisrelinumab and atezolizumab). PK / ADA samples are interchangeable for PK / ADA-related assessments;

[0307] 2. Serum and plasma samples were used for ADA analysis using validated assays (tisreliumab, atezolizumab, and rHuPH20).

[0308] 3. Plasma sample for rHuPH20 concentration using a validated assay;

[0309] 4. Blood, plasma, serum, and peripheral blood mononuclear cells (PBMCs) are used for exploratory studies of biomarkers; and

[0310] 5. Archived tissue samples obtained at baseline (if available) may be used for exploratory biomarkers, including but not limited to PD-L1 and TIGIT.

[0311] a. Prior to enrollment in the study, a representative FFPE tumor specimen (in a paraffin block) or 10 to 15 slides containing unstained, freshly cut serial sections (on a slide from the FFPE tumor specimen) should be submitted, along with the associated pathology report.

[0312] b. Based on total tumor content and viable tumor content, tumor tissue should be of good quality. Priority will be given to the most recent tissue biopsies with the highest tumor content and lowest necrotic area. Samples collected via resection, core needle biopsy (at least 3 cores embedded in a single paraffin block), or excisional, open, drill-type, forceps-type biopsies, or EBUS-TBNA are acceptable. Fine-needle aspiration (defined as samples that do not preserve tissue structure and produce a cell suspension and / or smear), brushing, cell sediment from pleural effusion, and irrigation samples are unacceptable. Decalcified tumor tissue from bone metastases is unacceptable.

[0313] c. If the stored tumor tissue is unavailable or determined to be unsuitable for the required examination, a fresh pre-processed tumor biopsy may be required.

[0314] Exploratory biomarker studies may include, but are not limited to, the analysis of genes or genomic imprints associated with tumor immunobiology (e.g., PD-L1 and TIGIT), lymphocyte subsets, T cell receptor repertoires, or cytokines associated with T cell activation. Studies may involve the extraction of DNA, cell-free DNA, or RNA; analysis of mutations, single nucleotide polymorphisms, and other genomic variants; and genomic analysis using next-generation sequencing (NGS) of a comprehensive set of genes. DNA extracted from blood can be compared with DNA extracted from tissues to identify somatic variants by distinguishing germline variants from somatic variants. NGS methods may include whole-genome sequencing (WGS) or whole-exome sequencing (WES) of blood samples, but are limited to the sites involved and are optional.

[0315] The safety assessments performed in this study included monitoring and recording adverse events (e.g., serious adverse events and adverse events of particular concern), conducting laboratory safety assessments, measuring vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature), and performing other tests deemed essential to the safety assessment of the study.

[0316] PK Analysis

[0317] The pharmacokinetic analysis of subjects in cohort 1 provided sufficient data to estimate key parameters (e.g., area under the concentration-time curve [AUC], time to reach maximum concentration [t]). max Maximum concentration [C] max Half-life, C 谷 Subjects were grouped according to treatment. Estimates of these parameters were tabulated and summarized (mean, standard deviation, coefficient of variation, median, minimum, and maximum). See Table 4. Inter-subject variability and drug accumulation were assessed. Additional pharmacokinetic analysis may be performed as appropriate.

[0318] Subcutaneous injection

[0319] The atezolizumab SC and tislelizumab SC co-mixture is derived from atezolizumab SC and tislelizumab SC drugs, each containing rHuPH20 at a concentration of 2000 U / mL. This drug is administered subcutaneously in the anterior thigh region or lower abdomen. In Cohort 1, subjects received one dose of the atezolizumab SC and tislelizumab SC co-mixture via the SC route. In Cohorts 2 and 3, subjects will receive three doses of the atezolizumab SC and tislelizumab SC co-mixture via the SC route. The atezolizumab SC and tislelizumab SC co-mixture is administered according to the instructions outlined in Table 6.

