Antibody compositions and methods of use thereof

Abstract

This invention provides pharmaceutical compositions comprising antibodies and at least two antioxidants. In some embodiments, the pharmaceutical composition is formulated for subcutaneous delivery. In some embodiments, the pharmaceutical composition further comprises an endoglucosidase hydrolase. Other embodiments of the invention relate to methods for subcutaneous delivery of the pharmaceutical composition.

Description

Technical field

[0001] The present invention provides pharmaceutical compositions comprising antibodies and methods of using them to treat individuals suffering from tumors.

Prior technology

[0002] Human cancers have many genetic and epigenetic alterations that generate neoantigens potentially recognizable by the immune system (Sjoblom et al., Science (2006) 314(5797):268-274). The adaptive immune system composed of T and B lymphocytes has a strong anti-cancer potential, and the ability to respond to different tumor antigens is broad and specific. In addition, the immune system exhibits considerable plasticity and memory components. Successfully harnessing all of these properties of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

[0003] Until recently, cancer immunotherapy has focused a great deal of effort on methods that enhance anti-tumor immune responses by the transfer of activated effector cells, immunity against relevant antigens, or the provision of non-specific immunostimulatory agents such as cytokines. . However, over the past decade, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for the treatment of cancer, including the development of specific binding to the programmed death-1 (PD-1) receptor Antibodies that block the inhibitory PD-1 / PD-1 ligand pathway, such as nivolumab and pembrolizumab (formerly known as lambrolizumab; USAN Council Statement, 2013) (Topalian et al., 2012a, b; Topalian et al., 2014; Hamid et al., 2013; Hamid and Carvajal, 2013; McDermott and Atkins, 2013).

[0004] Current methods of delivering anti-PD-1 and / or anti-PD-L1 antibodies use periodic intravenous administration, usually in a clinic or hospital by a clinician. The inconvenience and invasiveness of the treatment may adversely affect the patient experience. Subcutaneous delivery, such as via the use of auto-injectors or wearable pumps, can greatly improve patient compliance. However, there remains a need in the art for formulations comprising anti-PD-1 antibodies or anti-PD-L1 antibodies suitable for subcutaneous delivery to a patient.

Content of invention

[0005] Certain aspects of the present invention relate to a pharmaceutical composition comprising (i) an antibody specifically binding to PD-1 ("anti-PD-1 antibody"), (ii) an endoglycosidase hydrolase and (iii) at least two antioxidants. In some aspects, at least one of the at least two antioxidants is a sacrificial antioxidant. In some aspects, the sacrificial antioxidant is selected from the group consisting of methionine, tryptophan and histidine, cysteine, ascorbic acid, glycine or other sacrificial agents.

[0006] In some aspects, at least one of the at least two antioxidants comprises a metal ion chelator. In some aspects, the metal ion chelating agent is selected from pentetic acid ("DTPA") and EDTA.

[0007] In some aspects, at least two antioxidants are selected from the group consisting of methionine, DTPA, and EDTA. In some aspects, one of the at least two antioxidants is methionine. In some aspects, one of the at least two antioxidants is DTPA. In some aspects, one of the at least two antioxidants is EDTA. In some aspects, the at least two antioxidants are methionine and DTPA. In some aspects, the at least two antioxidants are methionine and EDTA.

[0008] In some aspects, the at least one antioxidant comprises at least about 1 to about 20 mM methionine. In some aspects, at least one antioxidant comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM or at least about 20 mM methionine. In some aspects, the at least one antioxidant comprises about 5 mM methionine.

[0009] In some aspects, the at least one antioxidant comprises at least about 10 µM to about 200 µM DTPA. In some aspects, at least one antioxidant comprises at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least about 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, at least about 80 µM, at least about 85 µM, at least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, at least about 160 µM, at least about 170 µM, at least about 180 µM, at least about 190 µM or at least about 200 µM DTPA. In some aspects, the at least one antioxidant comprises about 50 µM DTPA.

[0010] In some aspects, the pharmaceutical composition comprises at least about 20 mg / mL to at least about 200 mg / mL of an anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 135 mg / mL to at least about 180 mg / mL anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 108 mg / mL to at least about 132 mg / mL anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL , at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 120 mg / mL anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 150 mg / mL anti-PD-1 antibody.

[0011] In some aspects, the pharmaceutical composition comprises at least about 5 U to at least about 100,000 U of an endoglycosidase hydrolase. In some aspects, the pharmaceutical composition comprises at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, ​​at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, At least about 70,000 U, at least about 80,000 U, at least about 90,000 U, or at least about 100,000 U of endoglycosidase hydrolase. In some aspects, the pharmaceutical composition comprises about 20,000 U of endoglycosidase hydrolase. In some aspects, the pharmaceutical composition comprises at least about 500 U / mL to at least about 5000 U / mL endoglycosidase hydrolytic enzyme. In some aspects, the pharmaceutical composition comprises at least about 1500 U / mL, at least about 1600 U / mL, at least about 1700 U / mL, at least about 1800 U / mL, at least about 1900 U / mL, at least about 2000 U / mL mL, at least about 2100 U / mL, at least about 2200 U / mL, at least about 2300 U / mL, at least about 2400 µM, at least about 2500 µM, at least about 3000 µM, at least about 3500 µM, at least about 4000 µM, at least about 4500 U / mL or at least about 5000 U / mL endoglycosidase hydrolase. In some aspects, the pharmaceutical composition comprises about 2000 U / mL endoglycosidase hydrolase.

[0012] In some aspects, the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosaminidase beta (1-4) or (1-3) bond. In some aspects, the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some aspects, the endoglycosidase hydrolase comprises at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% of amino acids 36-490 of SEQ ID NO: 1 %, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity of amino acid sequences. In some aspects, the endoglycosidase hydrolytic enzyme comprises hyaluronidase. In some aspects, the endoglycosidase hydrolase comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants and any isoforms thereof. In some aspects, the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof.

[0013] In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase relative to wild-type hyaluronic acid selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1 or fragments thereof Enzymes contain one or more amino acid substitutions. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof at alpha - Containing one or more amino acid substitutions in the helical region. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase linked to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1 or fragments thereof. Subregions contain one or more amino acid substitutions. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase wherein, relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof, one or more N-terminal and / or C-terminal amino acids are deleted. In some aspects, the endoglycosidase hydrolase comprises modified rHuPH20, wherein the modified rHuPH20 comprises: i. relative to wild-type rHuPH20, in the α-helical region, linker region, or α-helical region and junction One or more amino acid substitutions in both subregions; ii. one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amines relative to wild-type rHuPH20 amino acid and one or more C-terminal amino acids; or iii. both (i) and (ii).

[0014] In some aspects, the pharmaceutical composition further comprises a tonicity adjusting agent and / or a stabilizing agent. In some aspects, tonicity modifiers and / or stabilizers comprise sugars, amino acids, polyols, salts, or combinations thereof. In some aspects, the tonicity modifier and / or stabilizer comprises sucrose, sorbitol, trehalose, mannitol, glycerin, glycine, leucine, isoleucine, sodium chloride, proline , arginine, histidine, or any combination thereof. In some aspects, the tonicity modifier comprises sucrose. In some aspects, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, At least about 490 mM or at least about 500 mM sucrose. In some aspects, the pharmaceutical composition comprises about 250 mM sucrose.

[0015] In some aspects, the pharmaceutical composition further comprises a buffering agent. In some aspects, the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate. In some aspects, the buffer comprises histidine. In some aspects, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, At least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises about 20 mM histidine.

[0016] In some aspects, the pharmaceutical composition further comprises a surfactant. In some aspects, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In some aspects, the surfactant comprises polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, At least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises about 0.05% w / v polysorbate 80.

[0017] In some aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20. In some aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In some aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20. In some aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0018] In some aspects, the anti-PD-1 antibody is selected from nivolumab, palizumab, PDR001, MEDI-0680, cemiplimab, toripalimab ), tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, sasanlimab and its any combination. In some aspects, the anti-PD-1 antibody is nivolumab. In some aspects, the anti-PD-1 antibody is pembrolizumab.

[0019] In some aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05 % w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20. In some aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / vPolysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In some aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v Polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20. In some aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / vPolysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In some aspects, the pharmaceutical composition comprises: (a) about 672 mg nivolumab; (b) about 8.68 mg histidine; (c) about 11.8 mg histidine HCl H2O; (d) about 479 mg Sucrose; (e) about 2.80 mg polysorbate 80; (f) about 0.110 mg pentetic acid; (g) about 4.18 mg methionine; (h) about 0.102 mg rHuPH20; ) in water to a final volume of at least about 5.6 mL.

[0020] In some aspects, the pharmaceutical composition comprises a pH of about 5.2 to about 6.8. In some aspects, the pharmaceutical composition comprises about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about A pH of 6.5, about 6.6, about 6.7 or about 6.8. In some aspects, the pharmaceutical composition comprises a pH of about 6.0.

[0021] In some aspects, the pharmaceutical composition further comprises a second therapeutic agent. In some aspects, the second therapeutic agent is an antibody. In some aspects, the second therapeutic agent is a checkpoint inhibitor. In some aspects, the checkpoint inhibitor is an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA antibody, an anti-CD137 antibody , anti-KIR antibody, anti-TGFβ antibody, anti-IL-10 antibody, anti-IL-8 antibody, anti-B7-H4 antibody, anti-Fas ligand antibody, anti-CXCR4 antibody, anti-mesothelin antibody, anti-CD27 antibody, anti- GITR or any combination thereof. In some aspects, the pharmaceutical composition further comprises a third therapeutic agent. In some aspects, the second therapeutic agent, the third therapeutic agent, or both comprise IL-2 (eg, bempegaldesleukin) or IL12-Fc (eg, BMS-986415).

[0022] In some aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05 % w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-CTLA-4 antibody . In some aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / vPolysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-CTLA-4 antibody. In some aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / vPolysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / vPolysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / vPolysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-TIM3 antibody. In some aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / vPolysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-TIM3 antibody.

[0023] Certain aspects of the invention pertain to a vial comprising any of the pharmaceutical compositions disclosed herein.

[0024] Certain aspects of the invention relate to a syringe comprising any of the pharmaceutical compositions disclosed herein.

[0025] Certain aspects of the invention relate to autoinjectors comprising any of the pharmaceutical compositions disclosed herein.

[0026] Certain aspects of the invention relate to wearable pumps comprising any of the pharmaceutical compositions disclosed herein. In some aspects, the syringe further comprises a plunger.

[0027] Certain aspects of the invention pertain to a method of treating a disease or condition in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of any of the pharmaceutical compositions disclosed herein. In some aspects, pharmaceutical compositions are administered subcutaneously.

[0028] In some aspects, the disease or condition is an infectious disease. In some aspects, the disease or condition is cancer. In some aspects, the cancer is selected from squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, renal cancer , clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-refractory prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreas Cancer, Glioblastoma, Glioblastoma Multiforme, Cervical Cancer, Gastric Cancer, Bladder Cancer, Liver Cancer, Breast Cancer, Colon Cancer, Head and Neck Cancer, Gastric Cancer, Germ Cell Tumor, Pediatric Sarcoma, Nasal and Sinus Natural Killer, Melanoma, Bone Cancer, Skin Cancer, Uterine Cancer, Anal Region Cancer, Testicular Cancer, Fallopian Tube Cancer, Endometrial Cancer, Cervical Cancer, Vaginal Cancer, Vulva Cancer, Esophagus Cancer, Small Intestine Cancer, Endocrine System Cancer, Parathyroid Cancer Carcinoma, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, childhood solid tumors, ureteral cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal cord axis Tumors, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer (including asbestos-induced cancer), virus-related cancer or cancers of viral origin (such as human papillomavirus (HPV-associated or derived tumors)) and any combination thereof.

[0029] Certain aspects of the present invention relate to a method of treating an individual in need thereof, comprising subcutaneously administering to the individual an effective dose of a pharmaceutical composition comprising a compound that specifically binds to PD-1 or PD- Antibodies that are L1 and inhibit the interaction between PD-1 and PD-L1 (respectively "anti-PD-1 antibody" or "anti-PD-L1 antibody"); wherein the effective dose comprises one or more subcutaneous unit doses, wherein the subcutaneous unit At least one of the doses has a total volume of less than about 5 mL, less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 3 mL, or less than about 2.5 mL; and wherein the effective dose comprises At least about 250 mg to at least about 2400 mg of antibody. In some aspects, the pharmaceutical composition does not include hyaluronidase.

[0030] In some aspects, the effective dose comprises two or more subcutaneous unit doses, wherein the two or more subcutaneous unit doses are administered simultaneously or sequentially. In some aspects, two or more subcutaneous unit doses are administered sequentially, wherein each of the two or more subcutaneous unit doses is within about 10 minutes, About 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about one hour, about two hours, about three hours, about four hours, about five hours, about six hours, about nine hours, about twelve hours, about Administered at intervals of eighteen hours or about twenty-four hours. In some aspects, the effective dose is administered about every week, two weeks, three weeks, or four weeks.

[0031] In some aspects, the antibody comprises an anti-PD-1 antibody. In some aspects, the effective dosage of the antibody is about 250 mg to about 600 mg of the antibody administered weekly. In some aspects, the effective dose of the antibody is about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg administered about weekly. mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, About 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg. In some aspects, the effective dosage of the antibody is about 300 mg administered about weekly. In some aspects, an effective dose of an antibody comprises a single subcutaneous unit dose of about 300 mg. In some aspects, an effective dose of an antibody comprises a single subcutaneous unit dose of about 300 mg administered in a total volume of about 2 mL.

[0032] In some aspects, the effective dose of the antibody comprises (i) two subcutaneous unit doses, wherein each of the two subcutaneous unit doses comprises about 150 mg of the antibody; or (ii) three subcutaneous unit doses, Each of the three subcutaneous unit doses contained about 100 mg of antibody. In some aspects, (i) at least one of the two subcutaneous unit doses comprises about 150 mg of the antibody in a total volume of less than about 5 mL; and (ii) at least one of the three subcutaneous unit doses comprises about 100 mg The total volume is about 2 mL of antibody. In some aspects, (i) two subcutaneous unit doses are administered to the individual at two different body locations, or (ii) at least two of the three subcutaneous unit doses are administered to the individual at at least two different body locations .

[0033] In some aspects, an effective dose of the antibody is about 300 mg to about 900 mg administered about every two weeks. In some aspects, the effective dose of the antibody is about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg , about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg. In some aspects, the effective dose of the antibody is about 600 mg administered about every two weeks.

[0034] In some aspects, an effective dose of an antibody comprises a single subcutaneous unit dose. In some aspects, an effective dose of an antibody comprises two, three, or at least four subcutaneous unit doses. In some aspects, an effective dose of the antibody comprises two subcutaneous unit doses, wherein the two subcutaneous unit doses each comprise about 300 mg of the antibody. In some aspects, at least one of two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL. In some aspects, at least two of the subcutaneous unit doses are administered to at least two different body locations of the subject.

[0035] In some aspects, the effective dose of the antibody is 900 mg to about 1500 mg administered about every four weeks. In some aspects, the effective dose of the antibody is about 900, about 950, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, administered about every four weeks. About 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, About 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, or about 1500 mg. In some aspects, the effective dosage of the antibody is about 1200 mg administered about every four weeks. In some aspects, an effective dose of an antibody comprises two, three, four, six, or at least eight subcutaneous unit doses. In some aspects, an effective dose of an antibody comprises four subcutaneous unit doses, wherein each of the four subcutaneous unit doses comprises about 300 mg of the antibody. In some aspects, at least one of the four subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL. In some aspects, at least two of the subcutaneous unit doses are administered to at least two different body locations of the subject. In some aspects, two, three, four, six, or at least eight subcutaneous unit doses are administered on the same day.

[0036] In some aspects, the antibody comprises an anti-PD-L1 antibody. In some aspects, the effective dosage of the antibody is about 900 mg to about 1800 mg of the antibody administered about every two weeks. In some aspects, the effective dose of the antibody is about 900 mg, about 950 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg , about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg , about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, or about 1500 mg. In some aspects, the effective dosage of the antibody is about 1200 mg every two weeks. In some aspects, the effective dose comprises at least two, at least three, at least four, at least five, at least six, at least seven, or at least eight subcutaneous unit doses. In some aspects, an effective dose of an antibody comprises four subcutaneous unit doses, wherein each of the four subcutaneous unit doses comprises about 300 mg of the antibody. In some aspects, at least one of the four subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL. In some aspects, at least two of the subcutaneous unit doses are administered to at least two different body locations of the subject. In some aspects, two, three, four, five, six, seven, or at least eight subcutaneous unit doses are administered on the same day.

[0037] In some aspects, the anti-PD-1 antibody comprises an antibody comprising nivolumab, pilizumab, PDR001, MEDI-0680, milpilimumab, toripalimab , tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, KN035, sasanlizumab, or any combination thereof. In some aspects, the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1. In some aspects, the anti-PD-1 antibody comprises nivolumab. In some aspects, the anti-PD-1 antibody comprises pembrolizumab.

[0038] In some aspects, the anti-PD-L1 antibody comprises an antibody comprising BMS-936559, atezolizumab, durvalumab, avelumab ), STI-1014, CX-072, KN035, LY3300054, BGB-A333, CK-301 or any combination thereof.

[0039] In some aspects, the individual suffers from cancer. In some aspects, the cancer comprises squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, renal cancer, clear Cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone refractory prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, Glioblastoma, Glioblastoma Multiforme, Cervical Cancer, Gastric Cancer, Bladder Cancer, Liver Cancer, Breast Cancer, Colon Cancer, Head and Neck Cancer, Gastric Cancer, Germ Cell Tumors, Pediatric Sarcoma, Nasal and Sinus Natural Killers, Melanoma tumor, bone cancer, skin cancer, uterine cancer, anal region cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophagus cancer, small intestine cancer, endocrine system cancer, parathyroid cancer, Adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, childhood solid tumors, urinary tract cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumors, Brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer (including asbestos-induced cancer), virus-associated cancer or cancer of viral origin ( For example human papilloma virus (tumours associated or of HPV origin)) or any combination thereof.

[0040] In some aspects, the pharmaceutical composition is administered using an auto-injector. In some aspects, the pharmaceutical composition is administered using a wearable pump. In some aspects, the pharmaceutical composition is administered to an individual by subcutaneous infusion in less than about 10 minutes. In some aspects, the pharmaceutical composition is administered to an individual by subcutaneous infusion in less than about 5 minutes.

[0041] In some aspects, the pharmaceutical composition further comprises at least two antioxidants. In some aspects, the at least two antioxidants are selected from the group consisting of methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA, and EDTA. In some aspects, the at least two antioxidants comprise (i) methionine and EDTA or (ii) methionine and DTPA. In some aspects, the at least two antioxidants comprise at least about 1 to about 20 mM methionine. In some aspects, the at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM or at least about 20 mM methionine. In some aspects, the at least two antioxidants comprise about 5 mM methionine.

[0042] In some aspects, the at least two antioxidants comprise at least about 10 µM to about 200 µM DTPA. In some aspects, the at least two antioxidants comprise at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least about 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, at least about 80 µM, at least about 85 µM, at least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, at least about 160 µM, at least about 170 µM, at least about 180 µM, at least about 190 µM or at least about 200 µM DTPA. In some aspects, the at least two antioxidants comprise about 50 µM DTPA.

[0043] In some aspects, the pharmaceutical composition comprises at least about 20 mg / mL to at least about 200 mg / mL of an anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 135 mg / mL to at least about 180 mg / mL anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 108 mg / mL to at least about 132 mg / mL anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL , at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 120 mg / mL anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 150 mg / mL anti-PD-1 antibody.

[0044] In some aspects, the pharmaceutical composition further comprises a tonicity adjusting agent and / or a stabilizing agent. In some aspects, tonicity modifiers and / or stabilizers comprise sugars, amino acids, polyols, salts, or combinations thereof. In some aspects, the tonicity modifier and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerin, glycine, leucine, isoleucine, Sodium chloride, proline, arginine, histidine, and any combination thereof. In some aspects, the tonicity modifier comprises sucrose. In some aspects, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, At least about 490 mM or at least about 500 mM sucrose. In some aspects, the pharmaceutical composition comprises about 250 mM sucrose.

[0045] In some aspects, the pharmaceutical composition further comprises a buffering agent. In some aspects, the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate. In some aspects, the buffer comprises histidine. In some aspects, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, At least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises about 20 mM histidine.

[0046] In some aspects, the pharmaceutical composition further comprises a surfactant. In some aspects, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In some aspects, the surfactant comprises polysorbate 80. The method according to any one of technical schemes 1 to 81, wherein the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, At least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises about 0.05% w / v polysorbate 80.

[0047] In some aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0048] In some aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0049] In some aspects, the pharmaceutical composition comprises a pH of about 5.2 to about 6.8. In some aspects, the pharmaceutical composition comprises about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about A pH of 6.5, about 6.6, about 6.7 or about 6.8. In some aspects, the pharmaceutical composition comprises a pH of about 6.0.

[0050] Certain aspects of the invention pertain to pharmaceutical compositions for use in any of the methods disclosed herein.

[0051] Certain aspects of the invention relate to a pharmaceutical composition comprising (i) an antibody that specifically binds PD-1 ("anti-PD-1 antibody") and (ii) at least two antioxidants. In some aspects, the at least two antioxidants are selected from the group consisting of methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA, and EDTA. In some aspects, the at least two antioxidants comprise (i) methionine and EDTA or (ii) methionine and DTPA. In some aspects, the at least two antioxidants comprise at least about 1 to about 20 mM methionine. In some aspects, the at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM or at least about 20 mM methionine. In some aspects, the at least two antioxidants comprise about 5 mM methionine.

[0052] In some aspects, the at least two antioxidants comprise at least about 10 µM to about 200 µM DTPA. In some aspects, the at least two antioxidants comprise at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least about 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, at least about 80 µM, at least about 85 µM, at least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, at least about 160 µM, at least about 170 µM, at least about 180 µM, at least about 190 µM or at least about 200 µM DTPA. In some aspects, the at least two antioxidants comprise about 50 µM DTPA.

[0053] In some aspects, the composition comprises at least about 20 mg / mL to at least about 200 mg / mL anti-PD-1 antibody. In some aspects, the composition comprises at least about 135 mg / mL to at least about 180 mg / mL anti-PD-1 antibody. In some aspects, the composition comprises at least about 108 mg / mL to at least about 132 mg / mL anti-PD-1 antibody. In some aspects, the composition comprises at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL , at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL, At least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL anti-PD-1 antibody. In some aspects, the composition comprises about 120 mg / mL anti-PD-1 antibody. In some aspects, the composition comprises about 150 mg / mL anti-PD-1 antibody.

[0054] In some aspects, the composition further comprises a tonicity adjusting agent and / or a stabilizing agent. In some aspects, tonicity modifiers and / or stabilizers comprise sugars, amino acids, polyols, salts, or combinations thereof. In some aspects, the tonicity modifier and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerin, glycine, leucine, isoleucine, Sodium chloride, proline, arginine, histidine, and any combination thereof. In some aspects, the tonicity modifier comprises sucrose. In some aspects, the composition comprises at least about 10 mM to at least about 500 mM sucrose. In some aspects, the composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least About 490 mM or at least about 500 mM sucrose. In some aspects, the composition comprises about 250 mM sucrose.

[0055] In some aspects, the composition further comprises a buffering agent. In some aspects, the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate. In some aspects, the buffer comprises histidine. In some aspects, the composition comprises at least about 5 mM to at least about 100 mM histidine. In some aspects, the composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least About 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine. In some aspects, the composition comprises about 20 mM histidine.

[0056] In some aspects, the composition further comprises a surfactant. In some aspects, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In some aspects, the surfactant comprises polysorbate 80. In some aspects, the composition comprises at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80. In some aspects, the composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least About 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v polysorbate 80. In some aspects, the composition comprises about 0.05% w / v polysorbate 80.

[0057] In some aspects, the composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05 % w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0058] In some aspects, the composition comprises: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05 % w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0059] In some aspects, the composition comprises a pH of about 5.2 to about 6.8. In some aspects, the composition comprises about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5 , a pH of about 6.6, about 6.7, or about 6.8. In some aspects, the composition comprises a pH of about 6.0.

[0060] In some aspects, the pharmaceutical composition further comprises a second therapeutic agent. In some aspects, the second therapeutic agent is an antibody. In some aspects, the second therapeutic agent is a checkpoint inhibitor. In some aspects, the checkpoint inhibitor is an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA antibody , anti-CD137 antibody, anti-KIR antibody, anti-TGFβ antibody, anti-IL-10 antibody, anti-IL-8 antibody, anti-B7-H4 antibody, anti-Fas ligand antibody, anti-CXCR4 antibody, anti-mesothelin antibody, anti- CD27 antibody, anti-GITR or any combination thereof. In some aspects, the pharmaceutical composition further comprises a third therapeutic agent. In some aspects, the second therapeutic agent, the third therapeutic agent, or both comprise IL-2 (eg, bempidesleukin) or IL12-Fc (eg, BMS-986415).

