Antibody compositions and methods of use thereof

Abstract

The present disclosure provides a pharmaceutical composition comprising an antibody 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 endoglycosidase hydrolase enzyme. Another embodiment of the present disclosure is directed to a method of subcutaneously delivering the pharmaceutical composition.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application Nos. US63 / 131,234, filed December 28, 2020; US63 / 131,244, filed December 28, 2020; and US63 / 150,465, filed February 17, 2021, each of which is hereby incorporated by reference in its entirety.

[0002] Reference to sequence listings submitted electronically via EFS-WEB The contents of the electronically submitted Sequence Listing (Name: 3338_191PC03_Seqlisting_ST25.txt; Size: 1,011,388 bytes; and Creation Date: December 27, 2021) are hereby incorporated by reference herein in their entirety.

[0003] The present disclosure provides pharmaceutical compositions comprising the antibodies and methods for using same to treat subjects afflicted with tumors. [Background technology]

[0004] Human cancers harbor numerous genetic and epigenetic alterations, creating new antigens 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 broad ability and exquisite specificity to respond to diverse tumor antigens, giving it potent anticancer potential. Furthermore, the immune system exhibits considerable plasticity and memory components. Successfully harnessing all these attributes of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

[0005] Until recently, cancer immunotherapy has focused substantial efforts on enhancing antitumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or the delivery of nonspecific immune stimulators such as cytokines. However, over the past decade, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches to treat cancer, including the development of antibodies such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013), which specifically bind to the programmed death-1 (PD-1) receptor and block the inhibitory PD-1 / PD-1 ligand pathway (Topalian et al., 2012a, b; Topalian et al., 2014; Hamid et al., 2013; Hamid and Carvajal, 2013; McDermott and Atkins, 2013). Summary of the Invention [Problem to be solved by the invention]

[0006] Current methods of delivering anti-PD-1 and / or anti-PD-L1 antibodies often use regular intravenous administration administered by a clinician in a clinic or hospital. The inconvenience and invasiveness of the procedure can negatively impact the patient experience. Subcutaneous delivery, such as through the use of an auto-injector or wearable pump, can significantly improve patient compliance. However, there remains a need in the art for formulations containing anti-PD-1 or anti-PD-L1 antibodies that are suitable for subcutaneous delivery to patients. [Means for solving the problem]

[0007] Certain embodiments of the present disclosure are directed to pharmaceutical compositions comprising (i) an antibody that specifically binds to PD-1 (an "anti-PD-1 antibody"), (ii) an endoglycosidase hydrolase enzyme, and (iii) at least two antioxidants. In some embodiments, at least one of the at least two antioxidants is a sacrificial antioxidant. In some embodiments, the sacrificial antioxidant is selected from the group consisting of methionine, tryptophan, and histidine, cysteine, ascorbic acid, glycine, or other sacrificial substances.

[0008] In some embodiments, at least one of the at least two antioxidants comprises a metal ion chelator, hi some embodiments, the metal ion chelator is selected from pentetic acid ("DTPA") and EDTA.

[0009] In some embodiments, the at least two antioxidants are selected from the group consisting of methionine, DTPA, and EDTA. In some embodiments, one of the at least two antioxidants is methionine. In some embodiments, one of the at least two antioxidants is DTPA. In some embodiments, one of the at least two antioxidants is EDTA. In some embodiments, the at least two antioxidants are methionine and DTPA. In some embodiments, the at least two antioxidants are methionine and EDTA.

[0010] In some embodiments, the at least one antioxidant comprises at least about 1 to about 20 mM methionine. In some embodiments, 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. In some embodiments, the at least one antioxidant comprises about 5 mM methionine.

[0011] In some embodiments, the at least one antioxidant comprises at least about 10 μM to about 200 μM DTPA. In some embodiments, 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. In some embodiments, the at least one antioxidant comprises about 50 μM DTPA.

[0012] In some embodiments, the pharmaceutical composition comprises at least about 20 mg / mL to at least about 200 mg / mL of anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL to at least about 180 mg / mL of anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL to at least about 132 mg / mL of anti-PD-1 antibody. In some embodiments, 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 anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises about 150 mg / mL of anti-PD-1 antibody.

[0013] In some embodiments, the pharmaceutical composition comprises at least about 5 U to at least about 100,000 U of an endoglycosidase hydrolase enzyme. In some embodiments, 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, or at least The pharmaceutical composition may comprise at least about 6,000 U, at least about 7,000 U, at least about 8,000 U, at least about 9,000 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 enzyme. In some embodiments, the pharmaceutical composition comprises about 20,000 U of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition comprises at least about 500 U / mL to at least about 5,000 U / mL of endoglycosidase hydrolase enzyme. In some embodiments, 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, 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 enzyme. In some embodiments, the pharmaceutical composition comprises about 2000 U / mL of the endoglycosidase hydrolase enzyme.

[0014] In some embodiments, the endoglycosidase hydrolase enzyme cleaves hyaluronic acid at hexosaminidic β(1-4) or (1-3) linkages. In some embodiments, the endoglycosidase hydrolase enzyme comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme 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 to amino acids 36-490 of SEQ ID NO: 1. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant, and any isoform thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0015] In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises 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 a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the alpha-helical region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase in which one or more N-terminal and / or C-terminal amino acids are deleted compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20 that comprises: i. one or more amino acid substitutions in the alpha-helical region, the linker region, or both the alpha-helical region and the linker region compared 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 compared to wild-type rHuPH20; or iii. both (i) and (ii).

[0016] In some embodiments, the pharmaceutical composition further comprises a tonicity adjuster and / or stabilizer. In some embodiments, the tonicity adjuster and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof. In some embodiments, the tonicity adjuster and / or stabilizer comprises sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, or any combination thereof. In some embodiments, the tonicity adjuster comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose. In some embodiments, 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, at least about 500 mM, at least about 510 mM, at least about 520 mM, at least about 530 mM, at least about 540 mM, at least about 550 mM, at least about 560 mM, at least about 570 mM In some embodiments, the pharmaceutical composition contains 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 embodiments, the pharmaceutical composition contains about 250 mM sucrose.

[0017] In some embodiments, the pharmaceutical composition further comprises a buffering agent. In some embodiments, the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate. In some embodiments, the buffering agent comprises histidine. In some embodiments, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM histidine. In some embodiments, 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 embodiments, the pharmaceutical composition comprises about 20 mM histidine.

[0018] In some embodiments, the pharmaceutical composition further comprises a surfactant. In some embodiments, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In some embodiments, the surfactant comprises polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80. In some embodiments, 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 of polysorbate 80. In some embodiments, the pharmaceutical composition comprises about 0.05% w / v polysorbate 80.

[0019] In some embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of an 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 of rHuPH20. In some embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of an 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 of rHuPH20. In some embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an 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 of rHuPH20. In some embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an 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 of rHuPH20.

[0020] In some embodiments, 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. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0021] In some embodiments, 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 embodiments, 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 some embodiments, 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 embodiments, 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 some embodiments, the pharmaceutical composition comprises: (a) about 672 mg of nivolumab; (b) about 8.68 mg of histidine; (c) about 11.8 mg of histidine HCl HO; (d) about 479 mg of sucrose; (e) about 2.80 mg of polysorbate 80; (f) about 0.110 mg of pentetic acid; (g) about 4.18 mg of methionine; and (h) about 0.102 mg of rHuPH20; (a)-(h) are reconstituted in water to a final volume of at least about 5.6 mL.

[0022] In some embodiments, the pharmaceutical composition comprises a pH of about 5.2 to about 6.8. In some embodiments, the pharmaceutical composition comprises 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. In some embodiments, the pharmaceutical composition comprises a pH of about 6.0.

[0023] In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent. In some embodiments, the second therapeutic agent is an antibody. In some embodiments, the second therapeutic agent is a checkpoint inhibitor. In some embodiments, 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. In some embodiments, the pharmaceutical composition further comprises a third therapeutic agent. In some embodiments, the second therapeutic agent, the third therapeutic agent, or both comprise IL-2 (e.g., bempegaldesleukin) or IL12-Fc (e.g., BMS-986415).

[0024] In some embodiments, 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) an anti-CTLA-4 antibody. In some embodiments, 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) about 2000 U / mL rHuPH20; and (h) an anti-CTLA-4 antibody. In some embodiments, 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) an anti-LAG-3 antibody. In some embodiments, 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) about 2000 U / mL rHuPH20; and (h) an anti-LAG-3 antibody. In some embodiments, 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) an anti-TIM3 antibody. In some embodiments, 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) about 2000 U / mL rHuPH20; and (h) an anti-TIM3 antibody.

[0025] Certain aspects of the present disclosure are directed to a vial containing any of the pharmaceutical compositions disclosed herein.

[0026] Certain aspects of the present disclosure are directed to a syringe containing any of the pharmaceutical compositions disclosed herein.

[0027] Certain aspects of the present disclosure are directed to an auto-injector comprising any of the pharmaceutical compositions disclosed herein.

[0028] Certain aspects of the present disclosure are directed to a wearable pump comprising any of the pharmaceutical compositions disclosed herein. In some aspects, the syringe further comprises a plunger.

[0029] Certain aspects of the present disclosure are directed to methods of treating a disease or disorder 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, the pharmaceutical composition is administered subcutaneously.

[0030] In some embodiments, the disease or disorder is an infectious disease. In some embodiments, the disease or disorder is cancer. In some embodiments, 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, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, gastric cancer, cancer), germ cell tumors, childhood sarcoma, sinonasal natural killer, melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, rectal cancer, solid tumors of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers including those induced by asbestos, virus-associated cancers or cancers of viral origin (e.g., tumors related to or originating from human papillomavirus (HPV)), and any combination thereof.

[0031] Certain embodiments of the present disclosure are directed to methods of treating a subject in need thereof, comprising subcutaneously administering to the subject an effective dose of a pharmaceutical composition comprising an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction of PD-1 and PD-L1 (an "anti-PD-1 antibody" or "anti-PD-L1 antibody," respectively); the effective dose comprises one or more subcutaneous unit doses, at least one of which 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 the effective dose comprises at least about 250 mg to at least about 2400 mg of antibody. In some embodiments, the pharmaceutical composition does not comprise hyaluronidase.

[0032] In some embodiments, the effective dose comprises two or more subcutaneous unit doses, and the two or more subcutaneous unit doses are administered simultaneously or sequentially. In some embodiments, the two or more subcutaneous unit doses are administered sequentially, and each of the two or more subcutaneous unit doses is administered within about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 9 hours, about 12 hours, about 18 hours, or about 24 hours between the two or more subcutaneous unit doses. In some embodiments, the effective dose is administered about every 1, 2, 3, or 4 weeks.

[0033] In some embodiments, the antibody comprises an anti-PD-1 antibody. In some embodiments, the effective dose of the antibody is about 250 mg to about 600 mg of the antibody administered about weekly. In some embodiments, an 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, 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 administered about weekly. In some embodiments, the effective dose of the antibody is about 300 mg administered approximately weekly. In some embodiments, the effective dose of the antibody comprises a single subcutaneous unit dose of about 300 mg. In some embodiments, the effective dose of the antibody comprises a single subcutaneous unit dose of about 300 mg in a total dose volume of about 2 mL.

[0034] In some embodiments, the effective dose of antibody comprises (i) two subcutaneous unit doses, each comprising about 150 mg of antibody; or (ii) three subcutaneous unit doses, each comprising about 100 mg of antibody. In some embodiments, (i) at least one of the two subcutaneous unit doses comprises about 150 mg of antibody in a total volume of less than about 5 mL; (ii) at least one of the three subcutaneous unit doses comprises about 100 mg of antibody in a total volume of about 2 mL. In some embodiments, (i) the two subcutaneous unit doses are administered to two different physical locations of the subject, or (ii) at least two of the three subcutaneous unit doses are administered to at least two different physical locations of the subject.

[0035] In some embodiments, an effective dose of the antibody is about 300 mg to about 900 mg administered about every two weeks. In some embodiments, an 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, or about 660 mg administered about every two weeks. , 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 embodiments, the effective dose of the antibody is about 600 mg administered about every two weeks.

[0036] In some embodiments, the effective dose of the antibody comprises a single subcutaneous unit dose. In some embodiments, the effective dose of the antibody comprises two, three, or at least four subcutaneous unit doses. In some embodiments, the effective dose of the antibody comprises two subcutaneous unit doses, each of the two subcutaneous unit doses comprising about 300 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL. In some embodiments, at least two of the subcutaneous unit doses are administered to at least two different physical locations of the subject.

[0037] In some embodiments, an effective dose of the antibody is about 900 mg to about 1500 mg administered about every four weeks. In some embodiments, an 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, 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, about 1500 mg, about 1510 mg, about 1520 mg, about 1530 mg, about 1540 mg, about 1550 mg, about 1560 mg, about In some embodiments, the effective dose of the antibody is about 1200 mg administered about every four weeks. In some embodiments, the effective dose of the antibody comprises 2, 3, 4, 6, or at least 8 subcutaneous unit doses. In some embodiments, the effective dose of the antibody comprises 4 subcutaneous unit doses, each of the 4 subcutaneous unit doses comprising about 300 mg of antibody. In some embodiments, at least one of the 4 subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL. In some embodiments, at least two of the subcutaneous unit doses are administered to at least two different physical locations of the subject. In some embodiments, the 2, 3, 4, 6, or at least 8 subcutaneous unit doses are administered on the same day.

[0038] In some embodiments, the antibody comprises an anti-PD-L1 antibody. In some embodiments, an effective dose of the antibody is about 900 mg to about 1800 mg of antibody administered about every two weeks. In some embodiments, an 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 In some embodiments, the effective dose of the antibody is about 1200 mg about every two weeks. In some embodiments, an 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 embodiments, an effective dose of an antibody comprises four subcutaneous unit doses, each of which comprises about 300 mg of antibody. In some embodiments, 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 embodiments, at least two of the subcutaneous unit doses are administered to at least two different physical locations of the subject. In some embodiments, two, three, four, five, six, seven, or at least eight subcutaneous unit doses are administered on the same day.

[0039] In some embodiments, the anti-PD-1 antibody comprises an antibody comprising nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, KN035, sasanlimab, or any combination thereof. In some embodiments, the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1. In some embodiments, the anti-PD-1 antibody comprises nivolumab. In some embodiments, the anti-PD-1 antibody comprises pembrolizumab.

[0040] In some embodiments, the anti-PD-L1 antibody comprises an antibody including BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, CK-301, or any combination thereof.

[0041] In some embodiments, the subject is afflicted with cancer, including 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, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, intrauterine cancer, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, cancer of the rectum, solid tumors of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers including those induced by asbestos, virus-associated cancers or cancers of viral origin (e.g., tumors related to or originating from human papillomavirus (HPV)), or any combination thereof.

[0042] In some embodiments, the pharmaceutical composition is administered using an auto-injector. In some embodiments, the pharmaceutical composition is administered using a wearable pump. In some embodiments, the pharmaceutical composition is administered to the subject by subcutaneous injection for less than about 10 minutes. In some embodiments, the pharmaceutical composition is administered to the subject by subcutaneous injection for less than about 5 minutes.

[0043] In some embodiments, the pharmaceutical composition further comprises at least two antioxidants. In some embodiments, the at least two antioxidants are selected from methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA, and EDTA. In some embodiments, the at least two antioxidants comprise (i) methionine and EDTA, or (ii) methionine and DTPA. In some embodiments, the at least two antioxidants comprise at least about 1 to about 20 mM methionine. In some embodiments, 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 embodiments, the at least two antioxidants comprise about 5 mM methionine.

[0044] In some embodiments, the at least two antioxidants include at least about 10 μM to about 200 μM DTPA. In some embodiments, 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 embodiments, the at least two antioxidants include about 50 μM DTPA.

[0045] In some embodiments, the pharmaceutical composition comprises at least about 20 mg / mL to at least about 200 mg / mL of anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL to at least about 180 mg / mL of anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL to at least about 132 mg / mL of anti-PD-1 antibody. In some embodiments, 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 anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises about 120 mg / mL of anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises about 150 mg / mL of anti-PD-1 antibody.

[0046] In some embodiments, the pharmaceutical composition further comprises a tonicity adjuster and / or stabilizer. In some embodiments, the tonicity adjuster and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof. In some embodiments, the tonicity adjuster 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. In some embodiments, the tonicity adjuster comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose. In some embodiments, 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, at least about 500 mM, at least about 510 mM, at least about 520 mM, at least about 530 mM, at least about 540 mM, at least about 550 mM, at least about 560 mM, at least about 570 mM In some embodiments, the pharmaceutical composition contains 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 embodiments, the pharmaceutical composition contains about 250 mM sucrose.

[0047] In some embodiments, the pharmaceutical composition further comprises a buffering agent. In some embodiments, the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate. In some embodiments, the buffering agent comprises histidine. In some embodiments, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM histidine. In some embodiments, 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 embodiments, the pharmaceutical composition comprises about 20 mM histidine.

[0048] In some embodiments, the pharmaceutical composition further comprises a surfactant. In some embodiments, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In some embodiments, the surfactant comprises polysorbate 80. The method of any one of claims 1-81, wherein the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80. In some embodiments, 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 of polysorbate 80. In some embodiments, the pharmaceutical composition comprises about 0.05% w / v polysorbate 80.

[0049] In some embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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.

[0050] In some embodiments, 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.

[0051] In some embodiments, the pharmaceutical composition comprises a pH of about 5.2 to about 6.8. In some embodiments, the pharmaceutical composition comprises 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. In some embodiments, the pharmaceutical composition comprises a pH of about 6.0.

[0052] Certain aspects of the present disclosure are directed to pharmaceutical compositions for use in any of the methods disclosed herein.

[0053] Certain embodiments of the present disclosure are directed to pharmaceutical compositions comprising (i) an antibody that specifically binds to PD-1 (an "anti-PD-1 antibody") and (ii) at least two antioxidants. In some embodiments, the at least two antioxidants are selected from methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA, and EDTA. In some embodiments, the at least two antioxidants comprise (i) methionine and EDTA, or (ii) methionine and DTPA. In some embodiments, the at least two antioxidants comprise at least about 1 to about 20 mM methionine. In some embodiments, 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 embodiments, the at least two antioxidants comprise about 5 mM methionine.

