Antibody composition and method of use thereof

Abstract

The present invention provides a formulation containing an anti-PD-1 or anti-PD-L1 antibody that is suitable for subcutaneous delivery to patients. [Solution] This disclosure provides a pharmaceutical composition comprising (i) an antibody that specifically binds to PD-1 ("anti-PD-1 antibody"), (ii) an endoglycosidase hydrolase enzyme, and (iii) at least two antioxidants.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority and the benefit thereof to U.S. Provisional Application No. US63 / 131,234, filed on December 28, 2020; U.S. Provisional Application No. US63 / 131,244, filed on December 28, 2020; and U.S. Provisional Application No. US63 / 150,465, filed on February 17, 2021, each of which is hereby incorporated by reference in its entirety herein.

[0002] Reference to a Sequence Listing Submitted Electronically via EFS - WEB The content of the electronically submitted sequence listing (name: 3338_191PC03_Seqlisting_ST25.txt; size: 1,011,388 bytes; and creation date: December 27, 2021) is hereby incorporated by reference in its entirety herein.

[0003] The present disclosure provides a pharmaceutical composition comprising an antibody and a method for using the same to treat a subject suffering from a tumor.

Background Art

[0004] Human cancers possess numerous genetic and epigenetic alterations, creating neoantigens that are 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 excellent specificity to respond to diverse tumor antigens and has potent anti - cancer potential. Furthermore, the immune system exhibits considerable plasticity and a memory component. Harnessing all of these traits of the adaptive immune system would make immunotherapy unparalleled among all cancer treatment modalities.

[0005] Until recently, cancer immunotherapy has largely focused its efforts on methods to enhance the anti-tumor immune response through adoptive transfer of activated effector cells, immunization against relevant antigens, or providing nonspecific immunostimulants such as cytokines. However, in the last decade, a thorough effort to develop specific immune checkpoint pathway inhibitors has begun to offer new immunotherapeutic approaches to treat cancer, including the development of antibodies such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council Statement, 2013) that 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). [Overview of the Initiative] [Problems that the invention aims to solve]

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

[0007] Certain embodiments of this disclosure are directed to a pharmaceutical composition comprising (i) an antibody that specifically binds to PD-1 ("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 at least two antioxidants is a metal ion chelating agent. In some embodiments, the metal ion chelating agent is selected from pentetate ("DTPA") and EDTA.

[0009] In some embodiments, 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, at least two antioxidants are methionine and DTPA. In some embodiments, at least two antioxidants are methionine and EDTA.

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

[0011] In some embodiments, at least one antioxidant contains at least about 10 μM to about 200 μM of DTPA. In some embodiments, 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 of DTPA. In some embodiments, at least one antioxidant contains approximately 50 μM of DTPA.

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

[0013] In some embodiments, the pharmaceutical composition contains at least about 5 U to at least about 100,000 U of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition contains 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, and less The pharmaceutical composition contains at least 6,000 U, at least 7,000 U, at least 8,000 U, at least 9,000 U, at least 10,000 U, at least 20,000 U, at least 30,000 U, at least 40,000 U, at least 50,000 U, at least 60,000 U, at least 70,000 U, at least 80,000 U, at least 90,000 U, or at least 100,000 U of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition contains about 20,000 U of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition contains at least about 500 U / mL to at least about 5,000 U / mL of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition contains 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 endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition contains about 2000 U / mL of 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 contains the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme contains an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with amino acids 36-490 of SEQ ID NO: 1. In some embodiments, the endoglycosidase hydrolase enzyme contains hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant thereof, and any isoform. In some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0015] In some embodiments, the endoglycosidase hydrolase enzyme includes 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 fragments thereof. In some embodiments, the endoglycosidase hydrolase enzyme includes a modified hyaluronidase comprising one or more amino acid substitutions in the alpha-helix region compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase enzyme includes 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 fragments 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 fragments thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, the modified rHuPH20 comprising i. one or more amino acid substitutions in the alpha-helix region, linker region, or both the alpha-helix region and 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 of (i) and (ii).

[0016] In some embodiments, the pharmaceutical composition further comprises a tonicity modifier and / or stabilizer. In some embodiments, the tonicity modifier and / or stabilizer comprises sugars, amino acids, polyols, salts, or combinations thereof. In some embodiments, the tonicity modifier 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 modifier comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM of sucrose. In some embodiments, the pharmaceutical composition contains 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, and less Each contains approximately 260 mM, at least approximately 270 mM, at least approximately 280 mM, at least approximately 290 mM, at least approximately 300 mM, at least approximately 310 mM, at least approximately 320 mM, at least approximately 330 mM, at least approximately 340 mM, at least approximately 350 mM, at least approximately 360 mM, at least approximately 370 mM, at least approximately 380 mM, at least approximately 390 mM, at least approximately 400 mM, at least approximately 410 mM, at least approximately 420 mM, at least approximately 430 mM, at least approximately 440 mM, at least approximately 450 mM, at least approximately 460 mM, at least approximately 470 mM, at least approximately 480 mM, at least approximately 490 mM, or at least approximately 500 mM of sucrose. In some embodiments, the pharmaceutical composition contains approximately 250 mM of 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 of 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 of histidine. In some embodiments, the pharmaceutical composition comprises about 20 mM of 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 contains approximately 0.05% w / v of polysorbate 80.

[0019] In some embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM 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 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 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 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, semiprimab, tripalimab, tislerizumab, 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 of 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 of rHuPH20. In some embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of 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 of rHuPH20. In some embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20. In some embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of 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 H2O; (d) about 479 mg of sucrose; (e) about 2.80 mg of polysorbate 80; (f) about 0.110 mg of pentetate; (g) about 4.18 mg of methionine; and (h) about 0.102 mg of rHuPH2O; (a) to (h) are reconstituted in water to a final volume of at least about 5.6 mL.

[0022] In some embodiments, the pharmaceutical composition contains a pH of approximately 5.2 to approximately 6.8. In some embodiments, the pharmaceutical composition contains a pH of approximately 5.2, approximately 5.3, approximately 5.4, approximately 5.5, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6.0, approximately 6.1, approximately 6.2, approximately 6.3, approximately 6.4, approximately 6.5, approximately 6.6, approximately 6.7, or approximately 6.8. In some embodiments, the pharmaceutical composition contains a pH of approximately 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, 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 comprises 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 of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-CTLA-4 antibody. In some embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-CTLA-4 antibody. In some embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-TIM3 antibody. In some embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-TIM3 antibody.

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

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

[0027] Certain aspects of the present disclosure are directed to autoinjectors containing any of the pharmaceutical compositions disclosed herein.

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

[0029] Certain aspects of the present disclosure are directed to methods of treating a disease or disorder in a subject that needs it, comprising administering a pharmaceutically effective amount of any of the pharmaceutical compositions disclosed herein to the subject. 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, cancer is squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, kidney cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-resistant prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma pleomorphonosum, cervical cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, gastric cancer Cancer, germ cell tumors, pediatric sarcomas, sinus natural killer tumors, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, vaginal carcinoma, vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcomas, urethral cancer, penile cancer, rectal cancer, solid tumors in childhood, ureteral cancer, renal pelvis carcinoma, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axial tumors, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermal carcinoma, squamous cell carcinoma, environmentally induced cancers including those induced by asbestos, virus-associated cancers or cancers of virus origin [e.g., human papillomavirus (HPV-associated or originating tumors)], and any combination thereof.

[0031] Certain embodiments of this disclosure relate to a method for treating a subject in need of such treatment, comprising subcutaneously administering 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 ("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, or less than about 2.5 mL; the effective dose is directed to a method comprising at least about 250 mg to at least about 2400 mg of antibody. In some embodiments, the pharmaceutical composition does not contain hyaluronidase.

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

[0033] In some embodiments, the antibody contains an anti-PD-1 antibody. In some embodiments, the effective dose of the antibody is approximately 250 mg to 600 mg, administered approximately weekly. In some embodiments, the effective dose of the antibody is approximately 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, or 600 mg, administered approximately weekly. In some embodiments, the effective dose of the antibody is approximately 300 mg administered on a nearly weekly basis. In some embodiments, the effective dose of the antibody includes a single subcutaneous unit dose of approximately 300 mg. In some embodiments, the effective dose of the antibody includes a single subcutaneous unit dose of approximately 300 mg in a total administered volume of approximately 2 mL.

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

[0035] In some embodiments, the effective dose of the antibody is approximately 300 mg to 900 mg administered approximately every two weeks. In some embodiments, the effective dose of the antibody is approximately 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, and 660 mg administered approximately every two weeks. These are approximately 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, or 900 mg. In some embodiments, the effective dose of antibody is approximately 600 mg administered approximately 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 containing approximately 300 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses contains approximately 300 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least two subcutaneous unit doses are administered to at least two different physical sites of the target.

[0037] In some embodiments, the effective dose of the antibody is approximately 900 mg to 1500 mg administered approximately every four weeks. In some embodiments, the effective dose of the antibody is approximately 900, 950, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, and 1200 mg administered approximately every four weeks. The dosages are approximately 30 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, 1280 mg, 1290 mg, 1300 mg, 1310 mg, 1320 mg, 1330 mg, 1340 mg, 1350 mg, 1360 mg, 1370 mg, 1380 mg, 1390 mg, 1400 mg, 1410 mg, 1420 mg, 1430 mg, 1440 mg, 1450 mg, 1460 mg, 1470 mg, 1480 mg, 1490 mg, or 1500 mg. In some embodiments, the effective dose of antibody is approximately 1200 mg administered approximately 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 which contains approximately 300 mg of antibody. In some embodiments, at least one of the 4 subcutaneous unit doses contains approximately 300 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least two of the subcutaneous unit doses are administered to at least two different physical sites of the target. 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 contains an anti-PD-L1 antibody. In some embodiments, the effective dose of the antibody is approximately 900 mg to approximately 1800 mg of antibody administered approximately every two weeks. In some embodiments, the effective dose of the antibody is approximately 900 mg, approximately 950 mg, approximately 1000 mg, approximately 1010 mg, approximately 1020 mg, approximately 1030 mg, approximately 1040 mg, approximately 1050 mg, approximately 1060 mg, approximately 1070 mg, approximately 1080 mg, approximately 1090 mg, approximately 1100 mg, approximately 1110 mg, approximately 1120 mg, approximately 1130 mg, approximately 1140 mg, approximately 1150 mg, approximately 1160 mg, approximately 1170 mg, approximately 1180 mg, approximately 1190 mg, approximately 1200 mg, approximately 1210 mg, approximately 1220 mg, approximately The dosages are approximately 1230 mg, 1240 mg, 1250 mg, 1260 mg, 1270 mg, 1280 mg, 1290 mg, 1300 mg, 1310 mg, 1320 mg, 1330 mg, 1340 mg, 1350 mg, 1360 mg, 1370 mg, 1380 mg, 1390 mg, 1400 mg, 1410 mg, 1420 mg, 1430 mg, 1440 mg, 1450 mg, 1460 mg, 1470 mg, 1480 mg, 1490 mg, or 1500 mg. In some embodiments, the effective dose of antibody is approximately 1200 mg every two weeks. In some embodiments, the effective dose comprises at least two, three, four, five, six, seven, or eight subcutaneous unit doses. In some embodiments, the effective dose of antibody comprises four subcutaneous unit doses, each containing approximately 300 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses contains approximately 300 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least two of the subcutaneous unit doses are administered to at least two different physical sites 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 includes antibodies comprising nivolumab, pembrolizumab, PDR001, MEDI-0680, semiprimab, tripalimab, tislerizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, KN035, sasamrimab, 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 includes antibodies comprising BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, CK-301, or any combination thereof.

[0041] In some aspects, the subjects have cancer. In some aspects, the cancers include squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, kidney cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-resistant prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma pleomorphonosum, cervical cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, paranasal sinus natural killer cancer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube carcinoma, and intrauterine cancer. This includes carcinomas of the membranes, carcinomas of the neck, carcinomas of the vagina, carcinomas of the vulva, carcinomas of the esophagus, carcinomas of the small intestine, carcinomas of the endocrine system, carcinomas of the parathyroid gland, carcinomas of the adrenal gland, sarcomas of soft tissue, carcinomas of the urethra, carcinomas of the penis, carcinomas of the rectum, solid tumors of childhood, carcinomas of the ureter, carcinomas of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, axial tumors of the spinal cord, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermal carcinoma, squamous cell carcinoma, environmentally induced carcinomas including those induced by asbestos, virus-associated carcinomas or carcinomas of virus origin [e.g., human papillomavirus (HPV-associated or originating from it)], 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 over a period of less than approximately 10 minutes. In some embodiments, the pharmaceutical composition is administered to the subject by subcutaneous injection over a period of less than approximately 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 of methionine. In some embodiments, at least two antioxidants contain 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. In some embodiments, at least two antioxidants contain about 5 mM of methionine.

[0044] In some embodiments, at least two antioxidants contain at least about 10 μM to about 200 μM of DTPA. In some embodiments, at least two antioxidants include 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 of DTPA. In some embodiments, at least two antioxidants are included in a concentration of approximately 50 μM of DTPA.

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

[0046] In some embodiments, the pharmaceutical composition further comprises a tonicity modifier and / or stabilizer. In some embodiments, the tonicity modifier and / or stabilizer comprises sugars, amino acids, polyols, salts, or combinations thereof. In some embodiments, the tonicity modifier and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, and any combination thereof. In some embodiments, the tonicity modifier comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM of sucrose. In some embodiments, the pharmaceutical composition contains 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, and less Each contains approximately 260 mM, at least approximately 270 mM, at least approximately 280 mM, at least approximately 290 mM, at least approximately 300 mM, at least approximately 310 mM, at least approximately 320 mM, at least approximately 330 mM, at least approximately 340 mM, at least approximately 350 mM, at least approximately 360 mM, at least approximately 370 mM, at least approximately 380 mM, at least approximately 390 mM, at least approximately 400 mM, at least approximately 410 mM, at least approximately 420 mM, at least approximately 430 mM, at least approximately 440 mM, at least approximately 450 mM, at least approximately 460 mM, at least approximately 470 mM, at least approximately 480 mM, at least approximately 490 mM, or at least approximately 500 mM of sucrose. In some embodiments, the pharmaceutical composition contains approximately 250 mM of 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 of 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 of histidine. In some embodiments, the pharmaceutical composition comprises about 20 mM of 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 according to any one of claims 1 to 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 contains approximately 0.05% w / v of polysorbate 80.

[0049] In some embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine.

[0050] In some embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine.

[0051] In some embodiments, the pharmaceutical composition contains a pH of approximately 5.2 to approximately 6.8. In some embodiments, the pharmaceutical composition contains a pH of approximately 5.2, approximately 5.3, approximately 5.4, approximately 5.5, approximately 5.6, approximately 5.7, approximately 5.8, approximately 5.9, approximately 6.0, approximately 6.1, approximately 6.2, approximately 6.3, approximately 6.4, approximately 6.5, approximately 6.6, approximately 6.7, or approximately 6.8. In some embodiments, the pharmaceutical composition contains a pH of approximately 6.0.

[0052] Certain aspects of this disclosure are directed toward pharmaceutical compositions for use in any manner disclosed herein.