[0061] Certain aspects of the invention pertain to a vial comprising a pharmaceutical composition disclosed herein.

[0062] Certain aspects of the invention pertain to a unit dosage comprising any of the pharmaceutical compositions disclosed herein.

[0063] Certain aspects of the invention relate to a unit dose comprising: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM Sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0064] In some aspects, the vial is an autoinjector. Certain aspects of the invention relate to an autoinjector comprising a unit dose disclosed herein. In some aspects, the vial is a wearable device. Certain aspects of the invention relate to a wearable device comprising a unit dose disclosed herein. appearance

[0065] Pharmaceutical compositions and uses thereof.

[0066] Aspect A1. A pharmaceutical composition comprising (i) an antibody specifically binding to PD-1 ("anti-PD-1 antibody"), (ii) an endoglycosidase hydrolase and (iii) at least Two antioxidants.

[0067] Aspect A2. The pharmaceutical composition of Aspect Al, wherein at least one of the at least two antioxidants is a sacrificial antioxidant.

[0068] Aspect A3. The pharmaceutical composition of Aspect A2, wherein the sacrificial antioxidant is selected from the group consisting of methionine, tryptophan and histidine, cysteine, ascorbic acid, glycine amino acids or other sacrificial agents.

[0069] Aspect A4. The pharmaceutical composition of any one of aspects A1 to 3, wherein at least one of the at least two antioxidants comprises a metal ion chelating agent.

[0070] Aspect A5. The pharmaceutical composition of Aspect A4, wherein the metal ion chelating agent is selected from the group consisting of pentetic acid ("DTPA") and EDTA.

[0071] Aspect A6. The pharmaceutical composition according to any one of aspects A1 to 5, wherein the at least two antioxidants are selected from the group consisting of methionine, DTPA and EDTA.

[0072] Aspect A7. The pharmaceutical composition of any one of aspects A1 to 6, wherein one of the at least two antioxidants is methionine.

[0073] Aspect A8. The pharmaceutical composition of any one of aspects A1 to 7, wherein one of the at least two antioxidants is DTPA.

[0074] Aspect A9. The pharmaceutical composition of any one of aspects A1 to 7, wherein one of the at least two antioxidants is EDTA.

[0075] Aspect A10. The pharmaceutical composition of any one of aspects A1 to 8, wherein the at least two antioxidants are methionine and DTPA.

[0076] Aspect A11. The pharmaceutical composition of any one of aspects A1 to 7 and 9, wherein the at least two antioxidants are methionine and EDTA.

[0077] Aspect A12. The pharmaceutical composition of any one of aspects A1 to 11, wherein the at least one antioxidant comprises at least about 1 to about 20 mM methionine.

[0078] Aspect A13. The pharmaceutical composition of any one of aspects A1 to 12, wherein the at least one antioxidant comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, At least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine.

[0079] Aspect A14. The pharmaceutical composition of any one of Aspects A1 to 13, wherein the at least one antioxidant comprises about 5 mM methionine.

[0080] Aspect A15. The pharmaceutical composition of any one of Aspects A1 to 14, wherein the at least one antioxidant comprises at least about 10 µM to about 200 µM DTPA.

[0081] Aspect A16. The pharmaceutical composition of any one of aspects A1 to 15, wherein the at least one antioxidant comprises at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least about 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, At least about 80 µM, at least about 85 µM, at least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, At least about 160 µM, at least about 170 µM, at least about 180 µM, at least about 190 µM, or at least about 200 µM DTPA.

[0082] Aspect A17. The pharmaceutical composition of any one of Aspects A1 to 16, wherein the at least one antioxidant comprises about 50 μM DTPA.

[0083] Aspect A18. The pharmaceutical composition of any one of aspects A1 to 17, comprising at least about 20 mg / mL to at least about 200 mg / mL anti-PD-1 antibody.

[0084] Aspect A19. The pharmaceutical composition of any one of Aspects A1 to 18, comprising at least about 135 mg / mL to at least about 180 mg / mL anti-PD-1 antibody.

[0085] Aspect A20. The pharmaceutical composition of any one of aspects A1 to 17, comprising at least about 108 mg / mL to at least about 132 mg / mL of an anti-PD-1 antibody.

[0086] Aspect A21. The pharmaceutical composition of any one of aspects A1 to 20, comprising at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL , at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or At least about 200 mg / mL anti-PD-1 antibody.

[0087] Aspect A22. The pharmaceutical composition of any one of Aspects A1 to 21, comprising about 120 mg / mL of an anti-PD-1 antibody.

[0088] Aspect A23. The pharmaceutical composition of any one of Aspects A1 to 21, comprising about 150 mg / mL of an anti-PD-1 antibody.

[0089] Aspect A24. The pharmaceutical composition of any one of Aspects A1 to 23, comprising at least about 5 U to at least about 100,000 U of an endoglycosidase hydrolase.

[0090] Aspect A25. The pharmaceutical composition of any one of aspects A1 to 24, comprising at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, ​​at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least About 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U, at least about 80,000 U, at least about 90,000 U, or at least about 100,000 U of endoglycosidase hydrolase.

[0091] Aspect A26. The pharmaceutical composition of any one of aspects A1 to 25, comprising about 20,000 U of endoglycosidase hydrolase.

[0092] Aspect A27. The pharmaceutical composition of any one of aspects A1 to 26, comprising at least about 500 U / mL to at least about 5000 U / mL endoglycosidase hydrolase.

[0093] Aspect A28. The pharmaceutical composition of any one of aspects A1 to 27, comprising at least about 1500 U / mL, at least about 1600 U / mL, at least about 1700 U / mL, at least about 1800 U / mL mL, at least about 1900 U / mL, at least about 2000 U / mL, at least about 2100 U / mL, at least about 2200 U / mL, at least about 2300 U / mL, at least about 2400 µM, at least about 2500 U / mL, at least About 3000 U / mL, at least about 3500 U / mL, at least about 4000 U / mL, at least about 4500 U / mL, or at least about 5000 U / mL endoglycosidase hydrolase.

[0094] Aspect A29. The pharmaceutical composition of any one of aspects A1 to 28, comprising about 2000 U / mL endoglycosidase hydrolase.

[0095] Aspect A30. The pharmaceutical composition according to any one of aspects A1 to 29, wherein the endoglycosidase hydrolytic enzyme cleaves at the hexosaminidase β (1-4) or (1-3) bond hyaluronic acid.

[0096] Aspect A31. The pharmaceutical composition according to any one of aspects A1 to 30, wherein the endoglycosidase hydrolytic enzyme comprises hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4 or HYALPS1 catalytic domain.

[0097] Aspect A32. The pharmaceutical composition according to any one of aspects A1 to 31, wherein the endoglycosidase hydrolytic enzyme comprises amino acids 36-490 of SEQ ID NO: 1 having at least about 70%, At least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity Sexual amino acid sequence.

[0098] Aspect A33. The pharmaceutical composition according to any one of aspects A1 to 32, wherein the endoglycosidase hydrolytic enzyme comprises hyaluronidase.

[0099] Aspect A34. The pharmaceutical composition according to any one of aspects A1 to 33, wherein the endoglycosidase hydrolytic enzyme comprises hyaluronidase selected from the group consisting of: HuPH20, HYAL1, HYAL2, HYAL3, HYAL4 , any variants and any isoforms thereof.

[0100] Aspect A35. The pharmaceutical composition of any one of aspects A1 to 34, wherein the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof.

[0101] Aspect A36. The pharmaceutical composition according to any one of aspects A1 to 35, wherein the endoglycosidase hydrolytic enzyme comprises a modified hyaluronidase, which is selected from the group consisting of HuPH20, HYAL1, HYAL2, Wild-type hyaluronidases of the group consisting of HYAL3, HYAL4, HYALPS1 or fragments thereof comprise one or more amino acid substitutions.

[0102] Aspect A37. The pharmaceutical composition according to any one of aspects A1 to 36, wherein the endoglycosidase hydrolytic enzyme comprises a modified hyaluronidase, which is selected from the group consisting of HuPH20, HYAL1, HYAL2, Wild-type hyaluronidases of the group consisting of HYAL3, HYAL4, HYALPS1 or fragments thereof comprise one or more amino acid substitutions in the alpha-helical region.

[0103] Aspect A38. The pharmaceutical composition according to any one of aspects A1 to 37, wherein the endoglycosidase hydrolytic enzyme comprises a modified hyaluronidase, which is selected from the group consisting of HuPH20, HYAL1, HYAL2, Wild-type hyaluronidases of the group consisting of HYAL3, HYAL4, HYALPS1 or fragments thereof comprise one or more amino acid substitutions in the linker region.

[0104] Aspect A39. The pharmaceutical composition according to any one of aspects A1 to 38, wherein the endoglycosidase hydrolytic enzyme comprises a modified hyaluronidase, wherein relative to the group selected from HuPH20, HYAL1, HYAL2, HYAL3, In the wild-type hyaluronidase of the group consisting of HYAL4, HYALPS1 or fragments thereof, one or more N-terminal and / or C-terminal amino acids are deleted.

[0105] Aspect A40. The pharmaceutical composition according to any one of aspects A1 to 39, wherein the endoglycosidase hydrolase comprises modified rHuPH20, wherein the modified rHuPH20 comprises: relative to wild-type rHuPH20, at One or more amino acid substitutions in the α-helix region, the linker region, or both the α-helix region and the linker region; ii. relative to wild-type rHuPH20, one or more N-terminal amino acids, one or Deletion of multiple C-terminal amino acids or one or more N-terminal amino acids and one or more C-terminal amino acids; or iii. both (i) and (ii).

[0106] Aspect A41. The pharmaceutical composition according to any one of aspects A1 to 40, further comprising a tonicity regulator and / or a stabilizer.

[0107] Aspect A42. The pharmaceutical composition of Aspect A41, wherein the tonicity regulator and / or stabilizer comprises sugar, amino acid, polyol, salt or a combination thereof.

[0108] Aspect A43. The pharmaceutical composition according to aspect A41 or 42, wherein the tonicity regulator and / or stabilizer comprises sucrose, sorbitol, trehalose, mannitol, glycerin, glycine, leucamine acid, isoleucine, sodium chloride, proline, arginine, histidine, or any combination thereof.

[0109] Aspect A44. The pharmaceutical composition of any one of aspects A41 to 43, wherein the tonicity adjusting agent comprises sucrose.

[0110] Aspect A45. The pharmaceutical composition of any one of Aspects A1 to 44, comprising at least about 10 mM to at least about 500 mM sucrose. Aspect A46. The pharmaceutical composition of any one of aspects A1 to 45, comprising at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least About 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, or at least about 500 mM sucrose.

[0112] Aspect A47. The pharmaceutical composition of any one of Aspects A1 to 46, comprising about 250 mM sucrose.

[0113] Aspect A48. The pharmaceutical composition of any one of Aspects A1 to 47, further comprising a buffer.

[0114] Aspect A49. The pharmaceutical composition of Aspect A48, wherein the buffering agent is selected from the group consisting of histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate.

[0115] Aspect A50. The pharmaceutical composition of aspect A48 or 49, wherein the buffer comprises histidine.

[0116] Aspect A51. The pharmaceutical composition of any one of Aspects A1 to 50, comprising at least about 5 mM to at least about 100 mM histidine. Aspect A52. The pharmaceutical composition of any one of aspects A1 to 51, comprising at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histamine acid.

[0118] Aspect A53. The pharmaceutical composition of any one of Aspects A1 to 52, comprising about 20 mM histidine.

[0119] Aspect A54. The pharmaceutical composition of any one of Aspects A1 to 53, further comprising a surfactant.

[0120] Aspect A55. The pharmaceutical composition of aspect A54, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188.

[0121] Aspect A56. The pharmaceutical composition of Aspect A54 or 55, wherein the surfactant comprises polysorbate 80.

[0122] Aspect A57. The pharmaceutical composition of any one of Aspects Al to 56, comprising at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80.

[0123] Aspect A58. The pharmaceutical composition of any one of aspects A1 to 57, comprising at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v Polysorbate 80.

[0124] Aspect A59. The pharmaceutical composition of any one of Aspects A1 to 58, comprising about 0.05% w / v polysorbate 80. Aspect A60. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 59, comprising: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g ) about 0.0182 mg / mL rHuPH20. Aspect A61. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 59, comprising: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g ) about 2000 U / mL rHuPH20.

[0127] Aspect A62. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 59, comprising: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g ) about 0.0182 mg / mL rHuPH20.

[0128] Aspect A63. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 59, comprising: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g ) about 2000 U / mL rHuPH20.

[0129] Aspect A64. The pharmaceutical composition according to any one of aspects A1 to 63, wherein the anti-PD-1 antibody is selected from nivolumab, palivizumab, PDR001, MEDI-0680, and Mepi Monoclonal antibody, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, sasanlizumab and any combination thereof.

[0130] Aspect A65. The pharmaceutical composition of any one of Aspects A1 to 64, wherein the anti-PD-1 antibody is nivolumab.

[0131] Aspect A66. The pharmaceutical composition of any one of Aspects A1 to 64, wherein the anti-PD-1 antibody is pembrolizumab.

[0132] Aspect A67. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 65, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) Approximately 0.0182 mg / mL rHuPH20.

[0133] Aspect A68. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 65, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) About 2000 U / mL rHuPH20.

[0134] Aspect A69. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 65, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) Approximately 0.0182 mg / mL rHuPH20.

[0135] Aspect A70. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 65, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) About 2000 U / mL rHuPH20.

[0136] Aspect A71. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 65, comprising: (a) about 672 mg nivolumab; (b) about 8.68 mg histidine; (c) about 11.8 mg histidine HCl H2O; (d) about 479 mg sucrose; (e) about 2.80 mg polysorbate 80; (f) about 0.110 mg pentetic acid; (g) about 4.18 mg methylsulfide amino acid; (h) about 0.102 mg rHuPH20; wherein (a)-(h) are reconstituted in water to a final volume of at least about 5.6 mL.

[0137] Aspect A72. The pharmaceutical composition of any one of Aspects A1 to 71, comprising a pH of about 5.2 to about 6.8.

[0138] Aspect A73. The pharmaceutical composition of any one of aspects A1 to 72, comprising about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0 , about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7 or about 6.8 pH.

[0139] Aspect A74. The pharmaceutical composition of any one of Aspects A1 to 73, comprising a pH of about 6.0.

[0140] Aspect A75. The pharmaceutical composition of any one of Aspects A1 to 74, further comprising a second therapeutic agent.

[0141] Aspect A76. The pharmaceutical composition of Aspect A75, wherein the second therapeutic agent is an antibody.

[0142] Aspect A77. The pharmaceutical composition of Aspect A76, wherein the second therapeutic agent is a checkpoint inhibitor. Aspect A78. The pharmaceutical composition of aspect A77, wherein the checkpoint inhibitor is anti-CTLA-4 antibody, anti-LAG-3 antibody, anti-TIM3 antibody, anti-TIGIT antibody, anti-NKG2a antibody, anti-OX40 antibody , anti-ICOS antibody, anti-MICA antibody, anti-CD137 antibody, anti-KIR antibody, anti-TGFβ antibody, anti-IL-10 antibody, anti-IL-8 antibody, anti-B7-H4 antibody, anti-Fas ligand antibody, anti-CXCR4 antibody , anti-mesothelin antibody, anti-CD27 antibody, anti-GITR, or any combination thereof.

[0144] Aspect A79. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 78, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-CTLA-4 antibody.

[0145] Aspect A80. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 78, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-CTLA-4 antibody.

[0146] Aspect A81. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 78, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-LAG-3 antibody.

[0147] Aspect A82. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 78, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-LAG-3 antibody.

[0148] Aspect A83. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 78, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-TIM3 antibody.

[0149] Aspect A84. The pharmaceutical composition of any one of aspects A1 to 35 and 41 to 78, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histamine (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-TIM3 antibody.

[0150] Aspect A85. A vial comprising the pharmaceutical composition of any one of aspects A1-84.

[0151] Aspect A86. A syringe comprising the pharmaceutical composition of any one of aspects A1-84.

[0152] Aspect A87. An autoinjector comprising the pharmaceutical composition of any one of Aspects A1 to 84.

[0153] Aspect A88. A wearable pump comprising the pharmaceutical composition of any one of aspects A1-84.

[0154] Aspect A89. The syringe of Aspect A86, further comprising a plunger.

[0155] Aspect A90. A method of treating a disease or condition in an individual in need thereof, comprising administering to the individual a pharmaceutically effective amount of the pharmaceutical composition of any one of Aspects A1-84.

[0156] Aspect A91. The method of Aspect A90, wherein the pharmaceutical composition is administered subcutaneously.

[0157] Aspect A92. The method of Aspect A90 or 91, wherein the disease or condition is an infectious disease.

[0158] Aspect A93. The method of Aspect A90 or 91, wherein the disease or condition is cancer.

[0159] Aspect A94. The method of aspect A93, wherein the cancer is selected from the group consisting of squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glia Tumor, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-refractory prostate adenocarcinoma, thyroid Carcinoma, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, liver cancer, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumors , Pediatric Sarcoma, Nasal and Sinus Natural Killers, Melanoma, Bone Cancer, Skin Cancer, Uterine Cancer, Anal Area Cancer, Testicular Cancer, Fallopian Tube Cancer, Endometrial Cancer, Cervical Cancer, Vaginal Cancer, Vulvar Cancer, Esophageal Cancer, Small bowel cancer, endocrine system cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, childhood solid tumors, urinary tract cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS Lymphoma, tumor angiogenesis, spinal axis tumors, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer (including asbestos-induced cancer ), virus-associated cancer or cancer of viral origin (such as human papillomavirus (HPV-associated or derived tumors)), and any combination thereof.

[0160] Aspect 1. A method of treating an individual in need thereof, comprising subcutaneously administering to the individual an effective dose of a pharmaceutical composition comprising a compound that specifically binds to PD-1 or PD-L1 and inhibits PD- 1 An antibody that interacts with PD-L1 (respectively "anti-PD-1 antibody" or "anti-PD-L1 antibody"); wherein the effective dose comprises one or more subcutaneous unit doses, wherein in the subcutaneous unit doses At least one of them has a total volume of less than about 5 mL, less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 3 mL, or less than about 2.5 mL; and wherein the effective dose comprises at least From about 250 mg to at least about 2400 mg of the antibody.

[0161] Aspect B2. The method of Aspect B1, wherein the pharmaceutical composition does not comprise hyaluronidase.

[0162] Aspect B3. The method of Aspect B1 or 2, wherein the effective dose comprises two or more subcutaneous unit doses, and wherein the two or more subcutaneous unit doses are administered simultaneously or sequentially.

[0163] Aspect B4. The method of Aspect B3, wherein two or more subcutaneous unit doses are administered sequentially, wherein each of the two or more subcutaneous unit doses is administered within two or more Between about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about one hour, about two hours, about three hours, about four hours, about five hours, about six hours, about Administration is at intervals of nine hours, about twelve hours, about eighteen hours, or about twenty-four hours.

[0164] Aspect B5. The method of any one of Aspects B1 to 4, wherein the effective dose is administered about every week, two weeks, three weeks, or four weeks.

[0165] Aspect B6. The method of any one of Aspects B1 to 5, wherein the antibody comprises an anti-PD-1 antibody.

[0166] Aspect B7. The method of any one of aspects B1 to 6, wherein the effective dose of the antibody is about 250 mg to about 600 mg of the antibody administered about weekly.

[0167] Aspect B8. The method of any one of aspects B1 to 7, wherein the effective dose of the antibody is about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg administered about weekly , about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg , about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg.

[0168] Aspect B9. The method of any one of Aspects Bl to 8, wherein the effective dose of the antibody is about 300 mg administered about weekly.

[0169] Aspect B10. The method of Aspect B9, wherein the effective dose of the antibody comprises a single subcutaneous unit dose of about 300 mg.

[0170] Aspect B11. The method of Aspect B9 or 10, wherein the effective dose of the antibody comprises a single subcutaneous unit dose of about 300 mg administered in a total volume of about 2 mL.

[0171] Aspect B12. The method of aspect B9, wherein the effective dose of the antibody comprises (i) two subcutaneous unit doses, wherein each of the two subcutaneous unit doses comprises about 150 mg of the antibody; or (ii) Three subcutaneous unit doses, wherein each of the three subcutaneous unit doses contains about 100 mg of antibody.

[0172] Aspect B13. The method of Aspect B12, wherein (i) at least one of the two subcutaneous unit doses comprises about 150 mg of the antibody in a total volume of less than about 5 mL; and (ii) three subcutaneous unit doses At least one of which comprises about 100 mg of antibody in a total volume of about 2 mL.

[0173] Aspect B14. The method of aspect B12 or 13, wherein (i) the individual is administered two subcutaneous unit doses at two different body locations, or (ii) the individual is administered at least two different body locations At least two of three subcutaneous unit doses are administered.

[0174] Aspect B15. The method of any one of aspects B1 to 6, wherein the effective dose of the antibody is about 300 mg to about 900 mg administered about every two weeks.

[0175] Aspect B16. The method of aspect B15, wherein the effective dose of the antibody is about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 510 mg, about every two weeks. About 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, About 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg or about 900 mg.

[0176] Aspect B17. The method of Aspect B15 or 16, wherein the effective dose of the antibody is about 600 mg administered about every two weeks.

[0177] Aspect B18. The method of Aspect B17, wherein the effective dose of the antibody comprises a single subcutaneous unit dose.

[0178] Aspect B19. The method of Aspect B17, wherein the effective dose of the antibody comprises two, three or at least four subcutaneous unit doses.

[0179] Aspect B20. The method of Aspect B17 or 19, wherein the effective dose of the antibody comprises two subcutaneous unit doses, wherein the two subcutaneous unit doses each comprise about 300 mg of the antibody.

[0180] Aspect B21. The method of Aspect B20, wherein at least one of the two subcutaneous unit doses comprises about 300 mg of the antibody in a total volume of about 2 mL.

[0181] Aspect B22. The method of any one of Aspects B19 to 21, wherein at least two of the subcutaneous unit doses are administered to at least two different body locations of the individual.

[0182] Aspect B23. The method of any one of Aspects B1 to 6, wherein the effective dose of the antibody is about 900 mg to about 1500 mg administered about every four weeks.

[0183] Aspect B24. The method of aspect B23, wherein the effective dose of the antibody is about 900, about 950, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg administered about every four weeks , about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg , about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, or about 1500 mg.

[0184] Aspect B25. The method of Aspect B23 or 24, wherein the effective dose of the antibody is about 1200 mg administered about every four weeks.

[0185] Aspect B26. The method of any one of Aspects B23 to 25, wherein the effective dose of the antibody comprises two, three, four, six or at least eight subcutaneous unit doses.

[0186] Aspect B27. The method of any one of aspects B23 to 26, wherein the effective dose of the antibody comprises four subcutaneous unit doses, wherein each of the four subcutaneous unit doses comprises about 300 mg of the antibody.

[0187] Aspect B28. The method of Aspect B27, wherein at least one of the four subcutaneous unit doses comprises about 300 mg of the antibody in a total volume of about 2 mL.

[0188] Aspect B29. The method of any one of Aspects B26 to 28, wherein at least two of the subcutaneous unit doses are administered to at least two different body locations of the individual.

[0189] Aspect B30. The method of any one of aspects B26 to 29, wherein two, three, four, six or at least eight subcutaneous unit doses are administered on the same day.

[0190] Aspect B31. The method of any one of Aspects B1 to 5, wherein the antibody comprises an anti-PD-L1 antibody.

[0191] Aspect B32. The method of Aspect B31, wherein the effective dose of the antibody is about 900 mg to about 1800 mg of the antibody administered about every two weeks.

[0192] Aspect B33. The method of aspect B31 or 32, wherein the effective dose of the antibody is about 900, about 950, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about every two weeks About 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, About 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, or about 1500 mg.

[0193] Aspect B34. The method of any one of Aspects B31 to 33, wherein the effective dose of the antibody is about 1200 mg every two weeks.

[0194] Aspect B35. The method of any one of Aspects B31 to 34, wherein the effective dose comprises two, three, four, six or at least eight subcutaneous unit doses.

[0195] Aspect B36. The method of any one of aspects B31 to 35, wherein the effective dose of the antibody comprises four subcutaneous unit doses, wherein each of the four subcutaneous unit doses comprises about 300 mg of the antibody.

[0196] Aspect B37. The method of Aspect B36, wherein at least one of the four subcutaneous unit doses comprises about 300 mg of the antibody in a total volume of about 2 mL.

[0197] Aspect B38. The method of any one of aspects B35 to 37, wherein at least two of the subcutaneous unit doses are administered to at least two different body locations of the individual.

[0198] Aspect B39. The method of any one of aspects B35 to 38, wherein two, three, four, six or at least eight subcutaneous unit doses are administered on the same day.