[0320] Table 6. First and subsequent administrations of the atezolizumab SC and tirelinumab SC co-injection mixture

[0321]

[0322] SC injections are administered via a B. Braun Perfusor® Space infusion pump or a Smiths MedicalMedfusion infusion pump at a rate of 1.0 mL / min to 2.0 mL / min. Disposable Becton-Dickenson plastic syringes and KORU HigH-Flo 24G SC injection devices are used in conjunction with the infusion pump to administer the SC dose.

[0323] When applicable, injection sites alternate between the left and right thighs. New injections should be given at least 2.5 cm away from the previous site, and never injected into areas where the skin is red, bruised, tender, or hardened. If applied to the abdomen, the injection will be made in either of the two lower quadrants around the navel; it will not be applied above the navel. In all cases (abdomen or thigh), the start and stop times of SC injections will be recorded.

[0324] No prior medication is permitted for the first dose of the atezolizumab SC and tirelinumab SC co-drug mixture. The first dose may be administered at the discretion of the treating physician within one cycle. > Pre-administration should be administered within 2 hours. If a serious adverse reaction is observed at the injection site after the SC injection, digital imaging of the injection site will be performed. Following the first dose, patients will remain in their ward for 8 hours. They will then return on a designated date for safety assessment.

[0325] The subject’s vital signs (e.g., pulse rate, respiratory rate, blood pressure, and body temperature) will be determined within 60 minutes before injection and within 30 (± 10) minutes after injection, as indicated by clinical indications.

[0326] Intravenous administration

[0327] In Cohort 1, the IV administration of atezolizumab and tislelizumab, starting in Cycle 2, was performed in a monitored environment with immediate access to trained personnel and adequate equipment and medication to manage any serious adverse reactions. Dosage adjustments to either atezolizumab or tislelizumab were not permitted.

[0328] Atezolizumab IV infusion was administered according to the instructions outlined in Table 7. Following administration of atezolizumab and the observation period (see Table 7), subjects received 600 mg tirelinumab via IV infusion on day 1 of each 21-day cycle.

[0329] Table 7. Administration of initial and subsequent atezolizumab IV infusions

[0330]

[0331] Administer tyrene infusion according to the instructions outlined in Table 8.

[0332] Table 8. Administration of first and subsequent IV infusions of tisrelimumab

[0333]

[0334] If neither atezolizumab nor tisrelinumab has been permanently discontinued, the following rules apply:

[0335] • Treatment cycles begin on day 1 of each 21-day cycle with the administration of atezolizumab and tisrelimumab. If administration of one investigational drug is delayed due to drug-related toxicity, it is recommended that the other investigational drug be delayed concurrently, as atezolizumab and tisrelimumab have similar safety profiles; however, if deemed appropriate, the cycle may begin with the administration of the other investigational drug.

[0336] • If one investigational drug is delayed due to drug-related toxicity, while another investigational drug is administered as scheduled, it is recommended that the delayed investigational drug be administered at the next scheduled infusion (i.e., within the next planned 21-day cycle).

Claims

1. A method of treating cancer in a subject in need thereof, the method comprising subcutaneously administering to the subject a dose of about 1,000 mg of an anti-TIGIT monoclonal antibody; wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:

6.

2. Use of about 1,000 mg of an anti-TIGIT monoclonal antibody in the manufacture of a medicament for treating cancer in a subject in need thereof; wherein the medicament is formulated for subcutaneous administration, and wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising: a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:

6.

3. An anti-TIGIT monoclonal antibody for use in treating cancer in a subject in need thereof, wherein the anti-TIGIT monoclonal antibody is a full-length antibody and is administered subcutaneously at a dose of about 1,000 mg, the full-length antibody comprising: a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:

6.

4. The method of claim 1, the use of claim 2, or the anti-TIGIT monoclonal antibody of claim 3, wherein the anti-TIGIT monoclonal antibody is administered in the thigh or abdomen.

5. The method of claim 1 or 4, the use of claim 2 or 4, or the anti-TIGIT monoclonal antibody of claim 3 or 4, wherein the anti-TIGIT monoclonal antibody is administered every three weeks (Q3W).