[0053] Certain embodiments of this disclosure are directed to pharmaceutical compositions comprising (i) an antibody that specifically binds to PD-1 ("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 of methionine. In some embodiments, at least two antioxidants contain 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. In some embodiments, at least two antioxidants contain about 5 mM of methionine.

[0054] In some embodiments, at least two antioxidants contain at least about 10 μM to about 200 μM of DTPA. In some embodiments, at least two antioxidants include 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 of DTPA. In some embodiments, at least two antioxidants are included in a concentration of approximately 50 μM of DTPA.

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

[0056] In some embodiments, the composition further comprises a tension modifier and / or stabilizer. In some embodiments, the tension modifier and / or stabilizer comprises sugars, amino acids, polyols, salts, or combinations thereof. In some embodiments, the tension modifier and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, and any combination thereof. In some embodiments, the tension modifier comprises sucrose. In some embodiments, the composition comprises at least about 10 mM to at least about 500 mM of sucrose. In some embodiments, the composition contains 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, and at least The composition contains approximately 260 mM, at least approximately 270 mM, at least approximately 280 mM, at least approximately 290 mM, at least approximately 300 mM, at least approximately 310 mM, at least approximately 320 mM, at least approximately 330 mM, at least approximately 340 mM, at least approximately 350 mM, at least approximately 360 mM, at least approximately 370 mM, at least approximately 380 mM, at least approximately 390 mM, at least approximately 400 mM, at least approximately 410 mM, at least approximately 420 mM, at least approximately 430 mM, at least approximately 440 mM, at least approximately 450 mM, at least approximately 460 mM, at least approximately 470 mM, at least approximately 480 mM, at least approximately 490 mM, or at least approximately 500 mM of sucrose. In some embodiments, the composition contains approximately 250 mM of 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 of 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 of histidine. In some embodiments, the composition comprises about 20 mM of 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 of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine.

[0060] In some embodiments, the composition comprises (a) about 120 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; and (f) about 5 mM methionine.

[0061] In some embodiments, the composition contains a pH of about 5.2 to about 6.8. In some embodiments, the composition contains 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 contains 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, 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 comprises IL-2 (e.g., bempegaldesleukin) or IL12-Fc (e.g., BMS-986415).

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

[0064] Certain aspects of this disclosure are directed to unit doses comprising any pharmaceutical composition disclosed herein.

[0065] Certain aspects of this disclosure are directed to a unit dose comprising (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; and (f) about 5 mM methionine.

[0066] In some embodiments, the vial is an auto-injector. Certain embodiments of this disclosure are directed towards an auto-injector containing the unit doses disclosed herein. In some embodiments, the vial is a wearable device. Certain embodiments of this disclosure are directed towards a wearable device containing the unit doses disclosed herein.

[0067] manner Pharmaceutical compositions and their use.

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

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

[0070] Embodiment A3. The pharmaceutical composition according to Embodiment 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] Embodiment A4. A pharmaceutical composition according to any one of Embodiments A1 to A3, wherein at least one of the at least two antioxidants is a metal ion chelating agent.

[0072] Embodiment A5. The pharmaceutical composition according to Embodiment A4, wherein the metal ion chelating agent is selected from pentetic acid ("DTPA") and EDTA.

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

[0074] Embodiment A7. A pharmaceutical composition according to any one of Embodiments A1 to A6, wherein at least two antioxidants one of which is methionine.

[0075] Embodiment A8. A pharmaceutical composition according to any one of Embodiments A1 to A7, wherein at least one of the two antioxidants is DTPA.

[0076] Embodiment A9. A pharmaceutical composition according to any one of Embodiments A1 to A7, wherein at least two antioxidants one of which is EDTA.

[0077] Embodiment A10. The pharmaceutical composition according to any one of Embodiments A1 to A8, wherein at least two antioxidants are methionine and DTPA.

[0078] Embodiment A11. The pharmaceutical composition according to any one of Embodiments A1 to A7 and 9, wherein at least two antioxidants are methionine and EDTA.

[0079] Embodiment A12. A pharmaceutical composition according to any one of Embodiments A1 to A11, wherein at least one antioxidant contains at least about 1 to about 20 mM of methionine.

[0080] Embodiment A13. A pharmaceutical composition according to any one of Embodiments A1 to A12, wherein 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 of methionine.

[0081] Embodiment A14. A pharmaceutical composition according to any one of Embodiments A1 to A13, wherein at least one antioxidant comprises about 5 mM methionine.

[0082] Embodiment A15. A pharmaceutical composition according to any one of Embodiments A1 to A14, wherein at least one antioxidant comprises at least about 10 μM to about 200 μM of DTPA.

[0083] Embodiment A16. A pharmaceutical composition according to any one of Embodiments A1 to A15, wherein 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 of DTPA.

[0084] Embodiment A17. A pharmaceutical composition according to any one of Embodiments A1 to A16, wherein at least one antioxidant comprises about 50 μM of DTPA.

[0085] Embodiment A18. A pharmaceutical composition according to any one of Embodiments A1 to A17, comprising at least about 20 mg / mL to at least about 200 mg / mL of anti-PD-1 antibody.

[0086] Embodiment A19. A pharmaceutical composition according to any one of Embodiments A1 to A18, comprising at least about 135 mg / mL to at least about 180 mg / mL of anti-PD-1 antibody.

[0087] Embodiment A20. A pharmaceutical composition according to any one of Embodiments A1 to A17, comprising at least about 108 mg / mL to at least about 132 mg / mL of anti-PD-1 antibody.

[0088] Embodiment A21. A pharmaceutical composition according to any one of Embodiments A1 to A20, comprising an anti-PD-1 antibody in an amount of 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.

[0089] Embodiment A22. A pharmaceutical composition according to any one of Embodiments A1 to A21, comprising approximately 120 mg / mL of anti-PD-1 antibody.

[0090] Embodiment A23. A pharmaceutical composition according to any one of Embodiments A1 to A21, comprising approximately 150 mg / mL of anti-PD-1 antibody.

[0091] Embodiment A24. A pharmaceutical composition according to any one of Embodiments A1 to A23, comprising at least about 5 U to at least about 100,000 U of endoglycosidase hydrolase enzyme.

[0092] Appearance A25. At least about 5U, at least about 10U, at least about 20U, at least about 30U, at least about 40U, at least about 50U, at least about 75U, at least about 100U, at least about 200U, at least about 300U, at least about 400U, at least about 500U, at least about 750U, at least about 1000U, at least about 2000U, at least about 3000U, at least about 4000U, at least about 5000U, at least about 6000U, at least about 7 A pharmaceutical composition according to any one of embodiments A1 to 24, comprising 000U, at least about 8000U, at least about 9000U, at least about 10,000U, at least about 20,000U, at least about 30,000U, at least about 40,000U, at least about 50,000U, at least about 60,000U, at least about 70,000U, at least about 80,000U, at least about 90,000U, or at least about 100,000U of endoglycosidase hydrolase enzyme.

[0093] Embodiment A26. A pharmaceutical composition according to any one of Embodiments A1 to A25, comprising approximately 20,000 U of endoglycosidase hydrolase enzyme.

[0094] Embodiment A27. A pharmaceutical composition according to any one of Embodiments A1 to A26, comprising at least about 500 U / mL to at least about 5000 U / mL of endoglycosidase hydrolase enzyme.

[0095] Embodiment A28. A pharmaceutical composition according to any one of Embodiments A1 to A27, 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] Embodiment A29. A pharmaceutical composition according to any one of Embodiments A1 to A28, comprising approximately 2000 U / mL of endoglycosidase hydrolase enzyme.

[0097] Embodiment A30. The pharmaceutical composition according to any one of Embodiments A1 to A29, wherein the endoglycosidase hydrolase enzyme cleaves hyaluronic acid at the hexosaminide β(1-4) or (1-3) linkage.

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

[0099] Embodiment A32. The pharmaceutical composition according to any one of Embodiments 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 with amino acids 36 to 490 of SEQ ID NO: 1.

[0100] Embodiment A33. A pharmaceutical composition according to any one of Embodiments A1 to A32, wherein the endoglycosidase hydrolase enzyme comprises hyaluronidase.

[0101] Embodiment A34. The pharmaceutical composition according to any one of Embodiments A1 to 33, wherein the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant thereof, and any isoform.

[0102] Embodiment A35. A pharmaceutical composition according to any one of Embodiments A1 to A34, wherein the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0103] Embodiment A36. The pharmaceutical composition according to any one of Embodiments A1 to 35, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase having 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 fragments thereof.

[0104] Embodiment A37. The pharmaceutical composition according to any one of Embodiments A1 to 36, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase having one or more amino acid substitutions in the alpha-helix region, compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof.

[0105] Embodiment A38. The pharmaceutical composition according to any one of Embodiments A1 to 37, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase having 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 fragments thereof.

[0106] Embodiment A39. A pharmaceutical composition according to any one of Embodiments A1 to 38, comprising a modified hyaluronidase in which the endoglycosidase hydrolase enzyme is deleting one or more N-terminal and / or C-terminal amino acids compared to wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof.

[0107] Embodiment A40. A pharmaceutical composition according to any one of Embodiments A1 to 39, wherein the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, the modified rHuPH20 comprising: i. one or more amino acid substitutions in the alpha-helix region, linker region, or both the alpha-helix 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 of (i) and (ii).

[0108] Embodiment A41. A pharmaceutical composition according to any one of Embodiments A1 to A40, further comprising a tension modifier and / or stabilizer.

[0109] Embodiment A42. The pharmaceutical composition according to Embodiment A41, wherein the tension modifier and / or stabilizer comprises sugars, amino acids, polyols, salts, or a combination thereof.

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

[0111] Embodiment A44. A pharmaceutical composition according to any one of Embodiments A41 to A43, wherein the tension adjusting agent contains sucrose.

[0112] Embodiment A45. A pharmaceutical composition according to any one of Embodiments A1 to A44, comprising at least about 10 mM to at least about 500 mM of sucrose.

[0113] Appearance A46. At least about 10mM, at least about 20mM, at least about 30mM, at least about 40mM, at least about 50mM, at least about 60mM, at least about 70mM, at least about 80mM, at least about 90mM, at least about 100mM, at least about 110mM, at least about 120mM, at least about 130mM, at least about 140mM, at least about 150mM, at least about 160mM, at least about 170mM, at least about 180mM, at least about 190mM, at least about 200mM, at least about 210mM, at least about 220mM, at least about 230mM, at least about 240mM, at least about 250mM, at least about 260mM, at least about 27 A pharmaceutical composition according to any one of embodiments 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 of sucrose.

[0114] Embodiment A47. A pharmaceutical composition according to any one of Embodiments A1 to A46, comprising approximately 250 mM sucrose.

[0115] Embodiment A48. A pharmaceutical composition according to any one of Embodiments A1 to A47, further comprising a buffering agent.

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

[0117] Embodiment A50. The pharmaceutical composition according to Embodiment A48 or 49, wherein the buffering agent contains histidine.

[0118] Embodiment A51. A pharmaceutical composition according to any one of Embodiments A1 to A50, comprising at least about 5 mM to at least about 100 mM of histidine.

[0119] Embodiment A52. A pharmaceutical composition according to 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 of histidine.

[0120] Embodiment A53. A pharmaceutical composition according to any one of Embodiments A1 to A52, comprising approximately 20 mM histidine.

[0121] Embodiment A54. A pharmaceutical composition according to any one of Embodiments A1 to A53, further comprising a surfactant.

[0122] Embodiment A55. The pharmaceutical composition according to Embodiment A54, wherein the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188.

[0123] Embodiment A56. The pharmaceutical composition according to Embodiment A54 or 55, wherein the surfactant comprises polysorbate 80.

[0124] Embodiment A57. A pharmaceutical composition according to any one of Embodiments A1 to A56, comprising at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80.

[0125] Embodiment A58. A pharmaceutical composition according to any one of Embodiments A1 to 57, comprising polysorbate 80 in an amount of 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.

[0126] Embodiment A59. A pharmaceutical composition according to any one of Embodiments A1 to A58, comprising approximately 0.05% w / v of polysorbate 80.

[0127] A60. A pharmaceutical composition according to any one of A1 to 35 and 41 to 59, comprising (a) about 120 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL of rHuPH20.

[0128] A61. A pharmaceutical composition according to any one of A1 to 35 and 41 to 59, comprising (a) about 120 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL of rHuPH20.

[0129] A62. A pharmaceutical composition according to any one of A1 to 35 and 41 to 59, comprising (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) about 0.0182 mg / mL of rHuPH20.

[0130] A63. A pharmaceutical composition according to any one of A1 to 35 and 41 to 59, comprising (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL of rHuPH20.

[0131] Embodiment A64. A pharmaceutical composition according to any one of Embodiments A1 to A63, wherein the anti-PD-1 antibody is selected from nivolumab, pembrolizumab, PDR001, MEDI-0680, semiprimab, tripalimab, tislerizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, sasanlimab, and any combination thereof.

[0132] Embodiment A65. The pharmaceutical composition according to any one of Embodiments A1 to A64, wherein the anti-PD-1 antibody is nivolumab.

[0133] Embodiment A66. The pharmaceutical composition according to any one of Embodiments A1 to A64, wherein the anti-PD-1 antibody is pembrolizumab.

[0134] A67. A pharmaceutical composition according to any one of A1 to 35 and 41 to 65, comprising (a) about 120 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; and (g) about 0.0182 mg / mL of rHuPH20.

[0135] A68. A pharmaceutical composition according to any one of A1 to 35 and 41 to 65, comprising (a) about 120 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; and (g) about 2000 U / mL of rHuPH20.

[0136] A69. A pharmaceutical composition according to any one of A1 to 35 and 41 to 65, comprising (a) about 150 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; and (g) about 0.0182 mg / mL of rHuPH20.

[0137] A70. A pharmaceutical composition according to any one of A1 to 35 and 41 to 65, comprising (a) about 150 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; and (g) about 2000 U / mL of rHuPH20.

[0138] A71. A pharmaceutical composition according to any one of embodiments A1 to 35 and 41 to 65, comprising (a) about 672 mg of nivolumab; (b) about 8.68 mg of histidine; (c) about 11.8 mg of histidine HCl H2O; (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 rHuPH2O, wherein (a) to (h) are reconstituted in water to a final volume of at least about 5.6 mL.

[0139] Embodiment A72. A pharmaceutical composition according to any one of Embodiments A1 to A71, comprising a pH of approximately 5.2 to approximately 6.8.

[0140] A73. A pharmaceutical composition according to any one of A1 to A72, comprising a pH of approximately 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8.

[0141] Embodiment A74. A pharmaceutical composition according to any one of Embodiments A1 to A73, comprising a pH of approximately 6.0.

[0142] Embodiment A75. A pharmaceutical composition according to any one of Embodiments A1 to A74, further comprising a second therapeutic agent.

[0143] Embodiment A76. The pharmaceutical composition according to Embodiment A75, wherein the second therapeutic agent is an antibody.

[0144] Embodiment A77. The pharmaceutical composition according to Embodiment A76, wherein the second therapeutic agent is a checkpoint inhibitor.

[0145] Embodiment A78. The pharmaceutical composition according to Embodiment A77, wherein the checkpoint inhibitor is an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA antibody, an anti-CD137 antibody, an anti-KIR antibody, an anti-TGFβ antibody, an anti-IL-10 antibody, an anti-IL-8 antibody, an anti-B7-H4 antibody, an anti-Fas ligand antibody, an anti-CXCR4 antibody, an anti-mesothelin antibody, an anti-CD27 antibody, an anti-GITR, or any combination thereof.