[0199] Aspect B40. The method of any one of aspects B1 to 30, wherein the anti-PD-1 antibody comprises an antibody selected from the group consisting of: nivolumab, pembrolizumab, PDR001, MEDI -0680, milpirimumab, toripalimumab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308 , KN035, sasanlizumab, and any combination thereof.

[0200] Aspect B41. The method of any one of Aspects B1 to 30, wherein the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1.

[0201] Aspect B42. The method of Aspect B40, wherein the anti-PD-1 antibody comprises nivolumab.

[0202] Aspect B43. The method of Aspect B40, wherein the anti-PD-1 antibody comprises pembrolizumab.

[0203] Aspect B44. The method of any one of Aspects B1 to 5 and 7 to 39, wherein the anti-PD-L1 antibody comprises an antibody selected from the group consisting of: BMS-936559, atezolizumab, Durvalumab, Avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, CK-301, and any combination thereof.

[0204] Aspect B45. The method of any one of Aspects B1 to 44, wherein the individual suffers from cancer.

[0205] Aspect B46. The method of aspect B45, wherein the cancer is selected from the group consisting of squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, Glioma, Gastrointestinal Cancer, Renal Cancer, Clear Cell Carcinoma, Ovarian Cancer, Liver Cancer, Colorectal Cancer, Endometrial Cancer, Kidney Cancer, Renal Cell Carcinoma (RCC), Prostate Cancer, Hormone Refractory Prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, liver cancer, breast cancer, colon cancer, head and neck cancer, Stomach cancer, Germ cell tumors, Pediatric sarcoma, Nasal and sinus natural killers, Melanoma, Bone cancer, Skin cancer, Uterine cancer, Anal region cancer, Testicular cancer, Fallopian tube cancer, Endometrial cancer, Cervical cancer, Vaginal cancer, Vulva cancer Carcinoma, esophageal cancer, small bowel cancer, endocrine system cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, childhood solid tumors, urinary tract cancer, renal pelvis cancer, central nervous system (CNS) neoplasm , primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumors, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environment-induced cancer ( Includes asbestos-induced cancers), virus-associated cancers, or cancers of viral origin (such as human papillomavirus (HPV-associated or derived tumors)), and any combination thereof.

[0206] Aspect B47. The method of any one of aspects B1 to 46, wherein the pharmaceutical composition is administered using an automatic injector.

[0207] Aspect B48. The method of any one of Aspects B1 to 46, wherein the pharmaceutical composition is administered using a wearable pump.

[0208] Aspect B49. The method of any one of Aspects B1 to 48, wherein the pharmaceutical composition is administered to the individual by subcutaneous infusion in less than about 10 minutes.

[0209] Aspect B50. The method of any one of Aspects B1 to 49, wherein the pharmaceutical composition is administered to the individual by subcutaneous infusion in less than about 5 minutes.

[0210] Aspect B51. The method of any one of Aspects B1 to 50, wherein the pharmaceutical composition further comprises at least two antioxidants.

[0211] Aspect B52. The method of Aspect B51, wherein at least two antioxidants are selected from the group consisting of methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA, and EDTA .

[0212] Aspect B53. The method of Aspect B51 or 52, wherein the at least two antioxidants comprise (i) methionine and EDTA or (ii) methionine and DTPA.

[0213] Aspect B54. The method of any one of Aspects B51 to 53, wherein the at least two antioxidants comprise at least about 1 to about 20 mM methionine.

[0214] Aspect B55. The method of any one of Aspects B51 to 54, wherein at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine.

[0215] Aspect B56. The method of any one of Aspects B51 to 55, wherein the at least two antioxidants comprise about 5 mM methionine.

[0216] Aspect B57. The method of any one of Aspects B51 to 56, wherein the at least two antioxidants comprise at least about 10 µM to about 200 µM DTPA.

[0217] Aspect B58. The method of any one of Aspects B51 to 57, wherein the at least two antioxidants comprise at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least about 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, at least about 80 µM, at least about 85 µM, at least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, at least about 160 µM, at least about 170 µM, at least about 180 µM, at least about 190 µM, or at least about 200 µM DTPA.

[0218] Aspect B59. The method of any one of Aspects B51 to 58, wherein the at least two antioxidants comprise about 50 µM DTPA.

[0219] Aspect B60. The method of any one of Aspects B1 to 59, wherein the pharmaceutical composition comprises at least about 20 mg / mL to at least about 200 mg / mL of the anti-PD-1 antibody.

[0220] Aspect B61. The method of any one of Aspects B1 to 60, wherein the pharmaceutical composition comprises at least about 135 mg / mL to at least about 180 mg / mL anti-PD-1 antibody.

[0221] Aspect B62. The method of any one of Aspects B1 to 61, wherein the pharmaceutical composition comprises at least about 108 mg / mL to at least about 132 mg / mL of an anti-PD-1 antibody.

[0222] Aspect B63. The method of any one of aspects B1 to 60, wherein the pharmaceutical composition comprises at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL mL, at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL Or at least about 200 mg / mL anti-PD-1 antibody.

[0223] Aspect B64. The method of any one of Aspects B1 to 63, wherein the pharmaceutical composition comprises about 120 mg / mL of the anti-PD-1 antibody.

[0224] Aspect B65. The method of any one of Aspects B1 to 63, wherein the pharmaceutical composition comprises about 150 mg / mL of the anti-PD-1 antibody.

[0225] Aspect B66. The method of any one of Aspects B1 to 65, wherein the pharmaceutical composition further comprises a tonicity adjusting agent and / or a stabilizing agent.

[0226] Aspect B67. The method of Aspect B66, wherein the tonicity modifier and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof.

[0227] Aspect B68. The method of Aspect B66 or 67, wherein the tonicity modifier and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerol, glycerin Amino acid, leucine, isoleucine, sodium chloride, proline, arginine, histidine and any combination thereof.

[0228] Aspect B69. The method of any one of Aspects B66 to 68, wherein the tonicity modifier comprises sucrose.

[0229] Aspect B70. The method of any one of Aspects Bl to 69, wherein the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose.

[0230] Aspect B71. The method of any one of aspects B1 to 70, wherein the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, At least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, or at least about 500 mM sucrose.

[0231] Aspect B72. The method of any one of Aspects B1 to 71, wherein the pharmaceutical composition comprises about 250 mM sucrose.

[0232] Aspect B73. The method of any one of Aspects B1 to 72, wherein the pharmaceutical composition further comprises a buffer.

[0233] Aspect B74. The method of Aspect B73, wherein the buffer is selected from the group consisting of histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate.

[0234] Aspect B75. The method of Aspect B73 or 74, wherein the buffer comprises histidine.

[0235] Aspect B76. The method of any one of Aspects B1 to 75, wherein the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM histidine. Aspect B77. The method of any one of aspects B1 to 76, wherein the pharmaceutical composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, At least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM Amino acid.

[0237] Aspect B78. The method of any one of Aspects Bl to 49, wherein the pharmaceutical composition comprises about 20 mM histidine.

[0238] Aspect B79. The method of any one of Aspects B1 to 78, wherein the pharmaceutical composition further comprises a surfactant.

[0239] Aspect B80. The method of Aspect B79, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188.

[0240] Aspect B81. The method of Aspect B79 or 80, wherein the surfactant comprises polysorbate 80.

[0241] Aspect B82. The method of any one of Aspects B1 to 81, wherein the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80.

[0242] Aspect B83. The method of any one of aspects B1 to 82, wherein the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1 % w / v Polysorbate 80.

[0243] Aspect B84. The method of any one of Aspects B1 to 83, wherein the pharmaceutical composition comprises about 0.05% w / v polysorbate 80.

[0244] Aspect B85. The method of any one of Aspects B1 to 30, 40 to 43, and 45 to 84, wherein the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; ( b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM formazan Thiamine.

[0245] Aspect B86. The method of any one of Aspects B1 to 30, 40 to 43, and 45 to 84, wherein the pharmaceutical composition comprises: (a) about 120 mg / mL anti-PD-1 antibody; ( b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM formazan Thiamine.

[0246] Aspect B87. The method of any one of Aspects Bl to 86, wherein the pharmaceutical composition comprises a pH of about 5.2 to about 6.8.

[0247] Aspect B88. The method of any one of aspects B1 to 87, wherein the pharmaceutical composition comprises about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, A pH of about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8.

[0248] Aspect B89. The method of any one of Aspects Bl to 88, wherein the pharmaceutical composition comprises a pH of about 6.0.

[0249] Aspect B90. A pharmaceutical composition for use in the method of any one of Aspects B1-89.

[0250] Aspect B91. A pharmaceutical composition comprising (i) an antibody that specifically binds PD-1 ("anti-PD-1 antibody") and (ii) at least two antioxidants.

[0251] Aspect B92. The pharmaceutical composition of aspect B91, wherein at least two antioxidants are selected from the group consisting of methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA and EDTA.

[0252] Aspect B93. The pharmaceutical composition of Aspect B91 or 92, wherein the at least two antioxidants comprise (i) methionine and EDTA or (ii) methionine and DTPA.

[0253] Aspect B94. The pharmaceutical composition of any one of Aspects B91 to 93, wherein the at least two antioxidants comprise at least about 1 to about 20 mM methionine.

[0254] Aspect B95. The pharmaceutical composition of any one of aspects B91 to 94, wherein at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least About 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine.

[0255] Aspect B96. The pharmaceutical composition of any one of Aspects B91 to 95, wherein the at least two antioxidants comprise about 5 mM methionine.

[0256] Aspect B97. The pharmaceutical composition of any one of Aspects B91 to 96, wherein the at least two antioxidants comprise at least about 10 µM to about 200 µM DTPA.

[0257] Aspect B98. The pharmaceutical composition of any one of aspects B91 to 97, wherein the at least two antioxidants comprise at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least About 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, at least About 80 µM, at least about 85 µM, at least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, at least about 160 µM, at least about 170 µM, at least about 180 µM, at least about 190 µM, or at least about 200 µM DTPA.

[0258] Aspect B99. The pharmaceutical composition of any one of Aspects B91 to 98, wherein the at least two antioxidants comprise about 50 µM DTPA.

[0259] Aspect B100. The pharmaceutical composition of any one of Aspects B91 to 99, comprising at least about 20 mg / mL to at least about 200 mg / mL of an anti-PD-1 antibody.

[0260] Aspect B101. The pharmaceutical composition of any one of Aspects B91 to 100, comprising at least about 135 mg / mL to at least about 180 mg / mL of an anti-PD-1 antibody.

[0261] Aspect B102. The pharmaceutical composition of any one of Aspects B91 to 101, comprising at least about 108 mg / mL to at least about 132 mg / mL of an anti-PD-1 antibody.

[0262] Aspect B103. The pharmaceutical composition of any one of aspects B91 to 100, comprising at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL , at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or At least about 200 mg / mL anti-PD-1 antibody.

[0263] Aspect B104. The pharmaceutical composition of any one of Aspects B91 to 103, comprising about 120 mg / mL of an anti-PD-1 antibody.

[0264] Aspect B105. The pharmaceutical composition of any one of Aspects B91 to 103, comprising about 150 mg / mL of an anti-PD-1 antibody.

[0265] Aspect B106. The pharmaceutical composition according to any one of Aspects B91 to 105, further comprising a tonicity adjusting agent and / or a stabilizing agent.

[0266] Aspect B107. The pharmaceutical composition of aspect B106, wherein the tonicity modifier and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof.

[0267] Aspect B108. The pharmaceutical composition according to aspect B106 or 107, wherein the tonicity regulator and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerin , glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, and any combination thereof.

[0268] Aspect B109. The pharmaceutical composition of any one of Aspects B106 to 108, wherein the tonicity adjusting agent comprises sucrose.

[0269] Aspect B110. The pharmaceutical composition of any one of Aspects B91 to 109, comprising at least about 10 mM to at least about 500 mM sucrose.

[0270] Aspect B111. The pharmaceutical composition of any one of aspects B91 to 110, comprising at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least About 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, or at least about 500 mM sucrose.

[0271] Aspect B112. The pharmaceutical composition of any one of Aspects B91 to 111, comprising about 250 mM sucrose.

[0272] Aspect B113. The pharmaceutical composition of any one of Aspects B91 to 112, further comprising a buffer.

[0273] Aspect B114. The pharmaceutical composition of Aspect B113, wherein the buffering agent is selected from the group consisting of histidine, succinate, tromethamine, sodium phosphate, sodium acetate and sodium citrate.

[0274] Aspect B115. The pharmaceutical composition of Aspect B113 or 114, wherein the buffer comprises histidine.

[0275] Aspect B116. The pharmaceutical composition of any one of Aspects B91 to 115, comprising at least about 5 mM to at least about 100 mM histidine. Aspect B117. The pharmaceutical composition of any one of aspects B91 to 116, comprising at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histamine acid.

[0277] Aspect B118. The pharmaceutical composition of any one of Aspects B91 to 117, comprising about 20 mM histidine.

[0278] Aspect B119. The pharmaceutical composition of any one of Aspects B91 to 118, further comprising a surfactant.

[0279] Aspect B120. The pharmaceutical composition of aspect B119, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188.

[0280] Aspect B121. The pharmaceutical composition of Aspect B119 or 120, wherein the surfactant comprises polysorbate 80.

[0281] Aspect B122. The pharmaceutical composition of any one of Aspects B91 to 121, comprising at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80.

[0282] Aspect B123. The pharmaceutical composition of any one of aspects B91 to 122, comprising at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v Polysorbate 80.

[0283] Aspect B124. The pharmaceutical composition of any one of Aspects B91 to 123, comprising about 0.05% w / v polysorbate 80.

[0284] Aspect B125. The pharmaceutical composition of any one of aspects B91 to 124, comprising: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; ( c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0285] Aspect B126. The pharmaceutical composition of any one of aspects B91 to 124, comprising: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; ( c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0286] Aspect B127. The pharmaceutical composition of any one of Aspects B91 to 126, comprising a pH of about 5.2 to about 6.8.

[0287] Aspect B128. The pharmaceutical composition of any one of aspects B91 to 127, comprising about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0 , about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7 or about 6.8 pH.

[0288] Aspect B129. The pharmaceutical composition of any one of Aspects B91 to 128, comprising a pH of about 6.0.

[0289] Aspect B130. The pharmaceutical composition of any one of Aspects B1 to 129, further comprising a second therapeutic agent.

[0290] Aspect B131. The pharmaceutical composition of Aspect B130, wherein the second therapeutic agent is an antibody.

[0291] Aspect B132. The pharmaceutical composition of Aspect B131, wherein the second therapeutic agent is a checkpoint inhibitor.

[0292] Aspect B133. The pharmaceutical composition of aspect B132, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-NKG2a antibody , anti-OX40 antibody, anti-ICOS antibody, anti-MICA antibody, anti-CD137 antibody, anti-KIR antibody, anti-TGFβ antibody, anti-IL-10 antibody, anti-IL-8 antibody, anti-B7-H4 antibody, anti-Fas ligand antibody , anti-CXCR4 antibody, anti-mesothelin antibody, anti-CD27 antibody, anti-GITR, or any combination thereof.

[0293] Aspect B134. A vial comprising the pharmaceutical composition of any one of aspects B87-133.

[0294] Aspect B135. A unit dose comprising the pharmaceutical composition of any one of aspects B87-133.

[0295] Aspect B136. A unit dose comprising: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0296] Aspect B137. The vial of Aspect B134, which is an autoinjector.

[0297] Aspect B138. An autoinjector comprising the unit dose of aspect B135 or 136.

[0298] Aspect B139. The vial of aspect B134, which is a wearable device.

[0299] Aspect B140. A wearable device comprising the unit dose of aspect B135 or 136.

Implementation

[0329] CROSS-REFERENCE TO RELATED APPLICATIONS

[0330] This application asserts U.S. Provisional Application No. US 63 / 131,234, filed December 28, 2020; US 63 / 131,244, filed December 28, 2020; and US 63, filed February 17, 2021 / 150,465 priority and interest; each of which is incorporated herein by reference in its entirety.

[0331] Current methods of delivering anti-PD-1 and / or anti-PD-L1 antibodies require periodic intravenous administration, usually in a clinic or hospital by a clinician. This solution is often very inconvenient for the patient, and the nature of the treatment itself can negatively impact the patient experience. Subcutaneous delivery, such as via the use of auto-injectors or wearable pumps, can greatly improve patient compliance, potentially allowing patients to receive this potentially life-saving therapy in the comfort of their own home. The present invention provides a method for treating an individual in need, comprising subcutaneously administering a certain dose of a pharmaceutical composition to the individual, the pharmaceutical composition comprising (i) specifically binding to PD-1 or PD-L1 and inhibiting PD-1 and Antibody interacting with PD-L1 ("anti-PD-1 antibody" or "anti-PD-L1 antibody", respectively). In some aspects, the pharmaceutical composition further comprises (ii) an endoglycosidase hydrolase. In some aspects, a dose comprises one or more subcutaneous unit doses.

[0332] In some aspects, the pharmaceutical composition does not comprise an endoglycosidase hydrolase. In some aspects, at least one of the subcutaneous unit doses has a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 3 mL, or less than about 2.5 mL). In certain aspects, the dose comprises at least about 250 mg to at least about 2400 mg of antibody. I. Terminology

[0333] In order to facilitate the understanding of the present invention, certain terms are first defined. As used in this application, unless expressly provided otherwise herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0334] It should be understood that whenever the language "comprising" is used herein to describe an aspect, then similar aspects described using the terms "consisting of" and / or "consisting essentially of" are also provided.

[0335] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd Edition, 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd Edition, 1999, Academic Press; and the Oxford Dictionary of Biochemistry And Molecular Biology, revised, 2000, Oxford University Press provides the skilled person with a general dictionary of many of the terms used in the present invention.

[0336] Units, prefixes and symbols are expressed in the form recognized by the International System of Units (Système International de Unites; SI). Numerical ranges include the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written left to right in the 5' to 3' direction. Amino acid sequences are written left to right in amine to carboxyl orientation. The headings provided herein are not limitations of the various aspects or aspects of the invention, which may be referred to by the specification as a whole. Accordingly, terms defined immediately below are more fully defined throughout the specification.

[0337] "Administering" refers to the physical introduction of a composition comprising a therapeutic agent to a subject using any of a variety of methods and delivery systems known to those skilled in the art. Administration can refer to any form of administration of immunotherapy, such as anti-PD-1 antibody or anti-PD-L1 antibody including intravenous, intramuscular, subcutaneous, intraperitoneal, spinal or other parenteral routes of administration, such as by injection or infusion . The phrases "subcutaneous administration" and "subcutaneous injection" are used interchangeably and refer to a mode of administration in which a substance, such as a composition comprising an antibody that specifically binds PD1 or PD-L1 and inhibits the interaction of PD1 and PD-L1, is administered in the Delivery to the individual subcutaneously, between the dermis and eg muscle.

[0338] Subcutaneous administration can be achieved using any method. In some aspects, subcutaneous administration is achieved using a needle or needles. In some aspects, the needle or at least one of the plurality of needles is less than about 1 inch, less than about 7 / 8 inch, less than about 6 / 8 inch, less than about 5 / 8 inch, less than about 1 / 2 inch . In some aspects, the needle, or at least one of the plurality of needles, is about 5 / 8 inch in length.

[0339] Administration can be performed, for example, once, a plurality of times, and / or over one or more extended periods. Thus, as used herein, administering can refer to a single unit dose or more than one unit dose.

[0340] As used herein, the term "dose" or "dosage" is defined as the amount of a therapeutic agent that can be administered at a given point. The dose or dose may be an amount sufficient to achieve, or at least partially achieve, a desired effect, although such desired effect may not be visible or detectable. A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug which, alone or in combination with another therapeutic agent, promotes regression of disease as evidenced by the severity of disease symptoms Decreased, increased frequency and duration of asymptomatic periods of disease, increased overall survival (the length of time a patient diagnosed with a disease such as cancer is alive since the date of diagnosis or initiation of treatment for the disease) or Prevention of injury or disability due to illness. The amount or dose of a drug includes a "prophylactically effective amount" or "prophylactically effective dose" which, when administered to an individual at risk of developing the disease or suffering from a recurrence of the disease, alone or in combination with another therapeutic agent, inhibits the development of the disease or any amount of drug that relapsed. The ability of a therapeutic agent to promote disease regression or inhibit disease progression or recurrence can be achieved using a variety of methods available to those skilled in the art, such as in human subjects during clinical trials, in animal model systems predicting efficacy in humans, or by Assessed by analyzing the activity of the agent in an in vitro assay). A "dosage" may comprise a single unit dose or a plurality of unit doses. In some aspects, a dose comprises a single unit dose. In some aspects, a dose comprises a plurality of unit doses.

[0341] As used herein, a subcutaneous "unit dose" refers to a single quantity of a substance delivered by subcutaneous injection, eg, from a single vial, single auto-injector and / or single syringe. In some aspects, multiple subcutaneous doses are administered to achieve a therapeutically effective dose. When multiple unit doses are administered, the individual unit doses can be administered simultaneously or sequentially. In some aspects, each unit dose of the therapeutically effective dose is administered on the same day. Each unit dose can be administered at the same body location or at different body locations. In some aspects, the first unit dose is administered at a first body location and the second unit dose is administered at a second body location. Any body location known in the art to be suitable for subcutaneous delivery can be used in the methods disclosed herein. In some aspects, at least one subcutaneous unit dose of the dose is administered to a body location selected from the arm (eg, side or back of the upper arm), abdomen, and front of the thigh.

[0342] As used herein, an "adverse event" (AE) is any unfavorable and generally undesirable or undesirable sign (including abnormal laboratory findings), symptom or disease associated with the use of a medical treatment. For example, an adverse event can be associated with immune system activation or expansion of immune system cells (eg, T cells) in response to treatment. A medical treatment may have one or more associated AEs and each AE may be of the same or different level of severity. Reference to a method capable of "modifying an adverse event" means a treatment regimen that reduces the incidence and / or severity of one or more AEs associated with the use of a different treatment regimen.

[0343] "Antibody" (Ab) shall include, but is not limited to, a glycoprotein immunoglobulin that specifically binds to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds protein or antigen-binding portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region comprises three constant domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region comprises one constant domain, CL. The VH and VL regions can be further subdivided into hypervariable regions, called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL comprises three CDRs and four FRs, which are arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant regions of the antibodies mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system. Thus, the term "anti-PD-1 antibody" includes complete antibodies having two heavy chains and two light chains that specifically bind to PD-1 and the antigen-binding portion of the complete antibody. Non-limiting examples of antigen binding moieties are shown elsewhere herein.

[0344] Immunoglobulins may be derived from any commonly known isotype, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgGl, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (eg, IgM or IgGl) encoded by the heavy chain constant region genes. The term "antibody" includes, for example, naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or non-human antibodies; fully synthetic antibodies; Non-human antibodies can be humanized by recombinant means to reduce their immunogenicity in humans. Where not expressly stated, and unless the context dictates otherwise, the term "antibody" also includes antigen-binding fragments or antigen-binding portions of any of the foregoing immunoglobulins, and includes monovalent and bivalent fragments or portions, and single-chain antibodies .

[0345] In some aspects, an "antibody" of the invention is capable of binding to more than one antigen, such as a "multispecific" antibody or a "bispecific" antibody. As used herein, a "bispecific" antibody is an antibody capable of specifically binding two antigens, wherein the first and second antigens are the same or different. As used herein, a "multispecific" antibody is capable of specifically binding more than one antigen, such as at least two (ie, "bispecific" antibodies), at least three (ie, "trispecific" antibodies), at least four one, at least five, or at least six antigens. A variety of multispecific antibodies are known and can be used in the compositions and / or methods disclosed herein, including but not limited to bispecific antibodies that bind PD-1 and a second target and bispecific antibodies that bind PD-L1 and a second target bispecific antibodies. In some aspects, the multispecific antibody is a T cell dependent bispecific antibody. In some aspects, the multispecific antibody is an anti-FcRH5 / CD3 bispecific antibody targeting the B cell lineage markers FcRH5 and CD3, eg, for the treatment of multiple myeloma.

[0346] In some aspects, an "antibody" of the invention is engineered to activate at a target site, eg, a "proantibody." In some aspects, the antibody (eg, proantibody) is proteolytically cleaved at the target tissue (eg, tumor).

[0347] "Isolated antibody" refers to an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds to PD-1 is substantially free of specific binding to other than PD-1 Antibodies to the antigen). However, an isolated antibody that specifically binds PD-1 may be cross-reactive with other antigens, such as PD-1 molecules from different species. Furthermore, an isolated antibody can be substantially free of other cellular material and / or chemicals.

[0348] The term "monoclonal antibody" ("mAb") refers to a preparation of non-naturally occurring antibody molecules of a single molecular composition, that is, one that is substantially identical in primary sequence and that exhibits a single binding specificity and affinity for a particular epitope. antibody molecule. A monoclonal antibody is an example of an isolated antibody. Monoclonal antibodies can be produced by fusionoma, recombination, transgenic or other techniques known to those skilled in the art.