6. A method of treating cancer in a subject in need thereof, the method comprising subcutaneously administering to the subject a dose of about 1,000 mg of an anti-TIGIT monoclonal antibody and administering to the subject about 1,875 mg to about 2,000 mg of an anti-PD-Ll monoclonal antibody; wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-Ll monoclonal antibody is a full-length antibody comprising a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:

15.

7. Use of about 1,000 mg of an anti-TIGIT monoclonal antibody and about 1,875 mg to about 2,000 mg of an anti-PD-Ll monoclonal antibody in the manufacture of a medicament for treating cancer in a subject in need thereof; wherein the medicament is formulated for subcutaneous administration, and wherein the anti-TIGIT monoclonal antibody is a full-length antibody comprising a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-Ll monoclonal antibody is a full-length antibody comprising a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:

15.

8. The use of claim 7, wherein the anti-TIGIT monoclonal antibody is administered at a dose of about 1,000 mg and the anti-PD-Ll monoclonal antibody is administered at a dose of about 1,875 mg to about 2,000 mg.

9. The use of claim 7, wherein the anti-TIGIT monoclonal antibody is administered at a dose of about 1,000 mg and the anti-PD-Ll monoclonal antibody is administered at a dose of about 2,000 mg.

10. The use of claim 7, wherein the anti-TIGIT monoclonal antibody is administered at a dose of about 1,000 mg and the anti-PD-Ll monoclonal antibody is administered at a dose of about 1,875 mg.

8. An anti-TIGIT monoclonal antibody and an anti-PD-Ll monoclonal antibody for use in treating cancer in a subject in need thereof, wherein the anti-TIGIT monoclonal antibody is a full-length antibody and is administered subcutaneously at a dose of about 1,000 mg, the full-length antibody comprising: a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6; and wherein the anti-PD-Ll monoclonal antibody is a full-length antibody and is administered at a dose of about 1,875 mg to about 2,000 mg, the full-length antibody comprising: a heavy chain variable region comprising: an HVR-H1 comprising the amino acid sequence of SEQ ID NO: 10; an HVR-H2 comprising the amino acid sequence of SEQ ID NO: 11; and an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 12; and a light chain variable region comprising: an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 14; and an HVR-L3 comprising the amino acid sequence of SEQ ID NO:

15.

9. The method of claim 6, the use of claim 7, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of claim 8, wherein the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody are administered simultaneously.

10. The method of claim 6 or 9, the use of claim 7 or 9, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of claim 8 or 9, wherein the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody are co-formulated.

11. The method of claim 6 or 9, the use of claim 7 or 9, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of claim 8 or 9, wherein the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody are mixed within 24 hours or less prior to administration to the subject.

12. The method, use or anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of claim 11, wherein the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody are admixed during administration to the subject.

13. The method of claim 6, the use of claim 7 or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of claim 8, wherein the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody are administered sequentially.

14. The method of any one of claims 6 and 9-13, the use of any one of claims 7 and 9-13 or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-13, wherein the anti-PD-Ll monoclonal antibody is administered intravenously.

15. The method of any one of claims 6 and 9-13, the use of any one of claims 7 and 9-13 or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-13, wherein the anti-PD-Ll monoclonal antibody is administered subcutaneously.

16. The method of any one of claims 6 and 9-15, the use of any one of claims 7 and 9-15 or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-15, wherein the anti-TIGIT monoclonal antibody is administered every three weeks (Q3W).

17. The method of any one of claims 1, 4 to 6, and 9 to 16, the use of any one of claims 2, 4, 5, 7, and 9 to 16, the anti-TIGIT monoclonal antibody of any one of claims 3 to 5, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of any one of claims 8 to 16, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer, renal cell carcinoma, urothelial carcinoma, ureteral cancer, urethral cancer, colorectal cancer, colon cancer, rectal cancer, kidney cancer, sarcoma, ovarian cancer, breast cancer, cervical cancer, fallopian tube cancer, endometrial cancer, uterine cancer, pancreatic cancer, gastric cancer, bladder cancer, esophageal cancer, mesothelioma, melanoma, head and neck cancer, thyroid cancer, sarcoma, prostate cancer, penile cancer, glioblastoma, thymic carcinoma, esophageal cancer, nasopharyngeal cancer, mesothelioma, liver cancer, biliary tract cancer, HPV-positive cancer, leukemia, lymphoma, brain cancer, neuroendocrine cancer, myeloma, mycosis fungoides, Merkel cell carcinoma, hematological malignancy, mismatch repair deficient (dMMR) cancer, and microsatellite instability-high (MSI-H) cancer.