[0054] In some embodiments, the at least two antioxidants include at least about 10 μM to about 200 μM DTPA. In some embodiments, 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 embodiments, the at least two antioxidants include about 50 μM DTPA.

[0055] In some embodiments, the composition comprises at least about 20 mg / mL to at least about 200 mg / mL of anti-PD-1 antibody. In some embodiments, the composition comprises at least about 135 mg / mL to at least about 180 mg / mL of anti-PD-1 antibody. In some embodiments, the composition comprises at least about 108 mg / mL to at least about 132 mg / mL of anti-PD-1 antibody. In some embodiments, 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 of anti-PD-1 antibody. In some embodiments, the composition comprises about 120 mg / mL of anti-PD-1 antibody. In some embodiments, the composition comprises about 150 mg / mL of anti-PD-1 antibody.

[0056] In some embodiments, the composition further comprises a tonicity adjuster and / or stabilizer. In some embodiments, the tonicity adjuster and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof. In some embodiments, the tonicity adjuster 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. In some embodiments, the tonicity adjuster comprises sucrose. In some embodiments, the composition comprises at least about 10 mM to at least about 500 mM sucrose. In some embodiments, 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, at least about 500 mM, at least about 510 mM, at least about 520 mM, at least about 530 mM, at least about 540 mM, at least about 550 mM, at least about 560 mM, at least about 570 mM, In some embodiments, the composition comprises 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 embodiments, the composition comprises about 250 mM sucrose.

[0057] In some embodiments, the composition further comprises a buffering agent. In some embodiments, the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate. In some embodiments, the buffering agent comprises histidine. In some embodiments, the composition comprises at least about 5 mM to at least about 100 mM histidine. In some embodiments, 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 embodiments, the composition comprises about 20 mM histidine.

[0058] In some embodiments, the composition further comprises a surfactant. In some embodiments, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In some embodiments, the surfactant comprises polysorbate 80. In some embodiments, the composition comprises at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80. In some embodiments, 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 of polysorbate 80. In some embodiments, the composition comprises about 0.05% w / v of polysorbate 80.

[0059] In some embodiments, 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.

[0060] In some embodiments, 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.

[0061] In some embodiments, the composition comprises a pH of about 5.2 to about 6.8. In some embodiments, the composition comprises 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. In some embodiments, the composition comprises a pH of about 6.0.

[0062] In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent. In some embodiments, the second therapeutic agent is an antibody. In some embodiments, the second therapeutic agent is a checkpoint inhibitor. In some embodiments, 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, 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. In some embodiments, the pharmaceutical composition further comprises a third therapeutic agent. In some embodiments, the second therapeutic agent, the third therapeutic agent, or both comprise IL-2 (e.g., bempegaldesleukin) or IL12-Fc (e.g., BMS-986415).

[0063] Certain aspects of the present disclosure are directed to vials containing the pharmaceutical compositions disclosed herein.

[0064] Certain aspects of the present disclosure are directed to a unit dose comprising any of the pharmaceutical compositions disclosed herein.

[0065] Certain embodiments of the present disclosure are directed 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.

[0066] In some aspects, the vial is an auto-injector. Certain aspects of the present disclosure are directed to auto-injectors comprising the unit doses disclosed herein. In some aspects, the vial is a wearable device. Certain aspects of the present disclosure are directed to wearable devices comprising the unit doses disclosed herein.

[0067] Aspects Pharmaceutical compositions and uses thereof.

[0068] Embodiment A1. A pharmaceutical composition comprising: (i) an antibody that specifically binds to PD-1 (an "anti-PD-1 antibody"), (ii) an endoglycosidase hydrolase enzyme, and (iii) at least two antioxidants.

[0069] Aspect A2. The pharmaceutical composition of Aspect A1, wherein at least one of the at least two antioxidants is a sacrificial antioxidant.

[0070] 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, or other sacrificial substances.

[0071] Aspect A4. The pharmaceutical composition of any one of Aspects A1 to A3, wherein at least one of the at least two antioxidants comprises a metal ion chelator.

[0072] Aspect A5. The pharmaceutical composition of Aspect A4, wherein the metal ion chelator is selected from pentetic acid ("DTPA") and EDTA.

[0073] Aspect A6. The pharmaceutical composition of any one of Aspects A1 to A5, wherein the at least two antioxidants are selected from the group consisting of methionine, DTPA, and EDTA.

[0074] Aspect A7. The pharmaceutical composition of any one of Aspects A1 to A6, wherein one of the at least two antioxidants is methionine.

[0075] Aspect A8. The pharmaceutical composition of any one of Aspects A1 to A7, wherein one of the at least two antioxidants is DTPA.

[0076] Aspect A9. The pharmaceutical composition of any one of Aspects A1 to A7, wherein one of the at least two antioxidants is EDTA.

[0077] Aspect A10. The pharmaceutical composition of any one of aspects A1 to 8, wherein the at least two antioxidants are methionine and DTPA.

[0078] 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.

[0079] 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.

[0080] Embodiment A13. The pharmaceutical composition of any one of embodiments A1 to A12, 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.

[0081] Aspect A14. The pharmaceutical composition of any one of aspects A1 to 13, wherein the at least one antioxidant comprises about 5 mM methionine.

[0082] Aspect A15. The pharmaceutical composition of any one of Aspects A1 to A14, wherein the at least one antioxidant comprises at least about 10 μM to about 200 μM DTPA.

[0083] Embodiment A16. The pharmaceutical composition of any one of embodiments A1 to A15, 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.

[0084] Aspect A17. The pharmaceutical composition of any one of aspects A1 to 16, wherein the at least one antioxidant comprises about 50 μM DTPA.

[0085] 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 of the anti-PD-1 antibody.

[0086] 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 of the anti-PD-1 antibody.

[0087] 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 the anti-PD-1 antibody.

[0088] Embodiment A21. The pharmaceutical composition of any one of embodiments A1 to A20 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 an anti-PD-1 antibody.

[0089] Aspect A22. The pharmaceutical composition of any one of aspects A1 to 21, comprising about 120 mg / mL of the anti-PD-1 antibody.

[0090] Aspect A23. The pharmaceutical composition of any one of aspects A1 to 21, comprising about 150 mg / mL of the anti-PD-1 antibody.

[0091] Aspect A24. The pharmaceutical composition of any one of aspects A1 to A23, comprising from at least about 5 U to at least about 100,000 U of the endoglycosidase hydrolase enzyme.

[0092] Embodiment A25. 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 7 25. The pharmaceutical composition of any one of aspects A1 to 24, comprising at least about 10,000 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 enzyme.

[0093] Aspect A26. The pharmaceutical composition of any one of aspects A1 to 25, comprising about 20,000 U of the endoglycosidase hydrolase enzyme.

[0094] 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 of endoglycosidase hydrolase enzyme.

[0095] Embodiment A28. The pharmaceutical composition of any one of embodiments 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, 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 of endoglycosidase hydrolase enzyme.

[0096] Aspect A29. The pharmaceutical composition of any one of aspects A1 to 28, comprising about 2000 U / mL of an endoglycosidase hydrolase enzyme.

[0097] Aspect A30. The pharmaceutical composition of any one of aspects A1 to 29, wherein the endoglycosidase hydrolase enzyme cleaves hyaluronic acid at hexosaminide β(1-4) or (1-3) linkages.

[0098] Aspect A31. The pharmaceutical composition of any one of aspects A1 to 30, wherein the endoglycosidase hydrolase enzyme comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1.

[0099] Aspect A32. The pharmaceutical composition of any one of aspects A1 to A31, wherein the endoglycosidase hydrolase enzyme 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 to amino acids 36-490 of SEQ ID NO:1.

[0100] Aspect A33. The pharmaceutical composition of any one of aspects A1 to 32, wherein the endoglycosidase hydrolase enzyme comprises a hyaluronidase.

[0101] Aspect A34. The pharmaceutical composition of any one of aspects A1 to A33, wherein the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant, and any isoform thereof.

[0102] Aspect A35. The pharmaceutical composition of any one of aspects A1 to A34, wherein the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0103] Aspect A36. The pharmaceutical composition of any one of aspects A1 to A35, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase comprising one or more amino acid substitutions compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof.

[0104] Aspect A37. The pharmaceutical composition of any one of aspects A1 to A36, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase comprising one or more amino acid substitutions in the alpha-helical region compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof.

[0105] Aspect A38. The pharmaceutical composition of any one of aspects A1 to A37, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase comprising one or more amino acid substitutions in the linker region compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof.

[0106] Aspect A39. The pharmaceutical composition of any one of aspects A1 to A38, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase in which one or more N-terminal and / or C-terminal amino acids are deleted compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof.

[0107] Aspect A40. The pharmaceutical composition of any one of aspects A1 to 39, wherein the endoglycosidase hydrolase enzyme comprises a modified rHuPH20 comprising: i. one or more amino acid substitutions in the alpha-helical region, the linker region, or both the alpha-helical region and the linker region relative to wild-type rHuPH20; ii. a 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).

[0108] Aspect A41. A pharmaceutical composition according to any one of aspects A1 to 40, further comprising a tonicity adjusting agent and / or a stabilizer.

[0109] Aspect A42. The pharmaceutical composition of aspect A41, wherein the tonicity adjusting agent and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof.

[0110] Aspect A43. The pharmaceutical composition of aspect A41 or 42, wherein the tonicity agent and / or stabilizer comprises sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, or any combination thereof.

[0111] Aspect A44. The pharmaceutical composition of any one of aspects A41 to 43, wherein the tonicity adjusting agent comprises sucrose.

[0112] Aspect A45. A pharmaceutical composition according to any one of aspects A1 to 44 comprising at least about 10 mM to at least about 500 mM sucrose.

[0113] Embodiment A46. 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 46. ​​The pharmaceutical composition of any one of aspects A1 to 45, comprising 0 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.

[0114] Aspect A47. The pharmaceutical composition of any one of aspects A1 to 46, comprising about 250 mM sucrose.

[0115] Aspect A48. A pharmaceutical composition according to any one of aspects A1 to 47, further comprising a buffering agent.

[0116] Aspect A49. The pharmaceutical composition of Aspect A48, wherein the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate.

[0117] Aspect A50. The pharmaceutical composition of aspect A48 or 49, wherein the buffering agent comprises histidine.

[0118] 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.

[0119] Embodiment A52. The pharmaceutical composition of any one of embodiments 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 histidine.

[0120] Aspect A53. The pharmaceutical composition of any one of aspects A1 to 52, comprising about 20 mM histidine.

[0121] Aspect A54. A pharmaceutical composition according to any one of aspects A1 to 53, further comprising a surfactant.

[0122] 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.

[0123] Aspect A56. The pharmaceutical composition of aspect A54 or 55, wherein the surfactant comprises polysorbate 80.

[0124] Aspect A57. The pharmaceutical composition of any one of aspects A1 to 56, comprising at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80.

[0125] Embodiment A58. The pharmaceutical composition of any one of embodiments 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 of polysorbate 80.

[0126] Aspect A59. The pharmaceutical composition of any one of aspects A1 to 58, comprising about 0.05% w / v Polysorbate 80.

[0127] Embodiment A60. The pharmaceutical composition of any one of embodiments A1-35 and 41-59, comprising: (a) about 120 mg / mL of an 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 of rHuPH20.

[0128] Embodiment A61. The pharmaceutical composition of any one of embodiments A1-35 and 41-59, comprising: (a) about 120 mg / mL of an 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 of rHuPH20.

[0129] Embodiment A62. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 59, comprising: (a) about 150 mg / mL of an 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 of rHuPH20.

[0130] Embodiment A63. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 59, comprising: (a) about 150 mg / mL of an 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 of rHuPH20.

[0131] Aspect A64. The pharmaceutical composition of any one of aspects A1 to 63, 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.

[0132] Aspect A65. The pharmaceutical composition of any one of aspects A1 to 64, wherein the anti-PD-1 antibody is nivolumab.

[0133] Aspect A66. The pharmaceutical composition of any one of aspects A1 to 64, wherein the anti-PD-1 antibody is pembrolizumab.

[0134] Embodiment A67. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 65, 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 pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20.

[0135] Embodiment A68. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 65, 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 pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0136] Embodiment A69. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 65, 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 pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL rHuPH20.

[0137] Embodiment A70. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 65, 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 pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0138] Embodiment A71. The pharmaceutical composition of any one of embodiments A1-35 and 41-65, comprising: (a) about 672 mg of nivolumab; (b) about 8.68 mg of histidine; (c) about 11.8 mg of histidine HCl HO; (d) about 479 mg of sucrose; (e) about 2.80 mg of polysorbate 80; (f) about 0.110 mg of pentetic acid; (g) about 4.18 mg of methionine; and (h) about 0.102 mg of rHuPH20, wherein (a)-(h) are reconstituted in water to a final volume of at least about 5.6 mL.

[0139] Aspect A72. The pharmaceutical composition of any one of Aspects A1 to 71, comprising a pH of about 5.2 to about 6.8.

[0140] Aspect A73. The pharmaceutical composition of any one of aspects A1 to A72, 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.

[0141] Aspect A74. The pharmaceutical composition of any one of aspects A1 to 73, comprising a pH of about 6.0.

[0142] Aspect A75. The pharmaceutical composition of any one of aspects A1 to 74, further comprising a second therapeutic agent.

[0143] Aspect A76. The pharmaceutical composition of aspect A75, wherein the second therapeutic agent is an antibody.

[0144] Aspect A77. The pharmaceutical composition of aspect A76, wherein the second therapeutic agent is a checkpoint inhibitor.

[0145] Aspect A78. The pharmaceutical composition of aspect A77, wherein the checkpoint inhibitor is an 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.

[0146] Embodiment A79. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 78, 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 pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) an anti-CTLA-4 antibody.

[0147] Embodiment A80. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 78, 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 pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) an anti-CTLA-4 antibody.

[0148] Embodiment A81. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 78, 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 pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) an anti-LAG-3 antibody.

[0149] Embodiment A82. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 78, 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 pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) an anti-LAG-3 antibody.

[0150] Embodiment A83. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 78, 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 pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) an anti-TIM3 antibody.

[0151] Embodiment A84. The pharmaceutical composition of any one of embodiments A1 to 35 and 41 to 78, 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 pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL rHuPH20; and (h) an anti-TIM3 antibody.

[0152] Aspect A85. A vial comprising the pharmaceutical composition of any one of aspects A1 to 84.

[0153] Aspect A86. A syringe comprising the pharmaceutical composition of any one of aspects A1 to A84.

[0154] Aspect A87. An auto-injector comprising the pharmaceutical composition of any one of aspects A1 to A84.

[0155] Aspect A88. A wearable pump comprising the pharmaceutical composition of any one of aspects A1 to A84.

[0156] Embodiment A89. The syringe of embodiment A86, further comprising a plunger.

[0157] Aspect A90. A method of treating a disease or disorder in a subject in need thereof comprising administering to the subject a pharmaceutically effective amount of a pharmaceutical composition according to any one of aspects A1 to A84.

[0158] Aspect A91. The method of aspect A90, wherein the pharmaceutical composition is administered subcutaneously.

[0159] Embodiment A92. The method of embodiment A90 or 91, wherein the disease or disorder is an infectious disease.

[0160] Embodiment A93. The method of embodiment A90 or 91, wherein the disease or disorder is cancer.

[0161] Aspect A94. The cancer is 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, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, cervical cancer. The method of embodiment A93, wherein the cancer is selected from tumors of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, cancer of the rectum, solid tumors of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers including those induced by asbestos, virus-associated cancers or cancers of viral origin (e.g., tumors related to or originating from human papillomavirus (HPV)), and any combination thereof.

[0162] Embodiment 1. A method of treating a subject in need thereof, comprising subcutaneously administering to the subject an effective dose of a pharmaceutical composition comprising an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction of PD-1 and PD-L1 (an "anti-PD-1 antibody" or "anti-PD-L1 antibody", respectively); 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 the effective dose comprises at least about 250 mg to at least about 2400 mg of antibody.

[0163] Aspect B2. The method of Aspect B1, wherein the pharmaceutical composition does not contain hyaluronidase.

[0164] Aspect B3. The method of Aspect B1 or 2, wherein the effective dose comprises two or more subcutaneous unit doses, wherein the two or more subcutaneous unit doses are administered simultaneously or subsequently.

[0165] Aspect B4. The method of aspect B3, wherein two or more subcutaneous unit doses are administered subcutaneously, and wherein each of the two or more subcutaneous unit doses is administered within an interval of about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 9 hours, about 12 hours, about 18 hours, or about 24 hours between the two or more subcutaneous unit doses.

[0166] Aspect B5. The method of any one of aspects B1 to 4, wherein the effective dose is administered about every 1, 2, 3, or 4 weeks.

[0167] Embodiment B6. The method of any one of embodiments B1 to 5, wherein the antibody comprises an anti-PD-1 antibody.

[0168] Aspect B7. The method of any one of Aspects B1 to 6, wherein the effective dose of antibody is about 250 mg to about 600 mg of antibody administered about weekly.

[0169] Embodiment B8. The method of any one of embodiments 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, 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 administered about weekly.

[0170] Aspect B9. The method of any one of aspects B1 to 8, wherein the effective dose of the antibody is about 300 mg administered about weekly.

[0171] Aspect B10. The method of aspect B9, wherein the effective dose of the antibody comprises a single subcutaneous unit dose of about 300 mg.

[0172] Aspect B11. The method of aspect B9 or B10, wherein the effective dose of the antibody comprises a single subcutaneous unit dose of about 300 mg in a total dose volume of about 2 mL.

[0173] Embodiment B12. The method of embodiment B9, 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 antibody; or (ii) three subcutaneous unit doses, each of the three subcutaneous unit doses comprising about 100 mg of antibody.

[0174] Aspect B13. The method of aspect B12, wherein (i) at least one of the two subcutaneous unit doses comprises about 150 mg of 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 of antibody in a total volume of about 2 mL.