[0349] "Human antibody" (HuMAb) refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Additionally, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. Human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (eg, mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The term "human antibody" is used synonymously with "fully human antibody".

[0350] "Humanized antibody" refers to an antibody in which some, most or all of the amino acids outside the CDRs of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulins. In one aspect of the humanized form of the antibody, some, most, or all of the amino acids outside the CDRs have been replaced with amino acids from human immunoglobulins, while some, most, or all of the amines are internal to one or more CDRs. The base acid remains unchanged. Minor additions, deletions, insertions, substitutions or modifications of amino acids are permissible so long as they do not eliminate the ability of the antibody to bind to a particular antigen. A "humanized antibody" retains antigen specificity similar to that of the original antibody.

[0351] "Chimeric antibody" refers to an antibody in which the variable regions are derived from one species and the constant regions are derived from another species, such as antibodies in which the variable regions are derived from a mouse antibody and the constant regions are derived from a human antibody.

[0352] "Anti-antigen antibody" refers to an antibody that specifically binds to an antigen. For example, an anti-PD-1 antibody specifically binds to PD-1, and an anti-PD-L1 antibody specifically binds to PD-L1.

[0353] An "antigen-binding portion" (also known as an antigen-binding fragment) of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen to which the whole antibody binds. It has been shown that the antigen binding function of antibodies can be performed by fragments of full length antibodies. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody (e.g., anti-PD-1 antibody or anti-PD-L1 antibody) as described herein include: (i) Fab fragments (fragments from papain cleavage) or similar monovalent fragments consisting of VL, VH, LC and CH1 domains; (ii) F(ab')2 fragments (fragments from pepsin cleavage) or similar bivalent fragments comprising Two Fab fragments linked by a disulfide bridge; (iii) Fd fragment, which consists of VH and CH1 domains; (iv) Fv fragment, which consists of VL and VH domains of a single arm of an antibody; (v) dAb fragment ( Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; (vi) an isolated complementarity determining region (CDR); and (vii) a combination of two or more isolated CDRs, The CDRs are optionally joined by synthetic linkers. Furthermore, although the two domains (VL and VH) of the Fv fragment are encoded by separate genes, they can be linked using recombinant methods by a synthetic linker that enables them to be produced as a single protein chain in which VL Pairs with the VH region to form a monovalent molecule (termed single-chain Fv (scFv); see for example Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc.Natl.Acad.Sci.USA85 :5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. Such antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for use in the same manner as whole antibodies. Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.

[0354] "Cancer" refers to a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth Divide and grow to form malignant tumors that invade adjacent tissues and can also metastasize to distant parts of the body via the lymphatic system or bloodstream.

[0355] The term "immunotherapy" refers to the treatment of an individual suffering from a disease or at risk of infection or suffering relapse of the disease by methods involving inducing, enhancing, suppressing or otherwise modifying an immune response. "Treatment" or "therapy" of a subject means any type of intervention or process performed on a subject, or administration of an active agent to a subject, with the goal of reversing, alleviating, ameliorating, inhibiting, slowing or preventing the onset, progression, development, severe Degree or recurrence of symptoms, complications or conditions or biochemical markers associated with disease.

[0356] "Planned Death-1" (PD-1) refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed primarily on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms, and species homologues of hPD-1, and at least one common antigenic determinant of hPD-1. base analogs. The complete hPD-1 sequence can be found under GenBank Accession No. U64863.

[0357] "Planned death ligand-1" (PD-L1) is one of the two cell surface glycoprotein ligands of PD-1 (the other being PD-L2), which binds to PD- After 1, it down-regulates T cell activation and cytokine secretion. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, isoforms and species homologues of hPD-L1, and hPD-L1 having at least one common epitope analogs of The complete hPD-L1 sequence can be found under Genbank accession number Q9NZQ7. The human PD-L1 protein is encoded by the human CD274 gene (NCBI Gene ID: 29126).

[0358] As used herein, "hyaluronidase" refers to an enzyme capable of catalyzing the cleavage of hyaluronic acid. Hyaluronic acid is a repeating polymer of N-acetyl-glucosamine and glucuronic acid, which exists in the subcutaneous space and contributes to the soluble gel-like component of the extracellular matrix of the skin and by rapid turnover (resynthesis) recover. In some aspects, the hyaluronidase comprises rHuPH20, which is a glycosylated 447 amino acid single chain polypeptide that locally depolymerizes hyaluronic acid in the subcutaneous space at the site of injection in the skin. The depolymerization of hyaluronic acid by hyaluronidase is achieved through the hydrolysis of polysaccharide polymers. The depolymerization of hyaluronic acid makes the viscosity of the gel-like phase of the extracellular matrix decrease instantaneously and increases the hydraulic conductivity, which facilitates the dispersion and absorption of co-administered therapeutic agents. Thus, hyaluronidases, such as rHuPH20, can improve the speed and ease of subcutaneous delivery of injectable biologics and drugs by acting as penetration enhancers. In certain aspects, the hyaluronidase comprises ENHANZE™.

[0359] "Individual" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates such as non-human primates, sheep, dogs, and rodents such as mice, rats, and guinea pigs. In preferred aspects, the individual is human. The terms "individual" and "patient" are used interchangeably herein.

[0360] The term "uniform dose" as used in connection with the methods and dosages of the present invention means a dose administered to a patient regardless of the patient's body weight or body surface area (BSA). Thus, a uniform dose is not provided as a mg / kg dose, but rather as an absolute amount of agent (eg, anti-PD-1 antibody). For example, a 60 kg person and a 100 kg person should receive the same dose of antibody (eg, 240 mg anti-PD-1 antibody).

[0361] As referred to herein, the term "body weight based dose" means that the dose administered to a patient is calculated based on the patient's weight. For example, when a patient weighing 60 kg requires 3 mg / kg of anti-PD-1 antibody, we can calculate and use an appropriate amount of anti-PD-1 antibody (ie, 180 mg) for administration.

[0362] For example, an "anticancer agent" promotes the regression of cancer in a subject. In some aspects, a therapeutically effective amount of the drug promotes regression of the cancer to the point of elimination of the cancer. "Promoting cancer regression" means administering an effective amount of the drug, alone or in combination with an antineoplastic agent, resulting in a decrease in tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, frequency of periods without disease symptoms and duration, or to prevent damage or disability due to disease or illness. In addition, the terms "effective" and "effectiveness" in relation to treatment include both pharmacological effectiveness and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity caused by drug administration or other adverse physiological effects (side effects) at the level of cells, organs and / or organisms.

[0363] As an example of the treatment of tumors, a therapeutically effective amount of an anticancer agent preferably inhibits cell growth or tumor growth by at least about 20%, preferably at least about 40%, more preferably at least about 20%, compared to an untreated individual. 60%, and more preferably at least about 80%. In other preferred aspects of the invention, tumor regression is observed for a period of at least about 20 days, more preferably at least about 40 days or even more preferably at least about 60 days. Regardless of these final measures of therapeutic effectiveness, evaluation of immunotherapeutic agents must also take into account immune-related response patterns.

[0364] "Immune response" as understood in the art, and generally refers to a biological response in a vertebrate to a foreign agent or abnormality (such as a cancer cell) that protects the organism from such agents and from them The effects of the disease caused. The immune response consists of one or more cells of the immune system (such as T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, or neutrophils) and Mediated by the action of soluble macromolecules (including antibodies, cytokines, and complement) produced by any of these cells or the liver, which elicit resistance to invasive pathogens, cells or tissues infected with pathogens, cancer cells, or Selective targeting, binding, damage, destruction and / or elimination from vertebrates of other abnormal cells or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues. An immune response includes, for example, the activation or suppression of T cells such as effector T cells, Th cells, CD4+ cells, CD8+ T cells or Treg cells, or any other cell of the immune system such as NK cells.

[0365] "Immune-related response pattern" refers to the clinical response pattern commonly observed in cancer patients treated with an immunotherapeutic agent that produces an antitumor effect by inducing a cancer-specific immune response or by modifying native immune processes. This pattern of response is characterized by a beneficial therapeutic effect following an initial increase in tumor burden or appearance of new lesions that would be classified as disease progression and would be synonymous with drug failure in the assessment of traditional chemotherapeutic agents. Accordingly, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease.

[0366] As used herein, the term "stable" in reference to a formulation or drug product is a term in which one or more antibodies or molecules therein substantially retain their physical and chemical stability and integrity upon storage. The stability of the formulations herein can be measured after a selected period of time at a selected temperature. For example, aggregate formation or an increase in low molecular weight species are indicators of instability. Retention of original clarity and / or color throughout the storage period is also an indicator used to monitor stability. In some aspects, a "stable" drug product is a drug product in which aggregation increases by less than about 5%, and preferably less than about 3%, when the formulation is stored at 2-8°C for at least about one year, as measured by high Measured by increase in percent molecular weight species (%HMW).

[0367] As used herein, the term "treat / treating / treatment" means to reverse, alleviate, ameliorate, inhibit or slow down or prevent the progression, development, Any type of intervention or method performed on an individual or administering an active agent to an individual with the goal of severity or relapse or enhancing overall survival. Individuals with a disease or those without a disease can be treated (eg, for prophylaxis).

[0368] As used herein, the term "about every week", "about every two weeks" or any other similar dosing interval term means approximate values. "About every week" may include every seven days ± one day, that is, every six days to every eight days. "About every two weeks" may include every fourteen days ± three days, that is, every eleven days to every seventeen days. Similar approximations apply, for example, to about every three weeks, about every four weeks, about every five weeks, about every six weeks, and about every twelve weeks. In some aspects, a dosing interval of about every six weeks or about every twelve weeks means that the first dose may be administered on any day of the first week and then the next dose may be administered at the sixth or tenth week, respectively. Administer any day in two weeks. In other aspects, a dosing interval of about every six weeks or about every twelve weeks means that the first dose is administered on a particular day of the first week (eg, Monday) and then the next dose is administered on the sixth or second week, respectively. Dosing on the same day (that is, Monday) in the twelve weeks. When multiple subcutaneous unit doses are administered to achieve a dose, the dosing interval refers to the period of time between administration of the first subcutaneous unit dose of the first effective dose and the first subcutaneous unit dose of the second effective dose. For example, where the method comprises administering a dose of about 600 mg about every two weeks, wherein the dose of the antibody comprises two subcutaneous unit doses, wherein each of the two subcutaneous unit doses comprises about 300 mg of the antibody, A first subcutaneous unit dose of about 300 mg of the primary antibody effective dose is administered on day 1 and a first subcutaneous unit dose of about 300 mg of the second antibody effective dose is administered on about day 14. In this example, a second unit dose of an effective dose of about 300 mg of the primary antibody may be administered on Day 1 or any other time prior to administration of the first subcutaneous unit dose of an effective dose of about 300 mg of the second antibody.

[0369] Use of an alternative (eg, "or") should be understood to mean either, both, or any combination of the alternatives. It should be understood that, as used herein, the indefinite article "a" or "an" refers to "one or more" of any stated or listed component.

[0370] The term "about" or "comprising essentially" refers to a value or composition within an acceptable error range for a particular value or composition, as determined by one of ordinary skill in the art, which will depend in part on How to measure or determine the value or composition, that is, the limitations of the measurement system. For example, "about" or "consisting essentially of" can mean within 1 or more than 1 standard deviation, as practiced in the art. Alternatively, "about" or "comprising substantially" can mean a range of up to 10%. Furthermore, especially in terms of biological systems or methods, these terms can mean up to an order of magnitude, or up to 5 times, a value. When a specific value or composition is provided in this application and claims, unless otherwise stated, the meaning of "about" or "substantially comprising" should be assumed to be within an acceptable error range for the specific value or composition .

[0371] As described herein, unless otherwise specified, any concentration range, percentage range, ratio range or integer range should be understood to include any integer value and (where appropriate) fractions thereof (such as integers) within the recited range. one-tenth and one-hundredth).

[0372] Various aspects of the invention are described in further detail in the following subsections. II. Compositions of the present invention

[0373] Some aspects of the invention pertain to pharmaceutical compositions comprising (i) an antibody, or antigen-binding portion thereof, and (ii) at least two antioxidants. In some aspects, more than one antioxidant, eg, two antioxidants, prevents oxidation of formulation components and / or increases antibody stability. In some aspects, the antibody, or antigen-binding portion thereof, is a checkpoint inhibitor. In some aspects, the antibody, or antigen-binding portion thereof, specifically binds PD-1 ("anti-PD-1 antibody"). In some aspects, pharmaceutical compositions are formulated for subcutaneous administration. In some aspects, the pharmaceutical composition further comprises (iii) an endoglycosidase hydrolase. In some aspects, the pharmaceutical composition does not contain endoglycosidase hydrolytic enzymes. In some aspects, the pharmaceutical composition comprises at least two antibodies or antigen-binding portions thereof.

[0374] Pharmaceutical compositions comprising anti-PD-1 antibodies or anti-PD-L1 antibodies are also within the scope of the invention. In some aspects, pharmaceutical compositions are formulated for subcutaneous administration according to the methods disclosed herein. In some aspects, a pharmaceutical composition is formulated such that it exhibits improved properties compared to a composition without both antioxidants or at least one antioxidant.

[0375] The therapeutic agents of the invention may be formulated in the form of a composition, such as a pharmaceutical composition comprising an antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible . Preferably, the carrier of the antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion) and contains a combination of antibodies and / or cytokines The pharmaceutical carrier is suitable for non-parenteral, eg oral administration.

[0376] In some aspects, the pharmaceutical composition comprises (i) an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody), (ii) at least two antioxidants, (iii) a tonicity modifier or stabilizer, (iv) Buffer and (v) Surfactant. In some aspects, the pharmaceutical composition comprises (i) an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody), (ii) at least two antioxidants, (iii) a tonicity modifier or stabilizer, (iv) buffer, (v) surfactant and (vi) endoglycosidase hydrolase. In some aspects, the antibody is a bispecific antibody or a multispecific antibody.

[0377] In some aspects, the pharmaceutical composition comprises (i) a primary antibody or antigen-binding portion thereof (eg, an anti-PD-1 antibody), (ii) at least two antioxidants, (iii) a tonicity modifier or a stabilizing agent, (iv) buffer and (v) surfactant. In some aspects, the pharmaceutical composition comprises (i) an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody), (ii) at least two antioxidants, (iii) a tonicity modifier or stabilizer, (iv) Buffer, (v) surfactant, (vi) secondary antibody or antigen binding portion thereof, and (vii) endoglycosidase hydrolase. In some aspects, the primary antibody is a bispecific antibody or a multispecific antibody. II.A. Antibodies and Antigen Binding Portions

[0378] In some aspects, a pharmaceutical composition comprises an antibody or antigen-binding portion thereof. The pharmaceutical compositions described herein can include any antibody or antigen-binding portion thereof. In some aspects, the antibody, or antigen-binding portion thereof, is a checkpoint inhibitor. In some aspects, an antibody or antigen-binding portion thereof specifically binds a checkpoint protein. In some aspects, the antibody or antigen-binding portion thereof that specifically binds a protein is selected from PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM3, NKG2a, OX40, ICOS, MICA, CD137, KIR , TGFβ, IL-10, IL-8, B7-H4, Fas ligand, CXCR4, mesothelin, CD27, GITR, and any combination thereof. In some aspects, the pharmaceutical composition comprises an anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises an anti-PD-L1 antibody. In some aspects, a pharmaceutical composition comprises an anti-CTLA-4 antibody. In some aspects, a pharmaceutical composition comprises an anti-LAG-3 antibody. In some aspects, a pharmaceutical composition comprises an anti-TIM3 antibody.

[0379] In some aspects, the antibody is a multispecific antibody. In some aspects, the antibody is a bispecific antibody. In some aspects, the antibody is a trispecific antibody. In some aspects, the antibody specifically binds (i) PD-1 and (ii) a second antigen. In some aspects, the antibody specifically binds (i) PD-1, (ii) a second antigen, and (iii) a third antigen. In some aspects, the antibody specifically binds (i) PD-L1 and (ii) a second antigen. In some aspects, the antibody specifically binds (i) PD-L1, (ii) a second antigen, and (iii) a third antigen. In some aspects, the second antigen is the same as the third antigen. In some aspects, the second antigen is different from the third antigen. In some aspects, the second antigen is CD3. In some aspects, the second antigen is TIGIT. In some aspects, the second antigen is LAG-3.

[0380] In some aspects, the antibody specifically binds (i) TIGIT and (ii) an inhibitory receptor expressed on T cells, NK cells, or both. In some aspects, the antibody specifically binds (i) CD40 and (ii) CD20. In some aspects, the antibody specifically binds (i) PD-1 and (ii) TIGIT. In some aspects, the antibody specifically binds (i) PD-1 and (ii) LAG-3.

[0381] In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of an antibody (eg, an anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL, at least about 10 mg / mL to at least about 400 mg / mL, at least about 10 mg / mL to at least about 300 mg / mL mL, at least about 10 mg / mL to at least about 250 mg / mL, at least about 10 mg / mL to at least about 200 mg / mL, at least about 10 mg / mL to at least about 190 mg / mL, at least about 10 mg / mL to at least about 180 mg / mL, at least about 10 mg / mL to at least about 170 mg / mL, at least about 10 mg / mL to at least about 160 mg / mL, at least about 10 mg / mL to at least about 150 mg / mL, At least about 20 mg / mL to at least about 500 mg / mL, at least about 20 mg / mL to at least about 400 mg / mL, at least about 20 mg / mL to at least about 300 mg / mL, at least about 20 mg / mL to at least About 250 mg / mL, at least about 20 mg / mL to at least about 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 135 mg / mL to at least about 180 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 130 mg / mL, or at least about 108 mg / mL to at least about 132 mg / mL mL antibodies (such as anti-PD-1 or anti-PD-L1 antibodies). In some aspects, the pharmaceutical composition comprises at least about 50 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 60 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 70 mg / mL antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 75 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 80 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 90 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 100 mg / mL antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 108 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 110 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 120 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 130 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 132 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 135 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 140 mg / mL antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 150 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 160 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 170 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 175 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 180 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 190 mg / mL antibody (eg, anti-PD-1 or anti-PD-L1 antibody). In some aspects, the pharmaceutical composition comprises at least about 200 mg / mL of antibody (eg, anti-PD-1 or anti-PD-L1 antibody). II.A.1 Anti-PD-1 antibodies applicable to the present invention

[0382] In some aspects, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds PD-1 ("anti-PD-1 antibody"). Any anti-PD-1 antibody can be used in the compositions and methods described herein. Various human monoclonal antibodies that specifically bind to PD-1 with high affinity have been disclosed in US Patent No. 8,008,449. It has been demonstrated that the anti-PD-1 human antibodies disclosed in U.S. Patent No. 8,008,449 exhibit one or more of the following characteristics: (a) bind to human PD-1 with a KD of 1×10-7 M or less, as determined by As determined by surface plasmon resonance using the Biacore biosensor system; (b) substantially no binding to human CD28, CTLA-4, or ICOS; (c) increased T cells in a mixed lymphocyte reaction (MLR) assay Proliferation; (d) increased interferon-γ production in the MLR assay; (e) increased IL-2 secretion in the MLR assay; (f) binding to human PD-1 and cynomolgus PD-1; (g ) inhibiting the binding of PD-L1 and / or PD-L2 to PD-1; (h) stimulating antigen-specific memory responses; (i) stimulating antibody responses; and (j) inhibiting tumor cell growth in vivo. Anti-PD-1 antibodies useful in the present invention include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some aspects at least five, of the aforementioned characteristics.

[0383] Other anti-PD-1 monoclonal antibodies have been described, for example, in U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509; 145493, WO 2008 / 156712, WO 2015 / 112900, WO 2012 / 145493, WO 2015 / 112800, WO 2014 / 206107, WO 2015 / 35606, WO 2015 / 085847 No., WO 2014 / 179664, WO 2017 / 020291, WO 2017 / 020858, WO 2016 / 197367, WO 2017 / 024515, WO 2017 / 025051, WO 2017 / 123557 , WO 2016 / 106159, WO 2014 / 194302, WO 2017 / 040790, WO 2017 / 133540, WO 2017 / 132827, WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 106061, WO 2017 / 19846, WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825 and WO 2017 / 133540, each of which is represented by Incorporated by reference in its entirety.

[0384] In some aspects, the anti-PD-1 antibody is selected from the group consisting of nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), palisumab Monoclonal antibodies (Merck; also known as KEYTRUDA®, Larizumab, and MK-3475; see WO2008 / 156712), PDR001 (Novartis; see WO 2015 / 112900), MEDI-0680 (AstraZeneca; also known as AMP-514 ; see WO 2012 / 145493), milpirimumab (Regeneron; also known as REGN-2810; see WO 2015 / 112800), JS001 (TAIZHOU JUNSHI PHARMA; also known as toripalimab; see Si-Yang Liu et al., J.Hematol.Oncol.10:136 (2017)), BGB-A317 (Beigene; also known as tislelizumab; see WO 2015 / 35606 and US 2015 / 0079109), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210; see WO 2015 / 085847; Si-Yang Liu et al., J.Hematol.Oncol.10:136 (2017)), TSR-042 (Tesaro Biopharmaceutical; also known as ANB011; see WO2014 / 179664), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; also known as WBP3055; see Si-Yang Liu et al., J.Hematol.Oncol.10:136 (2017)), AM-0001 (Armo), STI- 1110 (Sorrento Therapeutics; see WO 2014 / 194302), AGEN2034 (Agenus; see WO 2017 / 040790), MGA012 (Macrogenics, see WO 2017 / 19846), BCD-100 (Biocad; Kaplon et al., mAbs 10(2):183 - 203 (2018), IBI308 (Innovent; see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825 and WO 2017 / 133540); and sasanlimumab (PF-06801591).

[0385] In one aspect, the anti-PD-1 antibody is nivolumab. Nivolumab is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interactions with PD-1 ligands (PD-L1 and PD-L2), thereby blocking Downregulation of anti-tumor T cell function (US Patent No. 8,008,449; Wang et al., 2014 Cancer ImmunolRes. 2(9):846-56). The heavy and light chain variable regions of nivolumab are shown in Table 1A (SEQ ID NOs: 2 and 3). In some aspects, an anti-PD-1 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2; and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 3 Amino acid sequence described. In some aspects, the antibody comprises a heavy chain complementarity determining region (CDR) 1, CDR2 and CDR3 sequence comprising the amino acid sequence of the heavy chain CDR1, CDR2 and CDR3 of SEQ ID NO:2. In some aspects, the antibody comprises a light chain CDR1, CDR2, and CDR3 sequence comprising the amino acid sequence of the light chain CDR1, CDR2, and CDR3 of SEQ ID NO:3. Table 1A: Anti-PD-1 antibody sequences Anti-PD-1 antibody heavy chain variable region QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV IWYDGSKRYY ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND DYWGQGTLVT VSS (SEQ ID NO: 2) Anti-PD-1 antibody light chain variable region EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ GTKVEIK (SEQ ID NO: 3)

[0386] In another aspect, the anti-PD-1 antibody is paclizumab. Pellizumab is a humanized monoclonal IgG4 (S228P) antibody against the human cell surface receptor PD-1 (planned death-1 or planned cell death-1). Pembrolizumab is described, eg, in US Patent Nos. 8,354,509 and 8,900,587.

[0387] In another aspect, the anti-PD-1 antibody is sasanlimab. Anti-PD-1 antibodies that can be used in the disclosed compositions and methods also include those that specifically bind to human PD-1 and cross-compete for binding with any of the anti-PD-1 antibodies disclosed herein (e.g., nivolumab) Isolated antibodies to human PD-1 (see eg US Pat. Nos. 8,008,449 and 8,779,105; WO 2013 / 173223). In some aspects, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein, eg, nivolumab. The ability of antibodies to cross-compete for binding to an antigen indicates that these monoclonal antibodies bind to the same epitope of the antigen and sterically block the binding of other cross-competing antibodies to that particular epitope. By virtue of the fact that these cross-competing antibodies bind to the same epitopic region of PD-1 as a reference antibody (eg, nivolumab), they are expected to have very similar functional properties. Cross-competing antibodies can be readily identified based on their ability to cross-compete with nivolumab in standard PD-1 binding assays, such as Biacore analysis, ELISA analysis or flow cytometry (see eg WO 2013 / 173223).

[0389] In certain aspects, the antibody that cross-competes for binding to human PD-1 with nivolumab or that binds to the same epitopic region of a human PD-1 antibody as nivolumab is a monoclonal antibody. For administration to human subjects, such cross-competing antibodies are chimeric antibodies, engineered antibodies or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0390] Anti-PD-1 antibodies useful in the compositions and methods of the invention also include antigen-binding portions of the above antibodies. It is well established that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies. Anti-PD-1 antibodies suitable for use in the disclosed methods or compositions are those that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and or PD-L2, and inhibit PD-1 signaling Antibodies for the immunosuppressive effect of the transduction pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 "antibody" includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits functional properties similar to those of full antibodies that inhibit ligand binding and upregulate the immune system . In certain aspects, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.