18. The method of any one of claims 1, 4 to 6, and 9 to 16, the use of any one of claims 2, 4, 5, 7, and 9 to 16, the anti-TIGIT monoclonal antibody of any one of claims 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8 to 16, wherein the cancer is selected from the group consisting of bladder cancer, muscle-invasive bladder cancer, urothelial cancer, ureter cancer, urethral cancer, ureteral urothelial cancer, urethral urothelial cancer, kidney cancer, renal pelvis cancer, renal cell carcinoma, clear cell kidney cancer, rectal cancer, colon cancer, colorectal cancer, sarcoma, osteosarcoma, leiomyosarcoma, pleomorphic sarcoma, myxofibrosarcoma, liposarcoma, chondrosarcoma, lung cancer, non-small cell lung cancer, fallopian tube cancer, peritoneal cancer, esophageal cancer, esophageal squamous cell carcinoma, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, ovarian cancer, cervical cancer, cervical adenosquamous carcinoma, breast cancer, triple-negative breast cancer, HER2-positive breast cancer, HER2-negative breast cancer, estrogen receptor-positive breast cancer, progesterone receptor-positive breast cancer, luminal B-type breast cancer, lymphoma, T-cell lymphoma, B-cell lymphoma, nasal-type lymphoma, non-Hodgkin lymphoma, follicular lymphoma, penile cancer, prostate cancer, castration-resistant prostate cancer, endometrial cancer, uterine cancer, myeloma, multiple myeloma, head and neck cancer, prostate cancer, melanoma, cutaneous melanoma, Merkel cell carcinoma, pancreatic cancer, hepatocellular carcinoma, gastric cancer, gastroesophageal junction adenocarcinoma, glioblastoma, glioblastoma multiforme, mycosis fungoides, HPV-positive cancer, HPV-associated cervical cancer, HPV-associated anal squamous cell carcinoma, HPV-associated penile squamous cell carcinoma, HPV-associated vulvar squamous cell carcinoma, vulvar cancer, vaginal cancer, anal cancer, oropharyngeal cancer, oropharyngeal squamous cell carcinoma, leukemia, acute myeloid leukemia, bone cancer, solitary plasmacytoma of bone, squamous cell carcinoma, cutaneous squamous cell carcinoma, thyroid cancer, microsatellite stable / mismatch repair intact (MSS / pMMR) metastatic colorectal cancer, mismatch repair deficient (dMMR) cancer, microsatellite instability-high (MSI-H) cancer, nasal-type extranodal NK / T-cell lymphoma, neuroendocrine cancer, biliary tract cancer, cholangiocarcinoma, and intrahepatic bile duct cancer.

19. The method of any one of claims 1, 4 to 6, and 9 to 16, the use of any one of claims 2, 4, 5, 7, and 9 to 16, the anti-TIGIT monoclonal antibody of any one of claims 3 to 5, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of any one of claims 8 to 16, wherein the cancer is selected from the group consisting of: Merkel cell carcinoma, urothelial cancer, renal cell carcinoma, non-small cell lung cancer, breast cancer, triple-negative breast cancer, hepatocellular carcinoma, melanoma, Hodgkin lymphoma, head and neck cancer, colorectal cancer, gastric cancer, cervical cancer, primary mediastinal large B-cell lymphoma, cutaneous squamous cell carcinoma, basal cell carcinoma, bladder cancer, endometrial cancer, esophageal cancer, malignant pleural mesothelioma, high tumor mutation burden (TMB) cancer, mismatch repair deficient (dMMR) cancer, and microsatellite instability-high (MSI-H) cancer.