[0146] A79. A pharmaceutical composition according to any one of A1 to 35 and 41 to 78, comprising (a) about 120 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-CTLA-4 antibody.

[0147] Apparent A80. A pharmaceutical composition according to any one of A1 to 35 and 41 to 78, comprising (a) about 150 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-CTLA-4 antibody.

[0148] A pharmaceutical composition according to any one of embodiments A1 to 35 and 41 to 78, comprising: (a) about 120 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-LAG-3 antibody.

[0149] A pharmaceutical composition according to any one of A1 to 35 and 41 to 78, comprising: (a) about 150 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-LAG-3 antibody.

[0150] A pharmaceutical composition according to any one of embodiments A1 to 35 and 41 to 78, comprising: (a) about 120 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-TIM3 antibody.

[0151] A pharmaceutical composition according to any one of A1 to 35 and 41 to 78, comprising: (a) about 150 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; (g) about 2000 U / mL of rHuPH20; and (h) an anti-TIM3 antibody.

[0152] Embodiment A85. A vial containing the pharmaceutical composition described in any one of Embodiments A1 to A84.

[0153] Embodiment A86. A syringe containing the pharmaceutical composition described in any one of Embodiments A1 to A84.

[0154] Embodiment A87. An automatic syringe comprising the pharmaceutical composition described in any one of Embodiments A1 to A84.

[0155] Embodiment A88. A wearable pump comprising the pharmaceutical composition described in any one of Embodiments A1 to A84.

[0156] Embodiment A89. The syringe according to Embodiment A86, further comprising a plunger.

[0157] Embodiment A90. A method for treating a disease or disorder in a subject requiring the use of a pharmaceutical composition described in any one of Embodiments A1 to A84, comprising administering a pharmaceutically effective amount of the composition to the subject.

[0158] Embodiment A91. The method according to Embodiment A90, wherein the pharmaceutical composition is administered subcutaneously.

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

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

[0161] Appearance A94. Cancers include squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, kidney cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, renal cell carcinoma (RCC), prostate cancer, hormone-resistant prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma pleomorphonosum, cervical cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, paranasal sinus natural killer cancer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube carcinoma, endometrial carcinoma, and cervical cancer. The method according to aspect A93, which includes tumors, vaginal carcinomas, vulvar carcinomas, esophageal cancers, small intestine cancers, endocrine system cancers, parathyroid cancers, adrenal gland cancers, soft tissue sarcomas, urethral cancers, penile cancers, rectal cancers, solid tumors in childhood, ureteral cancers, renal pelvis carcinomas, neoplasms of the central nervous system (CNS), primary CNS lymphomas, tumor angiogenesis, spinal axial tumors, brain cancers, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermal carcinomas, squamous cell carcinomas, environmentally induced cancers including those induced by asbestos, virus-associated cancers or cancers of virus origin [e.g., human papillomavirus (HPV-related or virus-derived tumors)], and any combination thereof.

[0162] Embodiment 1. A method for treating a subject in need of such treatment, comprising subcutaneously administering an effective dose of a pharmaceutical composition containing an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction of PD-1 and PD-L1 ("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 approximately 5 mL, less than approximately 4.5 mL, less than approximately 4.0 mL, less than approximately 3.5 mL, less than approximately 3.0 mL, or less than approximately 2.5 mL; and the effective dose contains at least approximately 250 mg to at least approximately 2400 mg of antibody.

[0163] Embodiment B2. The method according to Embodiment B1, wherein the pharmaceutical composition does not contain hyaluronidase.

[0164] Embodiment B3. The method according to Embodiment B1 or 2, wherein the effective dose comprises two or more subcutaneous unit doses, and the two or more subcutaneous unit doses are administered simultaneously or sequentially.

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

[0166] Embodiment B5. The method according to any one of Embodiments B1 to B4, wherein the effective dose is administered approximately every 1, 2, 3, or 4 weeks.

[0167] Embodiment B6. The method according to any one of Embodiments B1 to B5, wherein the antibody comprises an anti-PD-1 antibody.

[0168] Embodiment B7. The method according to any one of Embodiments B1 to B6, wherein the effective dose of the antibody is approximately 250 mg to approximately 600 mg of antibody administered on a nearly weekly basis.

[0169] Embodiment B8. The method according to any one of Embodiments B1 to B7, wherein the effective dose of the antibody is approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg, approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, or approximately 600 mg, administered approximately every week.

[0170] Embodiment B9. The method according to any one of Embodiments B1 to B8, wherein the effective dose of the antibody is approximately 300 mg administered on a nearly weekly basis.

[0171] Embodiment B10. The method according to Embodiment B9, wherein the effective dose of the antibody comprises a single subcutaneous unit dose of approximately 300 mg.

[0172] Embodiment B11. The method according to Embodiment B9 or B10, wherein the effective dose of the antibody comprises a single subcutaneous unit dose of approximately 300 mg in a total administration volume of approximately 2 mL.

[0173] Embodiment B12. The method according to Embodiment B9, wherein the effective dose of the antibody comprises (i) two subcutaneous unit doses, each containing approximately 150 mg of antibody; or (ii) three subcutaneous unit doses, each containing approximately 100 mg of antibody.

[0174] Embodiment B13. The method according to Embodiment B12, wherein (i) at least one of two subcutaneous unit doses contains about 150 mg of antibody in a total volume of less than about 5 mL, and (ii) at least one of three subcutaneous unit doses contains about 100 mg of antibody in a total volume of about 2 mL.

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

[0176] Embodiment B15. The method according to any one of Embodiments B1 to B6, wherein the effective dose of the antibody is approximately 300 mg to approximately 900 mg administered approximately every two weeks.

[0177] Appearance B16. The effective dose of the antibody is administered approximately every two weeks in doses of approximately 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, and 670 mg. The method according to embodiment B15, wherein the amount is approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, or approximately 900 mg.

[0178] Embodiment B17. The method according to Embodiment B15 or 16, wherein the effective dose of the antibody is approximately 600 mg administered approximately every two weeks.

[0179] Embodiment B18. The method according to Embodiment B17, wherein the effective dose of the antibody includes a single subcutaneous unit dose.

[0180] Embodiment B19. The method according to Embodiment B17, wherein the effective dose of the antibody comprises two, three, or at least four subcutaneous unit doses.

[0181] Embodiment B20. The method according to Embodiment B17 or 19, wherein the effective dose of the antibody comprises two subcutaneous unit doses, each of which contains approximately 300 mg of antibody.

[0182] Embodiment B21. The method according to Embodiment B20, wherein at least one of the two subcutaneous unit doses contains approximately 300 mg of antibody in a total volume of approximately 2 mL.

[0183] Embodiment B22. The method according to any one of Embodiments B19 to 21, wherein at least two subcutaneous unit doses are administered to at least two different physical sites of the subject.

[0184] Embodiment B23. The method according to any one of Embodiments B1 to B6, wherein the effective dose of the antibody is approximately 900 mg to approximately 1500 mg administered approximately every four weeks.

[0185] Appearance B24. The effective dose of the antibody is administered approximately every 4 weeks in doses of approximately 900, 950, 1000 mg, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, 1230 mg, and 1 The method according to embodiment B23, wherein the amount is 240 mg, approximately 1250 mg, approximately 1260 mg, approximately 1270 mg, approximately 1280 mg, approximately 1290 mg, approximately 1300 mg, approximately 1310 mg, approximately 1320 mg, approximately 1330 mg, approximately 1340 mg, approximately 1350 mg, approximately 1360 mg, approximately 1370 mg, approximately 1380 mg, approximately 1390 mg, approximately 1400 mg, approximately 1410 mg, approximately 1420 mg, approximately 1430 mg, approximately 1440 mg, approximately 1450 mg, approximately 1460 mg, approximately 1470 mg, approximately 1480 mg, approximately 1490 mg, or approximately 1500 mg.

[0186] Embodiment B25. The method according to Embodiment B23 or 24, wherein the effective dose of the antibody is approximately 1200 mg administered approximately every 4 weeks.

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

[0188] Embodiment B27. The method according to any one of Embodiments B23 to B26, wherein the effective dose of the antibody comprises four subcutaneous unit doses, and each of the four subcutaneous unit doses contains approximately 300 mg of antibody.

[0189] Embodiment B28. The method according to Embodiment B27, wherein at least one of the four subcutaneous unit doses contains approximately 300 mg of antibody in a total volume of approximately 2 mL.

[0190] Embodiment B29. The method according to any one of Embodiments B26 to 28, wherein at least two subcutaneous unit doses are administered to at least two different physical sites of the subject.

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

[0192] Embodiment B31. The method according to any one of Embodiments B1 to B5, wherein the antibody comprises an anti-PD-L1 antibody.

[0193] Embodiment B32. The method according to Embodiment B31, wherein the effective dose of the antibody is approximately 900 mg to approximately 1800 mg of antibody administered approximately every two weeks.

[0194] Appearance B33. The effective dose of the antibody is administered approximately every two weeks at approximately 900, 950, 1000, 1010 mg, 1020 mg, 1030 mg, 1040 mg, 1050 mg, 1060 mg, 1070 mg, 1080 mg, 1090 mg, 1100 mg, 1110 mg, 1120 mg, 1130 mg, 1140 mg, 1150 mg, 1160 mg, 1170 mg, 1180 mg, 1190 mg, 1200 mg, 1210 mg, 1220 mg, 1230 mg, and 124 mg. The method according to embodiment B31 or 32, wherein the amounts are 0 mg, approximately 1250 mg, approximately 1260 mg, approximately 1270 mg, approximately 1280 mg, approximately 1290 mg, approximately 1300 mg, approximately 1310 mg, approximately 1320 mg, approximately 1330 mg, approximately 1340 mg, approximately 1350 mg, approximately 1360 mg, approximately 1370 mg, approximately 1380 mg, approximately 1390 mg, approximately 1400 mg, approximately 1410 mg, approximately 1420 mg, approximately 1430 mg, approximately 1440 mg, approximately 1450 mg, approximately 1460 mg, approximately 1470 mg, approximately 1480 mg, approximately 1490 mg, and approximately 1500 mg.

[0195] Embodiment B34. The method according to any one of Embodiments B31 to B33, wherein the effective dose of the antibody is approximately 1200 mg every two weeks.

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

[0197] Embodiment B36. The method according to any one of Embodiments B31 to B35, wherein the effective dose of the antibody comprises four subcutaneous unit doses, and each of the four subcutaneous unit doses contains approximately 300 mg of antibody.

[0198] Embodiment B37. The method according to Embodiment B36, wherein at least one of the four subcutaneous unit doses contains approximately 300 mg of antibody in a total volume of approximately 2 mL.

[0199] Embodiment B38. The method according to any one of Embodiments B35 to 37, wherein at least two subcutaneous unit doses are administered to at least two different physical sites of the subject.

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

[0201] Embodiment B40. The method according to any one of Embodiments B1 to 30, wherein the anti-PD-1 antibody comprises an antibody selected from the group consisting of nivolumab, pembrolizumab, PDR001, MEDI-0680, semiprimab, tripalimab, tislerizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, KN035, sasamrimab, and any combination thereof.

[0202] Embodiment B41. The method according to any one of Embodiments B1 to 30, wherein the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1.

[0203] Embodiment B42. The method according to Embodiment B40, wherein the anti-PD-1 antibody comprises nivolumab.

[0204] Embodiment B43. The method according to Embodiment B40, wherein the anti-PD-1 antibody comprises pembrolizumab.

[0205] Embodiment B44. The method according to any one of embodiments B1 to B5 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] Embodiment B45. The method according to any one of Embodiments B1 to B44, wherein the subject is suffering from cancer.

[0207] Appearance B46. Cancers include squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, kidney cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-resistant prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma pleomorphonosum, cervical cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, paranasal sinus natural killer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, and vaginal cancer. The method according to aspect B45, selected from the group consisting of carcinomas of the body, carcinomas of the vulva, cancers of the esophagus, cancers of the small intestine, cancers of the endocrine system, cancers of the parathyroid gland, cancers of the adrenal gland, sarcomas of soft tissue, cancers of the urethra, cancers of the penis, cancers of the rectum, solid tumors of childhood, cancers of the ureter, carcinomas of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axial tumors, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environment-induced cancers including those induced by asbestos, virus-associated cancers or cancers of virus origin [e.g., human papillomavirus (HPV-related or virus-derived tumors)], and any combination thereof.

[0208] Embodiment B47. The method according to any one of Embodiments B1 to B46, wherein the pharmaceutical composition is administered using an auto-injector.

[0209] Embodiment B48. The method according to any one of Embodiments B1 to B46, wherein the pharmaceutical composition is administered using a wearable pump.

[0210] Embodiment B49. The method according to any one of Embodiments B1 to B48, wherein the pharmaceutical composition is administered to a subject by subcutaneous injection for a period of less than approximately 10 minutes.

[0211] Embodiment B50. The method according to any one of Embodiments B1 to B49, wherein the pharmaceutical composition is administered to a subject by subcutaneous injection for a period of less than approximately 5 minutes.

[0212] Embodiment B51. The method according to any one of Embodiments B1 to B50, wherein the pharmaceutical composition further comprises at least two antioxidants.

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

[0214] Embodiment B53. The method according to Embodiment B51 or 52, wherein at least two antioxidants comprise (i) methionine and EDTA, or (ii) methionine and DTPA.

[0215] Embodiment B54. The method according to any one of Embodiments B51 to B53, wherein at least two antioxidants contain at least about 1 to about 20 mM methionine.

[0216] Embodiment B55. The method according to any one of Embodiments B51 to B54, wherein at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM of methionine.

[0217] Embodiment B56. The method according to any one of Embodiments B51 to B55, wherein at least two antioxidants contain about 5 mM methionine.

[0218] Embodiment B57. The method according to any one of Embodiments B51 to B56, wherein at least two antioxidants contain at least about 10 μM to about 200 μM of DTPA.

[0219] Embodiment B58. The method according to any one of Embodiments B1 to B57, wherein at least two antioxidants include DTPA in an amount of 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.

[0220] Embodiment B59. The method according to any one of Embodiments B51 to B58, wherein at least two antioxidants comprise approximately 50 μM of DTPA.

[0221] Embodiment B60. The method according to any one of Embodiments B1 to B59, wherein the pharmaceutical composition comprises at least about 20 mg / mL to at least about 200 mg / mL of anti-PD-1 antibody.

[0222] Embodiment B61. The method according to any one of Embodiments B1 to B60, wherein the pharmaceutical composition comprises at least about 135 mg / mL to at least about 180 mg / mL of anti-PD-1 antibody.

[0223] Embodiment B62. The method according to any one of Embodiments B1 to B61, wherein the pharmaceutical composition comprises at least about 108 mg / mL to at least about 132 mg / mL of anti-PD-1 antibody.

[0224] Embodiment B63. The method according to any one of Embodiments B1 to 60, wherein the pharmaceutical composition comprises an anti-PD-1 antibody in an amount of 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.

[0225] Embodiment B64. The method according to any one of Embodiments B1 to B63, wherein the pharmaceutical composition comprises approximately 120 mg / mL of anti-PD-1 antibody.