[0175] Embodiment B14. The method of embodiment B12 or 13, wherein (i) two subcutaneous unit doses are administered to the subject at two different physical locations, or (ii) at least two of the three subcutaneous unit doses are administered to the subject at at least two different physical locations.

[0176] Aspect B15. The method of any one of Aspects B1 to 6, wherein the effective dose of the antibody is from about 300 mg to about 900 mg administered about every two weeks.

[0177] Embodiment B16. An effective dose of an 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 administered about every two weeks. , 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.

[0178] 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.

[0179] Aspect B18. The method of aspect B17, wherein the effective dose of the antibody comprises a single subcutaneous unit dose.

[0180] Aspect B19. The method of aspect B17, wherein the effective dose of the antibody comprises 2, 3, or at least 4 subcutaneous unit doses.

[0181] Aspect B20. The method of aspect B17 or 19, wherein the effective dose of the antibody comprises two subcutaneous unit doses, each of the two subcutaneous unit doses comprising about 300 mg of the antibody.

[0182] Aspect B21. The method of aspect B20, wherein at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL.

[0183] Aspect B22. The method of any one of aspects B19-21, wherein at least two of the subcutaneous unit doses are administered to the subject at least two different bodily locations.

[0184] Aspect B23. The method of any one of Aspects B1 to 6, wherein the effective dose of the antibody is from about 900 mg to about 1500 mg administered about every four weeks.

[0185] Embodiment B24. An effective dose of an 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, 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 2000 mg, about 2010 mg, about 2020 mg, about 2030 mg, about 2040 mg, about 2050 mg, about 2060 mg, about 2070 mg, about 2080 mg, about 2090 mg, about 3000 mg, about 3100 mg, about 3110 mg, about 3120 mg, about 3130 mg, about 3140 mg, about 3150 mg, about 3160 mg, about 3170 mg, about 3180 mg, about 3190 mg, about 3200 mg, about 3210 mg, about 3220 mg, about 3230 mg, about 3240 mg, about 3250 mg, about 3260 mg, about 3270 mg, about 3280 mg, about 3300 mg The method of aspect B23, wherein the hydroxybenzoate is 240 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.

[0186] 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.

[0187] Aspect B26. The method of any one of aspects B23 to 25, wherein the effective dose of the antibody comprises 2, 3, 4, 6, or at least 8 subcutaneous unit doses.

[0188] Aspect B27. The method of any one of aspects B23 to 26, wherein the effective dose of the antibody comprises four subcutaneous unit doses, each of the four subcutaneous unit doses comprising about 300 mg of the antibody.

[0189] Aspect B28. The method of aspect B27, wherein at least one of the four subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL.

[0190] Aspect B29. The method of any one of aspects B26 to 28, wherein at least two of the subcutaneous unit doses are administered to the subject at least two different bodily locations.

[0191] Aspect B30. The method of any one of aspects B26 to 29 wherein 2, 3, 4, 6, or at least 8 subcutaneous unit doses are administered on the same day.

[0192] Aspect B31. The method of any one of aspects B1 to 5, wherein the antibody comprises an anti-PD-L1 antibody.

[0193] Aspect B32. The method of aspect B31 wherein the effective dose of the antibody is from about 900 mg to about 1800 mg of antibody administered about every two weeks.

[0194] Aspect B33. An effective dose of an antibody is about 900, about 950, about 1000, 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 2000 mg, about 2010 mg, about 2020 mg, about 2030 mg, about 2040 mg, about 2050 mg, about 2060 mg, about 2070 mg, about 2080 mg, about 2090 mg, about 3000 mg, about 3100 mg, about 3110 mg, about 3120 mg, about 3130 mg, about 3140 mg, about 3150 mg, about 3160 mg, about 3170 mg, about 3180 mg, about 3190 mg, about 3200 mg, about 3210 mg, about 3220 mg, about 3230 mg, about 3240 mg, about 3250 mg, about 3260 mg, about 3270 mg, about 3280 mg, about 3290 mg The method of embodiment B31 or B32, wherein the amount of the hydroxybenzoate is 0 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.

[0195] Aspect B34. The method of any one of aspects B31 to 33, wherein the effective dose of the antibody is about 1200 mg about every two weeks.

[0196] Aspect B35. The method of any one of aspects B31 to 34, wherein the effective dose comprises 2, 3, 4, 6, or at least 8 subcutaneous unit doses.

[0197] Aspect B36. The method of any one of aspects B31 to 35, wherein the effective dose of the antibody comprises four subcutaneous unit doses, each of the four subcutaneous unit doses comprising about 300 mg of the antibody.

[0198] Aspect B37. The method of aspect B36, wherein at least one of the four subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL.

[0199] Aspect B38. The method of any one of aspects B35 to 37, wherein at least two of the subcutaneous unit doses are administered to the subject at least two different bodily locations.

[0200] Aspect B39. The method of any one of aspects B35 to 38, wherein 2, 3, 4, 6, or at least 8 subcutaneous unit doses are administered on the same day.

[0201] 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, cemiplimab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, KN035, sasanlimab, and any combination thereof.

[0202] 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.

[0203] Aspect B42. The method of aspect B40, wherein the anti-PD-1 antibody comprises nivolumab.

[0204] Aspect B43 The method of aspect B40, wherein the anti-PD-1 antibody comprises pembrolizumab.

[0205] 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.

[0206] Aspect B45. The method of any one of aspects B1 to 44, wherein the subject is suffering from cancer.

[0207] Aspect B46. The cancer is 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, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, vaginal the cancer is selected from the group consisting of carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, cancer of the rectum, solid tumors of childhood, cancer of the ureter, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers including those induced by asbestos, virus-associated cancers or cancers of viral origin (e.g., tumors related to or originating from human papillomavirus (HPV)), and any combination thereof.

[0208] Aspect B47. The method of any one of aspects B1 to 46, wherein the pharmaceutical composition is administered using an auto-injector.

[0209] Aspect B48. The method of any one of aspects B1 to 46, wherein the pharmaceutical composition is administered using a wearable pump.

[0210] Aspect B49. The method of any one of aspects B1 to 48, wherein the pharmaceutical composition is administered to the subject by subcutaneous infusion for less than about 10 minutes.

[0211] Aspect B50. The method of any one of aspects B1 to 49, wherein the pharmaceutical composition is administered to the subject by subcutaneous infusion for less than about 5 minutes.

[0212] Aspect B51. The method of any one of aspects B1 to 50, wherein the pharmaceutical composition further comprises at least two antioxidants.

[0213] Aspect B52. The method of Aspect B51, wherein the at least two antioxidants are selected from methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA, and EDTA.

[0214] 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.

[0215] 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.

[0216] Embodiment B55. The method of any one of embodiments B51 to B54, 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.

[0217] Aspect B56. The method of any one of aspects B51 to 55, wherein the at least two antioxidants comprise about 5 mM methionine.

[0218] Embodiment B57. The method of any one of embodiments B51 to 56, wherein the at least two antioxidants comprise at least about 10 μM to about 200 μM DTPA.

[0219] Embodiment B58. The method of any one of embodiments B1 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.

[0220] Embodiment B59. The method of any one of embodiments B51 to 58, wherein the at least two antioxidants comprise about 50 μM DTPA.

[0221] 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.

[0222] 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 of the anti-PD-1 antibody.

[0223] 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 the anti-PD-1 antibody.

[0224] 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, 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 an anti-PD-1 antibody.

[0225] 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.

[0226] 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.

[0227] 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 stabilizer.

[0228] Aspect B67. The method of aspect B66, wherein the tonicity adjusting agent and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof.

[0229] Aspect B68. The method of aspect B66 or 67, wherein the tonicity adjusting agent 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.

[0230] Aspect B69. The method of any one of aspects B66 to 68, wherein the tonicity adjusting agent comprises sucrose.

[0231] Aspect B70. The method of any one of aspects B1 to 69, wherein the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose.

[0232] Embodiment B71. The pharmaceutical composition comprises a soluble ... 71. The method of any one of aspects B1 to 70, wherein the sucrose concentration is 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.

[0233] Aspect B72. The method of any one of aspects B1 to 71, wherein the pharmaceutical composition comprises about 250 mM sucrose.

[0234] Aspect B73. The method of any one of aspects B1 to 72, wherein the pharmaceutical composition further comprises a buffering agent.

[0235] Aspect B74. The method of Aspect B73, wherein the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate.

[0236] Aspect B75. The method of aspect B73 or 74, wherein the buffering agent comprises histidine.

[0237] 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.

[0238] Embodiment B77. The method of any one of embodiments 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 histidine.

[0239] Aspect B78. The method of any one of aspects B1 to 49, wherein the pharmaceutical composition comprises about 20 mM histidine.

[0240] Aspect B79. The method of any one of aspects B1 to 78, wherein the pharmaceutical composition further comprises a surfactant.

[0241] Aspect B80. The method of aspect B79, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188.

[0242] Aspect B81. The method of aspect B79 or 80, wherein the surfactant comprises polysorbate 80.

[0243] 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.

[0244] Embodiment B83. The method of any one of embodiments 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 of Polysorbate 80.

[0245] Aspect B84. The method of any one of aspects B1 to 83, wherein the pharmaceutical composition comprises about 0.05% w / v Polysorbate 80.

[0246] 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 methionine.

[0247] Embodiment B86. The method of any one of embodiments 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 methionine.

[0248] Aspect B87. The method of any one of Aspects B1 to 86, wherein the pharmaceutical composition comprises a pH of about 5.2 to about 6.8.

[0249] Aspect B88. The method of any one of aspects B1 to 87, wherein the pharmaceutical composition comprises 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.

[0250] Aspect B89. The method of any one of aspects B1 to 88, wherein the pharmaceutical composition comprises a pH of about 6.0.

[0251] Aspect B90. A pharmaceutical composition for use in a method according to any one of aspects B1 to 89.

[0252] Embodiment B91. A pharmaceutical composition comprising: (i) an antibody that specifically binds to PD-1 (an "anti-PD-1 antibody"), and (ii) at least two antioxidants.

[0253] Aspect B92. The pharmaceutical composition of aspect B91, wherein the at least two antioxidants are selected from methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, DTPA, and EDTA.

[0254] 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.

[0255] 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.

[0256] Embodiment B95. The pharmaceutical composition of any one of embodiments B91 to B94, 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.

[0257] Aspect B96. The pharmaceutical composition of any one of aspects B91 to 95, wherein the at least two antioxidants comprise about 5 mM methionine.

[0258] 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.

[0259] Embodiment B98. At least two antioxidants are 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. The pharmaceutical composition of any one of aspects B91-97, comprising 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.

[0260] Aspect B99. The pharmaceutical composition of any one of aspects B91 to 98, wherein the at least two antioxidants comprise about 50 μM DTPA.

[0261] Embodiment B100. The pharmaceutical composition of any one of embodiments B91-99 comprising at least about 20 mg / mL to at least about 200 mg / mL of the anti-PD-1 antibody.

[0262] 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 the anti-PD-1 antibody.

[0263] 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 the anti-PD-1 antibody.

[0264] Embodiment B103. The pharmaceutical composition of any one of embodiments B91 to B100 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 an anti-PD-1 antibody.

[0265] Aspect B104. The pharmaceutical composition of any one of aspects B91 to 103, comprising about 120 mg / mL of the anti-PD-1 antibody.

[0266] Aspect B105. The pharmaceutical composition of any one of aspects B91 to 103, comprising about 150 mg / mL of the anti-PD-1 antibody.

[0267] Aspect B106. The pharmaceutical composition of any one of aspects B91 to 105, further comprising a tonicity agent and / or a stabilizer.

[0268] Aspect B107. The pharmaceutical composition according to aspect B106, wherein the tonicity adjusting agent and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof.

[0269] Aspect B108. The pharmaceutical composition of aspect B106 or 107, wherein the tonicity adjusting agent 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.

[0270] Aspect B109. The pharmaceutical composition of any one of aspects B106 to 108, wherein the tonicity agent comprises sucrose.

[0271] Aspect B110. The pharmaceutical composition of any one of aspects B91-109, comprising at least about 10 mM to at least about 500 mM sucrose.

[0272] Embodiment B111 . 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 110, or at least about 500 mM sucrose.

[0273] Aspect B112. The pharmaceutical composition of any one of aspects B91-111, comprising about 250 mM sucrose.

[0274] Aspect B113. The pharmaceutical composition of any one of aspects B91 to 112, further comprising a buffering agent.

[0275] Aspect B114. The pharmaceutical composition according to aspect B113, wherein the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate.

[0276] Aspect B115. The pharmaceutical composition of aspect B113 or 114, wherein the buffering agent comprises histidine.

[0277] 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.

[0278] Embodiment B117. The pharmaceutical composition of any one of embodiments B91-116, 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 histidine.

[0279] Aspect B118. The pharmaceutical composition of any one of aspects B91-117, comprising about 20 mM histidine.

[0280] Aspect B119. The pharmaceutical composition of any one of aspects B91 to 118, further comprising a surfactant.

[0281] Aspect B120. The pharmaceutical composition according to aspect B119, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188.

[0282] Aspect B121. The pharmaceutical composition of aspect B119 or 120, wherein the surfactant comprises polysorbate 80.

[0283] Aspect B122. The pharmaceutical composition of any one of aspects B91 to B121 comprising at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80.

[0284] Embodiment B123. The pharmaceutical composition of any one of embodiments B91 to B122, 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.

[0285] Aspect B124. The pharmaceutical composition of any one of aspects B91 to B123, comprising about 0.05% w / v polysorbate 80.

[0286] Embodiment B125. The pharmaceutical composition of any one of embodiments B91-124, 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.

[0287] Embodiment B126. The pharmaceutical composition of any one of embodiments B91-124, 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.

[0288] Aspect B127. The pharmaceutical composition of any one of aspects B91-126, comprising a pH of about 5.2 to about 6.8.

[0289] Aspect B128. The pharmaceutical composition of any one of aspects B91-127, 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.

[0290] Aspect B129. The pharmaceutical composition of any one of aspects B91-128, comprising a pH of about 6.0.

[0291] Aspect B130. The pharmaceutical composition of any one of aspects B1 to 129, further comprising a second therapeutic agent.

[0292] Aspect B131. The pharmaceutical composition of aspect B130, wherein the second therapeutic agent is an antibody.

[0293] Aspect B132. The pharmaceutical composition of aspect B131, wherein the second therapeutic agent is a checkpoint inhibitor.

[0294] 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, 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, anti-GITR, or any combination thereof.

[0295] Aspect B134. A vial comprising the pharmaceutical composition of any one of aspects B87-133.

[0296] Aspect B135. A unit dose comprising the pharmaceutical composition of any one of aspects B87 to 133.

[0297] Embodiment 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.

[0298] Aspect B137. The vial of aspect B134 which is an auto-injector.

[0299] Aspect B138. An auto-injector comprising a unit dose according to aspect B135 or 136.

[0300] Embodiment B139. The vial of embodiment B134 which is a wearable device.

[0301] Aspect B140. A wearable device comprising a unit dose according to aspect B135 or 136. [Brief explanation of the drawings]