20. The method of any one of claims 1, 4 to 6, and 9 to 16, the use of any one of claims 2, 4, 5, 7, and 9 to 16, the anti-TIGIT monoclonal antibody of any one of claims 3 to 5, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8 to 16, wherein the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer, bronchogenic carcinoma, breast cancer, triple negative breast cancer, estrogen receptor positive breast cancer, HER2 positive breast cancer, lobular metastatic breast cancer, ductal breast cancer, cervical cancer, fallopian tube cancer, fallopian tube serous adenocarcinoma, ovarian cancer, ovarian endometrioid tumor, ovarian serous adenocarcinoma, ovarian seromucinous carcinoma, uterine cancer, endometrial carcinoma, skin cancer, melanoma, cutaneous melanoma, Merkel cell carcinoma, head and neck cancer, head and neck squamous cell carcinoma, hematological malignancy, leukemia, myeloid leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, myelomonocytic leukemia, thyroid cancer, thyroid gland carcinoma, thymus cancer, neuroendocrine cancer, pheochromocytoma, glioma, glioblastoma multiforme, paraganglioma, lymphoma, B-cell lymphoma, Hodgkin lymphoma, B-cell non-Hodgkin lymphoma, non-Hodgkin lymphoma, cutaneous T-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, pancreatic cancer, pancreatic ductal adenocarcinoma, rectal cancer, colon cancer, colorectal cancer, urological cancer, genitourinary cancer, mesothelioma, pleural mesothelioma, peritoneal mesothelioma, sarcoma, chondrosarcoma, clear cell sarcoma, liposarcoma, myxoid / round cell liposarcoma, synovial sarcoma, alveolar soft part sarcoma, gliomatous sarcoma, uterine carcinosarcoma, kidney cancer, non-clear cell kidney cancer, renal cell carcinoma, bladder cancer, urothelial cancer, muscle-invasive bladder cancer, non-muscle invasive bladder cancer, HER2 positive bladder cancer, gallbladder cancer, stomach cancer, esophageal cancer, esophageal squamous cell carcinoma, gastroenteric cancer, gastroesophageal cancer, gastroesophageal junction cancer, HER2 positive gastric cancer, primary peritoneal cancer, cutaneous squamous cell carcinoma, prostate cancer, prostate adenocarcinoma, castration-resistant prostate cancer, urogenital cancer, ureter urothelial cancer, renal pelvis urothelial cancer, urethral urothelial cancer, appendix cancer, penile cancer, anal canal cancer, hepatocellular carcinoma, hepatobiliary cancer, unresectable liver and intrahepatic bile duct cancer, biliary tract cancer, cholangiocarcinoma, intrahepatic bile duct cancer, extrahepatic bile duct cancer, HPV-associated cancer, HPV-associated anal squamous cell carcinoma, HPV-associated cervical squamous cell carcinoma, HPV-associated penile squamous cell carcinoma, HPV-associated vulvar squamous cell carcinoma, nasopharyngeal cancer, nasopharyngeal carcinoma, laryngeal squamous cell carcinoma, hypopharyngeal squamous cell carcinoma, oral squamous cell carcinoma, and mycosis fungoides.

21. The method of any one of claims 1, 4-6, and 9-16, the use of any one of claims 2, 4, 5, 7, and 9-16, the anti-TIGIT monoclonal antibody of any one of claims 3-5, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-16, wherein the cancer is selected from the group consisting of urothelial cancer, non-small cell lung cancer (NSCLC), breast cancer, triple negative breast cancer, hepatocellular carcinoma, and melanoma.

22. The method of any one of claims 1, 4-6, and 9-16, the use of any one of claims 2, 4, 5, 7, and 9-16, the anti-TIGIT monoclonal antibody of any one of claims 3-5, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-16, wherein the cancer is selected from the group consisting of multiple myeloma, cervical cancer, esophageal cancer, esophageal squamous cell carcinoma, lung cancer, non-small cell lung cancer, glioblastoma, endometrial cancer, ovarian cancer, squamous cell carcinoma, head and neck cancer.