[0226] Embodiment B65. The method according to any one of Embodiments B1 to B63, wherein the pharmaceutical composition comprises approximately 150 mg / mL of anti-PD-1 antibody.

[0227] Embodiment B66. The method according to any one of Embodiments B1 to B65, wherein the pharmaceutical composition further comprises a tonicity modifier and / or stabilizer.

[0228] Embodiment B67. The method according to Embodiment B66, wherein the tension modifier and / or stabilizer comprises sugars, amino acids, polyols, salts, or a combination thereof.

[0229] Embodiment B68. The method according to Embodiment B66 or 67, wherein the tension modifier and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, and any combination thereof.

[0230] Embodiment B69. The method according to any one of Embodiments B66 to 68, wherein the tension adjusting agent comprises sucrose.

[0231] Embodiment B70. The method according to any one of Embodiments B1 to B69, wherein the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM of sucrose.

[0232] Embodiment B71. The pharmaceutical composition contains 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, and at least The method according to any one of embodiments B1 to 70, comprising sucrose in amounts of approximately 270 mM, at least approximately 280 mM, at least approximately 290 mM, at least approximately 300 mM, at least approximately 310 mM, at least approximately 320 mM, at least approximately 330 mM, at least approximately 340 mM, at least approximately 350 mM, at least approximately 360 mM, at least approximately 370 mM, at least approximately 380 mM, at least approximately 390 mM, at least approximately 400 mM, at least approximately 410 mM, at least approximately 420 mM, at least approximately 430 mM, at least approximately 440 mM, at least approximately 450 mM, at least approximately 460 mM, at least approximately 470 mM, at least approximately 480 mM, at least approximately 490 mM, or at least approximately 500 mM.

[0233] Embodiment B72. The method according to any one of Embodiments B1 to B71, wherein the pharmaceutical composition comprises about 250 mM sucrose.

[0234] Embodiment B73. The method according to any one of Embodiments B1 to B72, wherein the pharmaceutical composition further comprises a buffering agent.

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

[0236] Embodiment B75. The method according to Embodiment B73 or 74, wherein the buffering agent contains histidine.

[0237] Embodiment B76. The method according to any one of Embodiments B1 to B75, wherein the pharmaceutical composition contains at least about 5 mM to at least about 100 mM of histidine.

[0238] Embodiment B77. The method according to any one of Embodiments B1 to B76, 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 of histidine.

[0239] Embodiment B78. The method according to any one of Embodiments B1 to B49, wherein the pharmaceutical composition contains about 20 mM histidine.

[0240] Embodiment B79. The method according to any one of Embodiments B1 to B78, wherein the pharmaceutical composition further comprises a surfactant.

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

[0242] Embodiment B81. The method according to Embodiment B79 or 80, wherein the surfactant comprises polysorbate 80.

[0243] Embodiment B82. The method according to any one of Embodiments B1 to B81, wherein the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80.

[0244] Embodiment B83. The method according to any one of Embodiments B1 to B82, wherein the pharmaceutical composition comprises polysorbate 80 in an amount of 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.

[0245] Embodiment B84. The method according to any one of Embodiments B1 to B83, wherein the pharmaceutical composition comprises about 0.05% w / v of polysorbate 80.

[0246] Embodiment B85. The method according to any one of Embodiments B1 to 30, 40 to 43, and 45 to 84, wherein the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine.

[0247] Embodiment B86. The method according to any one of Embodiments B1 to 30, 40 to 43, and 45 to 84, wherein the pharmaceutical composition comprises (a) about 120 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine.

[0248] Embodiment B87. The method according to any one of Embodiments B1 to B86, wherein the pharmaceutical composition has a pH of about 5.2 to about 6.8.

[0249] Embodiment B88. The method according to any one of Embodiments B1 to B87, 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] Embodiment B89. The method according to any one of Embodiments B1 to B88, wherein the pharmaceutical composition has a pH of about 6.0.

[0251] Embodiment B90. A pharmaceutical composition for use in the method according to any one of Embodiments B1 to B89.

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

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

[0254] Embodiment B93. The pharmaceutical composition according to Embodiment B91 or 92, wherein at least two antioxidants comprise (i) methionine and EDTA, or (ii) methionine and DTPA.

[0255] Embodiment B94. A pharmaceutical composition according to any one of Embodiments B91 to B93, wherein at least two antioxidants include at least about 1 to about 20 mM methionine.

[0256] Embodiment B95. A pharmaceutical composition according to any one of Embodiments B91 to B94, wherein at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM of methionine.

[0257] Embodiment B96. A pharmaceutical composition according to any one of Embodiments B91 to B95, wherein at least two antioxidants contain about 5 mM methionine.

[0258] Embodiment B97. A pharmaceutical composition according to any one of Embodiments B91 to B96, wherein at least two antioxidants contain at least about 10 μM to about 200 μM of DTPA.

[0259] Appearance B98. At least two antioxidants are present in concentrations of 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, and at least about 85 μM. A pharmaceutical composition according to any one of embodiments B91 to 97, comprising DTPA in an amount of 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.

[0260] Embodiment B99. A pharmaceutical composition according to any one of Embodiments B91 to B98, comprising at least two antioxidants, comprising approximately 50 μM of DTPA.

[0261] Embodiment B100. A pharmaceutical composition according to any one of Embodiments B91 to B99, comprising at least about 20 mg / mL to at least about 200 mg / mL of anti-PD-1 antibody.

[0262] Embodiment B101. A pharmaceutical composition according to any one of Embodiments B91 to B100, comprising at least about 135 mg / mL to at least about 180 mg / mL of anti-PD-1 antibody.

[0263] Embodiment B102. A pharmaceutical composition according to any one of Embodiments B91 to B101, comprising at least about 108 mg / mL to at least about 132 mg / mL of anti-PD-1 antibody.

[0264] Embodiment B103. A pharmaceutical composition according to any one of Embodiments B91 to 100, comprising an anti-PD-1 antibody in an amount of 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.

[0265] Embodiment B104. A pharmaceutical composition according to any one of Embodiments B91 to B103, comprising approximately 120 mg / mL of anti-PD-1 antibody.

[0266] Embodiment B105. A pharmaceutical composition according to any one of Embodiments B91 to B103, comprising approximately 150 mg / mL of anti-PD-1 antibody.

[0267] Embodiment B106. A pharmaceutical composition according to any one of Embodiments B91 to B105, further comprising a tension modifier and / or stabilizer.

[0268] Embodiment B107. The pharmaceutical composition according to Embodiment B106, wherein the tension modifier and / or stabilizer comprises sugars, amino acids, polyols, salts, or a combination thereof.

[0269] Embodiment B108. The pharmaceutical composition according to Embodiment B106 or 107, wherein the tonicity modifier and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, and any combination thereof.

[0270] Embodiment B109. A pharmaceutical composition according to any one of Embodiments B106 to B108, wherein the tension adjusting agent comprises sucrose.

[0271] Embodiment B110. A pharmaceutical composition according to any one of Embodiments B91 to B109, comprising at least about 10 mM to at least about 500 mM of sucrose.

[0272] Embodiment B111. At least about 10mM, at least about 20mM, at least about 30mM, at least about 40mM, at least about 50mM, at least about 60mM, at least about 70mM, at least about 80mM, at least about 90mM, at least about 100mM, at least about 110mM, at least about 120mM, at least about 130mM, at least about 140mM, at least about 150mM, at least about 160mM, at least about 170mM, at least about 180mM, at least about 190mM, at least about 200mM, at least about 210mM, at least about 220mM, at least about 230mM, at least about 240mM, at least about 250mM, at least about 260mM, at least about 27 A pharmaceutical composition according to any one of embodiments B91 to 110, 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 of sucrose.

[0273] Embodiment B112. A pharmaceutical composition according to any one of Embodiments B91 to B111, comprising approximately 250 mM sucrose.

[0274] Embodiment B113. A pharmaceutical composition according to any one of Embodiments B91 to B112, further comprising a buffering agent.

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

[0276] Embodiment B115. The pharmaceutical composition according to Embodiment B113 or 114, wherein the buffering agent contains histidine.

[0277] Embodiment B116. A pharmaceutical composition according to any one of Embodiments B91 to B115, comprising at least about 5 mM to at least about 100 mM of histidine.

[0278] Embodiment B117. A pharmaceutical composition according to any one of Embodiments B91 to B116, 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 of histidine.

[0279] Embodiment B118. A pharmaceutical composition according to any one of Embodiments B91 to B117, comprising approximately 20 mM histidine.

[0280] Embodiment B119. A pharmaceutical composition according to any one of Embodiments B91 to B18, further comprising a surfactant.

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

[0282] Embodiment B121. The pharmaceutical composition according to Embodiment B119 or 120, wherein the surfactant comprises polysorbate 80.

[0283] Embodiment B122. A pharmaceutical composition according to any one of Embodiments B91 to B121, comprising at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80.

[0284] Embodiment B123. A pharmaceutical composition according to any one of Embodiments B91 to B122, comprising polysorbate 80 in an amount of 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.

[0285] Embodiment B124. A pharmaceutical composition according to any one of Embodiments B91 to B123, comprising approximately 0.05% w / v of polysorbate 80.

[0286] A pharmaceutical composition according to any one of Aspects B91 to B124, comprising (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine.

[0287] A pharmaceutical composition according to any one of Aspects B91 to B124, comprising: (a) about 120 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; and (f) about 5 mM methionine.

[0288] Embodiment B127. A pharmaceutical composition according to any one of Embodiments B91 to B126, comprising a pH of approximately 5.2 to approximately 6.8.

[0289] Aspect B128. A pharmaceutical composition according to any one of Aspects B91 to 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. A pharmaceutical composition according to any one of Aspects B91 to 128, comprising a pH of about 6.0.

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

[0292] Aspect B131. A pharmaceutical composition according to Aspect B130, wherein the second therapeutic agent is an antibody.

[0293] Aspect B132. A pharmaceutical composition according to Aspect B131, wherein the second therapeutic agent is a checkpoint inhibitor.

[0294] Aspect B133. A pharmaceutical composition according to 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, an anti-GITR, or any combination thereof.

[0295] Aspect B134. A vial comprising a pharmaceutical composition according to any one of Aspects B87 to B133.

[0296] Aspect B135. A unit dose comprising a pharmaceutical composition according to any one of Aspects B87 to B133.

[0297] Aspect B136. A unit dose comprising: (a) an anti-PD-1 antibody at about 150 mg / mL; (b) histidine at about 20 mM; (c) sucrose at about 250 mM; (d) polysorbate 80 at about 0.05% w / v; (e) pentetic acid at about 50 μM; and (f) methionine at about 5 mM.

[0298] Aspect B137. The vial according to aspect B134, which is an autoinjector.

[0299] Aspect B138. An autoinjector comprising the unit dose according to aspect B135 or 136.

[0300] Aspect B139. The vial according to aspect B134, which is a wearable device.

[0301] Aspect B140. A wearable device comprising the unit dose according to aspect B135 or 136.

Brief Description of the Drawings

[0302] [Figure 1] Figure 1 shows a graphical representation of data related to the osmotic pressure and viscosity of a nivolumab subcutaneous (SC) injection formulation as a function of sucrose concentration in the formulation according to Example I. The x-axis represents the sucrose concentration in mM, and the y-axis represents the osmotic pressure of the formulation in mOsm / kg. The filled circles and solid line represent the osmotic pressure values, and the filled x's and dashed line represent the viscosity values. [Figure 2] Figure 2 shows a graphical representation of data related to the effect of 75 mM added arginine on the viscosity of a nivolumab subcutaneous (SC) injection formulation according to Example I. The x-axis represents the protein concentration in mg / mL, and the y-axis represents the viscosity in cP at 20°C. The filled squares represent the samples containing added arginine, and the filled diamonds represent the samples without added arginine. [Figure 3] Figure 3 is a schematic diagram of a study directed to evaluating the safety and efficacy of various doses of a subcutaneous-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 of the predictive check of the SC / IV PPK model for nivolumab administration. Each dot represents observed data. The lines represent the 5th, 50th, and 95th percentiles of the observed data, respectively. The shaded areas represent the 90% CI based on simulations of the 5th percentile (lowest trend line), 50th percentile (middle trend line), and 95th percentile (highest 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) exposures for each 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) exposures for each 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) exposures for each tumor type. CRC = colorectal cancer, HCC = hepatocellular carcinoma, Mel = melanoma, NSCLC = non-small cell lung cancer, and RCC = renal cell carcinoma. [Figure 6] Figure 6 is a schematic diagram of a study aimed at evaluating the safety and efficacy of 1200 mg of nivolumab combined with hyaluronidase (e.g., rHuPH20) administered subcutaneously every four weeks, compared to 3 mg / kg of nivolumab administered intravenously every two weeks. [Figure 7]Figure 7 is a box plot illustrating the distribution of nivolumab Cmind28 across dose and body weight for nivolumab IV at 3 mg / kg every two weeks, 10 mg / kg every two weeks, and 1200 mg subcutaneously every four weeks. [Figure 8] Figures 8A–8C are box plots illustrating the observed distribution of Cavg (Figure 8A), Ctau (Figure 8B), and Cmax (Figure 8C) by weight observed after subcutaneous delivery of 720 mg, 960 mg, or 1200 mg of nivolumab with rHuPH20. The dashed lines show the geometric mean Cavg (Figure 8A) and Ctau (Figure 8B) for nivolumab 3 mg / kg IV Q2W (historical) and the geometric mean Cmax (Figure 8C) for 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 (parts A, B, and D) of nivolumab and rHuPH20 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 (parts A, B, and D) of nivolumab and rHuPH20 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 effects of headspace nitrogen and air on the HMW species % of Nivo by SEC after combinations of metal, peroxide, and photostress with thermal stress at 30°C in Study 1. RT / light is continuous photostress, and the other photostress conditions have a duration of 3 days. Formulations 1 (air) and 6 (nitrogen) contain: 50 μm DTPA, 5 mM Met; Formulations 2 (air) and 7 (nitrogen) contain: 0 μm DTPA, 0 mM Met. All formulations also contain 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0, with rHuPH20 at 2,000 U / mL. [Figure 11] Figure 11 is a graphical representation of the effects of various stress conditions on the HMW species % of Nivo by SEC after combinations of metal, peroxide, and photostress with thermal stress at 30°C in Study 1. RT / light is continuous photostress, and the other photostress conditions have a duration of 3 days. 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, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0, with rHuPH2O of 2,000 U / mL. [Figure 12]Figure 12 is a graphical representation of HMW formation in Study 1 with metals - 0.5 ppm each of iron, chromium, and copper + light (100 lux at room temperature + 1 mM peroxide + 30°C thermal stress for 3 days). Note: Formulations 1 (air) and 6 (nitrogen) completely overlap each other and have the least HMW formation with the same formulation composition. 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 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, and pH 6.0, along with 2,000 U / mL rHuPH20. [Figure 13] Figure 13 is a graphical representation of HMW% in Study 1 after 3 months under various combinations of metals (0.5 ppm each of iron, chromium, and copper), light (1000 lux at room temperature for 3 days), and peroxides (1 mM peroxide) with thermal stress at 30°C, for formulations with / without 5 mM Met, 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 of iron, chromium, and copper), light (1000 lux at room temperature for 3 days), and peroxides (1 mM peroxide), with thermal stress at 30°C, as 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 under three days of RT / dark storage followed by 30°C / dark storage [control - left], three days of RT / RL storage followed by 30°C / dark storage [MPL - center] and room temperature / indoor light storage [RT / light - right] with metal and peroxide additions. Preparations 1 (air) and 6 (nitrogen): 50 μm DTPA 5 mM Met; Preparations 2 (air) and 7 (nitrogen): 0 μm DTPA, 0 mM Met; Preparation 3: 0 μm DTPA, 5 mM Met; Preparation 4: 50 μm DTPA, 0 mM Met. All preparations also contain 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0 along with 2,000 U / mL rHuPH20. [Figure 16] Figures 16A–16F are graphical representations of the formulation distribution in Study 2. The formulations represent the maximum and minimum range of excipients, and all other factors were in 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 rHPH2O (Figure 16F), 0.05% w / v PS80, pH 6.0 (Figure 16B). [Figure 17] Figure 17 shows a graphical representation of high molecular weight species by SEC at various time points up to 6 months for 0–200 μM DTPA in Study 2 under 25°C, 35°C, and MPL and RT / RL stress conditions. 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 under 25°C, 35°C, and MPL and RT / RL stress conditions, separated by DTPA and Met concentrations in the Study 2 formulation. 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 for 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] Figure 20 is a graphical representation of SEC HMW% and smooth curve trend estimates against methionine concentration at three last sampled stress conditions at 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 for 6 months (Figure 21A), 35°C for 3 months (Figure 21B), and 3 months using MPL stress (Figure 21C) as a function of Met level, for 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, having compatibility performance. [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 DTPA alone. 50 μM DTPA and 5 mM Met concentration. 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 22B]Figures 22A-22B show graphs of acidic species as a function of time under MPL conditions (Figure 22A) and 35°C stress (Figure 22B). Two sets of samples of formulations with DTPA and Met, as well as DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulations contain 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 and 23B are graphical representations of enzyme activity as a function of time under MPL conditions (Figure 23A) and 35°C stress (Figure 23B). Two sets of samples of formulations containing DTPA and Met, as well as DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulations contain 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, and pH 6.0. [Figure 23B] Figures 23A and 23B are graphical representations of enzyme activity as a function of time under MPL conditions (Figure 23A) and 35°C stress (Figure 23B). Two sets of samples of formulations containing DTPA and Met, as well as DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulations contain 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, and 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). Two sets of samples of formulations with DTPA and Met, as well as DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulation contains 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). Two sets of samples of formulations with DTPA and Met, as well as DTPA alone. 50 μM DTPA and 5 mM Met concentrations. The formulation contains 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 with and without the use of 2,000 U / mL of rHuPH20 enzyme at various Met levels for high molecular weight species under MPL conditions at 3 months. Figure 25B is a regression plot of Studies 1, 2, and 3 for high molecular weight species under SEC at 3 months under 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, 2,000 U / mL of rHuPH20, and pH 6.0 (Figures 25A-25B). [Figure 25B] Figure 25A is a graphical representation illustrating a comparison across Studies 1, 2, and 3 with and without the use of 2,000 U / mL of rHuPH20 enzyme at various Met levels for high molecular weight species under MPL conditions at 3 months. Figure 25B is a regression plot of Studies 1, 2, and 3 for high molecular weight species under SEC at 3 months under 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, 2,000 U / mL of rHuPH20, and pH 6.0 (Figures 25A-25B). [Figure 26] Figure 26 is a bar graph providing a comparison of the log10(kD) values ​​of glycine, mannitol, sucrose, trehalose, and succinate as shown. [Figure 27]Figure 27 is a bar graph showing the average count of excipient molecules interacting with the nivolumab Fab group during the last 8 ns of MD simulations for glycine, sorbitol, trehalose, mannitol, and sucrose, as shown. [Figure 28] Figures 28A–28E illustrate the binding poses found for glycine (Figure 28A), sorbitol (Figure 28B), mannitol (Figure 28C), sucrose (Figure 28D), and trehalose (Figure 28E) on nivolumab Fab, respectively. The Fab group is shown as a ribbon, lightly binding poses are shown as ball and stick representations, and tightly binding poses are shown as a filled space 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 moderate-strength interactions (Figure 29A) and strongly bound 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 moderate-strength interactions (Figure 29A) and strongly bound interactions (Figure 29B). [Modes for carrying out the invention]