[0302] [Figure 1] 1 shows a graphical representation of data relating to the osmolality and viscosity of a nivolumab subcutaneous (SC) injection formulation as a function of sucrose concentration in the formulation according to Example 1. The X-axis represents sucrose concentration in mM, and the Y-axis represents the osmolality of the formulation in mOsm / kg. The solid circles and solid lines represent osmolality values, and the solid Xs and dashed lines represent viscosity values. [Figure 2] 2 shows a graphical representation of data relating to the effect of 75 mM added arginine on the viscosity of nivolumab subcutaneous (SC) injection formulations according to Example 1. The X-axis represents protein concentration in mg / mL and the Y-axis represents viscosity in cP at 20° C. Filled squares represent samples with added arginine and filled diamonds represent samples without added arginine. [Figure 3] Figure 3 is a schematic diagram of a study directed at evaluating the safety and efficacy of various doses of subcutaneously administered anti-PD-1 antibody (e.g., nivolumab) alone or in combination with hyaluronidase (e.g., rHuPH20). [Figure 4] Figure 4 is a line graph diagram of the predictive check of the combined SC / IV PPK model for administration of nivolumab. Individual dots represent observed data. Lines represent the 5th, 50th, and 95th percentiles of the observed data, respectively. Shaded areas represent the 90% CI based on simulations of the 5th (lowest trend line), 50th (middle trend line), and 95th percentiles (top trend line) of the predicted data. Conc = concentration; Nivo = nivolumab; Pred-Corr = predicted corrected. [Figure 5A] Figures 5A-5C are box plots illustrating the predicted geometric mean ratios (SC / IV) of Cavgd28 (Figure 5A), Cmind28 (Figure 5B), and Cmax1 (Figure 5C) exposure by tumor type: CRC = colorectal cancer, HCC = hepatocellular carcinoma, Mel = melanoma, NSCLC = non-small cell lung cancer, and RCC = renal cell carcinoma. [Figure 5B] Figures 5A-5C are box plots illustrating the predicted geometric mean ratios (SC / IV) of Cavgd28 (Figure 5A), Cmind28 (Figure 5B), and Cmax1 (Figure 5C) exposure by tumor type: CRC = colorectal cancer, HCC = hepatocellular carcinoma, Mel = melanoma, NSCLC = non-small cell lung cancer, and RCC = renal cell carcinoma. [Figure 5C] Figures 5A-5C are box plots illustrating the predicted geometric mean ratios (SC / IV) of Cavgd28 (Figure 5A), Cmind28 (Figure 5B), and Cmax1 (Figure 5C) exposure by tumor type: CRC = colorectal cancer, HCC = hepatocellular carcinoma, Mel = melanoma, NSCLC = non-small cell lung cancer, and RCC = renal cell carcinoma. [Figure 6] FIG. 6 is a schematic diagram of a study directed at evaluating the safety and efficacy of 1200 mg of nivolumab in combination with hyaluronidase (e.g., rHuPH20) administered subcutaneously once every four weeks compared to 3 mg / kg of nivolumab administered IV once every two weeks. [Figure 7]Figure 7 is a box plot illustrating the distribution of nivolumab Cmind28 across dose and body weight for nivolumab 3 mg / kg IV every 2 weeks, nivolumab 10 mg / kg IV every 2 weeks, and nivolumab 1200 mg subcutaneously every 4 weeks. [Figure 8] 8A-8C are box plots illustrating the observed distribution of Cavg (FIG. 8A), Ctau (FIG. 8B), and Cmax (FIG. 8C) by weight observed after subcutaneous delivery of 720 mg, 960 mg, or 1200 mg of nivolumab with rHuPH20. Dashed lines indicate the geometric mean Cavg (FIG. 8A) and Ctau (FIG. 8B) of nivolumab 3 mg / kg IV Q2W (historical) and the geometric mean Cmax (FIG. 8C) of nivolumab 10 mg / kg IV Q2W (historical). [Figure 9A] Figures 9A-9B show tumor-infiltrating lymphocyte CD8 expression (Figure 9A) and PD-L1 tumor expression (Figure 9B) 14 days after the first subcutaneous dose of nivolumab and rHuPH20 (Parts A, B, and D) in subjects with non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma (Mel), hepatocellular carcinoma (HCC), and microsatellite instability-high / mismatch repair deficient colorectal cancer (MSI-H / dMMR CRC). [Figure 9B] Figures 9A-9B show tumor-infiltrating lymphocyte CD8 expression (Figure 9A) and PD-L1 tumor expression (Figure 9B) 14 days after the first subcutaneous dose of nivolumab and rHuPH20 (Parts A, B, and D) in subjects with non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma (Mel), hepatocellular carcinoma (HCC), and microsatellite instability-high / mismatch repair deficient colorectal cancer (MSI-H / dMMR CRC). [Figure 10]Figure 10 is a graphical representation of the effect of headspace nitrogen and air on the % HMW species of Nivo by SEC after combined metal, peroxide, and light stress with 30°C heat stress in Study 1. RT / light is continuous light stress, while the other light stress conditions are of 3-day duration. Formulations 1 (air) and 6 (nitrogen) have: 50 μM DTPA 5 mM Met; Formulations 2 (air) and 7 (nitrogen) have: 0 μM DTPA, 0 mM Met. All formulations also contain 120 mg / mL Nivo with 2,000 U / mL rHuPH20, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0. [Figure 11] Figure 11 is a graphical representation of the effect of various stress conditions on the % HMW species of Nivo by SEC after combined metal, peroxide, and light stress with 30°C heat stress in Study 1. RT / light is continuous light stress, while the other light stress conditions are of 3-day duration. Formulation 1: 50 μM DTPA, 5 mM Met; Formulation 2: 0 μM DTPA, 0 mM Met; Formulation 3: 0 μM DTPA, 5 mM Met; Formulation 4: 50 μM DTPA, 0 mM Met; and Formulation 5: 100 μM EDTA, 5 mM Met. All formulations also contain 120 mg / mL Nivo with 2,000 U / mL rHuPH20, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0. [Figure 12]Figure 12 is a graphical representation of HMW formation under metals—0.5 ppm each of iron, chromium, and copper—+light (100 lux at room temperature + 1 mM peroxide + 30°C heat stress for 3 days) in Study 1. Note: Formulations 1 (air) and 6 (nitrogen) are completely on top of each other and have the least HMW formation with identical formulation compositions. Formulations 1 (air) and 6 (nitrogen): 50 μM DTPA, 5 mM Met; Formulations 2 (air) and 7 (nitrogen): 0 μM DTPA, 0 mM Met; Formulation 3: 0 μM DTPA, 5 mM Met; Formulation 4: 50 μM DTPA, 0 mM Met; and Formulation 5: 100 μM EDTA, 5 mM Met. All formulations also contain 2,000 U / mL rHuPH20 along with 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0. [Figure 13] Figure 13 is a graphical representation of the %HMW in Study 1 after 3 months under various combinations of metals (0.5 ppm each iron, chromium, and copper), light (1000 lux at room temperature for 3 days), and peroxide (1 mM peroxide) with heat stress at 30°C, by formulation composition with and without 5 mM Met and 50 μM DTPA and 100 μM EDTA. All formulations also contain 120 mg / mL Nivo with 2,000 U / mL rHuPH20, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0. [Figure 14] Figure 14 is a graphical representation of HMW% in Study 1 after 3 months under various combinations of metals (0.5 ppm each iron, chromium, and copper), light (1000 lux at room temperature for 3 days), and peroxide (1 mM peroxide), with 30°C heat stress included in the main effects statistical model. The graph is separated by formulation composition with / without 5 mM Met and 50 μM DTPA. All formulations also contain 120 mg / mL Nivo with 2,000 U / mL rHuPH20, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0. [Figure 15]Figure 15 is a graphical representation of rHuPH20 enzyme activity in Study 1 after 3 days of storage at RT / dark followed by 30°C / dark [control—left], 3 days of storage at RT / RL with metal and peroxide addition followed by 30°C / dark [MPL—center], and room temperature / room light [RT / light—right]. Formulations 1 (air) and 6 (nitrogen): 50 μM DTPA, 5 mM Met; Formulations 2 (air) and 7 (nitrogen): 0 μM DTPA, 0 mM Met; Formulation 3: 0 μM DTPA, 5 mM Met; Formulation 4: 50 μM DTPA, 0 mM Met. All formulations also contain 2,000 U / mL rHuPH20 along with 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0. [Figure 16] Figures 16A-16F are graphical representations of the distribution of formulations from Study 2. The formulations were at the maximum and minimum range of excipients, and all other factors were at the target composition of 120 mg / mL Nivo (Figure 16A), 20 mM histidine (Figure 16C), 250 mM sucrose, 50 μM DTPA (Figure 16D), 5 mM Met (Figure 16E), 2,000 U / mL rHPH20 (Figure 16F), 0.05% w / v PS80, pH 6.0 (Figure 16B). [Figure 17] Figure 17 is a graphical representation of high molecular weight species by SEC at various time points up to 6 months for 0-200 μM DTPA at 25°C, 35°C, and MPL and RT / RL stress conditions in Study 2. The composition includes: 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 5 mM Met, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0. [Figure 18] Figure 18 is a graphical representation of high molecular weight species by SEC at various time points up to 6 months for 25°C, 35°C, and MPL and RT / RL stress conditions, separated by formulation DTPA and Met concentration in Study 2. The composition includes: 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0. [Figure 19]Figure 19 is a graphical representation of high molecular weight species by SEC at various time points up to 6 months, separated by formulation DTPA and Met concentration in Study 2. The composition includes: 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0. [Figure 20] FIG. 20 is a graphical representation of SEC HMW% and smooth curve trend estimates versus methionine concentration for the three last sampled stress conditions: 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 50 μM DTPA, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0. [Figure 21] Figures 21A-21C are graphical representations of linear regression models of total HMW% after 6 months at 25°C (Figure 21A), 3 months at 35°C (Figure 21B), and 3 months with MPL stress (Figure 21C) as a function of Met level, with performance matching of a formulation containing 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 50 μM DTPA, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0. [Figure 22A] Figures 22A-22B are graphical representations of acidic species as a function of time under MPL conditions (Figure 22A) and 35°C stress (Figure 22B). Duplicate samples of formulations with DTPA and Met and of DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulations are 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, pH 6.0. [Figure 22B]Figures 22A-22B are graphical representations of acidic species as a function of time under MPL conditions (Figure 22A) and 35°C stress (Figure 22B). Duplicate samples of formulations with DTPA and Met and of DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulations are 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, pH 6.0. [Figure 23A] Figures 23A-23B are graphical representations of enzyme activity as a function of time under MPL conditions (Figure 23A) and 35°C stress (Figure 23B). Duplicate samples of a formulation with DTPA and Met and of DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulation is 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, pH 6.0. [Figure 23B] Figures 23A-23B are graphical representations of enzyme activity as a function of time under MPL conditions (Figure 23A) and 35°C stress (Figure 23B). Duplicate samples of a formulation with DTPA and Met and of DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulation is 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, pH 6.0. [Figure 24A] Figures 24A-24B are graphical representations of PS80 levels as a function of time under MPL conditions (Figure 24A) and 35°C stress (Figure 24B). Duplicate samples of a formulation with DTPA and Met and of DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulation is 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, pH 6.0. [Figure 24B]Figures 24A-24B are graphical representations of PS80 levels as a function of time under MPL conditions (Figure 24A) and 35°C stress (Figure 24B). Duplicate samples of a formulation with DTPA and Met and of DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulation is 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, pH 6.0. [Figure 25A] Figure 25A is a graphical representation illustrating a comparison across Studies 1, 2, and 3 of high molecular weight species by SEC at 3 months in MPL conditions, separated by various Met levels with and without 2,000 U / mL rHuPH20 enzyme. Figure 25B is a regression plot using Studies 1, 2, and 3 for high molecular weight species by SEC at 3 months in MPL conditions as a function of Met. The composition includes 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 50 μM DTPA, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0 (Figures 25A-25B). [Figure 25B] Figure 25A is a graphical representation illustrating a comparison across Studies 1, 2, and 3 of high molecular weight species by SEC at 3 months in MPL conditions, separated by various Met levels with and without 2,000 U / mL rHuPH20 enzyme. Figure 25B is a regression plot using Studies 1, 2, and 3 for high molecular weight species by SEC at 3 months in MPL conditions as a function of Met. The composition includes 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 50 μM DTPA, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0 (Figures 25A-25B). [Figure 26] FIG. 26 is a bar graph providing a comparison of the log 10 (kd) of glycine, mannitol, sucrose, trehalose, and succinate as indicated. [Figure 27]FIG. 27 is a bar graph showing the average counts of the number of excipient molecules interacting with the nivolumab Fab group during the last 8 ns of MD simulations of glycine, sorbitol, trehalose, mannitol, and sucrose as indicated. [Figure 28] Figures 28A-28E are illustrations of the binding poses found for each of glycine (Figure 28A), sorbitol (Figure 28B), mannitol (Figure 28C), sucrose (Figure 28D), and trehalose (Figure 28E) on nivolumab Fab. Fab groups are shown as ribbons, loosely binding poses are shown in ball-and-stick representation, and tightly binding poses are shown in space-fill representation. [Figure 29A] Figures 29A-29B are bar graphs illustrating the number of unique binding poses found for each excipient (glycine, sorbitol, trehalose, mannitol, and sucrose) in MD simulations of medium strength interactions (Figure 29A) and strong binding interactions (Figure 29B). [Figure 29B] Figures 29A-29B are bar graphs illustrating the number of unique binding poses found for each excipient (glycine, sorbitol, trehalose, mannitol, and sucrose) in MD simulations of medium strength interactions (Figure 29A) and strong binding interactions (Figure 29B). DETAILED DESCRIPTION OF THE INVENTION

[0303] Detailed Description of the Disclosure Current methods of delivering anti-PD-1 and / or anti-PD-L1 antibodies require regular intravenous administration administered by a clinician, often in a clinic or hospital. This regimen often poses significant inconvenience to patients, and the nature of the treatment itself can negatively impact the patient experience. Subcutaneous delivery, such as through the use of an auto-injector or wearable pump, could significantly improve patient compliance, potentially allowing patients to receive this potentially life-saving therapy from the comfort of their own homes. The present disclosure provides methods of treating a subject in need thereof, comprising subcutaneously administering to the subject (i) a dose of a pharmaceutical composition comprising an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction of PD-1 and PD-L1 (an "anti-PD-1 antibody" or "anti-PD-L1 antibody," respectively). In some embodiments, the pharmaceutical composition further comprises (ii) an endoglycosidase hydrolase enzyme. In some embodiments, the dose comprises one or more subcutaneous unit doses.

[0304] In some embodiments, the pharmaceutical composition does not include an endoglycosidase hydrolase enzyme. In some embodiments, 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 embodiments, the dose comprises at least about 250 mg to at least about 2400 mg of antibody.

[0305] I. Terminology In order that this disclosure may be more readily understood, certain terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0306] Whenever an embodiment is described herein using the word "comprising," it is understood that otherwise similar embodiments described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0307] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art in the technical field to which this disclosure pertains.For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary for many of the terms used in this disclosure.

[0308] Units, prefixes, and symbols are denoted in their International System of Units (SI) recognized form. 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 the amino to carboxy direction. The headings provided herein are not limitations of the various aspects of this disclosure, which may be had by reference to the specification in its entirety. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0309] "Administering" refers to the physical introduction of a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Administration can refer to any form of administration for immunotherapy, e.g., an anti-PD-1 antibody or anti-PD-L1 antibody, including intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, e.g., by injection or infusion. The terms "subcutaneous administration" and "subcutaneous injection" are used interchangeably and refer to a mode of administration in which a substance, e.g., a composition containing an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction of PD-1 and PD-L1, is delivered to a subject beneath the skin, between the dermis and, e.g., muscle.

[0310] Subcutaneous administration can be achieved using any method. In some embodiments, subcutaneous administration is achieved using a short needle or multiple short needles. In some embodiments, the needle or at least one of the multiple 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, or less than about 1 / 2 inch. In some embodiments, the needle or at least one of the multiple needles is about 5 / 8 inch long.

[0311] Administering can be carried out, for example, once, multiple times, and / or over one or more extended periods of time. Thus, as used herein, administering can refer to a single unit dose or more than one unit dose.

[0312] As used herein, the term "dose" or "dosage" is defined as the amount of a therapeutic agent that can be administered at a given time. A dose or dosage may be sufficient to achieve or at least partially achieve a desired effect, although such a desired effect may be invisible or undetectable. A "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, promotes disease regression as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, an increase in overall survival (the length of time a patient diagnosed with the disease is still alive, from either the date of diagnosis or the start of treatment for a disease such as cancer), or prevention of functional impairment or disability due to the disease. An amount or dosage of a drug includes a "prophylactically effective amount" or "prophylactically effective dosage," which is any amount of drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing or experiencing a recurrence of a disease, inhibits the onset or recurrence of the disease. The ability of a therapeutic agent to promote disease regression or inhibit the onset or recurrence of disease can be evaluated using a variety of methods available to those skilled in the art, such as by assaying the activity of the agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays. A "dose" can include a single unit dose or multiple unit doses. In some embodiments, a dose includes a single unit dose. In some embodiments, a dose includes multiple unit doses.

[0313] As used herein, a subcutaneous "unit dose" refers to a single amount of a substance delivered by subcutaneous injection, for example, from a single vial, a single auto-injector, and / or a single syringe. In some embodiments, 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 embodiments, each unit dose of a therapeutically effective dose is administered on the same day. Each unit dose can be administered to the same or different physical locations. In some embodiments, a first unit dose is administered to a first physical location, and a second unit dose is administered to a second physical location. Any physical location known in the art that is suitable for subcutaneous delivery can be used in the methods disclosed herein. In some embodiments, at least one subcutaneous unit dose of the dose is administered to a physical location selected from the arm (e.g., the side or back of the upper arm), the abdomen, and the front of the thigh.

[0314] As used herein, an "adverse event" (AE) is any unfavorable, generally unintended, or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, an adverse event may be associated with immune system activation or an increase in immune system cells (e.g., T cells) in response to the treatment. A medical treatment may have one or more associated AEs, and each AE may have the same or different levels of severity. Reference to a method that may "modify an adverse event" refers to a treatment regimen that reduces the occurrence and / or severity of one or more AEs associated with the use of a different treatment regimen.

[0315] The term "antibody" (Ab) is intended to include, without limitation, a glycoprotein immunoglobulin, or antigen-binding portion thereof, that specifically binds to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain comprises 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 comprises 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 regions of hypervariability, termed complementarity-determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). Each VH and VL comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component of the classical complement system (C1q). Thus, the term "anti-PD-1 antibody" includes whole antibodies having two heavy chains and two light chains that specifically bind to PD-1, as well as antigen-binding portions of whole antibodies. Non-limiting examples of antigen-binding portions are provided elsewhere herein.

[0316] Immunoglobulins can be derived from any of the commonly known isotypes, 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 IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by the heavy chain constant region gene. The term "antibody" includes, by way of example, both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human or non-human antibodies; fully synthetic antibodies; and single-chain antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans. Unless explicitly stated and unless the context indicates otherwise, the term "antibody" also includes antigen-binding fragments or portions of any of the aforementioned immunoglobulins, including monovalent and bivalent fragments or portions, as well as single-chain antibodies.

[0317] In some embodiments, an "antibody" of the present disclosure can bind to more than one antigen, e.g., a "multispecific" or "bispecific" antibody. As used herein, a "bispecific" antibody is an antibody that can specifically bind to two antigens, where the first and second antigens are the same or different. As used herein, a "multispecific" antibody can specifically bind to more than one antigen, e.g., at least two (i.e., a "bispecific" antibody), at least three (i.e., a "trispecific" antibody), at least four, at least five, or at least six antigens. Various 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. In some embodiments, the multispecific antibody is a T cell-dependent bispecific antibody. In some embodiments, the multispecific antibody is an anti-FcRH5 / CD3 bispecific antibody that targets B cell lineage markers, FcRH5, and CD3, e.g., for use in treating multiple myeloma.

[0318] In some aspects, the "antibodies" of the present disclosure are engineered to be activated at the target site, e.g., a "probody." In some aspects, the antibody, e.g., probody, is proteolytically cleaved in the target tissue (e.g., tumor).

[0319] An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds PD-1 is substantially free of antibodies that specifically bind to antigens other than PD-1). However, an isolated antibody that specifically binds PD-1 may have cross-reactivity to other antigens, such as PD-1 molecules from different species. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0320] The term "monoclonal antibody" (mAb) refers to a non-naturally occurring preparation of antibody molecules of single molecular composition, i.e., antibody molecules essentially identical in primary sequence and displaying a single binding specificity and affinity for a particular epitope. Monoclonal antibodies are examples of isolated antibodies. Monoclonal antibodies may be produced by hybridoma, recombinant, transgenic, or other techniques known to those skilled in the art.

[0321] A "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. The human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, the term "human antibody," as used herein, 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 terms "human antibody" and "fully human antibody" are used interchangeably.