[0392] In some aspects, the anti-PD-1 antibody is between 0.1 mg / kg and 20.0 mg / kg body weight once every 2, 3, 4, 5, 6, 7 or 8 weeks, such as every 2, 3 or Doses ranging from 0.1 mg / kg to 10.0 mg / kg body weight were administered once every 4 weeks. In other aspects, the anti-PD-1 antibody is administered at about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg once every 2 weeks. kg, about 8 mg / kg, about 9 mg / kg, or 10 mg / kg body weight. In other aspects, the anti-PD-1 antibody is administered at about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg once every 3 weeks. kg, about 8 mg / kg, about 9 mg / kg, or 10 mg / kg body weight. In other aspects, the anti-PD-1 antibody is administered at a dose of about 5 mg / kg body weight about once every 3 weeks. In another aspect, an anti-PD-1 antibody, such as nivolumab, is administered at a dose of about 3 mg / kg body weight about once every 2 weeks. In other aspects, the anti-PD-1 antibody, such as pembrolizumab, is administered at a dose of about 2 mg / kg body weight about once every 3 weeks.

[0393] Anti-PD-1 antibodies suitable for use in the invention can be administered in a uniform dosage form. In some aspects, the anti-PD-1 antibody is present at about 100 to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg , about 100 mg to about 500 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about A uniform dose of 200 mg to about 500 mg, about 200 mg to about 480 mg, or about 240 mg to about 480 mg is administered. In one aspect, the anti-PD-1 antibody is dosed at least about 200 mg, at least about 220 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, at least about 520 mg, at least about 540 mg, at least about 550 mg, at least about 560 mg, at least about 580 mg, at least about 600 mg, A uniform dose of at least about 620 mg, at least about 640 mg, at least about 660 mg, at least about 680 mg, at least about 700 mg, or at least about 720 mg is administered. In another aspect, the anti-PD-1 antibody is dosed at about 1, 2, 3 or 4 week intervals at about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, administered in uniform doses of about 200 mg to about 500 mg.

[0394] In some aspects, the anti-PD-1 antibody is administered at a uniform dose of about 200 mg about once every 3 weeks. In other aspects, the anti-PD-1 antibody is administered at a uniform dose of about 200 mg about once every 2 weeks. In other aspects, the anti-PD-1 antibody is administered at a uniform dose of about 240 mg about once every 2 weeks. In certain aspects, the anti-PD-1 antibody is administered at a uniform dose of about 480 mg about once every 4 weeks.

[0395] In some aspects, nivolumab is administered at a uniform dose of about 240 mg about once every 2 weeks. In some aspects, nivolumab is administered at a uniform dose of about 240 mg about once every 3 weeks. In some aspects, nivolumab is administered at a uniform dose of about 360 mg about once every 3 weeks. In some aspects, nivolumab is administered at a uniform dose of about 480 mg about once every 4 weeks. In some aspects, nivolumab is administered at a uniform dose of about 720 mg about once every 6 weeks. In some aspects, nivolumab is administered at a uniform dose of about 960 mg about once every 8 weeks.

[0396] In some aspects, pembrolizumab is administered at a uniform dose of about 200 mg about once every 2 weeks. In some aspects, pembrolizumab is administered at a uniform dose of about 200 mg about once every 3 weeks. In some aspects, pembrolizumab is administered at a uniform dose of about 400 mg about once every 4 weeks.

[0397] In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL, at least about 10 mg / mL to at least about 400 mg / mL, at least about 10 mg / mL to at least about 300 mg / mL mL, at least about 10 mg / mL to at least about 250 mg / mL, at least about 10 mg / mL to at least about 200 mg / mL, at least about 10 mg / mL to at least about 190 mg / mL, at least about 10 mg / mL to at least about 180 mg / mL, at least about 10 mg / mL to at least about 170 mg / mL, at least about 10 mg / mL to at least about 160 mg / mL, at least about 10 mg / mL to at least about 150 mg / mL, At least about 20 mg / mL to at least about 500 mg / mL, at least about 20 mg / mL to at least about 400 mg / mL, at least about 20 mg / mL to at least about 300 mg / mL, at least about 20 mg / mL to at least About 250 mg / mL, at least about 20 mg / mL to at least about 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 135 mg / mL to at least about 180 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 130 mg / mL, or at least about 108 mg / mL to at least about 132 mg / mL mL of anti-PD-1 antibody (such as nivolumab or paclizumab). In some aspects, the pharmaceutical composition comprises at least about 50 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 60 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 70 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 75 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 80 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 108 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 110 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 120 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 130 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 132 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 135 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 140 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 150 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 160 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 170 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 175 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 180 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 190 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 200 mg / mL of an anti-PD-1 antibody (eg, nivolumab or pembrolizumab).

[0398] In some aspects, the pharmaceutical composition comprises a bispecific antibody or multispecific antibody comprising a first antigen binding portion and a second antigen binding portion, wherein the first antigen binding portion comprises an anti-PD-1 antigen binding portion (eg scFv of nivolumab). In some aspects, the second antigen binding portion is the antigen binding portion of any of the antibodies disclosed herein. In some aspects, the second antigen binding portion is the antigen binding portion of an anti-LAG-3 antibody, eg, rilamumab. In some aspects, the second antigen binding portion is the antigen binding portion of an anti-TIGIT antibody.

[0399] In some aspects, the pharmaceutical composition comprises a multispecific antibody comprising a first antigen binding portion, a second antigen binding portion and at least a third antigen binding portion, wherein the first antigen binding portion comprises an anti-PD-1 antigen Binding moieties (eg scFv of nivolumab). II.A.2. Anti-PD-L1 antibodies suitable for use in the present invention

[0400] In some aspects, a pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds PD-L1 ("anti-PD-L1 antibody"). In some aspects, an anti-PD-L1 antibody replaces an anti-PD-1 antibody in any of the compositions or methods disclosed herein. Any anti-PD-L1 antibody can be used in the compositions and methods of the invention. Examples of anti-PD-L1 antibodies suitable for use in the compositions and methods of the invention include the antibodies disclosed in US Patent No. 9,580,507. It has been demonstrated that the anti-PD-L1 human monoclonal antibody disclosed in U.S. Patent No. 9,580,507 exhibits one or more of the following characteristics: (a) binds to human PD-L1 with a KD of 1×10-7M or less, if used Biacore biosensor system as determined by surface plasmon resonance; (b) increased T cell proliferation in mixed lymphocyte reaction (MLR) assay; (c) increased interferon-γ production in MLR assay; (d ) increases IL-2 secretion in MLR assays; (e) stimulates antibody responses; (f) reverses the effect of T regulatory cells on T cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies useful in the present invention include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one, and in some aspects at least five, of the aforementioned characteristics.

[0401] In certain aspects, the anti-PD-L1 antibody is selected from the group consisting of: BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Patent No. 7,943,743 and WO 2013 / 173223), Atezolizumab (Roche; also known as TECENTRIQ®; MPDL3280A, RG7446; see US 8,217,149; see also Herbst et al. (2013) J Clin Oncol 31(suppl):3000), durvalumab (AstraZeneca; also known as IMFINZI™, MEDI-4736; see WO 2011 / 066389), avelumab (Pfizer; also known as BAVENCIO®, MSB-0010718C; see WO 2013 / 079174), STI-1014 (Sorrento; see WO2013 / 181634), CX-072 (Cytomx; see WO2016 / 149201), KN035 (3D Med / Alphamab; see Zhang et al., Cell Discov. 7:3 (March 2017), LY3300054 (Eli Lilly Co.; see eg WO 2017 / 034916), BGB-A333 (BeiGene; see Desai et al., JCO36 (15th Suppl):TPS3113 (2018)), and CK-301 (Checkpoint Therapeutics; see Gorelik et al., AACR: Abstract 4606 (April 2016 )).

[0402] In certain aspects, the PD-L1 antibody is atezolizumab (TECENTRIQ®). Atezolizumab is a fully human IgG1 monoclonal anti-PD-L1 antibody.

[0403] In certain aspects, the PD-L1 antibody is durvalumab (IMFINZI™). Durvalumab is a human IgG1κ monoclonal anti-PD-L1 antibody.

[0404] In certain aspects, the PD-L1 antibody is avelumab (BAVENCIO®). Avelumab is a human IgG1λ monoclonal anti-PD-L1 antibody. Anti-PD-L1 antibodies useful in the disclosed compositions and methods also include those that specifically bind to human PD-L1 and are compatible with any of the anti-PD-L1 antibodies disclosed herein (e.g., atezolizumab, Durvalumab and / or avelumab) cross-compete for isolated antibodies binding to human PD-L1. In some aspects, the anti-PD-L1 antibody binds to the same antibody as any of the anti-PD-L1 antibodies described herein, e.g., atezolizumab, durvalumab, and / or avelumab epitope. The ability of antibodies to cross-compete for antigen binding indicates that those antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to a particular epitope region. By virtue of the fact that these cross-competing antibodies bind to the same epitope region of PD-L1 as the reference antibody (eg atezolizumab and / or avelumab), they are expected to have very similar functional properties. Cross-competing antibodies can be readily identified based on their ability to cross-compete with atezolizumab and / or avelumab in standard PD-L1 binding assays, such as Biacore analysis, ELISA analysis, or flow cytometry ( See eg WO 2013 / 173223).

[0406] In certain aspects, atezolizumab, durvalumab, and / or avelumab cross-competes for binding to human PD-L1, or is the same as an antibody that binds to human PD-L1 Antibodies to epitope-determining regions are monoclonal antibodies. For administration to human subjects, such cross-competing antibodies are chimeric antibodies, engineered antibodies or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0407] Anti-PD-L1 antibodies useful in the compositions and methods of the invention also include antigen-binding portions of the above antibodies. It is well established that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies. Anti-PD-L1 antibodies suitable for use in the disclosed methods or compositions are immunosuppressive antibodies that bind to PD-L1 with high specificity and affinity, block PD-1 binding, and inhibit PD-1 signaling pathways Antibodies that act. In any of the compositions or methods disclosed herein, anti-PD-L1 "antibodies" include those that bind to PD-L1 and exhibit functional properties similar to those of full antibodies in terms of inhibiting receptor binding and upregulating the immune system. Antigen binding portion or fragment. In certain aspects, the anti-PD-L1 antibody, or antigen-binding portion thereof, cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0409] Anti-PD-L1 antibodies suitable for use in the present invention can be any PD-L1 antibody that specifically binds to PD-L1, for example cross-competes with durvalumab, avelumab or atezolizumab Antibodies that bind to human PD-1, such as antibodies that bind to the same epitope as durvalumab, avelumab, or atezolizumab. In certain aspects, the anti-PD-L1 antibody is durvalumab. In other aspects, the anti-PD-L1 antibody is avelumab. In some aspects, the anti-PD-L1 antibody is atezolizumab.

[0410] In some aspects, the anti-PD-L1 antibody is administered at a dose ranging from about 0.1 mg / kg to about 20.0 mg / kg body weight, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg , approximately every 2, 3, 4, 5, 6, 7, or 8 weeks.

[0411] In some aspects, the anti-PD-L1 antibody is administered at a dose of about 15 mg / kg body weight about once every 3 weeks. In other aspects, the anti-PD-L1 antibody is administered at a dose of about 10 mg / kg body weight about once every 2 weeks.

[0412] In other aspects, anti-PD-L1 antibodies suitable for use in the invention are in uniform doses. In some aspects, the anti-PD-L1 antibody is present at about 200 mg to about 1600 mg, about 200 mg to about 1500 mg, about 200 mg to about 1400 mg, about 200 mg to about 1300 mg, about 200 mg to about 1200 mg mg, about 200 mg to about 1100 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, A uniform dose of about 700 mg to about 1300 mg, about 800 mg to about 1200 mg, about 700 mg to about 900 mg, or about 1100 mg to about 1300 mg is administered. In some aspects, the anti-PD-L1 antibody is present in an amount of at least about 240 mg, at least about 300 mg, at least about 320 mg, at least about 400 mg, at least about 480 mg, at least about 500 mg, at least about 560 mg, at least about 600 mg mg, at least about 640 mg, at least about 700 mg, at least 720 mg, at least about 800 mg, at least about 840 mg, at least about 880 mg, at least about 900 mg, at least 960 mg, at least about 1000 mg, at least about 1040 mg, A uniform dose of at least about 1100 mg, at least about 1120 mg, at least about 1200 mg, at least about 1280 mg, at least about 1300 mg, at least about 1360 mg, or at least about 1400 mg given for about 1, 2, 3 or 4 weeks Dosing at intervals of time. In some aspects, the anti-PD-L1 antibody is administered at a uniform dose of about 1200 mg about once every 3 weeks. In other aspects, the anti-PD-L1 antibody is administered at a uniform dose of about 800 mg about once every 2 weeks. In other aspects, the anti-PD-L1 antibody is administered at a uniform dose of about 840 mg about once every 2 weeks.

[0413] In some aspects, atezolizumab is administered at a uniform dose of about 1200 mg about once every 3 weeks. In some aspects, atezolizumab is administered at a uniform dose of about 800 mg about once every 2 weeks. In some aspects, atezolizumab is administered at a uniform dose of about 840 mg about once every 2 weeks.

[0414] In some aspects, avelumab is administered at a uniform dose of about 800 mg about once every 2 weeks.

[0415] In some aspects, durvalumab is administered at a dose of about 10 mg / kg about once every 2 weeks. In some aspects, durvalumab is administered at a uniform dose of about 800 mg / kg about once every 2 weeks. In some aspects, durvalumab is administered at a uniform dose of about 1200 mg about once every 3 weeks.

[0416] In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL, at least about 10 mg / mL to at least about 400 mg / mL, at least about 10 mg / mL to at least about 300 mg / mL mL, at least about 10 mg / mL to at least about 250 mg / mL, at least about 10 mg / mL to at least about 200 mg / mL, at least about 10 mg / mL to at least about 190 mg / mL, at least about 10 mg / mL to at least about 180 mg / mL, at least about 10 mg / mL to at least about 170 mg / mL, at least about 10 mg / mL to at least about 160 mg / mL, at least about 10 mg / mL to at least about 150 mg / mL, At least about 20 mg / mL to at least about 500 mg / mL, at least about 20 mg / mL to at least about 400 mg / mL, at least about 20 mg / mL to at least about 300 mg / mL, at least about 20 mg / mL to at least About 250 mg / mL, at least about 20 mg / mL to at least about 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 135 mg / mL to at least about 180 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 130 mg / mL, or at least about 108 mg / mL to at least about 132 mg / mL mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 50 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 60 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 70 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 75 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 80 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 90 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 100 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 108 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 110 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 120 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 130 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 132 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 135 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 140 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 150 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 160 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 170 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 175 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 180 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 190 mg / mL anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 200 mg / mL anti-PD-L1 antibody.

[0417] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) PD-L1 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) PD-L1 and (ii) CD3. II.A.3. Anti-CTLA-4 antibodies

[0418] In some aspects, a pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds CTLA-4 ("anti-CTLA-4 antibody"). Any anti-CTLA-4 antibody known in the art may be used in the compositions and methods of the invention. The anti-CTLA-4 antibodies of the invention bind to human CTLA-4 so as to disrupt the interaction of CTLA-4 with the human B7 receptor. Because the interaction of CTLA-4 and B7 transduces signals that cause the inactivation of T cells bearing the CTLA-4 receptor, disruption of this interaction effectively induces, enhances or prolongs the activation of such T cells, thereby inducing , enhance or prolong the immune response.

[0419] Human monoclonal antibodies that specifically bind to CTLA-4 with high affinity have been disclosed in US Patent No. 6,984,720. Other anti-CTLA-4 monoclonal antibodies have been described, for example, in U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121 and in International Publication Nos. WO 2012 / 122444, WO 2007 / 113648, WO 2016 / 196237 and WO 2000 / 037504, each of which is incorporated herein by reference in its entirety. It has been demonstrated that the anti-CTLA-4 human monoclonal antibody disclosed in U.S. Patent No. 6,984,720 exhibits one or more of the following characteristics: (a) by at least about 107M-1, or about 109M-1, or about 1010M-1 Binding affinity reflected by an equilibrium association constant (Ka) of to 1011 M-1 or higher specifically binds to human CTLA-4, as determined by Biacore analysis; (b) at least about 103, about 104 or about 105 m-1s -1 kinetic association constant (ka); (c) kinetic dissociation constant (kd) of at least about 103, about 104 or about 105 m-1 s-1; and (d) inhibition of CTLA-4 and B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4 antibodies suitable for use in the present invention include monoclonal antibodies that specifically bind to human CTLA-4 and exhibit at least one, at least two, or at least three of the aforementioned characteristics.

[0420] In certain aspects, the CTLA-4 antibody is selected from the group consisting of Ipilimumab (also known as YERVOY®, MDX-010, 10D1; see U.S. Patent No. 6,984,720), MK-1308 ( Merck), AGEN-1884 (Agenus Inc.; see WO 2016 / 196237) and Tremezumab (AstraZeneca; also known as Teximab, CP-675,206; see WO 2000 / 037504 and Ribas, Update Cancer Ther. 2(3) : 133-39 (2007)). In certain aspects, the anti-CTLA-4 antibody is ipilimumab.

[0421] In certain aspects, the CTLA-4 antibody is ipilimumab for use in the compositions and methods disclosed herein. Ipilimumab is a fully human IgG1 monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligand, thereby stimulating T cell activation and improving overall survival (OS) in patients with advanced melanoma .

[0422] In certain aspects, the CTLA-4 antibody is tremelimumab. In certain aspects, the CTLA-4 antibody is MK-1308. In certain aspects, the CTLA-4 antibody is AGEN-1884.

[0423] In some aspects, the CTLA-4 antibody is afucosylated or hypofucosylated. In some aspects, CTLA-4 antibodies exhibit enhanced ADCC and / or ADCP activity. In some aspects, the CTLA-4 antibody is BMS-986218 as described in PCT / US18 / 19868. Anti-CTLA-4 antibodies that can be used in the disclosed compositions and methods also include those that specifically bind to human CTLA-4 and that are compatible with any anti-CTLA-4 antibodies disclosed herein (e.g., ipilimumab and / or trp Mezumab) cross-competes isolated antibody binding to human CTLA-4. In some aspects, an anti-CTLA-4 antibody binds to the same epitope as any of the anti-CTLA-4 antibodies described herein (eg, ipilimumab and / or tremelimumab). The ability of antibodies to cross-compete for antigen binding indicates that those antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to a particular epitope region. By virtue of the fact that these cross-competing antibodies bind to the same epitopic region of CTLA-4 as the reference antibody (eg ipilimumab and / or tremezumab), they are expected to have very similar functional properties. Cross-competing antibodies can be readily identified based on their ability to cross-compete with ipilimumab and / or tremelimumab in standard CTLA-4 binding assays, such as Biacore analysis, ELISA analysis, or flow cytometry (see, e.g., WO 2013 / 173223).

[0425] In certain aspects, antibodies that cross-compete for binding to human CTLA-4 with ipilimumab and / or tremelimumab, or that bind to the same epitopic region of a human CTLA-4 antibody, are monoclonal antibodies strain antibody. For administration to human subjects, such cross-competing antibodies are chimeric antibodies, engineered antibodies or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0426] Anti-CTLA-4 antibodies useful in the compositions and methods of the disclosed invention also include antigen-binding portions of the above antibodies. It is well established that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies.

[0427] In certain aspects, the pharmaceutical composition comprises: (a) anti-CTLA-4 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v Polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-CTLA-4 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0428] In some aspects, an anti-CTLA-4 antibody can be formulated together with an anti-PD-1 antibody in any of the formulations disclosed herein as a single formulation. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-CTLA-4 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-CTLA-4 antibody; and (h) about 2000 U / mL rHuPH20.

[0429] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-CTLA-4 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-CTLA-4 antibody; and (h) about 2000 U / mL rHuPH20. Anti-CTLA-4 antibodies suitable for use in the disclosed methods or compositions are those that bind to CTLA-4 with high specificity and affinity, block the activity of CTLA-4, and disrupt the interaction between CTLA-4 and the human B7 receptor interacting antibodies. In any of the compositions or methods disclosed herein, an anti-CTLA-4 "antibody" includes an antigen-binding portion or fragment that binds to CTLA-4 and is effective in inhibiting the interaction of CTLA-4 with the human B7 receptor and Upregulation in the immune system exhibits similar functional properties to those of whole antibodies. In certain aspects, the anti-CTLA-4 antibody, or antigen-binding portion thereof, cross-competes with ipilimumab and / or tremelimumab for binding to human CTLA-4.

[0431] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) CTLA-4 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) CTLA-4 and (ii) CD3. II.A.4. Anti-LAG-3 Antibodies

[0432] In some aspects, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds LAG-3 ("anti-LAG-3 antibody"), such as relatlimab. The anti-LAG-3 antibodies of the invention bind to human LAG-3. Any anti-LAG-3 antibody can be used in the pharmaceutical compositions and methods disclosed herein. Antibodies that bind to LAG-3 have been disclosed in International Publication No. WO / 2015 / 042246 and U.S. Publication Nos. 2014 / 0093511 and 2011 / 0150892, each of which is incorporated herein by reference in its entirety .

[0433] An exemplary LAG-3 antibody suitable for use in the invention is 25F7 (described in US Publication No. 2011 / 0150892). An additional exemplary LAG-3 antibody suitable for use in the present invention is BMS-986016 (rilamumab). In some aspects, anti-LAG-3 antibodies suitable for use in the invention cross-compete with 25F7 or BMS-986016. In some aspects, anti-LAG-3 antibodies suitable for use in the invention bind to the same epitope as 25F7 or BMS-986016. In some aspects, the anti-LAG-3 antibody comprises six CDRs of 25F7 or BMS-986016.

[0434] Other anti-LAG-3 antibodies recognized in the art that can be used in the methods and / or compositions of the present invention include IMP731 (H5L7BW) described in US 2011 / 007023; WO2016028672 and US Publication No. 2020 / MK-4280 (28G-10, favezelimab) described in No. 0055938; Burova E et al., J. Immunother. Cancer (2016); 4(Suppl 1):P195 and U.S. Patent No. 10,358,495 REGN3767 (fianlimab) described in; humanized BAP050 described in WO2017 / 019894; GSK2831781; IMP-701 described in US Patent No. 10,711,060 and US Publication No. 2020 / 0172617 ( aLAG3(0414); aLAG3(0416); Sym022; TSR-033; TSR-075; XmAb841 (formerly XmAb22841); MGD013 (tebotelimab) ; BI754111; FS118; P 13B02-30; AVA-017; AGEN1746; RO7247669; INCAGN02385; IBI-110; EMB-02; IBI-323; LBL-007; These and other anti-LAG-3 antibodies suitable for use in the claimed invention can be found, for example, in US 10,188,730, WO 2016 / 028672, WO 2017 / 106129, WO2017 / 062888, WO2009 / 044273, WO2018 / 069500 , WO2016 / 126858, WO2014 / 179664, WO2016 / 200782, WO2015 / 200119, WO2017 / 019846, WO2017 / 198741, WO2017 / 220555, WO2017 / 220569, WO2018 / 071500, WO20 17 / 015560, WO2017 / 025498, WO2017 / 087589, WO2017 / 087901, WO2018 / 083087, WO2017 / 149143, WO2017 / 219995, US2017 / 0260271, WO2017 / 086367, WO2017 / 086419, WO2018 / 034227, WO2018 / 185046, WO2018 / 185 043, WO2018 / 217940, WO19 / 011306, WO2018 / 208868 , WO2014 / 140180, WO2018 / 201096, WO2018 / 204374 and WO2019 / 018730. The contents of each of these references are incorporated by reference in their entirety.

[0435] Anti-LAG-3 antibodies useful in the methods and / or compositions of the invention also include those that specifically bind to human LAG-3 and are cross-linked with any of the anti-LAG-3 antibodies disclosed herein, e.g. Isolated antibodies that compete for binding to human LAG-3. In some aspects, an anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein, eg, rilamumab.

[0436] In some aspects, the antibody that cross-competes for binding to human LAG-3 or that binds to the same epitopic region as any anti-LAG-3 antibody disclosed herein (eg, rilamumab) is a monoclonal antibody. For administration to human subjects, such cross-competing antibodies are chimeric antibodies, engineered antibodies or humanized or human antibodies. Such chimeric, engineered, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0437] The ability of an antibody to cross-compete for binding to an antigen indicates that the antibody binds to the same epitope region of the antigen and sterically hinders the binding of other cross-competing antibodies to a particular epitope region. By virtue of the fact that these cross-competing antibodies bind to the same epitope region as a reference antibody (eg, rilamumab), they are expected to have very similar functional properties. Cross-competing antibodies can be readily identified based on their ability to compete with cross-competition in standard binding assays, such as Biacore analysis, ELISA analysis or flow cytometry (see eg WO 2013 / 173223).