[0303] Detailed explanation of this disclosure Current methods for delivering anti-PD-1 and / or anti-PD-L1 antibodies often require regular intravenous administration by a clinician in a clinic or hospital setting. This regimen often causes significant inconvenience to the patient, and the nature of the procedure itself can negatively impact the patient's experience. Subcutaneous delivery, such as through the use of an auto-injector or wearable pump, could greatly improve patient compliance and potentially allow patients to receive this potentially life-saving therapy in the comfort of their own homes. This disclosure provides a method for treating a target in need, comprising subcutaneously administering a dose of a pharmaceutical composition comprising an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction between PD-1 and PD-L1 ("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 contain the endoglycosidase hydrolase enzyme. In some embodiments, at least one subcutaneous unit dose 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, or less than about 2.5 mL). In certain embodiments, the dose contains at least about 250 mg to at least about 2400 mg of antibody.

[0305] I. Terminology To make this disclosure more easily understandable, certain terms are first defined. Where used in this application, each of the following terms shall have the meanings set forth below, unless otherwise expressly provided herein. Additional definitions are provided throughout this application.

[0306] Whenever an aspect is described herein using the word “including,” it is understood that other similar aspects are also provided, described in terms of “consisting of” and / or “essentially consisting of.”

[0307] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art in the field relating to this disclosure. 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 general dictionaries for many of the terms used herein.

[0308] Units, prefixes, and symbols are shown in the form recognized by their International System of Units (SI). Number ranges include the number defining the range. Unless otherwise indicated, nucleotide sequences are written from left to right in the 5' to 3' direction. Amino acid sequences are written from left to right in the amino to carboxy direction. Headings provided herein are not limitations on the various aspects of this disclosure, and may be held by reference to this specification as a whole. Thus, the terms defined immediately below are better defined by reference to this specification as a whole.

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

[0310] Subcutaneous administration can be achieved using any method. In some embodiments, subcutaneous administration is achieved using a short needle or a group of short needles. In some embodiments, at least one of the needles or group of needles is less than about 1 inch, less than about 7 / 8 inch, less than about 6 / 8 inch, less than about 5 / 8 inch, or less than about 1 / 2 inch. In some embodiments, at least one of the needles or group of needles is about 5 / 8 inch in length.

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

[0312] As used herein, the terms “dose” or “prescription” are defined as the amount of a therapeutic agent that can be administered at a given time. A dose or prescription may be sufficient to achieve, or at least partially achieve, a desired effect, although such a desired effect may be invisible or undetectable. A “therapeutic effective dose” or “therapeutic effective prescription” of a drug or therapeutic agent is any amount of the drug that, when used alone or in combination with another therapeutic agent, promotes disease regression, as demonstrated by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease-free periods, an increase in overall survival (the length of time that a patient diagnosed with a disease is still alive, either from the day of diagnosis or the start of treatment for the disease, such as cancer), or the prevention of impairment or physical disability resulting from the disease. A dose or prescription of a drug includes a “preventive effective dose” or “preventive effective prescription,” which is any amount of the drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing or experiencing a relapse of the disease, inhibits the development or relapse of the disease. The ability of therapeutic agents 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 in human subjects during clinical trials, in animal model systems to predict efficacy in humans, or by assaying the activity of the active agent in in vitro assays. "Dose" may include a single unit dose or multiple unit doses. In some embodiments, the dose includes a single unit dose. In some embodiments, the dose includes multiple unit doses.

[0313] As used herein, 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 may be administered at the same time or sequentially. In some embodiments, each unit dose of the therapeutically effective dose is administered on the same day. Each unit dose may 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 may be used in the manner 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, “adverse event” (AE) is any undesirable, generally unintended, or unwelcome sign (including abnormal laboratory findings), symptom, or illness associated with the use of a medical procedure. For example, an adverse event may be associated with the activation of the immune system or an increase in immune system cells (e.g., T cells) in response to a procedure. A medical procedure may have one or more associated AEs, each AE may have the same or different levels of severity. References to methods that “modify an adverse event” mean 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] An "antibody" (Ab) is defined without limitation as a glycoprotein immunoglobulin or an antigen-binding moiety thereof, comprising at least two heavy (H) chains and two light (L) chains that specifically bind to an antigen and are interconnected by disulfide bonds. Each H chain comprises a heavy chain variable region (hereinafter abbreviated 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 (hereinafter abbreviated as VL) and a light chain constant region. The light chain constant region comprises one constant domain CL. The VH and VL regions may be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL comprises three CDRs and four FRs arranged from the amino terminus to the carboxyl 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 the antigen. The constant region of the antibody can mediate the binding of immunoglobulins 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). Therefore, the term “anti-PD-1 antibody” includes a whole antibody having two heavy chains and two light chains that specifically binds to PD-1, as well as the antigen-binding portion of the whole antibody. Non-limiting examples of antigen-binding portions are shown elsewhere in this specification.

[0316] Immunoglobulins may originate 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, including but not limited to human IgG1, IgG2, IgG3, and IgG4. “Isotype” refers to an antibody class or subclass (e.g., IgM or IgG1) encoded by a heavy chain constant region gene. The term “antibody” includes, by 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 expressly stated otherwise or the context indicates otherwise, the term “antibody” also includes antigen-binding fragments or parts of any of the aforementioned immunoglobulins, including monovalent and bivalent fragments or parts, as well as single-chain antibodies.

[0317] In some embodiments, “antibodies” as used herein are, for example, “polyspecific” antibodies or “bispecific” antibodies that can bind to more than one antigen. As used herein, a “bispecific” antibody is an antibody that can specifically bind to two antigens, the first and second antigens being the same or different. As used herein, a “polyspecific” antibody can specifically bind to more than one antigen, for example, at least two (i.e., “bispecific” antibodies), at least three (i.e., “trispecific” antibodies), at least four, at least five, or at least six antigens. A variety of polyspecific antibodies are known, including but not limited to bispecific antibodies that bind to PD-1 and a second target, and bispecific antibodies that bind to PD-L1 and a second target, and may be used in compositions and / or methods disclosed herein. In some embodiments, the polyspecific antibody is a T cell-dependent bispecific antibody. In some embodiments, the polyspecific antibody is an anti-FcRH5 / CD3 bispecific antibody that targets the B cell lineage markers, FcRH5 and CD3, for use, for example, in the treatment of multiple myeloma.

[0318] In some embodiments, the “antibody” of this disclosure is, for example, a “probody” that is manipulated to be activated at a target site. In some embodiments, the antibody, for example, the probody, is proteolytically cleaved in a target tissue (e.g., a tumor).

[0319] "Isolated antibodies" refer to antibodies that are substantially free of other antibodies with different antigen specificities (for example, an isolated antibody that specifically binds to PD-1 is substantially free of antibodies that specifically bind to antigens other than PD-1). However, an isolated antibody that specifically binds to PD-1 may exhibit cross-reactivity to other antigens, such as PD-1 molecules from different species. Furthermore, isolated antibodies may be substantially free of other cellular materials and / or chemical substances.

[0320] The term "monoclonal antibody" (mAb) refers to an antibody molecule that does not exist in nature, having a single molecular composition, i.e., an antibody molecule whose primary sequence is essentially identical, exhibiting a single binding specificity and affinity for a specific epitope. Monoclonal antibodies are an example of isolated antibodies. Monoclonal antibodies can 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 in which both the framework and CDR region have variable regions derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also derives from a human germline immunoglobulin sequence. The human antibodies of this disclosure may contain amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro, or by somatic mutation in vivo). However, as used herein, the term “human antibody” is not intended to include antibodies in which a CDR sequence derived from the germline of another mammalian species, such as mouse, is grafted onto a human framework sequence. The terms “human antibody” and “fully human antibody” are used synonymously.

[0322] A "humanized antibody" refers to an antibody in which some, most, or all of the amino acids outside the CDR of a non-human antibody are replaced with corresponding amino acids derived from human immunoglobulin. In one form of a humanized antibody, some, most, or all of the amino acids outside the CDR are replaced with amino acids derived from 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 acceptable as long as they do not destroy the antibody's ability to bind to a particular antigen. Humanized antibodies retain similar antigen specificity to that of the original antibody.

[0323] A "chimeric antibody" refers to an antibody in which the variable region originates from one species and the constant region originates from another species, such as an antibody in which the variable region originates from a mouse antibody and the constant region originates 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] The "antigen-binding portion" (also called the "antigen-binding fragment") of an antibody refers to one or more fragments of the antibody that retain the ability to specifically bind to the antigen to which the entire antibody binds. It has been shown that the antigen-binding function of an antibody can be performed by fragments of the full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding moiety” of an antibody, such as an anti-PD-1 antibody or anti-PD-L1 antibody as described herein, include: (i) Fab fragments (fragments obtained by papain cleavage), or similar monovalent fragments consisting of VL, VH, LC, and CH1 domains; (ii) F(ab')2 fragments (fragments obtained by pepsin cleavage), or similar bivalent fragments containing two Fab fragments linked by disulfide crosslinking in the hinge region; (iii) Fd fragments consisting of VH and CH1 domains; (iv) Fv fragments consisting of VL and VH domains of a single arm of the antibody; (v) dAb fragments consisting of the VH domain [Ward et al., (1989) Nature 341:544-546]; (vi) isolated complementarity-determining regions (CDRs); and (vii) combinations of two or more isolated CDRs that may be appropriately joined by a synthetic linker. Furthermore, although the two domains VL and VH of the Fv fragment are encoded by separate genes, they can be joined by a synthetic linker that allows them to be produced as a single protein chain where the VL and VH regions pair up to form a monovalent molecule, using recombination techniques [known as 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 included 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 usability 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 diseases characterized by the uncontrolled growth of abnormal cells in the body. The division and growth of these unregulated cells leads to the formation of malignant tumors, which can invade neighboring tissues and metastasize to distant parts of the body through the lymphatic system or bloodstream.

[0327] The term “immunotherapy” refers to the treatment of a person who has a disease or is at risk of contracting or relapsing the disease, by means of inducing, enhancing, suppressing, or otherwise modifying the immune response. The “treatment” or “therapy” of a person refers to any type of intervention or process performed on a person, or the administration of an activator to a person, for the purpose of reversing, alleviating, improving, inhibiting, slowing, or preventing the onset, progression, onset, severity, or relapse of disease-related symptoms, complications, conditions, or biochemical signs.

[0328] "Programmed death-1" (PD-1) refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is primarily expressed on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, as well as analogs having at least one common 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 being PD-L2) that, upon binding to PD-1, downregulate T cell activation and cytokine secretion. 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 having at least one common epitope with hPD-L1. The complete hPD-L1 sequence can be found under GenBank accession number Q9NZQ7. The human PD-L1 protein is encoded by the human CD274 gene (NCBI Gene ID: 29126).