[0322] A "humanized antibody" refers to an antibody in which some, most, or all of the amino acids outside the CDRs of a non-human antibody have been replaced with the corresponding amino acids from a human immunoglobulin. In one embodiment of a humanized form of an antibody, some, most, or all of the amino acids outside the CDRs have been replaced with amino acids from a human immunoglobulin, while some, most, or all of the amino acids within one or more CDRs remain unchanged. Small additions, deletions, insertions, substitutions, or modifications of amino acids are permissible as long as they do not destroy the antibody's ability to bind to a specific antigen. A "humanized antibody" retains antigen specificity similar to that of the original antibody.

[0323] "Chimeric antibody" refers to an antibody whose variable region is derived from one species and whose constant region is derived from another species, such as an antibody whose variable region is derived from a mouse antibody and whose constant region is derived from a human antibody.

[0324] An "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.

[0325] An "antigen-binding portion" (also called 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 bound by the whole antibody. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody, such as an anti-PD-1 antibody or anti-PD-L1 antibody described herein, include: (i) a Fab fragment (a papain fragment) or similar monovalent fragment consisting of the VL, VH, LC, and CH1 domains; (ii) a F(ab')2 fragment (a pepsin fragment) or similar bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of the VH domain [Ward et al., (1989) Nature 341:544-546]; (vi) an isolated complementarity-determining region (CDR); and (vii) a combination of two or more isolated CDRs, which may be conveniently joined by a synthetic linker. Furthermore, although the two domains, VL and VH, of an Fv fragment are encoded by separate genes, they can be joined by a synthetic linker using recombinant techniques, allowing them to be produced as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as a single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antigen-binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.

[0326] "Cancer" refers to a broad group of diverse diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth leads to the formation of malignant tumors that can invade nearby tissues and even metastasize to distant parts of the body through the lymphatic system or bloodstream.

[0327] The term "immunotherapy" refers to the treatment of a subject afflicted with a disease or at risk of contracting or experiencing a recurrence of a disease by methods that involve inducing, enhancing, suppressing, or otherwise modifying the immune response. "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the onset, progression, development, severity, or recurrence of symptoms, complications, or conditions, or biochemical manifestations associated with a disease.

[0328] "Programmed death-1" (PD-1) refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is primarily expressed on pre-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 homologs of hPD-1, as well as analogs that share at least one epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank accession number U64863.

[0329] "Programmed death-ligand-1" (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2) that downregulates T cell activation and cytokine secretion upon binding to PD-1. The term "PD-L1," as used herein, includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, as well as analogs that share at least one epitope with hPD-L1. The complete hPD-L1 sequence can be found under GenBank accession number Q9NZQ7. Human PD-L1 protein is encoded by the human CD274 gene (NCBI Gene ID: 29126).

[0330] As used herein, "hyaluronidase" refers to an enzyme that can catalyze the cleavage of hyaluronan. Hyaluronan is a repeating polymer of N-acetyl-glucosamine and glucuronic acid that exists in the subcutaneous space and contributes to the soluble gel-like component of the skin's extracellular matrix, recovering through rapid turnover (resynthesis). In some embodiments, the hyaluronidase comprises rHuPH20, a glycosylated 447-amino acid single-chain polypeptide that locally depolymerizes hyaluronan in the subcutaneous space at the site of injection into the skin. Depolymerization of hyaluronan by hyaluronidase is accomplished by hydrolysis of the polysaccharide polymer. Depolymerization of hyaluronan results in a transient decrease in the viscosity of the gel-like phase of the extracellular matrix and an increase in hydrodynamic 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 embodiments, the hyaluronidase comprises ENHANZE™.

[0331] A "subject" 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 a preferred embodiment, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0332] The use of the term "flat dose" in connection with the methods and dosages of the present disclosure refers to a dose administered to a patient regardless of the patient's weight or body surface area (BSA). Thus, a flat dose is not provided as a mg / kg dose, but rather as an absolute amount of an agent (e.g., an anti-PD-1 antibody). For example, a 60 kg person and a 100 kg person would receive the same dose of antibody (e.g., 240 mg of an anti-PD-1 antibody).

[0333] The term "weight-based dose" referred to herein means that the dose administered to a patient is calculated based on the patient's weight. For example, if a patient weighing 60 kg requires 3 mg / kg of anti-PD-1 antibody, an appropriate amount of anti-PD-1 antibody (i.e., 180 mg) can be calculated and used for administration.

[0334] By way of example, an "anti-cancer drug" promotes cancer regression in a subject. In some embodiments, a therapeutically effective amount of a drug promotes cancer regression to the point of eliminating the cancer. "Promoting cancer regression" means that administering a therapeutically effective amount of a drug, alone or in combination with an anti-neoplastic agent, results in a decrease in tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of disease symptom-free periods, or prevention of functional impairment or disability due to the disease. Additionally, the terms "effective" and "efficacy" with respect to treatment include both pharmacological efficacy 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 or other adverse physiological effects (adverse effects) at the cellular, organ, and / or organismal level resulting from the administration of a drug.

[0335] For example, for tumor treatment, a therapeutically effective amount of an anticancer drug preferably inhibits cell growth or tumor growth by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% compared to untreated subjects. In other preferred embodiments of the present disclosure, tumor regression can be observed and can last 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 measurement results for therapeutic efficacy, the evaluation of immunotherapeutic agents must also take into account immune-related response patterns.

[0336] "Immune response," as understood in the art, generally refers to a biological response in a vertebrate to foreign agents or abnormal, e.g., cancerous, cells, which response protects the organism from these agents and the diseases they cause. The immune response is mediated by one or more cells of the immune system (e.g., T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells, or neutrophils) and soluble macromolecules produced by any of these cells, or the action of the liver (including antibodies, cytokines, and complement), which selectively target, bind to, damage, destroy, and / or eliminate from the vertebrate body invading pathogens, pathogen-infected cells or tissues, cancerous or 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 inhibition of T cells, such as effector T cells, Th cells, CD4+ cells, CD8+ T cells, or Treg cells, or the activation or inhibition of any other cells of the immune system, such as NK cells.

[0337] " Immune-related response pattern " refers to the clinical response pattern that is often observed in cancer patients who are treated with immunotherapeutic agents, which induce cancer-specific immune responses or modify natural immune processes to produce anti-tumor effects.This response pattern is characterized by an initial increase in tumor burden or the appearance of new lesions, followed by a beneficial therapeutic effect, which in the evaluation of traditional chemotherapy drugs would be classified as disease progression and would be synonymous with drug failure.Therefore, the proper evaluation of immunotherapeutic agents may require long-term monitoring of the effect of these agents on target diseases.

[0338] As used herein, the term "stable" in reference to a formulation or drug product means that the antibody, antibodies, or molecules therein essentially retain their physical and chemical stability and integrity upon storage. The stability of a formulation herein can be measured at a selected temperature after a selected period of time. For example, aggregate formation or an increase in low molecular weight species is an indicator of instability. Retention of original clarity and / or color throughout shelf life is also an indicator utilized to monitor stability. In some embodiments, a "stable" drug product is one in which the increase in aggregation, as measured by the increase in percentage of high molecular weight species (%HMW), is less than about 5%, preferably less than 3%, when the formulation is stored at 2-8°C for at least about one year.

[0339] The terms "treat," "treating," and "treatment," as used herein, refer to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, or slowing or preventing the progression, onset, severity, or recurrence of symptoms, complications, conditions, or biochemical manifestations associated with a disease, or enhancing overall survival. Treatment can be of subjects with disease or subjects without disease (e.g., for prophylaxis).

[0340] As used herein, the terms "about every week," "about every 2 weeks," or any other similar dosing interval term are intended to be approximations. "About every week" can include every 7 days ± 1 day, i.e., every 6 to 8 days. "About every 2 weeks" can include every 14 days ± 3 days, i.e., every 11 to 17 days. Similar approximations apply, for example, to about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, and about every 12 weeks. In some embodiments, a dosing interval of about every 6 weeks or about every 12 weeks means that the first dose can be administered on any day in the first week, and then the next dose can be administered on any day in the 6th or 12th week, respectively. In other embodiments, a dosing interval of about every 6 weeks or about every 12 weeks means that the first dose is administered on a specific day (e.g., Monday) in the first week, and then the next dose is administered on the same day (i.e., Monday) in the 6th or 12th week, respectively. When a dose is reached by administering multiple subcutaneous unit doses, the dosing interval refers to the period between the 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, when the method includes administering a dose of about 600 mg administered approximately every two weeks, the antibody dose includes two subcutaneous unit doses, each of which contains about 300 mg of antibody, and the first subcutaneous unit dose of about 300 mg of the first effective dose of the antibody is administered on day 1, and the first subcutaneous unit dose of about 300 mg of the second effective dose of the antibody is administered on about day 14.In this example, the second unit dose of about 300 mg of the first effective dose of the antibody can be administered on day 1 or at any other time before the administration of the first subcutaneous unit dose of about 300 mg of the second effective dose of the antibody.

[0341] The use of "alternatives" (e.g., "or") should be understood to mean either one or both of the alternatives, or any combination thereof. As used herein, the indefinite articles "a" or "an" should be understood to refer to "one or more" of any named or listed components.

[0342] The term "about" or "essentially consisting of" refers to a value or composition that is 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 the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "essentially consisting of" can mean within or more than 1 standard deviation, per practice in the art. Alternatively, "about" or "essentially consisting of" can mean a range of up to 10%. Furthermore, particularly with respect to biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. When a particular value or composition is provided in this application and claims, unless otherwise specified, the meaning of "about" or "essentially consisting of" should be inferred to be within an acceptable error range for that particular value or composition.

[0343] As described herein, any concentration range, percentage range, ratio range, or integer range should be understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as integer tenths and hundredths), unless otherwise indicated.

[0344] Various aspects of the disclosure are described in further detail in the following subsections.

[0345] II. Compositions of the Present Disclosure Some embodiments of the present disclosure are directed to pharmaceutical compositions comprising (i) an antibody, or antigen-binding portion thereof, and (ii) at least two antioxidants. In some embodiments, more than one antioxidant, e.g., two antioxidants, prevents oxidation of formulation components and / or improves antibody stability. In some embodiments, the antibody, or antigen-binding portion thereof, is a checkpoint inhibitor. In some embodiments, the antibody, or antigen-binding portion thereof, specifically binds to PD-1 (an "anti-PD-1 antibody"). In some embodiments, the pharmaceutical composition is formulated for subcutaneous administration. In some embodiments, the pharmaceutical composition further comprises (iii) an endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition does not comprise an endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition comprises at least two antibodies, or antigen-binding portions thereof.

[0346] Pharmaceutical compositions comprising anti-PD-1 antibodies or anti-PD-L1 antibodies are also within the scope of this disclosure. In some embodiments, the pharmaceutical compositions are formulated for subcutaneous administration according to the methods disclosed herein. In some embodiments, the pharmaceutical compositions are formulated such that they exhibit improved properties compared to compositions without two antioxidants or at least one antioxidant.

[0347] Therapeutic agents of the present disclosure can be formulated into compositions, such as pharmaceutical compositions containing an antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. Preferably, carriers for antibody-containing compositions are suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion), while carriers for antibody- and / or cytokine-containing compositions are suitable for non-parenteral administration, e.g., oral administration.

[0348] In some embodiments, 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 adjuster or stabilizer, (iv) a buffering agent, and (v) a surfactant. In some embodiments, 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 adjuster or stabilizer, (iv) a buffering agent, (v) a surfactant, and (vi) an endoglycosidase hydrolase enzyme. In some embodiments, the antibody is a bispecific antibody or a multispecific antibody.

[0349] In some embodiments, the pharmaceutical composition comprises (i) a first antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody), (ii) at least two antioxidants, (iii) a tonicity adjuster or stabilizer, (iv) a buffering agent, and (v) a surfactant. In some embodiments, 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 adjuster or stabilizer, (iv) a buffering agent, (v) a surfactant, (vi) a second antibody or antigen-binding portion thereof, and (vii) an endoglycosidase hydrolase enzyme. In some embodiments, the first antibody is a bispecific or multispecific antibody.

[0350] II.A. Antibodies and Antigen-Binding Moieties In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof. The pharmaceutical compositions described herein may comprise any antibody or antigen-binding portion thereof. In some embodiments, the antibody or antigen-binding portion thereof is a checkpoint inhibitor. In some embodiments, the antibody or antigen-binding portion thereof specifically binds to a checkpoint protein. In some embodiments, the antibody or antigen-binding portion thereof specifically binds to a protein 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 embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises an anti-CTLA-4 antibody. In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises an anti-TIM3 antibody.

[0351] In some embodiments, the antibody is a multispecific antibody. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody is a trispecific antibody. In some embodiments, the antibody specifically binds to (i) PD-1 and (ii) a second antigen. In some embodiments, the antibody specifically binds to (i) PD-1, (ii) a second antigen, and (iii) a third antigen. In some embodiments, the antibody specifically binds to (i) PD-L1 and (ii) a second antigen. In some embodiments, the antibody specifically binds to (i) PD-L1, (ii) a second antigen, and (iii) a third antigen. In some embodiments, the second antigen and the third antigen are the same. In some embodiments, the second antigen and the third antigen are different. In some embodiments, the second antigen is CD3. In some embodiments, the second antigen is TIGIT. In some embodiments, the second antigen is LAG-3.

[0352] In some embodiments, the antibody specifically binds to (i) TIGIT and (ii) an inhibitory receptor expressed on T cells, NK cells, or both. In some embodiments, the antibody specifically binds to (i) CD40 and (ii) CD20. In some embodiments, the antibody specifically binds to (i) PD-1 and (ii) TIGIT. In some embodiments, the antibody specifically binds to (i) PD-1 and (ii) LAG-3.

[0353] In some embodiments, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of an antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, 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, 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, or at least about 10 mg / mL to at least about 180 mg / mL. L, 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 300 mg / mL, 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 In some embodiments, the pharmaceutical composition comprises at least about 50 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody).In some embodiments, the pharmaceutical composition comprises at least about 60 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 70 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 75 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 80 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 90 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 100 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 110 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 120 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 130 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 132 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 140 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 150 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 160 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 170 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 175 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody).In some embodiments, the pharmaceutical composition comprises at least about 180 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 190 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition comprises at least about 200 mg / mL of the antibody (e.g., an anti-PD-1 or anti-PD-L1 antibody).

[0354] II.A.1 Anti-PD-1 Antibodies Useful in the Disclosure In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds to PD-1 (an "anti-PD-1 antibody"). Any anti-PD-1 antibody can be used in the presently described compositions and methods. Various human monoclonal antibodies that specifically bind to PD-1 with high affinity are disclosed in U.S. Patent No. 8,008,449. The anti-PD-1 human antibodies disclosed in U.S. Patent No. 8,008,449 have been demonstrated to exhibit one or more of the following characteristics: (a) bind to human PD-1 with a KD of 1×10 M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) do not substantially bind to human CD28, CTLA-4, or ICOS; (c) increase T-cell proliferation in a mixed lymphocyte reaction (MLR) assay; (d) increase interferon-γ production in an MLR assay; (e) increase IL-2 secretion in an MLR assay; (f) bind to human PD-1 and cynomolgus PD-1; (g) inhibit the binding of PD-L1 and / or PD-L2 to PD-1; (h) stimulate an antigen-specific memory response; (i) stimulate an antibody response; and (j) inhibit tumor cell growth in vivo. Anti-PD-1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some embodiments at least five, of the aforementioned characteristics.

[0355] Other anti-PD-1 monoclonal antibodies are described in, e.g., U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509, U.S. Publication No. 2016 / 0272708, and PCT Publication Nos. WO2012 / 145493, WO2008 / 156712, WO2015 / 1 No. 12900, No. WO2012 / 145493, No. WO2015 / 112800, No. WO2014 / 206107, No. WO2015 / 35606, No. WO201 No. 5 / 085847, No. WO2014 / 179664, No. WO2017 / 020291, No. WO2017 / 020858, No. WO2016 / 197367, No. WO 2017 / 024515, WO2017 / 025051, WO2017 / 123557, WO2016 / 106159, WO2014 / 194302 No., WO2017 / 040790, WO2017 / 133540, WO2017 / 132827, WO2017 / 024465, WO2017 / 02 5016, WO2017 / 106061, WO2017 / 19846, WO2017 / 024465, WO2017 / 025016, WO2017 / 132825, and WO2017 / 133540, each of which is hereby incorporated by reference in its entirety.

[0356] In some embodiments, 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), pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK-3475; see WO2008 / 156712), PDR001 (Novartis; see WO2015 / 112900), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO2012 / 145493), cemiplimab (Regeneron; also known as REGN-2810; see WO2015 / 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 WO2015 / 35606 and US2015 / 0079109), INCSHR1210 [Jiangsu Hengrui Medicine; also known as SHR-1210; see WO2015 / 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 WO2014 / 194302), AGEN2034 (Agenus; see WO2017 / 040790), MGA012 (Macrogenics; see WO2017 / 19846), BCD-100 [Biocad; Kaplon et al., mAbs 10(2):183-203 (2018)], IBI308 (Innovent; see WO2017 / 024465, WO2017 / 025016, WO2017 / 132825, and WO2017 / 133540); and sasanlimab (PF-06801591).

[0357] In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a fully human IgG4(S228P) PD-1 immune checkpoint inhibitor antibody that selectively blocks interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking downregulation of anti-tumor T cell function (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56). The heavy and light chain variable regions for nivolumab are shown in Table 1A (SEQ ID NOS: 2 and 3). In some embodiments, the 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. In some embodiments, the antibody comprises heavy chain complementarity-determining region (CDR) 1, CDR2, and CDR3 sequences comprising the heavy chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 2. In some embodiments, the antibody comprises light chain CDR1, CDR2, and CDR3 sequences comprising the light chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO:3.

[0358] [Table 1]

[0359] In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody directed against the human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1). Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.

[0360] In another embodiment, the anti-PD-1 antibody is sasanlimab.