[0438] Anti-LAG-3 antibodies useful in the methods and / or compositions of the invention also include antigen-binding portions of any of the above full-length antibodies. It is well established that the antigen-binding function of antibodies can be performed by fragments of full-length antibodies.

[0439] In some aspects, the anti-LAG-3 antibody is a full length antibody.

[0440] In some aspects, the anti-LAG-3 antibody is a monoclonal, human, humanized, chimeric or multispecific antibody. In some aspects, the multispecific antibody is a dual affinity retargeting antibody (DART), DVD-Ig, or bispecific antibody.

[0441] In some aspects, the anti-LAG-3 antibody is an F(ab')2 fragment, Fab' fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or a single chain binding polypeptide.

[0442] In some aspects, the anti-LAG-3 antibody is BMS-986016 (riselizumab), IMP731 (H5L7BW), MK4280 (28G-10, favizelimab), REGN3767 (furanlimumab), GSK2831781, humanized BAP050, IMP-701 (LAG525, elarimumab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (Teporizumab anti), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or comprising an antigen-binding portion thereof.

[0443] In some aspects, the anti-LAG-3 antibody is Rilamumab.

[0444] In some aspects, the anti-LAG-3 antibody is MGD013 (tepolizumab), which is a bispecific PD-1 x LAG-3 DART.

[0445] In some aspects, the anti-LAG-3 antibody is REGN3767 (furanlimumab).

[0446] In some aspects, the anti-LAG-3 antibody is LAG525 (eralimab).

[0447] In some aspects, the anti-LAG-3 antibody is MK4280 (favizelimab).

[0448] In certain aspects, the pharmaceutical composition comprises: (a) an anti-LAG-3 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v Polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) rilamumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate Ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-LAG-3 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) rilamumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0449] In some aspects, an anti-LAG-3 antibody (eg, rilamumab) can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-LAG-3 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) relamumab. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-LAG-3 antibody; and (h) about 2000 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) relimumab; and (h) about 2000 U / mL rHuPH20.

[0450] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-LAG-3 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) relimumab. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-LAG-3 antibody; and (h) about 2000 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) relimumab; and (h) about 2000 U / mL rHuPH20.

[0451] An exemplary LAG-3 antibody suitable for use in the invention is 25F7 (described in US Publication No. 2011 / 0150892). An additional exemplary LAG-3 antibody suitable for use in the present invention is BMS-986016. In one aspect, an anti-LAG-3 antibody suitable for use in the composition cross competes with 25F7 or BMS-986016. In another aspect, an anti-LAG-3 antibody suitable for use in the composition binds to the same epitope as 25F7 or BMS-986016. In other aspects, the anti-LAG-3 antibody comprises six CDRs of 25F7 or BMS-986016.

[0452] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) LAG-3 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) LAG-3 and (ii) CD3. II.A.5. Anti-CD137 antibodies

[0453] In some aspects, the second antibody comprises an anti-CD137 antibody. The anti-CD137 antibody specifically binds to and activates CD137-expressing immune cells, stimulating the immune response against tumor cells, especially the cytotoxic T cell response. Antibodies that bind to CD137 have been disclosed in U.S. Publication No. 2005 / 0095244 and U.S. Patent Nos. 7,288,638, 6,887,673, 7,214,493, 6,303,121, 6,569,997, 6,905,685, 6,355,476, 6,362 ,325 , Nos. 6,974,863 and 6,210,669.

[0454] In certain aspects, the pharmaceutical composition comprises: (a) an anti-CD137 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysaccharide Sorbitan ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-CD137 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0455] In some aspects, an anti-CD137 antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-CD137 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-CD137 antibody; and (h) about 2000 U / mL rHuPH20.

[0456] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-CD137 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-CD137 antibody; and (h) about 2000 U / mL rHuPH20.

[0457] In some aspects, the anti-CD137 antibody is urelumab (BMS-663513) (20H4.9-IgG4 [10C7 or BMS-663513]) described in US Patent No. 7,288,638. In some aspects, the anti-CD137 antibody is BMS-663031 (20H4.9-IgG1 ) described in US Patent No. 7,288,638. In some aspects, the anti-CD137 antibody is 4E9 or BMS-554271 described in US Patent No. 6,887,673. In some aspects, the anti-CD137 antibody is an antibody disclosed in US Patent Nos. 7,214,493; 6,303,121; 6,569,997; 6,905,685; or 6,355,476. In some aspects, the anti-CD137 antibody is 1D8 or BMS-469492; 3H3 or BMS-469497; or 3E1 described in US Patent No. 6,362,325. In some aspects, the anti-CD137 antibody is an antibody disclosed in issued US Patent No. 6,974,863 (such as 53A2). In some aspects, the anti-CD137 antibody is an antibody disclosed in issued US Patent No. 6,210,669 (such as 1D8, 3B8 or 3E1). In some aspects, the antibody is PF-05082566 (PF-2566) from Pfizer. In other aspects, anti-CD137 antibodies suitable for use in the invention cross-compete with the anti-CD137 antibodies disclosed herein. In some aspects, an anti-CD137 antibody binds to the same epitope as an anti-CD137 antibody disclosed herein. In other aspects, anti-CD137 antibodies suitable for use in the invention comprise the six CDRs of the anti-CD137 antibodies disclosed herein.

[0458] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) CD137 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) CD137 and (ii) CD3. II.A.6. Anti-KIR antibodies

[0459] In some aspects, the second antibody comprises an anti-KIR3 antibody. Antibodies that specifically bind to KIRs block the interaction between killer cell immunoglobulin-like receptors (KIRs) and their ligands on NK cells. Blocking these receptors promotes NK cell activation, which may destroy tumor cells. Examples of anti-KIR antibodies have been disclosed in International Publication Nos. WO / 2014 / 055648, WO 2005 / 003168, WO 2005 / 009465, WO 2006 / 072625, WO 2006 / 072626, WO 2007 / 042573, WO 2008 / 084106, WO 2010 / 065939, WO 2012 / 071411 and WO / 2012 / 160448.

[0460] In certain aspects, the pharmaceutical composition comprises: (a) an anti-KIR antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysaccharide Sorbitan ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-KIR antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0461] In some aspects, an anti-KIR antibody can be formulated together with an anti-PD-1 antibody in any of the formulations disclosed herein as a single formulation. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-KIR antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-KIR antibody; and (h) about 2000 U / mL rHuPH20.

[0462] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-KIR antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-KIR antibody; and (h) about 2000 U / mL rHuPH20.

[0463] One anti-KIR antibody suitable for use in the present invention is lisrelumab (also known as BMS-986015, IPH2102 or the S241P variant of 1-7F9), which was first described in International Publication No. WO 2008 / No. 084106. Another anti-KIR antibody suitable for use in the present invention is 1-7F9 (also known as IPH2101) described in International Publication No. WO 2006 / 003179. In one aspect, the anti-KIR antibody of the composition of the invention cross-competes with lisrelumab or I-7F9 for binding to KIR. In another aspect, the anti-KIR antibody binds to the same epitope as lisrelumab or I-7F9. In other aspects, the anti-KIR antibody comprises the six CDRs of lisrelumab or I-7F9.

[0464] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) a KIR and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) KIR and (ii) CD3. II.A.7. Anti-GITR antibodies

[0465] In some aspects, the second antibody comprises an anti-GITR antibody. Anti-GITR antibodies include any anti-GITR antibody that specifically binds to a human GITR target and activates glucocorticoid-induced tumor necrosis factor receptor (GITR). GITR is a member of the TNF receptor superfamily expressed on the surface of many types of immune cells including regulatory T cells, effector T cells, B cells, natural killer (NK) cells, and activated dendritic cells ("anti-GITR agonist antibody"). Specifically, GITR activation increases the proliferation and function of effector T cells, and abolishes the suppression induced by activated T regulatory cells. In addition, GITR stimulation promotes anti-tumor immunity by increasing the activity of other immune cells such as NK cells, antigen presenting cells and B cells. Examples of anti-GITR antibodies are disclosed in International Publication Nos. WO / 2015 / 031667, WO2015 / 184,099, WO2015 / 026,684, WO11 / 028683 and WO / 2006 / 105021, US Patent No. 7,812,135 and No. 8,388,967 and US Publication Nos. 2009 / 0136494, 2014 / 0220002, 2013 / 0183321 and 2014 / 0348841.

[0466] In certain aspects, the pharmaceutical composition comprises: (a) an anti-GITR antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysaccharide Sorbitan ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-GITR antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0467] In some aspects, an anti-GITR antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-GITR antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-GITR antibody; and (h) about 2000 U / mL rHuPH20.

[0468] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-GITR antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-GITR antibody; and (h) about 2000 U / mL rHuPH20.

[0469] In one aspect, an anti-GITR antibody suitable for use in the present invention is TRX518 (described, for example, in Schaer et al. Curr Opin Immunol. (2012) April; 24(2): 217-224 and WO / 2006 / 105021 ). In another aspect, the anti-GITR antibody is selected from MK4166, MK1248, and antibodies described in WO11 / 028683 and U.S. 8,709,424, and comprises, for example, a VH chain comprising SEQ ID NO: 104 and a VL chain comprising SEQ ID NO: 105 (wherein SEQ ID NO is from WO 11 / 028683 or U.S. 8,709,424). In certain aspects, the anti-GITR antibody is an anti-GITR antibody disclosed in WO2015 / 031667, for example comprising VH CDRs 1-3 comprising SEQ ID NO: 31, 71 and 63 of WO2015 / 031667 and comprising WO2015 / 031667 Antibodies to VL CDR 1-3 of SEQ ID NO: 5, 14 and 30. In certain aspects, the anti-GITR antibody is an anti-GITR antibody disclosed in WO2015 / 184099, such as antibody Hum231#1 or Hum231#2, or a CDR thereof, or a derivative thereof (such as pab1967, pab1975 or pab1979). In certain aspects, the anti-GITR antibody is an anti-GITR antibody disclosed in JP2008278814, WO09 / 009116, WO2013 / 039954, US20140072566, US20140072565, US20140065152, or WO2015 / 026684, or is INBRX-110 (INHIBRx ), LKZ-145 (Novartis) or MEDI-1873 (MedImmune). In certain aspects, the anti-GITR antibody is an anti-GITR antibody described in PCT / US2015 / 033991 (eg, an antibody comprising the variable region of 28F3, 18E10, or 19D3).

[0470] In certain embodiments, the anti-GITR antibody cross competes with an anti-GITR antibody described herein, eg, TRX518, MK4166, or an antibody comprising the VH domain and VL domain amino acid sequences described herein. In some aspects, an anti-GITR antibody binds to an epitope that binds to an anti-GITR antibody described herein (e.g., TRX518, MK4166, or an antibody comprising a VH domain and a VL domain amino acid sequence described herein). The epitopes are the same. In certain aspects, an anti-GITR antibody comprises the six CDRs of TRX518, MK4166, or the six CDRs of an antibody comprising the VH domain and VL domain amino acid sequences described herein.

[0471] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) GITR and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) GITR and (ii) CD3. II.A.8. Anti-TIM3 antibody

[0472] In some aspects, the second antibody comprises an anti-TIM3 antibody. In some aspects, the anti-TIM3 antibody comprises an anti-TIM3 antibody selected from those disclosed in International Publication Nos. WO2018013818, WO / 2015 / 117002 (e.g., MGB453, Novartis), WO / 2016 / 161270 No. (e.g. TSR-022, TESARO / Anaptysbio), No. 1 WO2011155607, WO2016 / 144803 (eg, STI-600, SORRENTO Therapeutics), WO2016 / 071448; WO1700 No. No.1700 55404, No. 1 WO17178493, No. 1 WO18036561, WO18039020 (eg Ly-3221367, Eli Lilly), WO2017205721, WO17079112; WO17079115; WO17079116, WO11159877, WO13006490, WO201 No. 6068802, No. WO2016068803, No. WO2016 / 111947, WO / 2017 / 031242.

[0473] In certain aspects, the pharmaceutical composition comprises: (a) an anti-TIM3 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysaccharide Sorbitan ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-TIM3 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0474] In some aspects, an anti-TIM3 antibody can be formulated together with an anti-PD-1 antibody in any of the formulations disclosed herein as a single formulation. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-TIM3 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-TIM3 antibody; and (h) about 2000 U / mL rHuPH20.

[0475] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-TIM3 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-TIM3 antibody; and (h) about 2000 U / mL rHuPH20.

[0476] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) TIM-3 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) TIM-3 and (ii) CD3. II.A.9. Anti-OX40 Antibodies

[0477] In some aspects, the second antibody comprises an anti-OX40 (also known as CD134, TNFRSF4, ACT35 and / or TXGP1L) antibody. In some aspects, the anti-OX40 antibody comprises BMS-986178 (Bristol-Myers Squibb Company) described in International Publication No. WO20160196228. In some aspects, the anti-OX40 antibody comprises an anti-OX40 antibody selected from the group consisting of those described in International Publication Nos. WO95012673, WO199942585, WO14148895, WO15153513, WO15153514, WO13038191, WO16057667, WO03106498, WO12027328, WO13028231, WO16200836, WO 17063162, WO17134292, WO 17096179, WO 17096281 and WO 17096182 no.

[0478] In certain aspects, the pharmaceutical composition comprises: (a) an anti-OX40 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysaccharide Sorbitan ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-OX40 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0479] In some aspects, an anti-OX40 antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-OX40 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-OX40 antibody; and (h) about 2000 U / mL rHuPH20.

[0480] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-OX40 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-OX40 antibody; and (h) about 2000 U / mL rHuPH20.

[0481] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) OX40 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) OX40 and (ii) CD3. II.A.10. Anti-NKG2A antibodies

[0482] In some aspects, the second antibody comprises an anti-NKG2A antibody. NKG2A is a member of the C-type lectin receptor family expressed on natural killer (NK) cells and a subset of T lymphocytes. Specifically, NKG2A is predominantly expressed on tumor-infiltrating innate immune effector NK cells as well as some CD8+ T cells. Its natural ligand, human leukocyte antigen E (HLA-E), is expressed on solid and hematological tumors. NKG2A is an inhibitory receptor that masks HLA-E.

[0483] In certain aspects, the pharmaceutical composition comprises: (a) an anti-NKG2A antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysaccharide Sorbitan ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-NKG2A antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0484] In some aspects, an anti-NKG2A antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-NKG2A antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-NKG2A antibody; and (h) about 2000 U / mL rHuPH20.

[0485] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-NKG2A antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-NKG2A antibody; and (h) about 2000 U / mL rHuPH20.

[0486] In some aspects, the anti-NKG2A antibody comprises BMS-986315, a human monoclonal antibody that blocks the interaction of NKG2A with its ligand HLA-E, thereby allowing activation of the anti-tumor immune response. In some aspects, an anti-NKG2A antibody comprises a checkpoint inhibitor that activates T cells, NK cells, and / or tumor infiltrating immune cells. In some aspects, the anti-NKG2A antibody comprises an anti-NKG2A antibody selected from, for example, those described in WO 2006 / 070286 (Innate Pharma S.A.; University of Genova); U.S. Patent No. 8,993,319 (Innate Pharma S.A.; University of Genova); Genova); WO 2007 / 042573 (Innate Pharma S / A; Novo Nordisk A / S; University of Genova); US Patent No. 9,447,185 (Innate Pharma S / A; Novo Nordisk A / S; University of Genova); WO 2008 / 009545 (Novo Nordisk A / S); US Patent Nos. 8,206,709; 8,901,283; 9,683,041 (Novo Nordisk A / S); WO 2009 / 092805 (Novo Nordisk A / S); 9,422,368 (Novo Nordisk A / S); WO 2016 / 134371 (Ohio State Innovation Foundation); WO 2016 / 032334 (Janssen); WO 2016 / 041947 (Innate); WO 2016 / 041945 (Academisch Ziekenhuis Leiden H.O.D.N .LUMC); WO 2016 / 041947 (Innate Pharma); and WO 2016 / 041945 (Innate Pharma).

[0487] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) NKG2A and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) NKG2A and (ii) CD3. II.A.11. Anti-ICOS antibodies

[0488] In some aspects, the second antibody comprises an anti-ICOS antibody. ICOS is an immune checkpoint protein that is a member of the CD28 superfamily. ICOS is a 55-60 kDa type I transmembrane protein that is expressed on T cells after T cell activation and co-stimulates T cell activation upon binding to its ligand ICOS-L (B7H2). ICOS is also known as inducible T cell co-stimulator, CVID1, AILIM, inducible co-stimulator, CD278, activation-inducible lymphocyte immune-mediating molecule, and CD278 antigen.

[0489] In certain aspects, the pharmaceutical composition comprises: (a) an anti-ICOS antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysaccharide Sorbitan ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-ICOS antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0490] In some aspects, an anti-ICOS antibody can be formulated together with an anti-PD-1 antibody in any of the formulations disclosed herein as a single formulation. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-ICOS antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-ICOS antibody; and (h) about 2000 U / mL rHuPH20.

[0491] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-ICOS antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-ICOS antibody; and (h) about 2000 U / mL rHuPH20.

[0492] In some aspects, the anti-ICOS antibody comprises BMS-986226, a humanized IgG monoclonal antibody that binds to and stimulates human ICOS. In some aspects, the anti-ICOS antibody comprises an anti-ICOS antibody selected from, for example, those described in WO 2016 / 154177 (Jounce Therapeutics, Inc.), WO 2008 / 137915 (MedImmune), WO 2012 / 131004 (INSERM , French National Institute of Health and Medical Research), EP3147297 (INSERM, French National Institute of Health and Medical Research), WO 2011 / 041613 (Memorial Sloan Kettering Cancer Center), EP 2482849 (Memorial Sloan Kettering Cancer Center), WO 1 999 / 15553 (Robert Koch Institute), U.S. Patent Nos. 7,259,247 and 7,722,872 (Robert Kotch Institute); WO 1998 / 038216 (Japan Tobacco Inc.), U.S. Patent Nos. 7,045,615, 7,112,655 and 8,389,690 (Jap an Tobacco Inc. .), US Patent Nos. 9,738,718 and 9,771,424 (GlaxoSmithKline) and WO 2017 / 220988 (Kymab Limited).

[0493] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) ICOS and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) ICOS and (ii) CD3. II.A.12. Anti-TIGIT antibodies

[0494] In some aspects, the second antibody comprises an anti-TIGIT antibody. In some aspects, the anti-TIGIT antibody comprises BMS-986207. In some aspects, the anti-TIGIT antibody comprises the clone 22G2, as described in WO 2016 / 106302. In some aspects, the anti-TIGIT antibody comprises MTIG7192A / RG6058 / RO7092284 or the clone 4.1D3, as described in WO 2017 / 053748. In some aspects, the anti-TIGIT antibody comprises an anti-TIGIT antibody selected from, for example, those described in WO 2016 / 106302 (Bristol-Myers Squibb Company) and WO 2017 / 053748 (Genentech).

[0495] In certain aspects, the pharmaceutical composition comprises: (a) an anti-TIGIT antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysaccharide Sorbitan ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-TIGIT antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0496] In some aspects, an anti-TIGIT antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-TIGIT antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-TIGIT antibody; and (h) about 2000 U / mL rHuPH20.

[0497] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-TIGIT antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-TIGIT antibody; and (h) about 2000 U / mL rHuPH20.

[0498] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) TIGIT and (ii) a second antigen. In some aspects, the antibody comprises a TIGIT bispecific antibody that specifically binds (i) TIGIT; and (ii) an inhibitory receptor expressed on T cells, NK cells, or both T cells and NK cells. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) TIGIT and (ii) CD3. II.A.13. Anti-IL-12 antibodies

[0499] In some aspects, the second antibody comprises an anti-IL-12 antibody. In certain aspects, the pharmaceutical composition comprises: (a) an anti-IL-12 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate alcohol ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-IL-12 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0500] In some aspects, an anti-IL-12 antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-IL-12 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-IL-12 antibody; and (h) about 2000 U / mL rHuPH20.

[0501] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-IL-12 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-IL-12 antibody; and (h) about 2000 U / mL rHuPH20.

[0502] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) IL-12 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) IL-12 and (ii) CD3. II.A.14. Anti-IL-13 antibodies

[0503] In some aspects, the second antibody comprises an anti-IL-13 antibody. In certain aspects, the pharmaceutical composition comprises: (a) an anti-IL-13 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate alcohol ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-IL-13 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0504] In some aspects, an anti-IL-13 antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-IL-13 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-IL-13 antibody; and (h) about 2000 U / mL rHuPH20.

[0505] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-IL-13 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-IL-13 antibody; and (h) about 2000 U / mL rHuPH20.

[0506] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) IL-13 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) IL-13 and (ii) CD3. II.A.15. Anti-IL-15 antibodies

[0507] In some aspects, the second antibody comprises an anti-IL-15 antibody. In certain aspects, the pharmaceutical composition comprises: (a) an anti-IL-15 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate alcohol ester 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-IL-15 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0508] In some aspects, an anti-IL-15 antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-IL-15 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-IL-15 antibody; and (h) about 2000 U / mL rHuPH20.

[0509] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-IL-15 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-IL-15 antibody; and (h) about 2000 U / mL rHuPH20.

[0510] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) IL-15 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) IL-15 and (ii) CD3. II.A.16. Anti-SIRPα antibodies

[0511] In some aspects, the second antibody comprises an anti-SIRPα antibody. In certain aspects, the pharmaceutical composition comprises: (a) an anti-SIRPα antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-SIRPα antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0512] In some aspects, an anti-SIRPα antibody can be formulated together with an anti-PD-1 antibody in any of the formulations disclosed herein as a single formulation. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-SIRPα antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-SIRPα antibody; and (h) about 2000 U / mL rHuPH20.

[0513] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-SIRPα antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-SIRPα antibody; and (h) about 2000 U / mL rHuPH20.

[0514] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) SIRPα and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) SIRPα and (ii) CD3. II.A.17. Anti-CD47 antibodies

[0515] In some aspects, the second antibody comprises an anti-CD47 antibody. In certain aspects, the pharmaceutical composition comprises: (a) an anti-CD47 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-CD47 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0516] In some aspects, an anti-CD47 antibody can be formulated together with an anti-PD-1 antibody as a single formulation in any of the formulations disclosed herein. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-CD47 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-CD47 antibody; and (h) about 2000 U / mL rHuPH20.

[0517] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-CD47 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-CD47 antibody; and (h) about 2000 U / mL rHuPH20.

[0518] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) CD47 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) CD47 and (ii) CD3. II.A.18. Anti-CCR8 antibodies

[0519] In some aspects, the second antibody comprises an anti-CCR8 antibody. In certain aspects, the pharmaceutical composition comprises: (a) an anti-CCR8 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-CCR8 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0520] In some aspects, an anti-CCR8 antibody can be formulated together with an anti-PD-1 antibody in any of the formulations disclosed herein as a single formulation. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-CCR8 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-CCR8 antibody; and (h) about 2000 U / mL rHuPH20.

[0521] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-CCR8 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-CCR8 antibody; and (h) about 2000 U / mL rHuPH20.

[0522] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) CCR8 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) CCR8 and (ii) CD3. II.A.19. Anti-MICA antibodies

[0523] In some aspects, the second antibody comprises an anti-MICA antibody. In certain aspects, the pharmaceutical composition comprises: (a) an anti-MICA antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-MICA antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0524] In some aspects, an anti-MICA antibody can be formulated together with an anti-PD-1 antibody in any of the formulations disclosed herein as a single formulation. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-MICA antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-MICA antibody; and (h) about 2000 U / mL rHuPH20.

[0525] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-MICA antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-MICA antibody; and (h) about 2000 U / mL rHuPH20.

[0526] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) MICA and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) MICA and (ii) CD3. II.A.20. Anti-ILT4 antibodies

[0527] In some aspects, the second antibody comprises an anti-ILT4 antibody. In certain aspects, the pharmaceutical composition comprises: (a) an anti-ILT4 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) an anti-ILT4 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0528] In some aspects, an anti-ILT4 antibody can be formulated together with an anti-PD-1 antibody in any of the formulations disclosed herein as a single formulation. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-ILT4 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-ILT4 antibody; and (h) about 2000 U / mL rHuPH20.

[0529] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) anti-ILT4 antibody. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; (g) anti-ILT4 antibody; and (h) about 2000 U / mL rHuPH20.

[0530] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) ILT4 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) ILT4 and (ii) CD3. II.B. Endoglycosidase hydrolases

[0531] In some aspects, the pharmaceutical composition comprises an endoglycosidase hydrolase. Any endoglycosidase hydrolytic enzyme can be used in the pharmaceutical compositions and methods disclosed herein. In some aspects, the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosaminidase beta (1-4) or (1-3) linkage. In some aspects, the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1.