[0330] As used herein, "hyaluronidase" refers to an enzyme capable of catalyzing the cleavage of hyaluronan. Hyaluronan is a repeating polymer of N-acetylglucosamine and glucuronic acid, which is present in the subcutaneous space and contributes to the soluble gel-like components of the extracellular matrix of the skin, which are restored (re-synthesis) by rapid metabolic turnover. In some embodiments, hyaluronidase comprises rHuPH20, a glycosylated 447-amino acid single-chain polypeptide that locally depolymerizes hyaluronan in the subcutaneous space at the injection site in the skin. Depolymerization of hyaluronan by hyaluronidase is carried out 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, as well as an increase in hydrodynamic conductivity, which facilitates the dispersion and absorption of co-administered therapeutic agents. Therefore, hyaluronidases, such as rHuPH20, can improve the rate and ease of subcutaneous delivery of injectable biologics and drugs by acting as permeability enhancers. In certain embodiments, hyaluronidases include ENHANZE®.

[0331] "Subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, non-human primates, sheep, dogs, and vertebrates such as mice, rats, and rodents such as guinea pigs. In a preferred embodiment, the subject is human. The terms "subject" and "patient" are used interchangeably herein.

[0332] The use of the term “uniform dose” in relation to the methods and dosages in this disclosure means the dose administered to a patient regardless of the patient’s weight or body surface area (BSA). Therefore, the uniform dose is provided not as a mg / kg dose, but rather as an absolute amount of the active ingredient (e.g., anti-PD-1 antibody). For example, a 60kg person and a 100kg person would receive the same dose of antibody (e.g., 240mg of anti-PD-1 antibody).

[0333] As used herein, the term “weight-based dose” 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] For example, “anticancer drugs” promote cancer regression in a subject. In some embodiments, a therapeutically effective dose of a drug promotes cancer regression to the point of eliminating the cancer. “Promoting cancer regression” means that administering a therapeutically effective dose of a drug, either alone or in combination with an antineoplastic agent, results in a reduction in tumor growth or size, tumor necrosis, a reduction in the severity of at least one disease symptom, an increase in the frequency and duration of disease-free periods, or the prevention of functional or physical impairment resulting from the disease. In addition, the terms “effective” and “efficacy” in relation to a 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 harmful physiological effects (adverse effects) at the cellular, organ, and / or biological level that result from the administration of a drug.

[0335] As an example of tumor treatment, a therapeutically effective dose of an anticancer agent inhibits cell growth or tumor growth by, preferably at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and still more preferably at least about 80%, compared to an untreated subject. In other preferred embodiments of the present disclosure, tumor regression may be observed and may 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 measurements of 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 the biological response within a vertebrate to an exogenous agent or abnormal, such as cancerous, cell, which protects the organism from these agents and the diseases they cause. The immune response is mediated by the action of 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 by the action of the liver (including antibodies, cytokines, and complement), resulting in the selective targeting, binding to, damage to, destruction of, and / or elimination from the vertebrate body of an invading pathogen, a pathogen-infected cell or tissue, a cancerous or other abnormal cell, or, in the case of autoimmune or pathological inflammation, normal human cells or tissue. An immune response includes, for example, activation or inhibition of T cells, such as effector T cells, Th cells, CD4+ cells, CD8+ T cells, or Treg cells, or activation or inhibition of any other cells of the immune system, such as NK cells.

[0337] The term "immune response pattern" refers to the clinical response patterns frequently observed in cancer patients treated with immunotherapeutic agents that produce antitumor effects by inducing cancer-specific immune responses or by modifying innate immune processes. This response pattern is characterized by beneficial therapeutic effects following an initial increase in tumor burden or the appearance of new lesions, which in the evaluation of traditional chemotherapy agents would be classified as disease progression and synonymous with drug failure. Therefore, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease.

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

[0339] The terms “to treat,” “to treat,” and “treatment” as used herein refer to any type of intervention or process performed on a subject, or the administration of an activator to a subject, for the purpose of reversing, alleviating, improving, inhibiting, slowing, or preventing the progression, onset, severity, or recurrence of disease-related symptoms, complications, conditions, or biochemical signs, or enhancing overall survival. Treatment may be performed on a subject with the disease or on a subject without the disease (e.g., for preventive purposes).

[0340] As used herein, the terms “approximately weekly,” “about every two weeks,” or any other similar dosing interval terms are approximate. “Approximately weekly” may include every 7 days ± 1 day, i.e., every 6 days to every 8 days. “About every two weeks” may include every 14 days ± 3 days, i.e., every 11 days to every 17 days. Similar approximations apply, for example, every 3 weeks, every 4 weeks, every 5 weeks, every 6 weeks, and every 12 weeks. In some embodiments, a dosing interval of about 6 weeks or about 12 weeks means that the first dose may be administered on any day in the first week, and then the next dose may be administered on any day in the 6th or 12th week, respectively. In other embodiments, a dosing interval of about 6 weeks or about 12 weeks means that the first dose is administered on a specific day in the first week (e.g., Monday), and then the next dose is administered on the same day (i.e., Monday) in the 6th or 12th week, respectively. When the dose is reached by administering multiple subcutaneous units, the dosing interval refers to the period between the administration of the first subcutaneous unit of the first effective dose and the first subcutaneous unit of the second effective dose. For example, if the method involves administering a dose of approximately 600 mg every two weeks, the antibody dose would consist of two subcutaneous units, each containing approximately 300 mg of antibody. The first subcutaneous unit of approximately 300 mg of the first effective dose of antibody would be administered on day 1, and the first subcutaneous unit of approximately 300 mg of the second effective dose of antibody would be administered on approximately day 14. In this example, the second unit of approximately 300 mg of the first effective dose of antibody may be administered on day 1, or at any other time prior to the administration of the first subcutaneous unit of approximately 300 mg of the second effective dose of antibody.

[0341] The use of “options” (e.g., “or”) should be understood to mean one or both of the options, or any combination thereof. Where used herein, the indefinite articles “a” or “an” should be understood to refer to “one or more” of any listed or enumerated components.

[0342] The terms “approximately” or “essentially composed of” refer to a value or composition that falls within an acceptable margin of error for a particular value or composition, as determined by those skilled in the art, and which will, in part, depend on how the value or composition is measured or determined, i.e., the limitations of the measuring system. For example, “approximately” or “essentially composed of” may mean a standard deviation of 1 or more than 1 per practice in the art. Alternatively, “approximately” or “essentially composed of” may mean a margin of error of up to 10%. Furthermore, particularly with respect to biological systems or processes, the term may mean up to one decimal place or up to five times the value. Where a particular value or composition is provided in this application and claims, unless otherwise stated, the meaning of “approximately” or “essentially composed of” should be inferred to be within an acceptable margin of error 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 range and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer), unless otherwise indicated.

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

[0345] II. Compositions of the Disclosure Some aspects of this disclosure are directed to pharmaceutical compositions comprising (i) an antibody or its antigen-binding moiety, and (ii) at least two antioxidants. In some aspects, more than one antioxidant, e.g., two antioxidants, inhibit oxidation of formulation components and / or improve the stability of the antibody. In some aspects, the antibody or its antigen-binding moiety is a checkpoint inhibitor. In some aspects, the antibody or its antigen-binding moiety specifically binds to PD-1 ("anti-PD-1 antibody"). In some aspects, the pharmaceutical composition is formulated for subcutaneous administration. In some aspects, the pharmaceutical composition further comprises (iii) an endoglycosidase hydrolase enzyme. In some aspects, the pharmaceutical composition does not contain an endoglycosidase hydrolase enzyme. In some aspects, the pharmaceutical composition comprises at least two antibodies or their antigen-binding moieties.

[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 to exhibit improved properties compared to compositions that do not have two antioxidants or at least one antioxidant.

[0347] The therapeutic agents of the present disclosure may be in the form of a pharmaceutical composition containing, for example, an antibody and a pharmaceutically acceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any physiologically compatible solvent, dispersion medium, coating, antibacterial and antifungal agents, isotonic agents and absorption retarders, etc. Preferably, the carrier for the antibody-containing composition is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal, or epidermal administration (e.g., by injection or infusion), while the carrier for the antibody and / or cytokine-containing composition is suitable for administration other than parenteral, for example, oral administration.

[0348] In some embodiments, the pharmaceutical composition comprises (i) an antibody or its antigen-binding moiety (e.g., an anti-PD-1 antibody), (ii) at least two antioxidants, (iii) a tonic modifier or stabilizer, (iv) a buffering agent, and (v) a surfactant. In some embodiments, the pharmaceutical composition comprises (i) an antibody or its antigen-binding moiety (e.g., an anti-PD-1 antibody), (ii) at least two antioxidants, (iii) a tonic modifier 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 polyspecific antibody.

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

[0350] II.A. Antibody and antigen-binding moieties In some embodiments, the pharmaceutical composition comprises an antibody or its antigen-binding moiety. The pharmaceutical compositions described herein may comprise any antibody or its antigen-binding moiety. In some embodiments, the antibody or its antigen-binding moiety is a checkpoint inhibitor. In some embodiments, the antibody or its antigen-binding moiety specifically binds to a checkpoint protein. In some embodiments, the antibody or its antigen-binding moiety 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 polyspecific antibody. In some embodiments, the antibody is a dispecific 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 and third antigens are the same. In some embodiments, the second and third antigens 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) inhibitory receptors 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 contains at least about 10 mg / mL to at least about 500 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains 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, and 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 approximately 200 mg / mL, at least approximately 20 mg / mL to at least approximately 190 mg / mL, at least approximately 20 mg / mL to at least approximately 180 mg / mL, at least approximately 20 mg / mL to at least approximately 170 mg / mL, at least approximately 20 mg / mL to at least approximately 160 mg / mL, at least approximately 20 mg / mL to at least approximately 150 mg / mL, at least approximately 50 mg / mL to at least approximately 200 mg / mL, at least approximately 100 mg / mL to at least approximately 200 The composition contains an antibody (e.g., anti-PD-1 or anti-PD-L1 antibody) in a concentration of mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 135 mg / mL to at least about 180 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 130 mg / mL, or at least about 108 mg / mL to at least about 132 mg / mL. In some embodiments, the pharmaceutical composition contains at least about 50 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody).In some embodiments, the pharmaceutical composition contains at least about 60 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 70 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 75 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 80 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 90 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 100 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 108 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 110 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 120 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 130 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 132 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 135 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 140 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 150 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 160 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 170 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 175 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody).In some embodiments, the pharmaceutical composition contains at least about 180 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 190 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody). In some embodiments, the pharmaceutical composition contains at least about 200 mg / mL of antibody (e.g., anti-PD-1 or anti-PD-L1 antibody).

[0354] II.A.1 Anti-PD-1 antibodies useful in this disclosure In some embodiments, the pharmaceutical composition comprises an antibody or its antigen-binding moiety that specifically binds to PD-1 ("anti-PD-1 antibody"). Any anti-PD-1 antibody may be used in the compositions and methods described herein. Various human monoclonal antibodies that bind specifically to PD-1 with high affinity are disclosed in U.S. Patent No. 8,008,449. The anti-PD-1 human antibody disclosed in U.S. Patent No. 8,008,449 has been demonstrated to exhibit one or more of the following characteristics: (a) binding to human PD-1 with a KD of ≤1 × 10⁻⁷ M as determined by surface plasmon resonance using a Biacore biosensor system; (b) substantially no binding to human CD28, CTLA-4, or ICOS; (c) increasing T cell proliferation in a mixed lymphocyte reaction (MLR) assay; (d) increasing interferon-γ production in an MLR assay; (e) increasing IL-2 secretion in an MLR assay; (f) binding to human PD-1 and cynomolgus monkey PD-1; (g) inhibiting the binding of PD-L1 and / or PD-L2 to PD-1; (h) stimulating antigen-specific memory responses; (i) stimulating antibody responses; and (j) inhibiting tumor cell growth in vivo. The anti-PD-1 antibodies available in this 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 features.

[0355] Other anti-PD-1 monoclonal antibodies include, for example, 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 Publications WO2012 / 145493, WO2008 / 156712, and 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 These are described in WO2017 / 106061, WO2017 / 19846, WO2017 / 024465, WO2017 / 025016, WO2017 / 132825, and WO2017 / 133540, each of which is thus incorporated herein by reference as a whole.

[0356] In some embodiments, the anti-PD-1 antibody is 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), semiprimab (Regeneron; also known as REGN-2810; see WO2015 / 112800), JS001 [TAIZHOU JUNSHI PHARMA; also known as tripalimab; see Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)], BGB-A317 (Beigene; also known as tislerizumab; see WO2015 / 35606 and US2015 / 0079109), INCSHR1210 [Jiangsu Hengrui Medicine; also known as SHR-1210; see WO2015 / 085847; see 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.The group consists of [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 the downregulation of antitumor T cell function [US Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56]. The heavy-chain 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 includes a heavy-chain variable region containing the amino acid sequence specified in SEQ ID NO: 2 and a light-chain variable region containing the amino acid sequence specified in SEQ ID NO: 3. In some embodiments, the antibody includes heavy-chain complementarity-determining regions (CDR) 1, CDR2, and CDR3 sequences containing the amino acid sequences of the heavy-chain CDR1, CDR2, and CDR3 of SEQ ID NO: 2. In some embodiments, the antibody comprises light chain CDR1, CDR2, and CDR3 sequences, which include the amino acid sequences of the light chains CDR1, CDR2, and CDR3 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 at 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 sasamrimab.

[0361] The anti-PD-1 antibodies usable in the disclosed compositions and methods include isolated antibodies that specifically bind to human PD-1 and cross-compete for binding to human PD-1 with any anti-PD-1 antibody disclosed herein, e.g., nivolumab (see, e.g., U.S. Patents 8,008,449 and 8,779,105; WO2013 / 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 the antigen indicates that these monoclonal antibodies bind to the same epitope region of the antigen and sterically prevent the binding of other cross-competitive antibodies to that particular epitope region. These cross-competitive antibodies are expected to have very similar functional properties to those of the reference antibody, e.g., nivolumab, due to their binding to the same epitope region of PD-1. Cross-competitive 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, for example, WO2013 / 173223).

[0362] In certain embodiments, an antibody that cross-competes with the human PD-1 antibody nivolumab for binding to human PD-1, or that binds to the same epitope region of human PD-1, is a monoclonal antibody. For administration to human subjects, these cross-competitive antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0363] The anti-PD-1 antibodies usable in the compositions and methods of this disclosure also include the antigen-binding moiety of the above-mentioned antibody. It has been well demonstrated that the antigen-binding function of an antibody can be performed by a fragment of a full-length antibody.

[0364] The anti-PD-1 antibodies suitable for use in the disclosed compositions and methods are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, the anti-PD-1 "antibody" comprises an antigen-binding moiety or fragment that binds to the PD-1 receptor and exhibits similar functional properties to the whole antibody in inhibiting ligand binding and upmodulating the immune system. In certain embodiments, the anti-PD-1 antibody or its antigen-binding moiety cross-competes with nivolumab for binding to human PD-1.

[0365] In some embodiments, the anti-PD-1 antibody is administered once every 2, 3, 4, 5, 6, 7, or 8 weeks in doses ranging from 0.1 mg / kg to 20.0 mg / kg body weight, for example, once every 2, 3, or 4 weeks in doses ranging from 0.1 mg / kg to 10.0 mg / kg body weight. In other embodiments, the anti-PD-1 antibody is administered once every 2 weeks in doses of approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, or 10 mg / kg body weight. In other embodiments, the anti-PD-1 antibody is administered once every 3 weeks in doses of approximately 2 mg / kg, approximately 3 mg / kg, approximately 4 mg / kg, approximately 5 mg / kg, approximately 6 mg / kg, approximately 7 mg / kg, approximately 8 mg / kg, approximately 9 mg / kg, or 10 mg / kg body weight. In one embodiment, the anti-PD-1 antibody is administered approximately once every three weeks at a dose of approximately 5 mg / kg body weight. In another embodiment, the anti-PD-1 antibody, such as nivolumab, is administered approximately once every two weeks at a dose of approximately 3 mg / kg body weight. In yet another embodiment, the anti-PD-1 antibody, such as pembrolizumab, is administered approximately once every three weeks at a dose of approximately 2 mg / kg body weight.