[0361] Anti-PD-1 antibodies that can be used in the disclosed compositions and methods also include isolated antibodies that specifically bind to human PD-1 and cross-compete for binding to human PD-1 with any of the anti-PD-1 antibodies disclosed herein, e.g., nivolumab (see, e.g., U.S. Patent Nos. 8,008,449 and 8,779,105; WO 2013 / 173223). In some embodiments, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein, e.g., nivolumab. The ability of antibodies to cross-compete for binding to an antigen indicates that these monoclonal antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of the reference antibody, e.g., nivolumab, due to their binding to the same epitope region of PD-1. 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 assays, or flow cytometry (see, e.g., WO2013 / 173223).

[0362] In certain embodiments, antibodies that cross-compete with the human PD-1 antibody nivolumab for binding to human PD-1 or that bind to the same epitope region thereof are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, 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.

[0363] Anti-PD-1 antibodies that can be used in the compositions and methods of the disclosure also include antigen-binding portions of the above antibodies. It is well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0364] Anti-PD-1 antibodies suitable for use in the disclosed compositions and methods are those that bind to PD-1 with high specificity and affinity, block binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effects of the PD-1 signaling 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 the whole antibody in inhibiting ligand binding and upregulating the immune system. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.

[0365] In some embodiments, the anti-PD-1 antibody is administered at a dose ranging from 0.1 mg / kg to 20.0 mg / kg body weight once every 2, 3, 4, 5, 6, 7, or 8 weeks, e.g., 0.1 mg / kg to 10.0 mg / kg body weight once every 2, 3, or 4 weeks. In other embodiments, the anti-PD-1 antibody is administered at a dose of 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, or 10 mg / kg body weight once every two weeks. In other embodiments, the anti-PD-1 antibody is administered at a dose of 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, or 10 mg / kg body weight once every three weeks. In one embodiment, the anti-PD-1 antibody is administered at a dose of about 5 mg / kg body weight about once every three weeks. In another embodiment, the anti-PD-1 antibody, e.g., nivolumab, is administered at a dose of about 3 mg / kg body weight about once every two weeks. In other embodiments, the anti-PD-1 antibody, e.g., pembrolizumab, is administered at a dose of about 2 mg / kg body weight about once every three weeks.

[0366] Anti-PD-1 antibodies useful in the present disclosure may be administered as a flat dose. In some embodiments, the anti-PD-1 antibody is administered at a flat dose of about 100 to about 1000 mg, about 100 to about 900 mg, about 100 to about 800 mg, about 100 to about 700 mg, about 100 to about 600 mg, about 100 to about 500 mg, about 200 to about 1000 mg, about 200 to about 900 mg, about 200 to about 800 mg, about 200 to about 700 mg, about 200 to about 600 mg, about 200 to about 500 mg, about 200 to about 480 mg, or about 240 to about 480 mg. In one embodiment, the anti-PD-1 antibody is administered as a flat dose of at least about 200 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, 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, with a dosing interval of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. In another embodiment, the anti-PD-1 antibody is administered as a flat dose of about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, or about 200 mg to about 500 mg at dosing intervals of about 1, 2, 3, or 4 weeks.

[0367] In some embodiments, the anti-PD-1 antibody is administered as a flat dose of about 200 mg about once every three weeks. In other embodiments, the anti-PD-1 antibody is administered as a flat dose of about 200 mg about once every two weeks. In other embodiments, the anti-PD-1 antibody is administered as a flat dose of about 240 mg about once every two weeks. In certain embodiments, the anti-PD-1 antibody is administered as a flat dose of about 480 mg about once every four weeks.

[0368] In some embodiments, nivolumab is administered at a flat dose of about 240 mg once every two weeks. In some embodiments, nivolumab is administered at a flat dose of about 240 mg once every three weeks. In some embodiments, nivolumab is administered at a flat dose of about 360 mg once every three weeks. In some embodiments, nivolumab is administered at a flat dose of about 480 mg once every four weeks. In some embodiments, nivolumab is administered at a flat dose of about 720 mg once every six weeks. In some embodiments, nivolumab is administered at a flat dose of about 960 mg once every eight weeks.

[0369] In some embodiments, pembrolizumab is administered at a flat dose of about 200 mg once every two weeks. In some embodiments, pembrolizumab is administered at a flat dose of about 200 mg once every three weeks. In some embodiments, pembrolizumab is administered at a flat dose of about 400 mg once every four weeks.

[0370] In some embodiments, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, 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, 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, or 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 300 mg / mL 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 L, 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 of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab).In some embodiments, the pharmaceutical composition comprises at least about 50 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 60 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 70 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 75 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 80 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 90 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 100 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 110 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 120 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 130 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 132 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 140 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 150 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab).In some embodiments, the pharmaceutical composition comprises at least about 160 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 170 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 175 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 180 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 190 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 200 mg / mL of the anti-PD-1 antibody (e.g., nivolumab or pembrolizumab).

[0371] In some embodiments, the pharmaceutical composition comprises a bispecific 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 (e.g., an scFv of nivolumab). In some embodiments, the second antigen-binding portion is an antigen-binding portion of any one of the antibodies disclosed herein. In some embodiments, the second antigen-binding portion is an antigen-binding portion of an anti-LAG-3 antibody, such as leratolimab. In some embodiments, the second antigen-binding portion is an antigen-binding portion of an anti-TIGIT antibody.

[0372] In some embodiments, 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 portion (e.g., an scFv of nivolumab).

[0373] II.A.2. Anti-PD-L1 Antibodies Useful in the Disclosure In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds to PD-L1 (an "anti-PD-L1 antibody"). In some embodiments, the anti-PD-L1 antibody is substituted for the anti-PD-1 antibody in any of the compositions or methods disclosed herein. Any anti-PD-L1 antibody may be used in the compositions and methods of the present disclosure. Examples of anti-PD-L1 antibodies useful in the compositions and methods of the present disclosure include the antibodies disclosed in U.S. Patent No. 9,580,507. The anti-PD-L1 human monoclonal antibodies disclosed in U.S. Patent No. 9,580,507 have been demonstrated to exhibit one or more of the following characteristics: (a) bind to human PD-L1 with a KD of 1 x 10-7 M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) increase T-cell proliferation in a mixed lymphocyte reaction (MLR) assay; (c) increase interferon-γ production in an MLR assay; (d) increase IL-2 secretion in an MLR assay; (e) stimulate antibody responses; and (f) reverse the effects of T regulatory cells on T-cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one, and in some embodiments at least five, of the foregoing characteristics.

[0374] In certain embodiments, the anti-PD-L1 antibody is selected from the group consisting of BMS-936559 (12A4, also known as MDX-1105; see, e.g., U.S. Patent No. 7,943,743 and WO 2013 / 173223), atezolizumab (Roche; TECENTRIQ®; MPDL3280A, also known as RG7446; see U.S. Patent No. 8,217,149; Herbst et al. (2013) J Clin Oncol 31(suppl):3000], durvalumab (AstraZeneca; also known as IMFINZI™, MEDI-4736; see WO2011 / 066389], avelumab (Pfizer; also known as BAVENCIO®, MSB-0010718C; see WO2013 / 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, e.g., WO2017 / 034916), BGB-A333 [BeiGene; see Desai et al., JCO 36 (15suppl):TPS3113 (2018)], and CK-301 [Checkpoint Therapeutics; see Gorelik et al., AACR:Abstract 4606 (Apr 2016)].

[0375] In one particular embodiment, the PD-L1 antibody is atezolizumab (TECENTRIQ®). Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody.

[0376] In one particular embodiment, the PD-L1 antibody is durvalumab (IMFINZI™). Durvalumab is a human IgG1 kappa monoclonal anti-PD-L1 antibody.

[0377] In one particular embodiment, the PD-L1 antibody is avelumab (BAVENCIO®). Avelumab is a human IgG1 lambda monoclonal anti-PD-L1 antibody.

[0378] Anti-PD-L1 antibodies that can be used in the disclosed compositions and methods also include isolated antibodies that specifically bind to human PD-L1 and cross-compete for binding to human PD-L1 with any of the anti-PD-L1 antibodies disclosed herein, such as atezolizumab, durvalumab, and / or avelumab. In some embodiments, the anti-PD-L1 antibody binds to the same epitope as any of the anti-PD-L1 antibodies described herein, such as atezolizumab, durvalumab, and / or avelumab. The ability of antibodies to cross-compete for binding to an antigen indicates that they bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of the reference antibody, such as atezolizumab and / or avelumab, due to their binding to the same epitope region of PD-L1. 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 assays, or flow cytometry (see, e.g., WO2013 / 173223).

[0379] In certain embodiments, antibodies that cross-compete for binding to human PD-L1 with, or bind to the same epitope region as, human PD-L1 antibodies, such as atezolizumab, durvalumab, and / or avelumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, 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.

[0380] Anti-PD-L1 antibodies that can be used in the compositions and methods of the disclosure also include antigen-binding portions of the above antibodies. It is well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0381] Anti-PD-L1 antibodies suitable for use in the disclosed compositions and methods are those that bind to PD-L1 with high specificity and affinity, block PD-1 binding, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to PD-L1 and exhibits functional properties similar to those of the whole antibody in inhibiting receptor binding and upregulating the immune system. In certain embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0382] The anti-PD-L1 antibody useful in the present disclosure can be any PD-L1 antibody that specifically binds to PD-L1, for example, an antibody that cross-competes with durvalumab, avelumab, or atezolizumab for binding to human PD-1, such as an antibody that binds to the same epitope as durvalumab, avelumab, or atezolizumab. In certain embodiments, the anti-PD-L1 antibody is durvalumab. In other embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab.

[0383] In some embodiments, the anti-PD-L1 antibody is administered at a dose ranging from about 0.1 mg / kg to about 20.0 mg / kg of 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 20.0 mg / kg, about once every 2, 3, 4, 5, 6, 7, or 8 weeks.

[0384] In some embodiments, the anti-PD-L1 antibody is administered at a dose of about 15 mg / kg body weight about once every three weeks. In other embodiments, the anti-PD-L1 antibody is administered at a dose of about 10 mg / kg body weight about once every two weeks.

[0385] In other embodiments, anti-PD-L1 antibodies useful in the present disclosure are administered as a flat dose of 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, 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, 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. In some embodiments, the anti-PD-L1 antibody is administered as a flat dose 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, 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, 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, with a dosing interval of about 1, 2, 3, or 4 weeks. In some embodiments, the anti-PD-L1 antibody is administered as a flat dose of about 1200 mg about once every three weeks. In other embodiments, the anti-PD-L1 antibody is administered as a flat dose of about 800 mg about once every two weeks. In other embodiments, the anti-PD-L1 antibody is administered as a flat dose of about 840 mg about once every two weeks.

[0386] In some embodiments, atezolizumab is administered as a flat dose of about 1200 mg once every about three weeks. In some embodiments, atezolizumab is administered as a flat dose of about 800 mg once every about two weeks. In some embodiments, atezolizumab is administered as a flat dose of about 840 mg once every about two weeks.

[0387] In some embodiments, avelumab is administered as a flat dose of about 800 mg once about every two weeks.

[0388] In some embodiments, durvalumab is administered at a dose of about 10 mg / kg once every two weeks. In some embodiments, durvalumab is administered as a flat dose of about 800 mg / kg once every two weeks. In some embodiments, durvalumab is administered as a flat dose of about 1200 mg / kg once every three weeks.

[0389] In some embodiments, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of anti-PD-L1 antibody. In some embodiments, 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, 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, or at least about 10 mg / mL to at least about 180 mg / mL. 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, In all cases, the concentration is 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, and at least about 100 mg / mL. The pharmaceutical composition may comprise at least about 50 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition may comprise at least about 60 mg / mL of anti-PD-L1 antibody.In some embodiments, the pharmaceutical composition comprises at least about 70 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 75 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 80 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 90 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 100 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 110 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 120 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 130 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 132 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 140 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 150 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 160 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 170 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 175 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 180 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 190 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 200 mg / mL of anti-PD-L1 antibody.

[0390] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) PD-L1 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) PD-L1 and (ii) CD3.

[0391] II.A.3. Anti-CTLA-4 antibody In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds to CTLA-4 (an "anti-CTLA-4 antibody"). Any anti-CTLA-4 antibody known in the art can be used in the compositions and methods of the present disclosure. The anti-CTLA-4 antibodies of the present invention bind to human CTLA-4 and disrupt the interaction of CTLA-4 with the human B7 receptor. Because the interaction between CTLA-4 and B7 transduces a signal that leads to the inactivation of T cells bearing the CTLA-4 receptor, disruption of the interaction effectively induces, enhances, or prolongs the activation of such T cells, thereby inducing, enhancing, or prolonging an immune response.

[0392] Human monoclonal antibodies that specifically bind to CTLA-4 with high affinity are disclosed in U.S. Patent No. 6,984,720. Other anti-CTLA-4 monoclonal antibodies are described, for example, in U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121, and International Publication Nos. WO 2012 / 122444, WO 2007 / 113648, WO 2016 / 196237, and WO 2000 / 037504, each of which is hereby incorporated by reference in its entirety. The anti-CTLA-4 human monoclonal antibodies disclosed in U.S. Patent No. 6,984,720 have been demonstrated to exhibit one or more of the following characteristics: (a) specifically bind to human CTLA-4 with a binding affinity reflected by an equilibrium association constant (Ka) of at least about 107 M-1, or about 109 M-1, or about 1010 M-1 to 1011 M-1 or greater, as determined by Biacore analysis; (b) a kinetic association constant (ka) of at least about 103, about 104, or about 105 m-1 s-1; (c) a kinetic dissociation constant (kd) of at least about 103, about 104, or about 105 m-1 s-1; and (d) inhibit the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4 antibodies useful 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.

[0393] In certain embodiments, the CTLA-4 antibody is selected from the group consisting of ipilimumab (also known as YERVOY®, MDX-010, 10D1; see U.S. Pat. No. 6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; see WO2016 / 196237), and tremelimumab (AstraZeneca; also known as ticilimumab, CP-675,206; see WO2000 / 037504 and Ribas, Update Cancer Ther. 2(3): 133-39 (2007)). In certain embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0394] In certain embodiments, 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.

[0395] In certain embodiments, the CTLA-4 antibody is tremelimumab. In certain embodiments, the CTLA-4 antibody is MK-1308. In certain embodiments, the CTLA-4 antibody is AGEN-1884.

[0396] In some embodiments, the CTLA-4 antibody is non-fucosylated or hypofucosylated. In some embodiments, the CTLA-4 antibody exhibits enhanced ADCC and / or ADCP activity. In some embodiments, the CTLA-4 antibody is BMS-986218, described in PCT / US18 / 19868.

[0397] Anti-CTLA-4 antibodies that can be used in the disclosed compositions and methods also include isolated antibodies that specifically bind to human CTLA-4 and cross-compete for binding to human CTLA-4 with any of the anti-CTLA-4 antibodies disclosed herein, such as ipilimumab and / or tremelimumab. In some embodiments, the anti-CTLA-4 antibody binds to the same epitope as any of the anti-CTLA-4 antibodies described herein, such as ipilimumab and / or tremelimumab. The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of the reference antibody, such as ipilimumab and / or tremelimumab, due to their binding to the same epitope region of CTLA-4. 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 assays, or flow cytometry (see, e.g., WO2013 / 173223).

[0398] In certain embodiments, antibodies that cross-compete with human CTLA-4 antibodies such as ipilimumab and / or tremelimumab for binding to human CTLA-4 or bind to the same epitope region thereof are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, 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.

[0399] Anti-CTLA-4 antibodies that can be used 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 an antibody can be performed by fragments of a full-length antibody.

[0400] In certain embodiments, 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 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine. In certain embodiments, 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 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0401] In some embodiments, the anti-CTLA-4 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-CTLA-4 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-CTLA-4 antibody; and (h) about 2000 U / mL of rHuPH20.

[0402] In certain embodiments, 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) an anti-CTLA-4 antibody. In certain embodiments, 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) an anti-CTLA-4 antibody; and (h) about 2000 U / mL rHuPH20.

[0403] 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 interfere with the interaction of CTLA-4 with the human B7 receptor. 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 exhibits functional properties similar to those of the whole antibody in inhibiting the interaction of CTLA-4 with the human B7 receptor and upregulating the immune system. In certain embodiments, the anti-CTLA-4 antibody or antigen-binding portion thereof cross-competes with ipilimumab and / or tremelimumab for binding to human CTLA-4.

[0404] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) CTLA-4 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) CTLA-4 and (ii) CD3.

[0405] II.A.4. Anti-LAG-3 antibody In some embodiments, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds to LAG-3 (an "anti-LAG-3 antibody"), such as leratolimab. The anti-LAG-3 antibodies of the present disclosure 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 are disclosed in International Publication No. WO / 2015 / 042246 and U.S. Publication Nos. 2014 / 0093511 and 2011 / 0150892, each of which is hereby incorporated by reference in its entirety.

[0406] An exemplary LAG-3 antibody useful in the present disclosure is 25F7 (described in U.S. Publication No. 2011 / 0150892). An additional exemplary LAG-3 antibody useful in the present disclosure is BMS-986016 (relatolimab). In some embodiments, an anti-LAG-3 antibody useful in the present disclosure cross-competes with 25F7 or BMS-986016. In some embodiments, an anti-LAG-3 antibody useful in the present disclosure binds to the same epitope as 25F7 or BMS-986016. In some embodiments, an anti-LAG-3 antibody comprises the six CDRs of 25F7 or BMS-986016.

[0407] Other art-recognized anti-LAG-3 antibodies that may be used in the methods and / or compositions of the disclosure include IMP731 (H5L7BW) described in US2011 / 007023, MK-4280 (28G-10, favezelimab) described in WO2016028672 and US Publication No. 2020 / 0055938, Burova E, et al., J. Immunother. Cancer (2016); 4(Supp. 1): REGN3767 (fianlimab), described in P195 and U.S. Pat. No. 10,358,495; humanized BAP050, described in WO2017 / 019894; GSK2831781; IMP-701 (LAG525; ieramilimab), described in U.S. Pat. No. 10,711,060 and U.S. 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, and ABL501.These and other anti-LAG-3 antibodies useful in the claimed invention are described in, e.g., US 10,188,730, WO2016 / 028672, WO2017 / 106129, WO2017 / 062888, WO2009 / 044273, WO2018 / 069500, WO2016 / 126858, WO2014 / 179664, WO2016 / 200782, WO2015 / 200119, WO2017 / 019846, WO2017 / 1987 41, WO2017 / 220555, WO2017 / 220569, WO2018 / 071500, WO2017 / 015560, WO2017 / 0 25498, WO2017 / 087589, WO2017 / 087901, WO2018 / 083087, WO2017 / 149143, WO20 17 / 219995, US2017 / 0260271, WO2017 / 086367, WO2017 / 086419, WO2018 / 034227, and WO2019 / 018730, the contents of each of which are hereby incorporated by reference in their entirety.