23. The method of any one of claims 1, 4-6, and 9-16, the use of any one of claims 2, 4, 5, 7, and 9-16, the anti-TIGIT monoclonal antibody of any one of claims 3-5, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-16, wherein the cancer is selected from the group consisting of cervical cancer, head and neck squamous cell carcinoma, head and neck cancer, non-small cell lung cancer, non-squamous non-small cell lung cancer, esophageal squamous cell carcinoma, esophageal cancer, breast cancer, triple negative breast cancer, gastric cancer, gastroesophageal junction adenocarcinoma, multiple myeloma, non-Hodgkin lymphoma, B-cell lymphoma, liver cancer, bladder cancer, urothelial cancer, pancreatic cancer, and pancreatic adenocarcinoma.

24. The method of any one of claims 1, 4-6, and 9-16, the use of any one of claims 2, 4, 5, 7, and 9-16, the anti-TIGIT monoclonal antibody of any one of claims 3-5, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-16, wherein the cancer is a solid tumor.

25. The method of any one of claims 1, 4-6, and 9-16, the use of any one of claims 2, 4, 5, 7, and 9-16, the anti-TIGIT monoclonal antibody of any one of claims 3-5, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of any one of claims 8-16, wherein the cancer is a hematological cancer.

26. The method of any one of claims 6 and 9-25, the use of any one of claims 7 and 9-25, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of any one of claims 8-25, wherein the heavy chain variable region of the anti-PD-Ll monoclonal antibody comprises the amino acid sequence of SEQ ID NO:

16.

27. The method of any one of claims 6 and 9-26, the use of any one of claims 7 and 9-26, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of any one of claims 8-26, wherein the light chain variable region of the anti-PD-Ll monoclonal antibody comprises the amino acid sequence of SEQ ID NO:

17.

28. The method of any one of claims 6 and 9-27, the use of any one of claims 7 and 9-27, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of any one of claims 8-27, wherein the heavy chain variable region of the anti-PD-Ll monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 16 and the light chain variable region of the anti-PD-Ll monoclonal antibody comprises the amino acid sequence of SEQ ID NO:

17.

29. The method of any one of claims 6 and 9-28, the use of any one of claims 7 and 9-28, or the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody of any one of claims 8-28, wherein the anti-PD-Ll monoclonal antibody is an IgG antibody.

30. The method, use, or anti-TIGIT monoclonal antibody and anti-PD-Ll antibody of claim 29, wherein the anti-PD-Ll monoclonal antibody is an IgGl or IgG4 antibody.

31. The method of any one of claims 6 and 9-30, the use of any one of claims 7 and 9-30, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-30, wherein the anti-PD-Ll monoclonal antibody or the anti-TIGIT monoclonal antibody is a human antibody.

32. The method of any one of claims 6 and 9-30, the use of any one of claims 7 and 9-30, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-30, wherein the anti-PD-Ll monoclonal antibody or the anti-TIGIT monoclonal antibody is a humanized antibody.

33. The method of any one of claims 6 and 9-30, the use of any one of claims 7 and 9-30, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-30, wherein the anti-PD-Ll monoclonal antibody is selected from the group consisting of atezolizumab (MPDL3280A), durvalumab (MEDI4736), avelumab, and MDX-1105.

34. The method of any one of claims 1, 4-6, and 9-33, the use of any one of claims 2, 4, 5, 7, and 9-33, the anti-TIGIT monoclonal antibody of any one of claims 3-5 and 17-25, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-33, wherein the heavy chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO:

8.

35. The method of any one of claims 1, 4-6, and 9-34, the use of any one of claims 2, 4, 5, 7, and 9-34, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-34, wherein the light chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO:

9.

36. The method of any one of claims 1, 4-6, and 9-35, the use of any one of claims 2, 4, 5, 7, and 9-35, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-35, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-35, wherein the heavy chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 7 or SEQ ID NO: 8, and the light chain variable region of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO:

9.