[0532] In some aspects, the endoglycosidase hydrolytic enzyme comprises hyaluronidase. In some aspects, the endoglycosidase hydrolase comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants and any isoforms thereof. In some aspects, the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% of amino acids 36-490 of SEQ ID NO: 1 %, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity of amino acid sequences. In some aspects, the endoglycosidase hydrolase comprises the catalytic domain of rHuPH20 (UniProt identifier P38567-1). In some aspects, the endoglycosidase hydrolase comprises rHuPH20 mature peptide (amino acids 36-490 of SEQ ID NO: 1). Table 1B: Amino acid sequence of rHuPH20 Signal peptide: underlined; mature protein: bold; propeptide: italic.

[0533] In some aspects, the pharmaceutical composition comprises Halozyme Therapeutics' ENHANZE® drug delivery technology (see US Patent No. 7,767,429, which is incorporated herein by reference in its entirety). ENHANZE® uses a co-formulation of antibodies and recombinant human hyaluronidase (rHuPH20), which eliminates traditional limitations on the volume of biologics and drugs that can be delivered subcutaneously due to the extracellular matrix (see US Patent No. 7,767,429). In some aspects, the pharmaceutical composition of the present invention may further comprise recombinant human hyaluronidase, such as rHuPH20.

[0534] Recombinant human hyaluronidase PH20 (rHuPH20, Halozyme Therapeutics Inc.) is a glycosylated single-chain recombinant human polypeptide of 447 amino acids, which locally depolymerizes hyaluronic acid in the subcutaneous (SC) space at the injection site. Hyaluronic acid is a repeating polymer of N-acetylglucosamine and glucuronic acid, which contributes to the soluble gel-like component of the extracellular matrix of the skin. The depolymerization of hyaluronic acid by rHuPH20 instantly reduces the viscosity of the gel-like phase of the extracellular matrix and increases hydraulic conductivity, facilitating the dispersion and absorption of injected drugs (see rHuPH20 IB). Use of rHuPH20 enables the delivery of large volumes for rapid SC injection (e.g., approximately 2 mL to 20 mL), which can shorten dose administration time, reduce dosing frequency, and allow for the potential to improve the PK profile of co-administered drugs, including improved absorption, Increased bioavailability, accelerated time to maximum concentration (Tmax), increased maximum concentration (Cmax), and reduced PK variability.

[0535] The half-life of rHuPH20 in the skin is <30 minutes, and the local permeability barrier in these tissues returns to the pre-injection level within 24 hours to 48 hours after hyaluronidase injection. The study showed that rHuPH20 was not detectable systemically in healthy volunteers and patients following SC administration at doses of 10,000 U and 30,000 U. Another PK study of rHuPH20 (Halozyme Study HALO-104-104) showed that for an IV dose of 10,000 or 30,000 units of rHuPH20, the plasma concentration of rHuPH20 decreased rapidly, with a very short t1 / 2 (≤10.4 minutes), and the plasma concentration was between Becomes undetectable (<0.03 ng / mL) within 1.5 hours after the end of the IV infusion.

[0536] Subcutaneous rHuPH20 is generally good in healthy participants, dehydrated pediatric participants, hospice and palliative care participants, participants with type 1 and type 2 diabetes, and participants with rheumatoid arthritis tolerated. rHuPH20 administered subcutaneously alone or co-administered with lactated Ringer's solution, saline, co-injected drugs (morphine base, ceftriaxone, insulin and insulin analogs) or biologics (immunoglobulin protein G [IgG] and adalimumab).

[0537] In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase relative to wild-type hyaluronic acid selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1 or fragments thereof Enzymes contain one or more amino acid substitutions. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof at alpha - Containing one or more amino acid substitutions in the helical region. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase linked to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1 or fragments thereof. Subregions contain one or more amino acid substitutions. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase wherein, relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof, one or more N-terminal and / or C-terminal amino acids are deleted.

[0538] In some aspects, the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20 is comprised in an α-helical region, a linker region, or an α-helical region and linker region relative to wild-type rHuPH20. One or more amino acid substitutions in both subregions. In some aspects, the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20 comprises one or more N-terminal amino acids, one or more C-terminal amino acids relative to wild-type rHuPH20 Or deletion of one or more N-terminal amino acids and one or more C-terminal amino acids. In some aspects, the endoglycosidase hydrolase comprises modified rHuPH20, wherein relative to wild-type rHuPH20, the modified rHuPH20 comprises an α-helical region, a linker region, or both an α-helical region and a linker region. One or more amino acid substitutions; and wherein relative to wild-type rHuPH20, the modified rHuPH20 comprises one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more Deletion of N-terminal amino acid and one or more C-terminal amino acids.

[0539] Additional non-limiting examples of endoglycosidase hydrolases are found in EP3636752, which is incorporated herein by reference in its entirety.

[0540] In some aspects, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in the following: U.S. Patent No. US 9,447,401; No. US 10,865,400; No. US 11,041,149 US 11,066,656; US 8,927,249; US 9,284,543; US 10,588,983; US 10 / 328,130; and / or US 9,993,529, each of which is incorporated herein by reference in its entirety. In some aspects, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in: International Publication Nos. WO / 13 / 102144, WO / 10 / 077297 , WO / 15 / 003167, WO / 04 / 078140, WO / 09 / 128917, WO / 12 / 174478 and / or WO / 12 / 174480, each of which is incorporated by reference in its entirety incorporated into this article. In some aspects, the endoglycosidase hydrolase comprises at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical amino acid sequences. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence selected from the amino acid sequences shown in SEQ ID NO: 5-52 and 264.

[0541] In some aspects, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in: U.S. Patent Application Publication No. US2021155913A1 and / or No. US2021363270A1; and / or International Publication Nos. WO / 20 / 022791, WO / 20 / 197230 and / or WO / 21 / 150079; each of which is incorporated herein by reference in its entirety. In some aspects, the endoglycosidase hydrolase comprises at least about 70%, at least about 75%, at least about 80% of the amino acid sequence selected from the amino acid sequence shown in SEQ ID NO: 53-263 , at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical amino acid sequences. In some aspects, the endoglycosidase hydrolase comprises at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90% of the amino acid sequence shown in SEQ ID NO: 92 %, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical amino acid sequences. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence selected from the amino acid sequences shown in SEQ ID NO: 53-263. In some aspects, the endoglycosidase hydrolase comprises the amino acid sequence shown in SEQ ID NO:92. In some aspects, the endoglycosidase hydrolase is HP46 (SEQ ID NO: 44 of International Publication No. WO / 20 / 197230).

[0542] In certain aspects, a pharmaceutical composition disclosed herein comprises hyaluronidase. In some aspects, the pharmaceutical composition comprises a concentration of hyaluronidase sufficient to administer at least about 20,000 units of hyaluronidase. In some aspects, the pharmaceutical composition comprises a concentration of hyaluronidase sufficient to administer at least about 50,000 units of hyaluronidase. In some aspects, the pharmaceutical composition comprises a concentration of hyaluronidase sufficient to administer at least about 75,000 units of hyaluronidase. In some aspects, the pharmaceutical composition comprises a concentration of hyaluronidase sufficient to administer at least about 100,000 units of hyaluronidase. In some aspects, the hyaluronidase is rHuPH20. In other aspects, the pharmaceutical composition does not include hyaluronidase.

[0543] In some aspects, the pharmaceutical composition comprises at least about 50 units to at least about 48,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 50 U / mL to at least about 5000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 50 U / mL, at least about 100 U / mL, at least about 150 U / mL, at least about 200 U / mL, at least about 250 U / mL, at least about 300 U / mL mL, at least about 350 U / mL, at least about 400 U / mL, at least about 450 U / mL, at least about 500 U / mL, at least about 750 U / mL, at least about 1000 U / mL, at least about 1500 U / mL , at least about 2000 U / mL, at least about 2500 U / mL, at least about 3000 U / mL, at least about 3500 U / mL, at least about 4000 U / mL, at least about 4500 U / mL, at least about 5000 U / mL, At least about 5500 U / mL, at least about 6000 U / mL, at least about 6500 U / mL, at least about 7000 U / mL, at least about 7500 U / mL, at least about 8000 U / mL, at least about 8500 U / mL, at least About 9000 U / mL, at least about 9500 U / mL, at least about 10,000 U / mL endoglycosidase hydrolase (eg rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 500 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 1000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 2000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 2500 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 3000 U / mL endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 3500 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 4000 U / mL endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 4500 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 5000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 6000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 7000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 8000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 9000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 10,000 U / mL endoglycosidase hydrolase (eg, rHuPH20).

[0544] In some aspects, the pharmaceutical composition comprises at least about 50 units to at least about 100,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 500 units to at least about 100,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 50 units, at least about 100 units, at least about 150 units, at least about 200 units, at least about 250 units, at least about 300 units, at least about 400 units, at least about 500 units, at least about 600 units, at least about 700 units, at least about 800 units, at least about 900 units, at least about 1000 units, at least about 1500 units, at least about 2000 units, at least about 2500 units, at least about 3000 units, at least about 4000 units, at least about 5000 units, at least about 10,000 units, at least about 15,000 units, at least about 20,000 units, at least about 25,000 units, at least about 30,000 units, at least about 35,000 units, at least about 40,000 units, at least about 45,000 units, at least about 48,000 units, or At least about 100,000 units of an endoglycosidase hydrolase (eg rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 20,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 30,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 40,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 50,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 60,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 70,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 80,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 90,000 units of an endoglycosidase hydrolase (eg, rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 100,000 units of an endoglycosidase hydrolase (eg, rHuPH20). It will be obvious to those skilled in the art that the amount of endoglycosidase hydrolytic enzyme (for example, rHuPH20) can be expressed in units or U / mL, or the amount of endoglycosidase hydrolytic enzyme (for example, HuPH20) can be expressed in mg / mL Expressed in mL (or other weight-based units). For example, in some aspects, the pharmaceutical composition comprises an endoglycosidase hydrolase (eg, rHuPH20) in an amount expressed as at least about 500 U / mL or at least about 0.00455 mg / mL. In another example, in some aspects, the pharmaceutical composition comprises an endoglycosidase hydrolase (eg, rHuPH20) in an amount expressed as at least about 2000 U / mL or at least about 0.0182 mg / mL.

[0546] In certain aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, such as nivolumab or pembrolizumab); (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM formazan Thiamine, and (g) about 2000 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody such as nivolumab or pembrolizumab); (b) About 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine , and (g) about 0.0182 mg / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) about 0.0182 mg / mL rHuPH20.

[0547] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, such as nivolumab or pembrolizumab); (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM formazan Thiamine, and (g) about 2000 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, such as nivolumab or pembrolizumab); (b) About 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine , and (g) about 0.0182 mg / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) about 0.0182 mg / mL rHuPH20.

[0548] In certain aspects, a unit dose described herein comprises: (a) about 120 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, such as nivolumab or pablizumab (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) approximately 2000 U / mL rHuPH20. In certain aspects, a unit dose described herein comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20. In certain aspects, a unit dose described herein comprises: (a) about 120 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, such as nivolumab or pembrolizumab); (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM formazan Thiamine, and (g) approximately 0.0182 mg / mL rHuPH20. In certain aspects, a unit dose described herein comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) about 0.0182 mg / mL rHuPH20.

[0549] In certain aspects, a unit dose described herein comprises: (a) about 150 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, such as nivolumab or pablizumab (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) approximately 2000 U / mL rHuPH20. In certain aspects, a unit dose described herein comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20. In certain aspects, a unit dose described herein comprises: (a) about 150 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, such as nivolumab or pembrolizumab); (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM formazan Thiamine, and (g) approximately 0.0182 mg / mL rHuPH20. In certain aspects, a unit dose described herein comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine, and (g) about 0.0182 mg / mL rHuPH20.

[0550] In certain aspects, the pharmaceutical composition comprises (a) about 672 mg nivolumab; (b) about 8.68 mg histidine; (c) about 11.8 mg histidine HCl H2O; (d) about 479 mg sucrose; (e) about 2.80 mg polysorbate 80; (f) about 0.110 mg pentetic acid; (g) about 4.18 mg methionine; (h) about 0.102 mg rHuPH20; -(h) Reconstitute in water to a final volume of at least about 5.6 mL. II.C. Antioxidants

[0551] In some aspects, the pharmaceutical composition further comprises an antioxidant. Any antioxidant can be used in the pharmaceutical compositions disclosed herein. In some aspects, the antioxidant is selected from the group consisting of methionine, tryptophan and histidine, cysteine, ascorbic acid, glycine, pentetic acid (DTPA), and EDTA. In some aspects, the pharmaceutical composition includes at least two antioxidants. In some aspects, at least one of the at least two antioxidants is a sacrificial antioxidant. Any sacrificial antioxidant can be used in the pharmaceutical compositions and methods disclosed herein. In some aspects, the sacrificial antioxidant is selected from the group consisting of methionine, tryptophan and histidine, cysteine, ascorbic acid, glycine or other sacrificial agents. In some aspects, at least one of the at least two antioxidants comprises a metal ion chelator. Any metal ion chelator can be used in the pharmaceutical compositions and methods disclosed herein. In some aspects, the metal ion chelator is pentetic acid ("DTPA") or EDTA.

[0552] In certain aspects, the pharmaceutical composition comprises methionine. In some aspects, the pharmaceutical composition includes at least two antioxidants. In some aspects, at least two antioxidants are selected from methionine, DTPA, and EDTA. In some aspects, the at least two antioxidants comprise methionine and EDTA. In some aspects, the at least two antioxidants comprise methionine and pentetic acid (DTPA).

[0553] In some aspects, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, such as nivolumab or pembrolizumab), methionine, and pentetic acid (DTPA ). In some aspects, the pharmaceutical composition comprises at least about 0.1 mM to at least about 100 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 1 mM to at least about 20 mM, at least about 1 mM to at least about 15 mM, at least about 1 mM to at least about 10 mM, at least about 1 mM to at least about 5 mM, at least about 5 mM to at least about 20 mM, at least about 5 mM to at least about 15 mM, at least about 5 mM to at least about 10 mM, at least about 2 mM to at least about 9 mM, at least about 3 mM to at least about 8 mM, At least about 4 mM to at least about 7 mM, or at least about 4 mM to at least about 6 mM, at least about 4 mM to at least about 5 mM, at least about 5 mM to at least about 6 mM, at least about 5 mM to at least about 7 mM Methionine. In some aspects, the pharmaceutical composition comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or At least about 20 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 10 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 9 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 8 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 7 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 6 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 4 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 3 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 2 mM methionine. In certain aspects, the pharmaceutical composition comprises at least about 1 mM methionine.

[0554] In some aspects, the pharmaceutical composition comprises at least about 1 µM to at least about 250 µM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 10 µM to at least about 200 µM, at least about 10 µM to at least about 175 µM, at least about 10 µM to at least about 150 µM, at least about 10 µM to at least about 125 µM, at least about 10 µM to at least about 100 µM, at least about 10 µM to at least about 75 µM, at least about 10 µM to at least about 70 µM, at least about 10 µM to at least about 60 µM, at least about 10 µM to at least about 50 µM, at least about 20 µM to at least about 100 µM, at least about 20 µM to at least about 75 µM, at least about 20 µM to at least about 70 µM, at least about 20 µM to at least about 60 µM, at least about 20 µM to at least about 50 µM, at least about 25 µM to at least about 100 µM, at least about 25 µM to at least about 75 µM, at least about 25 µM to at least about 50 µM, at least about 30 µM to at least about 100 µM, at least about 30 µM to at least about 75 µM, at least about 30 µM to at least about 70 µM, at least about 30 µM to at least about 30 µM, at least about 30 µM to at least about 50 µM, at least about 40 µM to at least about 100 µM, at least about 40 µM to at least about 75 µM, at least about 40 µM to at least about 70 µM, at least about 40 µM to at least about 60 µM, at least about 40 µM to at least about 50 µM, at least about 50 µM to at least about 100 µM, at least about 50 µM to at least about 75 µM, At least about 50 µM to at least about 70 µM or at least about 50 µM to at least about 60 µM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 1 µM, at least about 5 µM, at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least about 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, at least about 80 µM, at least about 85 µM, At least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, at least about 160 µM, at least about 170 µM, At least about 180 µM, at least about 190 µM, or at least about 200 µM DTPA. In certain aspects, the pharmaceutical composition comprises at least about 75 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 70 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 65 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 60 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 55 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 50 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 45 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 40 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 35 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 30 µM pentetic acid (DTPA). In certain aspects, the pharmaceutical composition comprises at least about 25 µM pentetic acid (DTPA). II.D. Tonicity modifier / stabilizer

[0555] In some aspects, the pharmaceutical composition further comprises a tonicity adjusting agent and / or a stabilizing agent. Any tonicity adjusting agent and / or any stabilizing agent can be used in the pharmaceutical compositions disclosed herein. In some aspects, tonicity modifiers and / or stabilizers comprise sugars, amino acids, polyols, salts, or any combination thereof. In some aspects, the tonicity modifier and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerin, glycine, leucine, isoleucine, chlorine Sodium chloride, proline, arginine, polyols, amino acids and salts.

[0556] In certain aspects, the pharmaceutical composition comprises sucrose. In some aspects, the pharmaceutical composition comprises at least about 1 mM to at least about 500 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM, at least about 10 mM to at least about 400 mM, at least about 50 mM to at least about 400 mM, at least about 100 mM to at least about 400 mM, at least about 150 mM to at least about 400 mM, at least about 200 mM to at least about 400 mM, at least about 250 mM to at least about 400 mM, at least about 300 mM to at least about 400 mM, at least about 350 mM to at least about 400 mM, at least about 50 mM to at least about 350 mM, at least about 100 mM to at least about 300 mM, at least about 100 mM to at least about 250 mM, at least about 100 mM to at least about 200 mM, at least about 100 mM to at least about 150 mM, At least about 200 mM to at least about 400 mM, at least about 200 mM to at least about 300 mM sucrose, or at least about 200 mM to at least about 250 mM. In some aspects, the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, At least about 490 mM or at least about 500 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 200 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 210 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 220 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 230 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 240 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 250 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 260 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 270 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 280 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 290 mM sucrose. In certain aspects, the pharmaceutical composition comprises at least about 300 mM sucrose. II.E. Buffer

[0557] In some aspects, the pharmaceutical composition further comprises a buffering agent. In some aspects, the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate. In certain aspects, the pharmaceutical composition comprises histidine. In certain aspects, the pharmaceutical composition comprises citrate. In some aspects, the pharmaceutical composition comprises at least about 1 mM to at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM, at least about 10 mM to at least about 100 mM, at least about 15 mM to at least about 100 mM, at least about 20 mM to at least about 100 mM, at least about 25 mM to at least about 100 mM, at least about 30 mM to at least about 100 mM, at least about 35 mM to at least about 100 mM, at least about 40 mM to at least about 100 mM, at least about 45 mM to at least about 100 mM, at least about 50 mM to at least about 100 mM, at least about 10 mM to at least about 75 mM, at least about 10 mM to at least about 50 mM, at least about 10 mM to at least about 40 mM, at least about 10 mM to at least about 30 mM, At least about 15 mM to at least about 30 mM, at least about 10 mM to at least about 25 mM, or at least about 15 mM to at least about 25 mM histidine.

[0558] In some aspects, the pharmaceutical composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 10 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 15 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 20 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 25 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 30 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 35 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 40 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 45 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 50 mM histidine.

[0559] In some aspects, the pharmaceutical composition comprises a pH of about 5.2 to about 6.8. In some aspects, the pH of the pharmaceutical composition is about 5.2. In some aspects, the pH of the pharmaceutical composition is about 5.3. In some aspects, the pH of the pharmaceutical composition is about 5.4. In some aspects, the pH of the pharmaceutical composition is about 5.5. In some aspects, the pH of the pharmaceutical composition is about 5.6. In some aspects, the pH of the pharmaceutical composition is about 5.7. In some aspects, the pH of the pharmaceutical composition is about 5.8. In some aspects, the pH of the pharmaceutical composition is about 5.9. In some aspects, the pH of the pharmaceutical composition is about 6.0. In some aspects, the pH of the pharmaceutical composition is about 6.1. In some aspects, the pH of the pharmaceutical composition is about 6.2. In some aspects, the pH of the pharmaceutical composition is about 6.3. In some aspects, the pH of the pharmaceutical composition is about 6.4. In some aspects, the pH of the pharmaceutical composition is about 6.5. In some aspects, the pH of the pharmaceutical composition is about 6.6. In some aspects, the pH of the pharmaceutical composition is about 6.7. In some aspects, the pH of the pharmaceutical composition is about 6.8. II.F. Surfactants

[0560] In some aspects, the pharmaceutical composition further comprises a surfactant. Any surfactant can be used in the pharmaceutical compositions disclosed herein. In some aspects, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In certain aspects, a pharmaceutical composition comprises polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.001% to at least about 1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% to at least about 0.1%, at least about 0.02% to at least about 0.1%, at least about 0.03% to at least about 0.1%, at least about 0.04% to at least about 0.1%, at least about 0.05% to at least about 0.1%, at least about 0.01% to at least about 0.09%, at least about 0.01% to at least about 0.8%, at least about 0.01% to at least about 0.7%, at least about 0.01% to at least about 0.6%, At least about 0.01% to at least about 0.5%, at least about 0.02% to at least about 0.09%, at least about 0.03% to at least about 0.08%, at least about 0.04% to at least about 0.07%, or at least about 0.04% to at least about 0.06% w / v Polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% to at least about 0.1% w / v polysorbate 80.

[0561] In some aspects, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v polysorbate 80. In certain aspects, the pharmaceutical composition comprises at least about 0.03% w / v polysorbate 80. In certain aspects, the pharmaceutical composition comprises at least about 0.04% w / v polysorbate 80. In certain aspects, the pharmaceutical composition comprises at least about 0.05% w / v polysorbate 80. In certain aspects, the pharmaceutical composition comprises at least about 0.06% w / v polysorbate 80. In certain aspects, the pharmaceutical composition comprises at least about 0.07% w / v polysorbate 80.

[0562] In certain aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL of an antibody (e.g., an anti-PD1 antibody, such as nivolumab or pembrolizumab); (b) about 20 mM of an antibody (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine.

[0563] In some aspects, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody, such as nivolumab; (b) a checkpoint inhibitor, such as an anti-CTLA-4 antibody; (c) about 20 mM Histidine; (d) about 250 mM sucrose; (e) about 0.05% w / v polysorbate 80; (f) about 50 µM pentetic acid; and (g) about 5 mM methionine. In some aspects, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody, such as nivolumab; (b) a checkpoint inhibitor, such as an anti-CTLA-4 antibody; (c) about 20 mM histidine (d) about 250 mM sucrose; (e) about 0.05% w / v polysorbate 80; (f) about 50 µM pentetic acid; (g) about 5 mM methionine; and (h) about 2000 U / mL rHuPH20.

[0564] In some aspects, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody, such as nivolumab; (b) a checkpoint inhibitor, such as an anti-LAG-3 antibody; (c) about 20 mM Histidine; (d) about 250 mM sucrose; (e) about 0.05% w / v polysorbate 80; (f) about 50 µM pentetic acid; and (g) about 5 mM methionine. In some aspects, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody, such as nivolumab; (b) a checkpoint inhibitor, such as an anti-LAG-3 antibody; (c) about 20 mM histidine (d) about 250 mM sucrose; (e) about 0.05% w / v polysorbate 80; (f) about 50 µM pentetic acid; (g) about 5 mM methionine; and (h) about 2000 U / mL rHuPH20.

[0565] In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0566] In certain aspects, a unit dose described herein comprises: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, a unit dose described herein comprises: (a) about 120 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) About 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In certain aspects, a unit dose described herein comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, a unit dose described herein comprises: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0567] In certain aspects, a unit dose described herein comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; and (f) about 5 mM methionine. In certain aspects, a unit dose described herein comprises: (a) about 150 mg / mL anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) About 0.05% w / v polysorbate 80; (e) about 50 µM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In certain aspects, a unit dose described herein comprises: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine;...

Claims

1. A pharmaceutical composition comprising (i) an antibody that specifically binds to PD-1 ("anti-PD-1 antibody"), (ii) an endoglucosidase hydrolase, and (iii) at least two antioxidants.

2. The pharmaceutical composition of claim 1, wherein at least one of the two antioxidants is a sacrificial antioxidant selected from the group consisting of: methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine or other sacrificial agents.

3. The pharmaceutical composition of claim 1 or 2, wherein at least one of the at least two antioxidants comprises a metal ion chelating agent.

4. The pharmaceutical composition of claim 3, wherein the metal ion chelating agent is selected from pentetic acid ("DTPA") and EDTA.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the at least two antioxidants are selected from the group consisting of methionine, DTPA and EDTA.

6. A pharmaceutical composition of any one of claims 1 to 5, wherein the at least two antioxidants are (i) methionine and DTPA or (ii) methionine and EDTA.

7. The pharmaceutical composition of any one of claims 1 to 6, wherein the at least one antioxidant comprises at least about 1 to about 20 mM methionine.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the at least one antioxidant comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine.