[0408] Anti-LAG-3 antibodies that can be used in the methods and / or compositions of the present disclosure also include isolated antibodies that specifically bind to human LAG-3 and cross-compete for binding to human LAG-3 with any of the anti-LAG-3 antibodies disclosed herein, e.g., leratolimab. In some embodiments, the anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein, e.g., leratolimab.

[0409] In certain embodiments, any anti-LAG-3 antibody disclosed herein, such as an antibody that cross-competes with leratolimab for binding to human LAG-3 or binds to the same epitope region as leratolimab, is a monoclonal antibody. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, 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.

[0410] 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 prevents other cross-competing antibodies from binding to that specific epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of a reference antibody, such as leratolimab, because they bind to the same epitope region. Cross-competing antibodies can be easily identified based on their ability to cross-compete in standard binding assays such as Biacore analysis, ELISA assays, or flow cytometry (see, for example, WO2013 / 173223).

[0411] Anti-LAG-3 antibodies that can be used in the methods and / or compositions of the present disclosure also include antigen-binding portions of any of the full-length antibodies described above. It is well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0412] In some embodiments, the anti-LAG-3 antibody is a full-length antibody.

[0413] In some embodiments, the anti-LAG-3 antibody is a monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is a dual affinity retargeting antibody (DART), DVD-Ig, or bispecific antibody.

[0414] In some embodiments, the anti-LAG-3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0415] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of BMS-986016 (leratolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yeramilimab), aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), 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.

[0416] In some embodiments, the anti-LAG-3 antibody is leratolimab.

[0417] In some embodiments, the anti-LAG-3 antibody is MGD013 (tebotelimab), which is a bispecific PD-1 x LAG-3 DART.

[0418] In some embodiments, the anti-LAG-3 antibody is REGN3767 (fianlimab).

[0419] In some embodiments, the anti-LAG-3 antibody is LAG525 (Ielamirimab).

[0420] In some embodiments, the anti-LAG-3 antibody is MK4280 (fabezelimab).

[0421] In certain embodiments, 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 embodiments, the pharmaceutical composition comprises (a) leratolimab; (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 embodiments, 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; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) leratolimab; (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.

[0422] In some embodiments, the anti-LAG-3 antibody, e.g., leratolimab, may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-LAG-3 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an 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) leratolimab. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an 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) an anti-LAG-3 antibody; and (h) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) leratolimab; and (h) about 2000 U / mL of rHuPH20.

[0423] In certain embodiments, 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) an anti-LAG-3 antibody. In certain embodiments, 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) leratolimab. In certain embodiments, 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) an anti-LAG-3 antibody; and (h) about 2000 U / mL rHuPH20. In certain embodiments, 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) leratolimab; and (h) about 2000 U / mL rHuPH20.

[0424] An exemplary LAG-3 antibody useful in the present disclosure is 25F7 (described in U.S. Publication No. 2011 / 0150892). An additional exemplary LAG-3 antibody useful in the present disclosure is BMS-986016. In one embodiment, an anti-LAG-3 antibody useful in the compositions cross-competes with 25F7 or BMS-986016. In another embodiment, an anti-LAG-3 antibody useful in the compositions binds to the same epitope as 25F7 or BMS-986016. In other embodiments, an anti-LAG-3 antibody comprises the six CDRs of 25F7 or BMS-986016.

[0425] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) LAG-3 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) LAG-3 and (ii) CD3.

[0426] II.A.5. Anti-CD137 antibody In some embodiments, the second antibody comprises an anti-CD137 antibody. The anti-CD137 antibody specifically binds to and activates CD137-expressing immune cells, stimulating an immune response, particularly a cytotoxic T cell response, against tumor cells. Antibodies that bind to CD137 are 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, 6,974,863, and 6,210,669.

[0427] In certain embodiments, 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; and (f) about 5 mM methionine. In certain embodiments, 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.

[0428] In some embodiments, the anti-CD137 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-CD137 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-CD137 antibody; and (h) about 2000 U / mL of rHuPH20.

[0429] In certain embodiments, 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) an anti-CD137 antibody. In certain embodiments, 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) an anti-CD137 antibody; and (h) about 2000 U / mL rHuPH20.

[0430] In some embodiments, the anti-CD137 antibody is urelumab (BMS-663513) (20H4.9-IgG4 [10C7 or BMS-663513]) described in U.S. Patent No. 7,288,638. In some embodiments, the anti-CD137 antibody is BMS-663031 (20H4.9-IgG1) described in U.S. Patent No. 7,288,638. In some embodiments, the anti-CD137 antibody is 4E9 or BMS-554271 described in U.S. Patent No. 6,887,673. In some embodiments, the anti-CD137 antibody is an antibody disclosed in U.S. Patent Nos. 7,214,493; 6,303,121; 6,569,997; 6,905,685; or 6,355,476. In some embodiments, the anti-CD137 antibody is 1D8 or BMS-469492; 3H3 or BMS-469497; or 3E1, as described in U.S. Patent No. 6,362,325. In some embodiments, the anti-CD137 antibody is an antibody disclosed in issued U.S. Patent No. 6,974,863 (such as 53A2). In some embodiments, the anti-CD137 antibody is an antibody disclosed in issued U.S. Patent No. 6,210,669 (such as 1D8, 3B8, or 3E1). In some embodiments, the antibody is PF-05082566 (PF-2566) from Pfizer. In other embodiments, the anti-CD137 antibody useful in the present invention cross-competes with the anti-CD137 antibodies disclosed herein. In some embodiments, the anti-CD137 antibody binds to the same epitope as the anti-CD137 antibodies disclosed herein. In other embodiments, anti-CD137 antibodies useful in this disclosure comprise the six CDRs of the anti-CD137 antibodies disclosed herein.

[0431] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) CD137 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) CD137 and (ii) CD3.

[0432] II.A.6. Anti-KIR antibody In some embodiments, the second antibody comprises an anti-KIR3 antibody. Antibodies that specifically bind to KIR block the interaction between killer cell immunoglobulin-like receptors (KIR) on NK cells and their ligands. Blocking these receptors promotes the activation of NK cells and, potentially, the destruction of tumor cells by the latter. Examples of anti-KIR antibodies are disclosed in International Publication Nos. WO / 2014 / 055648, WO2005 / 003168, WO2005 / 009465, WO2006 / 072625, WO2006 / 072626, WO2007 / 042573, WO2008 / 084106, WO2010 / 065939, WO2012 / 071411, and WO / 2012 / 160448.

[0433] In certain embodiments, 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; and (f) about 5 mM methionine. In certain embodiments, 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.

[0434] In some embodiments, the anti-KIR antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-KIR antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-KIR antibody; and (h) about 2000 U / mL of rHuPH20.

[0435] In certain embodiments, 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) an anti-KIR antibody. In certain embodiments, 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) an anti-KIR antibody; and (h) about 2000 U / mL rHuPH20.

[0436] One anti-KIR antibody useful in the present disclosure is lirilumab (also referred to as BMS-986015, IPH2102, or the S241P variant of 1-7F9), first described in International Publication WO 2008 / 084106. An additional anti-KIR antibody useful in the present disclosure is 1-7F9 (also referred to as IPH2101), described in International Publication WO 2006 / 003179. In one embodiment, the anti-KIR antibody for the present composition cross-competes with lirilumab or I-7F9 for binding to KIR. In another embodiment, the anti-KIR antibody binds to the same epitope as lirilumab or I-7F9. In other embodiments, the anti-KIR antibody comprises the six CDRs of lirilumab or I-7F9.

[0437] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) a KIR and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) a KIR and (ii) CD3.

[0438] II.A.7. Anti-GITR antibody In some embodiments, the second antibody comprises an anti-GITR antibody. Anti-GITR antibodies include any anti-GITR antibody that specifically binds to the human GITR target and activates the glucocorticoid-inducible tumor necrosis factor receptor (GITR). GITR is a member of the TNF receptor superfamily that is expressed on the surface of multiple 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 reverses 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, U.S. Patent Nos. 7,812,135 and 8,388,967, and U.S. Publication Nos. 2009 / 0136494, 2014 / 0220002, 2013 / 0183321, and 2014 / 0348841.

[0439] In certain embodiments, 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; and (f) about 5 mM methionine. In certain embodiments, 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.

[0440] In some embodiments, the anti-GITR antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-GITR antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-GITR antibody; and (h) about 2000 U / mL of rHuPH20.

[0441] In certain embodiments, 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) an anti-GITR antibody. In certain embodiments, 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) an anti-GITR antibody; and (h) about 2000 U / mL rHuPH20.

[0442] In one embodiment, an anti-GITR antibody useful in the present disclosure is TRX518 (described, e.g., in Schaer et al. Curr Opin Immunol. (2012) Apr; 24(2): 217-224, and WO / 2006 / 105021). In another embodiment, the anti-GITR antibody is selected from MK4166, MK1248, and the antibodies described in WO11 / 028683 and US8,709,424, e.g., comprising a VH chain comprising SEQ ID NO: 104 and a VL chain comprising SEQ ID NO: 105 (the SEQ ID NOs are from WO11 / 028683 or US8,709,424). In certain embodiments, the anti-GITR antibody is an anti-GITR antibody disclosed in WO2015 / 031667, e.g., an antibody comprising VH CDR1-3 comprising SEQ ID NOs: 31, 71, and 63 of WO2015 / 031667, and VL CDR1-3 comprising SEQ ID NOs: 5, 14, and 30 of WO2015 / 031667, respectively. In certain embodiments, the anti-GITR antibody is an anti-GITR antibody disclosed in WO2015 / 184099, e.g., antibody Hum231#1 or Hum231#2, or CDRs thereof, or derivatives thereof (e.g., pab1967, pab1975, or pab1979). In certain embodiments, 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 embodiments, the anti-GITR antibody is an anti-GITR antibody described in PCT / US2015 / 033991 (e.g., an antibody comprising the variable region of 28F3, 18E10, or 19D3).

[0443] In certain embodiments, the anti-GITR antibody cross-competes with the anti-GITR antibody described herein, e.g., TRX518, MK4166, or an antibody comprising the VH and VL domain amino acid sequences described herein. In some embodiments, the anti-GITR antibody binds to the same epitope as the anti-GITR antibody described herein, e.g., TRX518, MK4166, or an antibody comprising the VH and VL domain amino acid sequences described herein. In certain embodiments, the anti-GITR antibody comprises the six CDRs of TRX518, MK4166, or an antibody comprising the VH and VL domain amino acid sequences described herein.

[0444] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) GITR and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) GITR and (ii) CD3.

[0445] II.A.8. Anti-TIM3 antibody In some embodiments, the second antibody comprises an anti-TIM3 antibody. In some embodiments, the anti-TIM3 antibody is described in International Publication Nos. WO2018013818, WO / 2015 / 117002 (e.g., MGB453, Novartis), WO / 2016 / 161270 (e.g., TSR-022, Tesaro / AnaptysBio), WO2011155607, WO2016 / 144803 (e.g., STI-600, Sorrento Therapeutics), WO2016 / 071448, WO17055399; WO17055404, WO17178493, WO18036561, WO18039020 (e.g., Ly-3221367, Eli Lilly), WO2017205721, WO17079112; WO17079115; WO17079116, WO11159877, WO13006490, WO2016068802, WO2016068803, WO2016 / 111947, WO / 2017 / 031242.

[0446] In certain embodiments, 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; and (f) about 5 mM methionine. In certain embodiments, 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.

[0447] In some embodiments, the anti-TIM3 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-TIM3 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-TIM3 antibody; and (h) about 2000 U / mL of rHuPH20.

[0448] In certain embodiments, 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) an anti-TIM3 antibody. In certain embodiments, 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) an anti-TIM3 antibody; and (h) about 2000 U / mL rHuPH20.

[0449] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) TIM-3 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) TIM-3 and (ii) CD3.

[0450] II.A.9. Anti-OX40 antibody In some embodiments, the second antibody comprises an anti-OX40 (also known as CD134, TNFRSF4, ACT35, and / or TXGP1L) antibody. In some embodiments, the anti-OX40 antibody comprises BMS-986178 (Bristol-Myers Squibb Company), which is described in International Publication No. WO20160196228. In some embodiments, the anti-OX40 antibody comprises an anti-OX40 antibody described in International Publication Nos. WO95012673, WO199942585, WO14148895, WO15153513, WO15153514, WO13038191, WO16057667, WO03106498, WO12027328, WO13028231, WO16200836, WO17063162, WO17134292, WO17096179, WO17096281, and WO17096182.

[0451] In certain embodiments, 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; and (f) about 5 mM methionine. In certain embodiments, 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.

[0452] In some embodiments, the anti-OX40 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-OX40 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-OX40 antibody; and (h) about 2000 U / mL of rHuPH20.

[0453] In certain embodiments, 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) an anti-OX40 antibody. In certain embodiments, 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) an anti-OX40 antibody; and (h) about 2000 U / mL rHuPH20.

[0454] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) OX40 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) OX40 and (ii) CD3.

[0455] II.A.10. Anti-NKG2A antibody In some embodiments, 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 primarily expressed on tumor-infiltrating innate immune effector NK cells and some CD8+ T cells. Its natural ligand, human leukocyte antigen E (HLA-E), is expressed on solid tumors and hematological tumors. NKG2A is an inhibitory receptor that blocks HLA-E.

[0456] In certain embodiments, 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; and (f) about 5 mM methionine. In certain embodiments, 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.

[0457] In some embodiments, the anti-NKG2A antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-NKG2A antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-NKG2A antibody; and (h) about 2000 U / mL of rHuPH20.

[0458] In certain embodiments, 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) an anti-NKG2A antibody. In certain embodiments, 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) an anti-NKG2A antibody; and (h) about 2000 U / mL rHuPH20.

[0459] In some embodiments, the anti-NKG2A antibody comprises BMS-986315, a human monoclonal antibody that blocks the interaction of NKG2A with its ligand HLA-E, thus allowing activation of an anti-tumor immune response. In some embodiments, the anti-NKG2A antibody comprises a checkpoint inhibitor that activates T cells, NK cells, and / or tumor-infiltrating immune cells. In some embodiments, the anti-NKG2A antibody is a cytotoxic antibody, e.g., as described in WO2006 / 070286 (Innate Pharma SA; University of Genova); U.S. Patent No. 8,993,319 (Innate Pharma SA; University of Genova); WO2007 / 042573 (Innate Pharma S / A; Novo Nordisk A / S; University of Genova); U.S. Patent No. 9,447,185 (Innate Pharma S / A; Novo Nordisk A / S; University of Genova); WO2008 / 009545 (Novo Nordisk A / S); U.S. Patent Nos. 8,206,709; 8,901,283; 9,683,041 (Novo Nordisk A / S); WO2009 / 092805 (Novo Nordisk A / S); U.S. Patent Nos. 8,796,427 and 9,422,368 (Novo Nordisk A / S); WO2016 / 134371 (Ohio State Innovation Foundation); WO2016 / 032334 (Janssen); WO2016 / 041947 (Innate); WO2016 / 041945 (Academisch Ziekenhuis Leiden HODNLUMC); WO2016 / 041947 (Innate Pharma); and anti-NKG2A antibodies described in WO2016 / 041945 (Innate Pharma).

[0460] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) NKG2A and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) NKG2A and (ii) CD3.

[0461] II.A.11. Anti-ICOS antibodies In some embodiments, 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 costimulates T cell activation after binding to its ligand, ICOS-L (B7H2). ICOS is also known as inducible T cell costimulator, CVID1, AILIM, inducible costimulator, CD278, activation-induced lymphocyte immune mediator molecule, and CD278 antigen.

[0462] In certain embodiments, 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; and (f) about 5 mM methionine. In certain embodiments, 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.

[0463] In some embodiments, the anti-ICOS antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-ICOS antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-ICOS antibody; and (h) about 2000 U / mL of rHuPH20.

[0464] In certain embodiments, 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) an anti-ICOS antibody. In certain embodiments, 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) an anti-ICOS antibody; and (h) about 2000 U / mL rHuPH20.

[0465] In some embodiments, the anti-ICOS antibody comprises BMS-986226, a humanized IgG monoclonal antibody that binds to and stimulates human ICOS. In some embodiments, the anti-ICOS antibody is described in, for example, WO2016 / 154177 (Jounce Therapeutics, Inc.), WO2008 / 137915 (MedImmune), WO2012 / 131004 [INSERM, French National Institute of Health and Medical Research], EP3147297 (INSERM, French National Institute of Health and Medical Research), WO2011 / 041613 (Memorial Sloan Kettering Cancer Center), EP2482849 (Memorial Sloan Kettering Cancer Center), WO1999 / 15553 [Robert Koch Institute]. Nos. 7,045,615; 7,112,655; and 8,389,690 (Japan Tobacco Inc.), U.S. Patent Nos. 9,738,718 and 9,771,424 (GlaxoSmithKline), and WO2017 / 220988 (Kymab Limited).

[0466] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) ICOS and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) ICOS and (ii) CD3.

[0467] II.A.12. Anti-TIGIT antibody In some embodiments, the second antibody comprises an anti-TIGIT antibody. In some embodiments, the anti-TIGIT antibody comprises BMS-986207. In some embodiments, the anti-TIGIT antibody comprises clone 22G2 described in WO2016 / 106302. In some embodiments, the anti-TIGIT antibody comprises MTIG7192A / RG6058 / RO7092284 or clone 4.1D3 described in WO2017 / 053748. In some embodiments, the anti-TIGIT antibody comprises an anti-TIGIT antibody described, for example, in WO2016 / 106302 (Bristol-Myers Squibb Company) and WO2017 / 053748 (Genentech).