37. The method of any one of claims 1, 4-6, and 9-36, the use of any one of claims 2, 4, 5, 7, and 9-36, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-36, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-36, wherein the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO:

24.

38. The method of any one of claims 1, 4-6, and 9-37, the use of any one of claims 2, 4, 5, 7, and 9-37, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-37, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-37, wherein the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO:

25.

39. The method of any one of claims 1, 4-6, and 9-38, the use of any one of claims 2, 4, 5, 7, and 9-38, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-38, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-38, wherein the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO:

20.

40. The method of any one of claims 1, 4-6, and 9-39, the use of any one of claims 2, 4, 5, 7, and 9-39, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-39, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-39, wherein the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 18 or SEQ ID NO: 24, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO:

20.

41. The method of any one of claims 1, 4-6, and 9-39, the use of any one of claims 2, 4, 5, 7, and 9-39, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-39, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-39, wherein the heavy chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO: 19 or SEQ ID NO: 25, and the light chain of the anti-TIGIT monoclonal antibody comprises the amino acid sequence of SEQ ID NO:

20.

42. The method of any one of claims 1, 4-6, and 9-41, the use of any one of claims 2, 4, 5, 7, and 9-41, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-41, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-41, wherein the anti-TIGIT monoclonal antibody is an IgG antibody.

43. The method, use, anti-TIGIT monoclonal antibody, or anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of claim 42, wherein the anti-TIGIT monoclonal antibody is an IgGl or IgG4 antibody.

44. The method of any one of claims 1, 4-6, and 9-43, the use of any one of claims 2, 4, 5, 7, and 9-43, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-43, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-43, wherein the anti-TIGIT monoclonal antibody is a human antibody.

45. The method of any one of claims 1, 4-6, and 9-43, the use of any one of claims 2, 4, 5, 7, and 9-43, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-43, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-43, wherein the anti-TIGIT monoclonal antibody is a humanized antibody.

46. The method of any one of claims 1, 4-6, and 9-43, the use of any one of claims 2, 4, 5, 7, and 9-43, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-43, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-43, wherein the anti-TIGIT monoclonal antibody inhibits or blocks the interaction of CD226 with TIGIT.

47. The method of any one of claims 1, 4-6, and 9-43, the use of any one of claims 2, 4, 5, 7, and 9-43, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-43, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-43, wherein the anti-TIGIT monoclonal antibody is tiragulimab.

48. The method of any one of claims 1, 4-6, and 9-47, the use of any one of claims 2, 4, 5, 7, and 9-47, the anti-TIGIT monoclonal antibody of any one of claims 3-5, 17-25, and 34-47, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-47, wherein the anti-TIGIT monoclonal antibody is in a liquid pharmaceutical composition comprising 160 mg / mL tiragolumab and 2000 U / mL hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.

5.

49. The method of any one of claims 6 and 9-47, the use of any one of claims 7 and 9-47, or the anti-TIGIT monoclonal antibody and anti-PD-Ll monoclonal antibody of any one of claims 8-47, wherein the anti-TIGIT monoclonal antibody and the anti-PD-Ll monoclonal antibody are in a liquid pharmaceutical formulation comprising 40 mg / ml tiragolumab, 80 mg / ml atezolizumab, 2000 U / ml hyaluronidase in 20 mM histidine acetate, 240 mM sucrose, 10 mM methionine, 0.06% polysorbate 20, pH 5.

8.

50. An article of manufacture comprising a formulation comprising 1,000 mg of tiragolumab.

51. The article of manufacture of claim 50, wherein the formulation further comprises 1,875 mg or 2,000 mg of atezolizumab.

52. The article of manufacture of claim 50, wherein the formulation further comprises 1,875 mg of atezolizumab.

53. The article of manufacture of claim 50, wherein the formulation further comprises 2,000 mg of atezolizumab.

54. The article of manufacture of any one of claims 50-53, wherein the formulation further comprises hyaluronidase.

55. An article of manufacture comprising a formulation comprising 1,000 mg of tiragolumab and 1,875 mg or 2,000 mg of atezolizumab.