[0366] Anti-PD-1 antibodies useful for this disclosure can be administered in uniform doses. In some embodiments, anti-PD-1 antibodies are administered in uniform doses of approximately 100 to 1000 mg, 100 mg to 900 mg, 100 mg to 800 mg, 100 mg to 700 mg, 100 mg to 600 mg, 100 mg to 500 mg, 200 mg to 1000 mg, 200 mg to 900 mg, 200 mg to 800 mg, 200 mg to 700 mg, 200 mg to 600 mg, 200 mg to 500 mg, 200 mg to 480 mg, or 240 mg to 480 mg. In one embodiment, the anti-PD-1 antibody is administered at dosing intervals of approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks in a uniform dose of at least approximately 200 mg, at least approximately 220 mg, at least approximately 240 mg, at least approximately 260 mg, at least approximately 280 mg, at least approximately 300 mg, at least approximately 320 mg, at least approximately 340 mg, at least approximately 360 mg, at least approximately 380 mg, at least approximately 400 mg, at least approximately 420 mg, at least approximately 440 mg, at least approximately 460 mg, at least approximately 480 mg, at least approximately 500 mg, at least approximately 520 mg, at least approximately 540 mg, at least approximately 550 mg, at least approximately 560 mg, at least approximately 580 mg, at least approximately 600 mg, at least approximately 620 mg, at least approximately 640 mg, at least approximately 660 mg, at least approximately 680 mg, at least approximately 700 mg, or at least approximately 720 mg. In another embodiment, the anti-PD-1 antibody is administered at a uniform dose of approximately 200 mg to 800 mg, 200 mg to 700 mg, 200 mg to 600 mg, or 200 mg to 500 mg at intervals of approximately 1, 2, 3, or 4 weeks.

[0367] In some embodiments, the anti-PD-1 antibody is administered as a uniform dose of approximately 200 mg approximately once every three weeks. In other embodiments, the anti-PD-1 antibody is administered as a uniform dose of approximately 200 mg approximately once every two weeks. In yet another embodiment, the anti-PD-1 antibody is administered as a uniform dose of approximately 240 mg approximately once every two weeks. In a specific embodiment, the anti-PD-1 antibody is administered as a uniform dose of approximately 480 mg approximately once every four weeks.

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

[0369] In some embodiments, pembrolizumab is administered in a uniform dose of approximately 200 mg once every two weeks. In some embodiments, pembrolizumab is administered in a uniform dose of approximately 200 mg once every three weeks. In some embodiments, pembrolizumab is administered in a uniform dose of approximately 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, and 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 At least approximately 200 mg / mL, at least approximately 20 mg / mL to at least approximately 190 mg / mL, at least approximately 20 mg / mL to at least approximately 180 mg / mL, at least approximately 20 mg / mL to at least approximately 170 mg / mL, at least approximately 20 mg / mL to at least approximately 160 mg / mL, at least approximately 20 mg / mL to at least approximately 150 mg / mL, at least approximately 50 mg / mL to at least approximately 200 mg / mL, at least approximately 100 mg / mL to at least approximately 200 mg / mL L contains an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab) in an amount of at least approximately 150 mg / mL to at least approximately 200 mg / mL, at least approximately 135 mg / mL to at least approximately 180 mg / mL, at least approximately 100 mg / mL to at least approximately 200 mg / mL, at least approximately 150 mg / mL to at least approximately 200 mg / mL, at least approximately 100 mg / mL to at least approximately 130 mg / mL, or at least approximately 108 mg / mL to at least approximately 132 mg / mL.In some embodiments, the pharmaceutical composition contains at least about 50 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 60 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 70 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 75 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 80 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 90 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 100 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 108 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 110 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 120 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 130 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 132 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 135 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 140 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 150 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab).In some embodiments, the pharmaceutical composition contains at least about 160 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 170 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 175 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 180 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 190 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition contains at least about 200 mg / mL of anti-PD-1 antibody (e.g., nivolumab or pembrolizumab).

[0371] In some embodiments, the pharmaceutical composition comprises a bispecific or polyspecific antibody having a first antigen-binding moiety and a second antigen-binding moiety, wherein the first antigen-binding moiety comprises an anti-PD-1 antigen-binding moiety (e.g., scFv of nivolumab). In some embodiments, the second antigen-binding moiety is an antigen-binding moiety of any one of the antibodies disclosed herein. In some embodiments, the second antigen-binding moiety is an antigen-binding moiety of an anti-LAG-3 antibody, e.g., relatrimab. In some embodiments, the second antigen-binding moiety is an antigen-binding moiety of an anti-TIGIT antibody.

[0372] In some embodiments, the pharmaceutical composition comprises a polyspecific antibody having a first antigen-binding moiety, a second antigen-binding moiety, and at least a third antigen-binding moiety, wherein the first antigen-binding moiety includes an anti-PD-1 antigen-binding moiety (e.g., scFv of nivolumab).

[0373] II.A.2. Anti-PD-L1 antibodies useful in this disclosure In some embodiments, the pharmaceutical composition comprises an antibody or its antigen-binding moiety that specifically binds to PD-L1 ("anti-PD-L1 antibody"). In some embodiments, the anti-PD-L1 antibody is substituted for an 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 this disclosure. Examples of anti-PD-L1 antibodies useful in the compositions and methods of this disclosure include the antibody 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) binding to human PD-L1 with a KD of 1 × 10⁻⁷ M or less, as determined by surface plasmon resonance using a Biacore biosensor system; (b) increasing T cell proliferation in a mixed lymphocyte reaction (MLR) assay; (c) increasing interferon-γ production in an MLR assay; (d) increasing IL-2 secretion in an MLR assay; (e) stimulating an antibody response; and (f) reversing the effect of T regulatory cells on T cell effector cells and / or dendritic cells. The anti-PD-L1 antibodies available in this 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 aforementioned characteristics.

[0374] In certain embodiments, the anti-PD-L1 antibody is BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Patent No. 7,943,743 and WO2013 / 173223), atezolizumab [Roche; TECENTRIQ®; also known as MPDL3280A, RG7446; see, U.S. 8,217,149; Herbst et al. (2013) J Clin Oncol]. See also 31(suppl):3000], durvalumab [AstraZeneca; IMFINZI(trademark), also known as MEDI-4736; see WO2011 / 066389], avelumab [Pfizer; BAVENCIO(registered trademark), also known as 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 The selection is made from the group consisting of Co. (see, for example, 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 certain embodiments, the PD-L1 antibody is atezolizumab [TECENTRIQ®]. Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody.

[0376] In certain embodiments, the PD-L1 antibody is durvalumab [IMFINZI®]. Durvalumab is a human IgG1 kappa monoclonal anti-PD-L1 antibody.

[0377] In certain embodiments, the PD-L1 antibody is avelumab [BAVENCIO®]. Avelumab is a human IgG1 lambda monoclonal anti-PD-L1 antibody.

[0378] The anti-PD-L1 antibodies available for use in the disclosed compositions and methods 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, e.g., 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, e.g., atezolizumab, durvalumab, and / or avelumab. The ability of antibodies to cross-compete for binding to the antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically prevent the binding of other cross-competitive antibodies to that particular epitope region. These cross-competitive antibodies are expected to have very similar functional properties to those of the reference antibody, e.g., atezolizumab and / or avelumab, due to their binding to the same epitope region of PD-L1. Cross-competitive 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, for example, WO2013 / 173223).

[0379] In certain embodiments, antibodies that cross-compete with human PD-L1 antibodies, such as atezolizumab, durvalumab, and / or avelumab, for binding to human PD-L1, or that bind to the same epitope region of human PD-L1, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0380] The anti-PD-L1 antibodies usable in the compositions and methods of this disclosure also include the antigen-binding moiety of the above-mentioned antibody. It has been well demonstrated that the antigen-binding function of an antibody can be performed by a fragment of a full-length antibody.

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

[0382] An anti-PD-L1 antibody useful in this disclosure may 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, for example, 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, anti-PD-L1 antibodies are administered approximately once every 2, 3, 4, 5, 6, 7, or 8 weeks in doses ranging from approximately 0.1 mg / kg to approximately 20.0 mg / kg of body weight, such as approximately 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 11 mg / kg, 12 mg / kg, 13 mg / kg, 14 mg / kg, 15 mg / kg, 16 mg / kg, 17 mg / kg, 18 mg / kg, 19 mg / kg, or 20.0 mg / kg.

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

[0385] In other embodiments, the anti-PD-L1 antibody useful for this disclosure is a uniform dose. In some embodiments, the anti-PD-L1 antibody is administered in uniform doses of approximately 200 mg to 1600 mg, 200 mg to 1500 mg, 200 mg to 1400 mg, 200 mg to 1300 mg, 200 mg to 1200 mg, 200 mg to 1100 mg, 200 mg to 1000 mg, 200 mg to 900 mg, 200 mg to 800 mg, 200 mg to 700 mg, 200 mg to 600 mg, 700 mg to 1300 mg, 800 mg to 1200 mg, 700 mg to 900 mg, or 1100 mg to 1300 mg. In some embodiments, the anti-PD-L1 antibody is administered at dosing intervals of approximately 1, 2, 3, or 4 weeks in a uniform dose of at least approximately 240 mg, at least approximately 300 mg, at least approximately 320 mg, at least approximately 400 mg, at least approximately 480 mg, at least approximately 500 mg, at least approximately 560 mg, at least approximately 600 mg, at least approximately 640 mg, at least approximately 700 mg, at least approximately 720 mg, at least approximately 800 mg, at least approximately 840 mg, at least approximately 880 mg, at least approximately 900 mg, at least approximately 960 mg, at least approximately 1000 mg, at least approximately 1040 mg, at least approximately 1100 mg, at least approximately 1120 mg, at least approximately 1200 mg, at least approximately 1280 mg, at least approximately 1300 mg, at least approximately 1360 mg, or at least approximately 1400 mg. In some embodiments, the anti-PD-L1 antibody is administered as a uniform dose of approximately 1200 mg approximately once every three weeks. In other embodiments, the anti-PD-L1 antibody is administered as a uniform dose of approximately 800 mg approximately once every two weeks. In still other embodiments, the anti-PD-L1 antibody is administered as a uniform dose of approximately 840 mg approximately once every two weeks.

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

[0387] In some configurations, avelumab is administered as a uniform dose of approximately 800 mg once every two weeks.

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

[0389] In some embodiments, the pharmaceutical composition contains at least about 10 mg / mL to at least about 500 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains 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, at least about 10 mg / mL to at least about 180 mg 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, less All are approximately 20 mg / mL to at least approximately 200 mg / mL, at least approximately 20 mg / mL to at least approximately 190 mg / mL, at least approximately 20 mg / mL to at least approximately 180 mg / mL, at least approximately 20 mg / mL to at least approximately 170 mg / mL, at least approximately 20 mg / mL to at least approximately 160 mg / mL, at least approximately 20 mg / mL to at least approximately 150 mg / mL, at least approximately 50 mg / mL to at least approximately 200 mg / mL, and at least approximately 100 mg / The composition contains an anti-PD-L1 antibody in an amount of at least 200 mg / mL, at least 150 mg / mL to at least 200 mg / mL, at least 135 mg / mL to at least 180 mg / mL, at least 100 mg / mL to at least 200 mg / mL, at least 150 mg / mL to at least 200 mg / mL, at least 100 mg / mL to at least 130 mg / mL, or at least 108 mg / mL to at least 132 mg / mL. In some embodiments, the pharmaceutical composition contains at least 50 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least 60 mg / mL of anti-PD-L1 antibody.In some embodiments, the pharmaceutical composition contains at least about 70 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 75 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 80 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 90 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 100 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 108 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 110 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 120 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 130 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 132 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 135 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 140 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 150 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 160 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 170 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 175 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 180 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 190 mg / mL of anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition contains at least about 200 mg / mL of anti-PD-L1 antibody.

[0390] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) PD-L1 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 its antigen-binding moiety that specifically binds to CTLA-4 ("anti-CTLA-4 antibody"). Any anti-CTLA-4 antibody known in the art may be used in the compositions and methods of the present disclosure. The anti-CTLA-4 antibody of the present invention binds to human CTLA-4 and interferes with the interaction between CTLA-4 and the human B7 receptor. Since the interaction between CTLA-4 and B7 converts signals that lead to the inactivation of T cells having a CTLA-4 receptor, interference with the interaction effectively induces, enhances, or prolongs the activation of such T cells, thereby inducing, enhancing, or prolonging an immune response.

[0392] A human monoclonal antibody that specifically binds to CTLA-4 with high affinity is disclosed in U.S. Patent No. 6,984,720. Other anti-CTLA-4 monoclonal antibodies are described, for example, in U.S. Patents No. 5,977,318, 6,051,227, 6,682,736, and 7,034,121, and in International Publications WO2012 / 122444, WO2007 / 113648, WO2016 / 196237, and WO2000 / 037504, each of which is thus incorporated herein by reference as a whole. The anti-CTLA-4 human monoclonal antibody disclosed in U.S. Patent No. 6,984,720 has been demonstrated to exhibit one or more of the following characteristics: (a) specific binding to human CTLA-4 with a binding affinity reflected by an equilibrium association constant (Ka) of at least about 10⁷M⁻¹, or about 10⁹M⁻¹, or greater, as determined by Biacore analysis; (b) kinetic association constant (ka) of at least about 10³, about 10⁴, or about 10⁵m⁻¹s⁻¹; (c) kinetic dissociation constant (kd) of at least about 10³, about 10⁴, or about 10⁵m⁻¹s⁻¹; and (d) inhibition of 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 [YERVOY®, also known as MDX-010, 10D1; see U.S. Patent No. 6,984,720], MK-1308 (Merck), AGEN-1884 (Agenus Inc.; see WO2016 / 196237), and tremelimumab [AstraZeneca; also known as tisilimmab, 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 progressive 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 unfucosylated or low-fucosylated. In some embodiments, the CTLA-4 antibody exhibits enhanced ADCC and / or ADCP activity. In some embodiments, the CTLA-4 antibody is BMS-986218 as described in PCT / US18 / 19868.