[0468] In certain embodiments, 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; and (f) about 5 mM methionine. In certain embodiments, 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.

[0469] In some embodiments, the anti-TIGIT antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-TIGIT antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-TIGIT antibody; and (h) about 2000 U / mL of rHuPH20.

[0470] In certain embodiments, 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) an anti-TIGIT antibody. In certain embodiments, 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) an anti-TIGIT antibody; and (h) about 2000 U / mL rHuPH20.

[0471] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) TIGIT and (ii) a second antigen. In some embodiments, the antibody comprises a TIGIT bispecific antibody that specifically binds to (i) TIGIT and (ii) an inhibitory receptor expressed on T cells, NK cells, or both T cells and NK cells. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) TIGIT and (ii) CD3.

[0472] II.A.13. Anti-IL-12 antibody In some embodiments, the second antibody comprises an anti-IL-12 antibody. In certain embodiments, 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 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine. In certain embodiments, 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 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0473] In some embodiments, the anti-IL-12 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-IL-12 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-IL-12 antibody; and (h) about 2000 U / mL of rHuPH20.

[0474] In certain embodiments, 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) an anti-IL-12 antibody. In certain embodiments, 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) an anti-IL-12 antibody; and (h) about 2000 U / mL rHuPH20.

[0475] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) IL-12 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) IL-12 and (ii) CD3.

[0476] II.A.14. Anti-IL-13 antibody In some embodiments, the second antibody comprises an anti-IL-13 antibody. In certain embodiments, 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 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine. In certain embodiments, 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 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0477] In some embodiments, the anti-IL-13 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-IL-13 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-IL-13 antibody; and (h) about 2000 U / mL of rHuPH20.

[0478] In certain embodiments, 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) an anti-IL-13 antibody. In certain embodiments, 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) an anti-IL-13 antibody; and (h) about 2000 U / mL rHuPH20.

[0479] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) IL-13 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) IL-13 and (ii) CD3.

[0480] II.A.15. Anti-IL-15 antibody In some embodiments, the second antibody comprises an anti-IL-15 antibody. In certain embodiments, 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 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine. In certain embodiments, 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 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20.

[0481] In some embodiments, the anti-IL-15 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-IL-15 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-IL-15 antibody; and (h) about 2000 U / mL of rHuPH20.

[0482] In certain embodiments, 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) an anti-IL-15 antibody. In certain embodiments, 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) an anti-IL-15 antibody; and (h) about 2000 U / mL rHuPH20.

[0483] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) IL-15 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) IL-15 and (ii) CD3.

[0484] II.A.16. Anti-SIRP alpha antibodies In some embodiments, the second antibody comprises an anti-SIRP alpha antibody. In certain embodiments, the pharmaceutical composition comprises: (a) an anti-SIRP alpha 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 embodiments, the pharmaceutical composition comprises: (a) an anti-SIRP alpha 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.

[0485] In some embodiments, the anti-SIRP alpha antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-SIRP alpha antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-SIRP alpha antibody; and (h) about 2000 U / mL of rHuPH20.

[0486] In certain embodiments, 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) an anti-SIRP alpha antibody. In certain embodiments, 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) an anti-SIRP alpha antibody; and (h) about 2000 U / mL rHuPH20.

[0487] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) SIRPalpha and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) SIRPalpha and (ii) CD3.

[0488] II.A.17. Anti-CD47 antibody In some embodiments, the second antibody comprises an anti-CD47 antibody. In certain embodiments, 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 embodiments, 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.

[0489] In some embodiments, the anti-CD47 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-CD47 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-CD47 antibody; and (h) about 2000 U / mL of rHuPH20.

[0490] In certain embodiments, 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) an anti-CD47 antibody. In certain embodiments, 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) an anti-CD47 antibody; and (h) about 2000 U / mL rHuPH20.

[0491] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) CD47 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) CD47 and (ii) CD3.

[0492] II.A.18. Anti-CCR8 antibody In some embodiments, the second antibody comprises an anti-CCR8 antibody. In certain embodiments, 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 embodiments, 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.

[0493] In some embodiments, the anti-CCR8 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-CCR8 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-CCR8 antibody; and (h) about 2000 U / mL of rHuPH20.

[0494] In certain embodiments, 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) an anti-CCR8 antibody. In certain embodiments, 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) an anti-CCR8 antibody; and (h) about 2000 U / mL rHuPH20.

[0495] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) CCR8 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) CCR8 and (ii) CD3.

[0496] II.A.19. Anti-MICA antibodies In some embodiments, the second antibody comprises an anti-MICA antibody. In certain embodiments, 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 embodiments, 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.

[0497] In some embodiments, the anti-MICA antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-MICA antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-MICA antibody; and (h) about 2000 U / mL of rHuPH20.

[0498] In certain embodiments, 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) an anti-MICA antibody. In certain embodiments, 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) an anti-MICA antibody; and (h) about 2000 U / mL rHuPH20.

[0499] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) MICA and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) MICA and (ii) CD3.

[0500] II.A.20. Anti-ILT4 antibody In some embodiments, the second antibody comprises an anti-ILT4 antibody. In certain embodiments, 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 embodiments, 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.

[0501] In some embodiments, the anti-ILT4 antibody may be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, 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 pentetic acid; (f) about 5 mM methionine; and (g) the anti-ILT4 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an 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) an anti-ILT4 antibody; and (h) about 2000 U / mL of rHuPH20.

[0502] In certain embodiments, 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) an anti-ILT4 antibody. In certain embodiments, 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) an anti-ILT4 antibody; and (h) about 2000 U / mL rHuPH20.

[0503] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) ILT4 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, that specifically binds to (i) ILT4 and (ii) CD3.

[0504] II.B. Endoglycosidase Hydrolase Enzymes In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase enzyme. Any endoglycosidase hydrolase enzyme can be used in the pharmaceutical compositions and methods disclosed herein. In some embodiments, the endoglycosidase hydrolase enzyme cleaves hyaluronic acid at hexosaminide β(1-4) or (1-3) linkages. In some embodiments, the endoglycosidase hydrolase enzyme comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1.

[0505] In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants thereof, and any isoforms thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme 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 to amino acids 36-490 of SEQ ID NO: 1. In some embodiments, the endoglycosidase hydrolase enzyme comprises the catalytic domain of rHuPH20 (UniProt ID No. P38567-1). In some embodiments, the endoglycosidase hydrolase enzyme comprises the rHuPH20 mature peptide (amino acids 36-490 of SEQ ID NO:1).

[0506] [Table 2]

[0507] In some embodiments, the pharmaceutical composition comprises ENHANZE® drug delivery technology from Halozyme Therapeutics (see U.S. Patent No. 7,767,429, hereby incorporated by reference in its entirety). ENHANZE® uses a co-formulation of an antibody with a recombinant human hyaluronidase enzyme (rHuPH20), which removes traditional limitations on the volume of biologics and drugs, and which can be delivered subcutaneously due to the extracellular matrix (see U.S. Patent No. 7,767,429). In some embodiments, the pharmaceutical composition for the present disclosure may further comprise a recombinant human hyaluronidase enzyme, such as rHuPH20.

[0508] Recombinant human hyaluronidase PH20 (rHuPH20, Halozyme Therapeutics Inc.) is a glycosylated, 447-amino acid, single-chain recombinant human polypeptide that locally depolymerizes hyaluronan in the subcutaneous (SC) space at the site of injection. Hyaluronan is a repeating polymer of N-acetyl-glucosamine and glucuronic acid, which contributes to the soluble gel-like component of the skin's extracellular matrix. Depolymerization of hyaluronan by rHuPH20 results in a transient decrease in the viscosity of the gel-like phase of the extracellular matrix and an increase in hydrodynamic conductivity, which facilitates the dispersion and absorption of injected drugs (see rHuPH20 IB). The use of rHuPH20 allows for the delivery of large volumes (e.g., approximately 2 mL to 20 mL) for rapid SC injection, which may shorten dose administration time, reduce dosing frequency, and potentially 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.

[0509] The half-life of rHuPH20 in the skin is <30 minutes, and the local permeability barrier in these tissues returns to pre-injection levels within 24 to 48 hours after injection of hyaluronidase. Studies have shown that rHuPH20 is systemically undetectable in healthy volunteers and patients after SC administration at doses of 10,000 U and 30,000 U. Another study of the PK of rHuPH20 (Halozyme study HALO-104-104) demonstrated that plasma concentrations of rHuPH20 declined rapidly with a very short t (≤10.4 minutes), and plasma concentrations became undetectable (<0.03 ng / mL) within 1.5 hours after the end of IV infusion for IV doses of 10,000 or 30,000 units of rHuPH20.

[0510] Subcutaneous injections of rHuPH20 have been generally well tolerated in healthy participants, dehydrated pediatric participants, hospice and palliative care participants, participants with type 1 and 2 diabetes, and participants with rheumatoid arthritis. Subcutaneous injections of rHuPH20 alone or coadministered with lactated Ringer's, saline, co-injected medications (morphine, ceftriaxone, insulin, and insulin analogs), or biologic products (immunoglobulin G [IgG] and adalimumab) have been well tolerated.

[0511] In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises 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 a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the alpha-helical region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase in which one or more N-terminal and / or C-terminal amino acids are deleted compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof.

[0512] In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, wherein the modified rHuPH20 comprises one or more amino acid substitutions in the alpha-helical region, the linker region, or both the alpha-helical region and the linker region relative to wild-type rHuPH20. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, wherein the modified rHuPH20 comprises a 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. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, wherein the modified rHuPH20 comprises one or more amino acid substitutions in the alpha-helical region, the linker region, or both the alpha-helical region and the linker region relative to wild-type rHuPH20; the modified rHuPH20 comprises a 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.

[0513] Additional non-limiting examples of endoglycosidase hydrolase enzymes are found in EP 3636752, hereby incorporated by reference in its entirety.

[0514] In some aspects, the endoglycosidase hydrolase enzyme is any polypeptide having endoglycosidase hydrolase enzyme activity disclosed in U.S. Patent Nos. US9,447,401; US10,865,400; US11,041,149; US11,066,656; US8,927,249; US9,284,543; US10,588,983; US10 / 328,130; and / or US9,993,529, each of which is hereby incorporated by reference in its entirety. In some embodiments, the endoglycosidase hydrolase enzyme is any polypeptide having endoglycosidase hydrolase enzyme 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 hereby incorporated by reference in its entirety. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence that is 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 to an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs:5-52 and 264. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs:5-52 and 264.

[0515] In some embodiments, the endoglycosidase hydrolase enzyme is any polypeptide having endoglycosidase hydrolase enzyme activity disclosed in U.S. Patent Application Publication Nos. US2021155913A1 and / or US2021363270A1; and / or International Publication Nos. WO / 20 / 022791, WO / 20 / 197230, and / or WO / 21 / 150079, each of which is hereby incorporated by reference in its entirety. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence 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 to an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs:53-263. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence 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 to the amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 53-263. In some embodiments, the endoglycosidase hydrolase enzyme comprises the amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the endoglycosidase hydrolase enzyme is HP46 (SEQ ID NO: 44 of International Publication WO / 20 / 197230).

[0516] In certain embodiments, the pharmaceutical compositions disclosed herein comprise hyaluronidase. In some embodiments, the pharmaceutical compositions comprise a sufficient concentration of hyaluronidase for administration of at least about 20,000 units of hyaluronidase. In some embodiments, the pharmaceutical compositions comprise a sufficient concentration of hyaluronidase for administration of at least about 50,000 units of hyaluronidase. In some embodiments, the pharmaceutical compositions comprise a sufficient concentration of hyaluronidase for administration of at least about 75,000 units of hyaluronidase. In some embodiments, the pharmaceutical compositions comprise a sufficient concentration of hyaluronidase for administration of at least about 100,000 units of hyaluronidase. In some embodiments, the hyaluronidase is rHuPH20. In other embodiments, the pharmaceutical compositions do not comprise hyaluronidase.

[0517] In some embodiments, the pharmaceutical composition comprises at least about 50 units to at least about 48,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50 U / mL to at least about 5,000 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, 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, 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 1,000 U / mL, at least about 1,500 U / mL, at least about 2,000 U / mL, at least about 2,500 U / mL, at least about 3,000 U / mL, or at least about The pharmaceutical composition may comprise 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, or at least about 10,000 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 500 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 1000 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 2000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 2500 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 3000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20).In some embodiments, the pharmaceutical composition comprises at least about 3500 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 4000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 4500 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 5000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 6000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 7000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 8000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 9000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 10,000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20).

[0518] In some embodiments, the pharmaceutical composition comprises at least about 50 units to at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 500 units to at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, 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, The pharmaceutical composition may comprise 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, at least about 50,000 units, at least about 55,000 units, at least about 60,000 units, at least about 65,000 units, at least about 70,000 units, at least about 75,000 units, at least about 80,000 units, at least about 85,000 units, at least about 90,000 units, at least about 95,000 units, or at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 20,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 30,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 40,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20).In some embodiments, the pharmaceutical composition comprises at least about 50,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 60,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 70,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 80,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 90,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20).

[0519] It will be readily apparent to one of skill in the art that the amount of an endoglycosidase hydrolase enzyme (e.g., rHuPH20) can be expressed in terms of units or U / mL, or the amount of an endoglycosidase hydrolase enzyme (e.g., rHuPH20) can be expressed in terms of mg / mL (or other weight-based units). For example, in some embodiments, a pharmaceutical composition comprises an amount of an endoglycosidase hydrolase enzyme (e.g., rHuPH20) expressed as at least about 500 U / mL or at least about 0.00455 mg / mL. In another example, in some embodiments, a pharmaceutical composition comprises an amount of an endoglycosidase hydrolase enzyme (e.g., rHuPH20) expressed as at least about 2000 U / mL or at least about 0.0182 mg / mL.

[0520] In certain embodiments, the pharmaceutical composition comprises: (a) about 120 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, e.g., 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 2000 U / mL rHuPH20. In certain embodiments, 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 embodiments, the pharmaceutical composition comprises: (a) about 120 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, e.g., 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 of rHuPH20. In certain embodiments, 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.

[0521] In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, e.g., 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 2000 U / mL rHuPH20. In certain embodiments, 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 embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an antibody or antigen-binding portion thereof (e.g., an anti-PD-1 antibody, e.g., 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 of rHuPH20. In certain embodiments, 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.

[0522] In certain embodiments, 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, e.g., 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 2000 U / mL of rHuPH20. In certain embodiments, 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 embodiments, 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, e.g., 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 of rHuPH20. In certain embodiments, 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.

[0523] In certain embodiments, 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, e.g., 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 2000 U / mL of rHuPH20. In certain embodiments, 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 embodiments, 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, e.g., 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 of rHuPH20. In certain embodiments, 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.

[0524] In certain embodiments, the pharmaceutical composition comprises: (a) about 672 mg of nivolumab; (b) about 8.68 mg of L-histidine; (c) about 11.8 mg of histidine HCl HO; (d) about 479 mg of sucrose; (e) about 2.80 mg of polysorbate 80; (f) about 0.110 mg of pentetic acid; (g) about 4.18 mg of methionine; and (h) about 0.102 mg of rHuPH20; (a)-(h) are reconstituted in water to a final volume of at least about 5.6 mL.

[0525] II.C. Antioxidants In some embodiments, the pharmaceutical composition further comprises an antioxidant. Any antioxidant may be used in the pharmaceutical compositions disclosed herein. In some embodiments, the antioxidant is selected from methionine, tryptophan, and histidine, cysteine, ascorbic acid, glycine, pentetic acid (DTPA), and EDTA. In some embodiments, the pharmaceutical composition comprises at least two antioxidants. In some embodiments, at least one of the at least two antioxidants is a sacrificial antioxidant. Any sacrificial antioxidant may be used in the pharmaceutical compositions and methods disclosed herein. In some embodiments, the sacrificial antioxidant is selected from the group consisting of methionine, tryptophan, and histidine, cysteine, ascorbic acid, glycine, or other sacrificial substances. In some embodiments, at least one of the at least two antioxidants comprises a metal ion chelator. Any metal ion chelator may be used in the pharmaceutical compositions and methods disclosed herein. In some embodiments, the metal ion chelator is pentetic acid (“DTPA”) or EDTA.

[0526] In certain embodiments, the pharmaceutical composition comprises methionine. In some embodiments, the pharmaceutical composition comprises at least two antioxidants. In some embodiments, the at least two antioxidants are selected from methionine, DTPA, and EDTA. In some embodiments, the at least two antioxidants comprise methionine and EDTA. In some embodiments, the at least two antioxidants comprise methionine and pentetic acid (DTPA).

[0527] In some embodiments, the phar...

Claims

1. (i) (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; or (ii) (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 13. A pharmaceutical composition 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 pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20 The pharmaceutical composition of claim 1 , 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 pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20 The pharmaceutical composition of claim 1 , comprising:

4. A pharmaceutical composition described in any one of claims 1 to 3, having a pH of about 5.2 to about 6.

8.

5. The pharmaceutical composition of claim 1, comprising a pH of about 6.

0.

6. A pharmaceutical composition described in any one of claims 1 to 5, wherein rHuPH20 comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 5-52 and 264.

7. A pharmaceutical composition described in any one of claims 1 to 6, wherein rHuPH20 comprises the amino acid sequence set forth in SEQ ID NO:

5.

8. The pharmaceutical composition of claim 2 or 3, comprising a pH of about 6.0, wherein rHuPH20 comprises the amino acid sequence set forth in SEQ ID NO:

5.

9. A vial comprising a pharmaceutical composition according to any one of claims 1 to 8.

10. A syringe comprising a pharmaceutical composition according to any one of claims 1 to 8.

11. An automatic injector comprising a pharmaceutical composition according to any one of claims 1 to 8.

12. A wearable pump comprising a pharmaceutical composition according to any one of claims 1 to 8.

13. A pharmaceutical composition according to any one of claims 1 to 8 for use in treating a disease or disorder in a subject in need thereof, comprising administering to the subject a pharma- ceutical effective amount of the pharmaceutical composition.

14. The pharmaceutical composition for use according to claim 13, wherein the pharmaceutical composition is administered subcutaneously.

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