56. The article of manufacture of claim 55, wherein the formulation comprises 1,875 mg of atezolizumab.

57. The article of manufacture of claim 55, wherein the formulation comprises 2,000 mg of atezolizumab.

58. The article of manufacture of any one of claims 55-57, wherein the formulation further comprises a hyaluronidase.

59. The article of manufacture of claim 54 or 58, wherein the concentration of the hyaluronidase is 2000 U / mL.

60. The article of manufacture of any one of claims 54 and 58-59, wherein the hyaluronidase is a recombinant human hyaluronidase.

61. The article of manufacture of claim 60, wherein the recombinant hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

62. The article of manufacture of any one of claims 50-61, wherein the article of manufacture is a vial.

63. The article of manufacture of claim 62, wherein the vial is a single dose vial.

64. The article of manufacture of claim 62 or 63, wherein the vial is stoppered with a chlorobutyl elastomer stopper.

65. The article of manufacture of any one of claims 50-61, wherein the article of manufacture is a pre-filled syringe.

66. The article of manufacture of any one of claims 50-61, wherein the article of manufacture is a syringe pump.

67. The article of manufacture of any one of claims 50-61, wherein the article of manufacture is a subcutaneous administration device.

68. The article of manufacture of claim 67, wherein the subcutaneous administration device is selected from the group consisting of a syringe, a syringe pump, an injection device, an infusion pump, an injection pen, a needleless device, an auto-injector, and a subcutaneous patch delivery system.

69. An article of manufacture comprising a subcutaneous administration device, wherein the subcutaneous administration device contains and delivers to a patient a 1,000 mg fixed dose of tiragolumab.

70. The article of manufacture of claim 69, wherein the subcutaneous administration device further contains and delivers to the patient a 1,875 mg or 2,000 mg fixed dose of atezolizumab.

71. The article of manufacture of claim 70, wherein the subcutaneous administration device further contains and delivers to the patient a 1,875 mg fixed dose of atezolizumab.

72. The article of manufacture of claim 70, wherein the subcutaneous administration device further contains and delivers to the patient a 2,000 mg fixed dose of atezolizumab.

73. The article of manufacture of any one of claims 69-72, wherein the subcutaneous administration device further contains and delivers to the patient a hyaluronidase.

74. The article of manufacture of claim 73, wherein the hyaluronidase is a human soluble PH20 hyaluronidase glycoprotein, such as rHuPH20.

75. The article of manufacture of any one of claims 69-74, wherein the subcutaneous administration device is selected from the group consisting of a syringe, a syringe pump, an injection device, an infusion pump, an injection pen, a needleless device, an auto-injector, and a subcutaneous patch delivery system.

76. The article of manufacture of any one of claims 69-75, wherein the subcutaneous administration device is a syringe.

77. The article of manufacture of claims 69-75, wherein the subcutaneous administration device is a syringe pump.

78. The article of manufacture of any one of claims 50-77, wherein the article of manufacture comprises about 3 mL to about 60 mL of an anti-TIGIT full-length monoclonal antibody, and one or more of a hyaluronidase, a histidine buffer, sucrose, and polysorbate 20.

79. The article of manufacture of claim 78, wherein the article of manufacture comprises about 10 mL of tiragolumab, and one or more of a hyaluronidase, a histidine buffer, sucrose, and polysorbate 20.

80. The article of manufacture of claim 78, wherein the article of manufacture comprises about 7 mL of tiragolumab, and one or more of a hyaluronidase, a histidine buffer, sucrose, and polysorbate 20.

81. The article of manufacture of claim 78, wherein the article of manufacture comprises about 6.5 mL of tiragolumab, and one or more of a hyaluronidase, a histidine buffer, sucrose, and polysorbate 20.

82. The article of manufacture of claim 78, wherein the article of manufacture comprises about 21 mL of tiragolumab, and one or more of a hyaluronidase, a histidine buffer, sucrose, and polysorbate 20.

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