9. The pharmaceutical composition of any one of claims 1 to 8, wherein the at least one antioxidant comprises about 5 mM methionine.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein the at least one antioxidant comprises at least about 10 µM to about 200 µM DTPA.

11. A pharmaceutical composition of any one of claims 1 to 10, wherein the at least one antioxidant comprises at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least about 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, at least about 80 µM, at least about 85 µM, at least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, at least about 160 µM, at least about 170 µM, at least about 180 µM, at least about 190 µM, or at least about 200 µM DTPA.

12. The pharmaceutical composition of any one of claims 1 to 11, wherein the at least one antioxidant comprises about 50 µM DTPA.

13. The pharmaceutical composition of any one of claims 1 to 12, comprising at least about 20 mg / mL to at least about 200 mg / mL of the anti-PD-1 antibody.

14. The pharmaceutical composition of any one of claims 1 to 13, comprising at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL of the anti-PD-1 antibody.

15. The pharmaceutical composition of any one of claims 1 to 14, comprising about 120 mg / mL or about 150 mg / mL of the anti-PD-1 antibody.

16. The pharmaceutical composition of any one of claims 1 to 15, comprising at least about 5 U to at least about 100,000 U of the endoglycosidase hydrolase.

17. A pharmaceutical composition as claimed in any of claims 1 to 16, comprising at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, ​​at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U. U, at least about 80,000 U, at least about 90,000 U, or at least about 100,000 U of this endoglycosidase hydrolase.

18. The pharmaceutical composition of any one of claims 1 to 17, comprising about 20,000 U of the endoglycosidase hydrolase.

19. The pharmaceutical composition of any one of claims 1 to 18, comprising at least about 500 U / mL to at least about 5000 U / mL of the endoglycosidase hydrolase.

20. The pharmaceutical composition of any one of claims 1 to 19, comprising at least about 1500 U / mL, at least about 1600 U / mL, at least about 1700 U / mL, at least about 1800 U / mL, at least about 1900 U / mL, at least about 2000 U / mL, at least about 2100 U / mL, at least about 2200 U / mL, at least about 2300 U / mL, at least about 2400 µM, at least about 2500 µM, at least about 3000 µM, at least about 3500 µM, at least about 4000 µM, at least about 4500 U / mL, or at least about 5000 U / mL of the endoglycosidase hydrolase.

21. The pharmaceutical composition of any one of claims 1 to 20, comprising about 2000 U / mL of the endoglycosidase hydrolase.

22. The pharmaceutical composition of any one of claims 1 to 21, wherein the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosamine β (1-4) or (1-3) bond.

23. The pharmaceutical composition of any one of claims 1 to 22, wherein the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4 or HYALPS1.

24. The pharmaceutical composition of any one of claims 1 to 23, wherein the endoglycosidase hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with amino acids 36-490 of SEQ ID NO:

1.

25. The pharmaceutical composition of any one of claims 1 to 24, wherein the endoglycosidase hydrolase comprises hyaluronidase.

26. The pharmaceutical composition of any one of claims 1 to 25, wherein the endoglycosidase hydrolase comprises a hyaluronidase selected from the group consisting of: HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant thereof and any isoform thereof.

27. The pharmaceutical composition of any one of claims 1 to 26, wherein the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof.

28. The pharmaceutical composition of any one of claims 1 to 27, wherein the endoglycosidase hydrolase comprises a modified hyaluronidase, the hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1 or fragments thereof.

29. A pharmaceutical composition of any one of claims 1 to 28, wherein the endoglycosidase hydrolase comprises a modified hyaluronidase, the hyaluronidase comprising, relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1 or fragments thereof, (i) substitution of one or more amino acids in the α-helical region, (ii) substitution of one or more amino acids in the linker region, (iii) deletion of one or more N-terminal and / or C-terminal amino acids, or (iv) any combination of (i)-(iii).

30. A pharmaceutical composition of any one of claims 1 to 29, wherein the endoglycosidase hydrolase comprises modified rHuPH20, wherein the modified rHuPH20 comprises: i. substitution of one or more amino acids in the α-helix region, the linker region, or both the α-helix region and the linker region relative to wild-type rHuPH20; ii. deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids relative to wild-type rHuPH20; or iii. both (i) and (ii).

31. The pharmaceutical composition of any one of claims 1 to 30, further comprising a tension modifier and / or a stabilizer.

32. The pharmaceutical composition of claim 31, wherein the tension modifier and / or stabilizer comprises sugar, amino acid, polyol, salt or combination thereof.

33. The pharmaceutical composition of claim 31 or 32, wherein the tension modifier and / or stabilizer comprises sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, or any combination thereof.

34. The pharmaceutical composition of any one of claims 31 to 33, wherein the tension modifier comprises sucrose.

35. The pharmaceutical composition of any one of claims 1 to 34, comprising at least about 10 mM to at least about 500 mM sucrose.

36. A pharmaceutical composition as claimed in any of claims 1 to 35, comprising at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, or at least about 200 mM. At least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, or at least about 500 mM sucrose.

37. The pharmaceutical composition of any one of claims 1 to 36, comprising about 250 mM sucrose.

38. The pharmaceutical composition of any one of claims 1 to 37 further comprises a buffer.

39. The pharmaceutical composition of claim 38, wherein the buffer is selected from histidine, succinate, thiamethoxam, sodium phosphate, sodium acetate and sodium citrate.

40. The pharmaceutical composition of claim 38 or 39, wherein the buffer comprises histidine.

41. The pharmaceutical composition of any one of claims 1 to 40, comprising at least about 5 mM to at least about 100 mM histidine.

42. The pharmaceutical composition of any one of claims 1 to 41, comprising at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine.

43. The pharmaceutical composition of any one of claims 1 to 42, comprising about 20 mM histidine.

44. The pharmaceutical composition of any one of claims 1 to 43 further comprises a surfactant.

45. The pharmaceutical composition of claim 44, wherein the surfactant is selected from the group consisting of: polysorbate 20, polysorbate 80 and poloxamer 188.

46. ​​The pharmaceutical composition of claim 44 or 45, wherein the surfactant comprises polysorbate 80.

47. The pharmaceutical composition of any one of claims 1 to 46, comprising at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80.

48. The pharmaceutical composition of any one of claims 1 to 47, comprising at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v of polysorbate 80.

49. The pharmaceutical composition of any one of claims 1 to 48, comprising about 0.05% w / v polysorbate 80.

50. A pharmaceutical composition of any one of claims 1 to 27 and 31 to 49, comprising: (a) about 120 mg / mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20.

51. A pharmaceutical composition of any one of claims 1 to 27 and 31 to 49, comprising: (a) about 120 mg / mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentimic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

52. A pharmaceutical composition of any one of claims 1 to 27 and 31 to 49, comprising: (a) about 150 mg / mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20.

53. A pharmaceutical composition of any one of claims 1 to 27 and 31 to 49, comprising: (a) about 150 mg / mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

54. The pharmaceutical composition of any one of claims 1 to 53, wherein the anti-PD-1 antibody is selected from nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, sasanlimab, and any combination thereof.

55. The pharmaceutical composition of any one of claims 1 to 64, wherein the anti-PD-1 antibody is nivolumab.

56. The pharmaceutical composition of any one of claims 1 to 64, wherein the anti-PD-1 antibody is pelizumab.

57. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 55, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20.

58. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 55, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

59. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 55, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20.

60. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 55, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

61. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 55, comprising: (a) about 672 mg nivolumab; (b) about 8.68 mg histidine; (c) about 11.8 mg histidine HCl H2O; (d) about 479 mg sucrose; (e) about 2.80 mg polysorbate 80; (f) about 0.110 mg pentiformin; (g) about 4.18 mg methionine; (h) about 0.102 mg rHuPH20; wherein (a)-(h) are reconstituted in water to a final volume of at least about 5.6 mL.

62. The pharmaceutical composition of any one of claims 1 to 61, comprising a pH of about 5.2 to about 6.

8.

63. The pharmaceutical composition of any one of claims 1 to 62, comprising a pH of about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7 or about 6.

8.

64. The pharmaceutical composition of any one of claims 1 to 63, comprising a pH of about 6.

0.

65. The pharmaceutical composition of any one of claims 1 to 64, further comprising a second therapeutic agent.

66. The pharmaceutical composition of claim 65, wherein the second therapeutic agent is an antibody.

67. The pharmaceutical composition of claim 66, wherein the second therapeutic agent is a checkpoint inhibitor.

68. The pharmaceutical composition of claim 67, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA antibody, an anti-CD137 antibody, an anti-KIR antibody, an anti-TGFβ antibody, an anti-IL-10 antibody, an anti-IL-8 antibody, an anti-B7-H4 antibody, an anti-Fas ligand antibody, an anti-CXCR4 antibody, an anti-mesothelin antibody, an anti-CD27 antibody, an anti-GITR antibody, or any combination thereof.

69. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 68, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-CTLA-4 antibody.

70. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 68, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-CTLA-4 antibody.

71. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 68, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-LAG-3 antibody.

72. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 68, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-LAG-3 antibody.

73. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 68, comprising: (a) about 120 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-TIM3 antibody.

74. A pharmaceutical composition comprising any one of claims 1 to 27 and 31 to 68, comprising: (a) about 150 mg / mL nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentiazem; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) anti-TIM3 antibody.

75. A vial containing a pharmaceutical composition as claimed in any one of claims 1 to 74.

76. A syringe comprising a pharmaceutical composition as claimed in any one of claims 1 to 74.

77. An autoinjector comprising a pharmaceutical composition as claimed in any one of claims 1 to 74.

78. A wearable pump comprising a pharmaceutical composition as claimed in any one of claims 1 to 74.

79. The syringe as claimed in claim 76, further comprising a plunger.

80. A method of treating a disease or ailment of an individual in need, comprising administering to the individual a pharmaceutically effective amount of any one of claims 1 to 74.

81. The method of claim 80, wherein the pharmaceutical composition is administered subcutaneously.

82. The method of claim 80 or 81, wherein the disease or condition is an infectious disease.

83. The method of claim 80 or 81, wherein the disease or condition is cancer.

84. The method of claim 83, wherein the cancer is selected from squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-refractory prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, colon cancer, head and neck cancer, and gastric cancer. Cancer), germ cell tumors, pediatric sarcomas, nasal and sinus natural killers, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, pediatric solid tumors, ureteral cancer, renal pelvis cancer, central nervous system (CNS) lesions, primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumors, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers including asbestos-induced cancers, virus-related cancers or cancers of virus origin (e.g., human papillomavirus (HPV-related or originating tumors)) and any combination thereof.

85. A method of treating an individual in need, comprising subcutaneously administering an effective dose of a pharmaceutical composition to the individual, the pharmaceutical composition comprising an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction between PD-1 and PD-L1 (referred to as "anti-PD-1 antibody" or "anti-PD-L1 antibody"); wherein the effective dose comprises one or more subcutaneous unit doses, wherein at least one of the subcutaneous unit doses has a total volume of less than about 5 mL, less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 3 mL, or less than about 2.5 mL; and wherein the effective dose comprises at least about 250 mg to at least about 2400 mg of the antibody.

86. The method of claim 85, wherein the pharmaceutical composition does not contain hyaluronidase.

87. The method of claim 85 or 86, wherein the effective dose comprises two or more subcutaneous unit doses, and wherein the two or more subcutaneous unit doses are administered simultaneously or sequentially.

88. The method of claim 87, wherein the two or more subcutaneous unit doses are administered sequentially, wherein each of the two or more subcutaneous unit doses is administered at intervals of approximately 10 minutes, approximately 15 minutes, approximately 20 minutes, approximately 30 minutes, approximately 45 minutes, approximately one hour, approximately two hours, approximately three hours, approximately four hours, approximately five hours, approximately six hours, approximately nine hours, approximately twelve hours, approximately eighteen hours, or approximately twenty-four hours between the two or more subcutaneous unit doses.

89. The method of any of claims 1 to 88, wherein the effective dose is administered approximately every week, two weeks, three weeks or four weeks.

90. The method of any one of claims 85 to 89, wherein the antibody comprises an anti-PD-1 antibody.

91. The method of any one of claims 85 to 90, wherein the effective dose of the antibody is about 250 mg to about 600 mg of the antibody administered weekly.

92. The method of any one of claims 85 to 91, wherein the effective dose of the antibody is approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, or approximately 600 mg per week.

93. The method of any one of claims 1 to 92, wherein the effective dose of the antibody is approximately 300 mg administered weekly.

94. The method of claim 93, wherein the effective dose of the antibody comprises a single subcutaneous unit dose of about 300 mg.

95. The method of claim 93 or 94, wherein the effective dose of the antibody comprises administering a single subcutaneous unit dose of about 300 mg in a total volume of about 2 mL.

96. The method of claim 93, wherein the effective dose of the antibody comprises (i) two subcutaneous unit doses, each of the two subcutaneous unit doses comprising about 150 mg of the antibody; or (ii) three subcutaneous unit doses, each of the three subcutaneous unit doses comprising about 100 mg of the antibody.

97. The method of claim 96, wherein (i) at least one of the two subcutaneous unit doses contains about 150 mg of the antibody in a total volume of less than about 5 mL; and (ii) at least one of the three subcutaneous unit doses contains about 100 mg of the antibody in a total volume of about 2 mL.

98. The method of claim 96 or 97, wherein (i) the two subcutaneous unit doses are administered to the individual at two different body locations, or (ii) at least two of the three subcutaneous unit doses are administered to the individual at at least two different body locations.

99. The method of any one of claims 85 to 90, wherein the effective dose of the antibody is about 300 mg to about 900 mg every two weeks.

100. The method of claim 99, wherein the effective dose of the antibody is administered approximately every two weeks at the following doses: approximately 300 mg, approximately 350 mg, approximately 400 mg, approximately 450 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg. mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, or approximately 900 mg.

101. The method of claim 99 or 100, wherein the effective dose of the antibody is approximately 600 mg administered every two weeks.

102. The method of claim 101, wherein the effective dose of the antibody comprises a single subcutaneous unit dose.

103. The method of claim 101, wherein the effective dose of the antibody comprises two, three, or at least four subcutaneous unit doses.

104. The method of claim 101 or 103, wherein the effective dose of the antibody comprises two subcutaneous unit doses, wherein each of the two subcutaneous unit doses comprises approximately 300 mg of the antibody.

105. The method of claim 104, wherein at least one of the two subcutaneous unit doses comprises about 300 mg of the antibody in a total volume of about 2 mL.

106. The method of any one of claims 103 to 105, wherein at least two of the subcutaneous unit doses are administered to at least two different body locations of the individual.

107. The method of any one of claims 85 to 90, wherein the effective dose of the antibody is about 900 mg to about 1500 mg every four weeks.

108. The method of claim 107, wherein the effective dose of the antibody is administered approximately every four weeks at doses of approximately 900, approximately 950, approximately 1000 mg, approximately 1010 mg, approximately 1020 mg, approximately 1030 mg, approximately 1040 mg, approximately 1050 mg, approximately 1060 mg, approximately 1070 mg, approximately 1080 mg, approximately 1090 mg, approximately 1100 mg, approximately 1110 mg, approximately 1120 mg, approximately 1130 mg, approximately 1140 mg, approximately 1150 mg, approximately 1160 mg, approximately 1170 mg, approximately 1180 mg, approximately 1190 mg, approximately 1200 mg, approximately 1210 mg, approximately 1220 mg, approximately 1230 mg, approximately 1240 mg, approximately 1250 mg, approximately 1260 mg, approximately 1270 mg, approximately 1280 mg, approximately 129 ...90 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 1290 mg, approximately 12 mg, approximately 1300 mg, approximately 1310 mg, approximately 1320 mg, approximately 1330 mg, approximately 1340 mg, approximately 1350 mg, approximately 1360 mg, approximately 1370 mg, approximately 1380 mg, approximately 1390 mg, approximately 1400 mg, approximately 1410 mg, approximately 1420 mg, approximately 1430 mg, approximately 1440 mg, approximately 1450 mg, approximately 1460 mg, approximately 1470 mg, approximately 1480 mg, approximately 1490 mg, or approximately 1500 mg.

109. The method of claim 107 or 108, wherein the effective dose of the antibody is approximately 1200 mg administered every four weeks.

110. The method of any one of claims 107 to 109, wherein the effective dose of the antibody comprises two, three, four, six or at least eight subcutaneous unit doses.

111. The method of any one of claims 107 to 110, wherein the effective dose of the antibody comprises four subcutaneous unit doses, wherein each of the four subcutaneous unit doses comprises about 300 mg of the antibody.

112. The method of claim 111, wherein at least one of the four subcutaneous unit doses comprises about 300 mg of the antibody in a total volume of about 2 mL.

113. The method of any of claims 110 to 112, wherein at least two of the subcutaneous unit doses are administered to at least two different body locations of the individual.

114. The method of any of claims 110 to 113, wherein the two, three, four, six or at least eight subcutaneous unit doses are administered on the same day.

115. The method of any one of claims 85 to 89, wherein the antibody comprises an anti-PD-L1 antibody.

116. The method of claim 115, wherein the effective dose of the antibody is about 900 mg to about 1800 mg of the antibody every two weeks.

117. The method of claim 115 or 116, wherein the effective dose of the antibody is administered approximately every two weeks at approximately 900, 950, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, 1230 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, or 1280 mg. mg, approximately 1290 mg, approximately 1300 mg, approximately 1310 mg, approximately 1320 mg, approximately 1330 mg, approximately 1340 mg, approximately 1350 mg, approximately 1360 mg, approximately 1370 mg, approximately 1380 mg, approximately 1390 mg, approximately 1400 mg, approximately 1410 mg, approximately 1420 mg, approximately 1430 mg, approximately 1440 mg, approximately 1450 mg, approximately 1460 mg, approximately 1470 mg, approximately 1480 mg, approximately 1490 mg, or approximately 1500 mg.

118. The method of any one of claims 115 to 117, wherein the effective dose of the antibody is about 1200 mg every two weeks.

119. The method of any one of claims 85 to 114, wherein the anti-PD-1 antibody comprises an antibody selected from the group consisting of: nivolumab, pelizumab, PDR001, MEDI-0680, cemipilimumab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, KN035, sasanlimab, and any combination thereof.

120. The method of any one of claims 85 to 114, wherein the anti-PD-1 antibody cross-competitively binds to human PD-1 with nivolumab.

121. The method of claim 119, wherein the anti-PD-1 antibody comprises nivolumab.

122. The method of claim 119, wherein the anti-PD-1 antibody comprises pelizumab.

123. The method of any one of claims 85 to 89 and 91 to 118, wherein the anti-PD-L1 antibody comprises an antibody selected from the group consisting of: BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, CK-301, and any combination thereof.

124. The method of any of claims 85 to 123, wherein the individual suffers from cancer.

125. The method of claim 124, wherein the cancer is selected from the group consisting of: squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, kidney cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-refractory prostate cancer, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, gastric cancer, bladder cancer, liver cancer, breast cancer, colon cancer, head and neck cancer, gastric cancer, germ cell tumors, pediatric sarcoma, nasal and sinus natural killer, melanoma, bone Cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small bowel cancer, endocrine system cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, pediatric solid tumors, ureteral cancer, renal pelvis cancer, central nervous system (CNS) lesions, primary CNS lymphoma, tumor angiogenesis, spinal cord axis tumors, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer including asbestos-induced cancer, virus-related cancers or cancers of virus origin (e.g., human papillomavirus (HPV-related or originating tumors)) and any combination thereof.

126. The method of any one of claims 85 to 125, wherein the pharmaceutical composition is administered using an auto-injector.

127. The method of any one of claims 85 to 125, wherein the pharmaceutical composition is administered using a wearable pump.

128. The method of any one of claims 85 to 127, wherein the pharmaceutical composition is administered to the individual by subcutaneous infusion for less than about 10 minutes.

129. The method of any one of claims 85 to 128, wherein the pharmaceutical composition is administered to the individual by subcutaneous infusion for less than about 5 minutes.

130. The method of any one of claims 85 to 129, wherein the pharmaceutical composition further comprises at least two antioxidants.

131. The method of claim 130, wherein the at least two antioxidants are selected from methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA and EDTA.

132. The method of claim 130 or 131, wherein the at least two antioxidants comprise (i) methionine and EDTA or (ii) methionine and DTPA.

133. The method of any one of claims 130 to 132, wherein the at least two antioxidants comprise at least about 1 to about 20 mM methionine.

134. The method of any one of claims 130 to 133, wherein the at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine.

135. The method of any one of claims 130 to 134, wherein the at least two antioxidants comprise about 5 mM methionine.

136. The method of any one of claims 130 to 135, wherein the at least two antioxidants comprise at least about 10 µM to about 200 µM DTPA.

137. The method of any one of claims 130 to 136, wherein the at least two antioxidants comprise at least about 10 µM, at least about 15 µM, at least about 20 µM, at least about 25 µM, at least about 30 µM, at least about 35 µM, at least about 40 µM, at least about 45 µM, at least about 50 µM, at least about 55 µM, at least about 60 µM, at least about 65 µM, at least about 70 µM, at least about 75 µM, at least about 80 µM, at least about 85 µM, at least about 90 µM, at least about 95 µM, at least about 100 µM, at least about 110 µM, at least about 120 µM, at least about 130 µM, at least about 140 µM, at least about 150 µM, at least about 160 µM, at least about 170 µM, at least about 180 µM, at least about 190 µM, or at least about 200 µM DTPA.

138. The method of any one of claims 130 to 137, wherein the at least two antioxidants comprise about 50 µM DTPA.

139. The method of any one of claims 85 to 138, wherein the pharmaceutical composition comprises at least about 20 mg / mL to at least about 200 mg / mL of the anti-PD-1 antibody.

140. The method of any one of claims 85 to 139, wherein the pharmaceutical composition comprises at least about 135 mg / mL to at least about 180 mg / mL of the anti-PD-1 antibody.

141. The method of any one of claims 85 to 140, wherein the pharmaceutical composition comprises at least about 108 mg / mL to at least about 132 mg / mL of the anti-PD-1 antibody.

142. The method of any one of claims 85 to 141, wherein the pharmaceutical composition comprises at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL of the anti-PD-1 antibody.

143. The method of any one of claims 85 to 142, wherein the pharmaceutical composition comprises about 120 mg / mL or about 150 mg / mL of the anti-PD-1 antibody.

144. The method of any one of claims 85 to 143, wherein the pharmaceutical composition further comprises a tension modifier and / or a stabilizer.

145. The method of claim 144, wherein the tension modifier and / or stabilizer comprises sugar, amino acid, polyol, salt or combination thereof.

146. The method of claim 144 or 145, wherein the tension modifier and / or stabilizer is selected from the group consisting of: sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, and any combination thereof.

147. The method of any one of claims 144 to 146, wherein the tension regulator comprises sucrose.

148. The method of any one of claims 85 to 147, wherein the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose.

149. The method of any one of claims 85 to 148, wherein the pharmaceutical composition comprises about 250 mM sucrose.

150. The method of any one of claims 85 to 149, wherein the pharmaceutical composition further comprises a buffer.

151. The method of claim 150, wherein the buffer is selected from histidine, succinate, thiamethoxam, sodium phosphate, sodium acetate and sodium citrate.

152. The method of claim 150 or 151, wherein the buffer comprises histidine.

153. The method of any one of claims 85 to 152, wherein the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM histidine.

154. The method of any one of claims 85 to 153, wherein the pharmaceutical composition comprises about 20 mM histidine.

155. The method of any one of claims 85 to 154, wherein the pharmaceutical composition further comprises a surfactant.

156. The method of claim 155, wherein the surfactant is selected from the group consisting of: polysorbate 20, polysorbate 80 and poloxamer 188.

157. The method of claim 155 or 156, wherein the surfactant comprises polysorbate 80.

158. The method of any one of claims 85 to 157, wherein the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80.

159. The method of any one of claims 85 to 158, wherein the pharmaceutical composition comprises about 0.05% w / v polysorbate 80.

160. The method of any one of claims 85 to 114, 119 to 122 and 124 to 159, wherein the pharmaceutical composition comprises: (a) about 150 mg / mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentimic acid; and (f) about 5 mM methionine.

161. The method of any one of claims 85 to 114, 119 to 122 and 124 to 159, wherein the pharmaceutical composition comprises: (a) about 120 mg / mL of the anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentimic acid; and (f) about 5 mM methionine.

162. The method of any one of claims 85 to 161, wherein the pharmaceutical composition comprises a pH of about 5.2 to about 6.

8.

163. The method of any one of claims 85 to 162, wherein the pharmaceutical composition comprises a pH of about 6.

0.

164. A pharmaceutical composition for use in any one of claims 85 to 163.

165. A unit dose comprising: (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 µM pentimic acid; and (f) about 5 mM methionine.

166. An autoinjector comprising a unit dose as claimed in claim 165.

167. A wearable device comprising a unit dose as claimed in claim 165.