[0397] The anti-CTLA-4 antibodies available for use in the disclosed compositions and methods include isolated antibodies that specifically bind to human CTLA-4 and cross-compete for binding to human CTLA-4 with any anti-CTLA-4 antibodies disclosed herein, e.g., 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, e.g., ipilimumab and / or tremelimumab. The ability of antibodies to cross-compete for binding to the antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically prevent the binding of other cross-competitive antibodies to that particular epitope region. These cross-competitive antibodies are expected to have very similar functional properties to those of the reference antibody, e.g., ipilimumab and / or tremelimumab, due to their binding to the same epitope region of CTLA-4. Cross-competitive 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 assay, or flow cytometry (see, for example, 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 that bind to the same epitope region of human CTLA-4, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0399] The anti-CTLA-4 antibodies usable in the compositions and methods of the disclosed invention also include the antigen-binding moiety of the antibody described above. It has been well demonstrated that the antigen-binding function of an antibody can be performed by a fragment of the 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-CTLA-4 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) 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 of 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 (h) an anti-CTLA-4 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

[0403] An anti-CTLA-4 antibody suitable for use in the disclosed methods or compositions is an antibody that binds to CTLA-4 with high specificity and affinity, blocks the activity of CTLA-4, and interferes with the interaction between CTLA-4 and the human B7 receptor. In any of the compositions or methods disclosed herein, the anti-CTLA-4 “antibody” comprises an antigen-binding moiety or fragment that binds to CTLA-4 and exhibits similar functional properties to the whole antibody in inhibiting the interaction between CTLA-4 and the human B7 receptor and in upmodulating the immune system. In certain embodiments, the anti-CTLA-4 antibody or its antigen-binding moiety cross-competes with ipilimumab and / or tremelimumab for binding to human CTLA-4.

[0404] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) CTLA-4 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 its antigen-binding moiety that specifically binds to LAG-3 ("anti-LAG-3 antibody"), such as relatrimab. The anti-LAG-3 antibodies of this disclosure bind to human LAG-3. Any anti-LAG-3 antibody may be used in the pharmaceutical compositions and methods disclosed herein. Antibodies that bind to LAG-3 are disclosed in International Publication WO / 2015 / 042246, and U.S. Publications 2014 / 0093511 and 2011 / 0150892, each of which is thus incorporated herein by reference as a whole.

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

[0407] Other anti-LAG-3 antibodies recognized in the art that may be used in the methods and / or compositions of this disclosure include IMP731(H5L7BW) described in US2011 / 007023, MK-4280(28G-10, fabezerimab) described in WO2016028672 and U.S. Publication No. 2020 / 0055938, and Burova E, et al., J. Immunother. Cancer (2016); 4(Supp. 1): REGN3767 [fianlimab] as described in P195 and U.S. Patent No. 10,358,495, humanized BAP050 as described in WO2017 / 019894, GSK2831781, IMP-701 (LAG525; yeramirimab) as described in U.S. Patent 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 Includes 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 include, for example, US10,188,730, 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, This information can be found in WO2018 / 185046, WO2018 / 185043, WO2018 / 217940, WO19 / 011306, WO2018 / 208868, WO2014 / 140180, WO2018 / 201096, WO2018 / 204374, and WO2019 / 018730. The contents of each of these references are thus incorporated herein by reference as a whole.

[0408] The anti-LAG-3 antibodies that may be used in the methods and / or compositions of this disclosure include isolated antibodies that specifically bind to human LAG-3 and cross-compete for binding to human LAG-3 with any anti-LAG-3 antibodies disclosed herein, e.g., relatrimab. 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., relatrimab.

[0409] In certain embodiments, any anti-LAG-3 antibody disclosed herein, such as relatrimab, that cross-competes with human LAG-3 for binding, or that binds to the same epitope region, is a monoclonal antibody. For administration to human subjects, these cross-competitive antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies may be prepared and isolated by methods well known in the art.

[0410] The ability of antibodies to cross-compete for binding to an antigen indicates that the antibody binds to the same epitope region of the antigen, sterically preventing the binding of other cross-competitive antibodies to that particular epitope region. These cross-competitive antibodies are expected to have very similar functional properties to a reference antibody, such as relatrimab, due to their binding to the same epitope region. Cross-competitive antibodies can be readily 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] The anti-LAG-3 antibody that may be used in the methods and / or compositions of this disclosure also includes the antigen-binding moiety of any of the full-length antibodies described above. It has been well demonstrated that the antigen-binding function of an antibody can be performed by a fragment 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 monoclonal, human, humanized, chimeric, or multispecific antibody. In some embodiments, the multispecific antibody is a biaffinity retargeting antibody (DART), DVD-Ig, or a bispecific antibody.

[0414] In some embodiments, the anti-LAG-3 antibody is an 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 linked polypeptide.

[0415] In some embodiments, the anti-LAG-3 antibodies include BMS-986016 (relatrimab), IMP731 (H5L7BW), MK4280 (28G-10, fabezerimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yeramirimab), aLAG3 (0414), aLAG3 (0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (teboterimab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or containing their antigen-binding moieties.

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

[0417] In some embodiments, the anti-LAG-3 antibody is MGD013 (teboterimab), which is a bispecific PD-1 × 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 (yeramirimab).

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

[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) relatrimab; (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) relatrimab; (b) about 20 mM 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, an anti-LAG-3 antibody, such as relatrimab, may be formulated as a monotherapy in combination with an anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-LAG-3 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) relatrimab. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-LAG-3 antibody; and (h) about 2000 U / mL of rHuPH20. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; (g) relatrimab; and (h) about 2000 U / mL of rHuPH20.

[0423] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) anti-LAG-3 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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) relatrimab. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of 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 nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; (g) relatrimab; and (h) about 2000 U / mL of rHuPH20.

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

[0425] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) LAG-3 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 against tumor cells, particularly a cytotoxic T cell response. Antibodies that bind to CD137 are disclosed in U.S. Publication No. 2005 / 0095244, and U.S. Patents 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 as a monotherapy product together with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-CD137 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-CD137 antibody; and (h) about 2000 U / mL of rHuPH20.

[0429] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) anti-CD137 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-CD137 antibody; and (h) about 2000 U / mL of rHuPH20.

[0430] In some embodiments, the anti-CD137 antibody is urelumab (BMS-663513) (20H4.9-IgG4 [10C7 or BMS-663513]) as described in U.S. Patent No. 7,288,638. In some embodiments, the anti-CD137 antibody is BMS-663031 (20H4.9-IgG1) as described in U.S. Patent No. 7,288,638. In some embodiments, the anti-CD137 antibody is 4E9 or BMS-554271 as described in U.S. Patent No. 6,887,673. In some embodiments, the anti-CD137 antibody is an antibody disclosed in U.S. Patent No. 7,214,493; No. 6,303,121; No. 6,569,997; No. 6,905,685; or No. 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 (e.g., 53A2) disclosed in issued U.S. Patent No. 6,974,863. In some embodiments, the anti-CD137 antibody is an antibody (e.g., 1D8, 3B8, or 3E1) disclosed in issued U.S. Patent No. 6,210,669. In some embodiments, the antibody is Pfizer PF-05082566 (PF-2566). In other embodiments, the anti-CD137 antibody useful for 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, the anti-CD137 antibodies useful in this disclosure include the six CDRs of anti-CD137 antibodies disclosed herein.

[0431] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) CD137 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 includes an anti-KIR3 antibody. Antibodies that specifically bind to KIRs block the interaction between killer cell immunoglobulin-like receptors (KIRs) 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 Publications 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-KIR antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-KIR antibody; and (h) about 2000 U / mL of rHuPH20.

[0435] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) an anti-KIR antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

[0436] One anti-KIR antibody useful in this disclosure is lirirumab (also known as BMS-986015, IPH2102, or the S241P variant of 1-7F9), first described in International Publication WO2008 / 084106. An additional anti-KIR antibody useful in this disclosure is 1-7F9 (also known as IPH2101), described in International Publication WO2006 / 003179. In one embodiment, the anti-KIR antibody for the composition cross-competes with lirirumab or I-7F9 for binding to KIR. In another embodiment, the anti-KIR antibody binds to the same epitope as lirirumab or I-7F9. In yet another embodiment, the anti-KIR antibody contains six CDRs of lirirumab or I-7F9.

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

[0438] II.A.7. Anti-GITR antibody In some embodiments, the second antibody includes an anti-GITR antibody. The anti-GITR antibody includes any anti-GITR antibody that specifically binds to the human GITR target and activates glucocorticoid-induced tumor necrosis factor receptor (GITR). GITR is a member of the TNF receptor superfamily expressed on the surface of 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 repression induced by activated regulatory T 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 Publications WO / 2015 / 031667, WO2015 / 184,099, WO2015 / 026,684, WO11 / 028683, and WO / 2006 / 105021, U.S. Publications 7,812,135 and 8,388,967, and U.S. Publications 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 as a monotherapy drug together with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-GITR antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-GITR antibody; and (h) about 2000 U / mL of rHuPH20.

[0441] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) an anti-GITR antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

[0442] In one embodiment, the anti-GITR antibody useful in this disclosure is TRX518 [e.g., as described 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 antibodies described in WO11 / 028683 and US8,709,424, and includes, for example, a VH chain containing SEQ ID NO: 104 and a VL chain containing SEQ ID NO: 105 (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, for example, an antibody comprising VH CDR1-3 including SEQ ID NOs. 31, 71, and 63 of WO2015 / 031667, and VL CDR1-3 including SEQ ID NOs. 5, 14, and 30 of WO2015 / 031667. In certain embodiments, the anti-GITR antibody is an anti-GITR antibody disclosed in WO2015 / 184099, for example, an antibody Hum231#1 or Hum231#2, or its CDR, or a derivative 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 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 containing the variable region 28F3, 18E10, or 19D3).

[0443] In certain embodiments, the anti-GITR antibody cross-competes with the anti-GITR antibodies described herein, such as TRX518, MK4166, or antibodies containing the VH and VL domain amino acid sequences described herein. In some embodiments, the anti-GITR antibody binds to the same epitopes as the anti-GITR antibodies described herein, such as TRX518, MK4166, or antibodies containing the VH and VL domain amino acid sequences described herein. In certain embodiments, the anti-GITR antibody includes the six CDRs of TRX518, MK4166, or antibodies containing the VH and VL domain amino acid sequences described herein.

[0444] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) GITR and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 includes an anti-TIM3 antibody. In some embodiments, anti-TIM3 antibodies are internationally published as 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 This includes anti-TIM3 antibodies disclosed in Lilly, WO2017205721, WO17079112; WO17079115; WO17079116, WO11159877, WO13006490, WO2016068802, WO2016068803, WO2016 / 111947, and 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-TIM3 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-TIM3 antibody; and (h) about 2000 U / mL of rHuPH20.

[0448] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) anti-TIM3 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-TIM3 antibody; and (h) about 2000 U / mL of rHuPH20.

[0449] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) TIM-3 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 antibody (also known as CD134, TNFRSF4, ACT35, and / or TXGP1L). In some embodiments, the anti-OX40 antibody comprises BMS-986178 (Bristol-Myers Squibb Company) as described in International Publication WO20160196228. In some embodiments, the anti-OX40 antibody includes the anti-OX40 antibody described in International Publications 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-OX40 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-OX40 antibody; and (h) about 2000 U / mL of rHuPH20.

[0453] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) anti-OX40 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-OX40 antibody; and (h) about 2000 U / mL of rHuPH20.

[0454] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) OX40 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 includes an anti-NKG2A antibody. NKG2A is a member of the type C lectin receptor family expressed on subsets of natural killer (NK) cells and T lymphocytes. Specifically, NKG2A is primarily expressed on tumor-infiltrating innate immune effector NK cells, as well as on some CD8+ T cells. Its natural ligand, human leukocyte antigen E (HLA-E), is expressed on solid tumors and hematological malignancies. 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 as a monotherapy drug together with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-NKG2A antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-NKG2A antibody; and (h) about 2000 U / mL of rHuPH20.

[0458] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) anti-NKG2A antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-NKG2A antibody; and (h) about 2000 U / mL of 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 enabling 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, for example, 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 No. 8,206,709; No. 8,901,283; No. 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 includes anti-NKG2A antibodies as described in WO2016 / 041945 (Innate Pharma).

[0460] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) NKG2A and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 includes an anti-ICOS antibody. ICOS is an immune checkpoint protein that is a member of the CD28 superfamily. ICOS is a 55-60 kDa type I transmembrane protein that is expressed on T cells after T cell activation and co-stimulates T cell activation after binding to its ligand ICOS-L(B7H2). ICOS is also known as inducible T cell costimulator, CVID1, AILIM, inducible costimulator, CD278, activation-inducible lymphocyte immune-mediated 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 as a monotherapy drug together with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-ICOS antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-ICOS antibody; and (h) about 2000 U / mL of rHuPH20.

[0464] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) an anti-ICOS antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of 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, 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]. This includes anti-ICOS antibodies as described in the following publications: Robert Koch Institute, U.S. Patent Nos. 7,259,247 and 7,722,872; WO1998 / 038216 (Japan Tobacco Inc.), U.S. Patent 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 polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) ICOS and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 as described in WO2016 / 106302. In some embodiments, the anti-TIGIT antibody comprises MTIG7192A / RG6058 / RO7092284, or clone 4.1D3 as described in WO2017 / 053748. In some embodiments, the anti-TIGIT antibody comprises anti-TIGIT antibodies as 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 as a monotherapy drug together with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-TIGIT antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-TIGIT antibody; and (h) about 2000 U / mL of rHuPH20.

[0470] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) an anti-TIGIT antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

[0471] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) TIGIT and (ii) a second antigen. In some embodiments, the antibody includes 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 polyspecific antibody, such as 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-IL-12 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) 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 of 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 (h) an anti-IL-12 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

[0475] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) IL-12 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-IL-13 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) 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 of 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 (h) an anti-IL-13 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

[0479] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) IL-13 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-IL-15 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) 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 of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) anti-IL-15 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-IL-15 antibody; and (h) about 2000 U / mL of rHuPH20.

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

[0484] II.A.16. Anti-SIRP alpha antibody 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-SIRP alpha antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) 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 of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; and (g) anti-SIRP alpha antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-SIRP alpha antibody; and (h) about 2000 U / mL of rHuPH20.

[0487] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) SIRP alpha and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) SIRP alpha 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 as a monotherapy drug together with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-CD47 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-CD47 antibody; and (h) about 2000 U / mL of rHuPH20.

[0490] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) anti-CD47 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-CD47 antibody; and (h) about 2000 U / mL of rHuPH20.

[0491] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) CD47 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-CCR8 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-CCR8 antibody; and (h) about 2000 U / mL of rHuPH20.

[0494] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) an anti-CCR8 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

[0495] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) CCR8 and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 as a monotherapy drug together with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-MICA antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-MICA antibody; and (h) about 2000 U / mL of rHuPH20.

[0498] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) an anti-MICA antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

[0499] In some embodiments, the antibody is a polyspecific antibody, such as a bispecific antibody, that specifically binds to (i) MICA and (ii) a second antigen. In some embodiments, the antibody is a polyspecific antibody, such as 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 as a monoform in combination with the anti-PD-1 antibody in any of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetate; (f) about 5 mM methionine; and (g) anti-ILT4 antibody. In a particular embodiment, the pharmaceutical composition comprises (a) about 150 mg / mL of anti-PD-1 antibody; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v polysorbate 80; (e) about 50 μM pentetic acid; (f) about 5 mM methionine; (g) anti-ILT4 antibody; and (h) about 2000 U / mL of rHuPH20.

[0502] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 (h) an anti-ILT4 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of 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 of rHuPH20.

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

[0504] II.B. Endoglycosidase hydrolase enzyme In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase enzyme. Any endoglycosidase hydrolase enzyme may 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 hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant thereof, and any isoform. 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 with amino acids 36-490 of SEQ ID NO: 1. In some embodiments, the endoglycosidase hydrolase enzyme comprises the catalytic domain of rHuPH20 (UniProt ID number P38567-1). In some embodiments, the endoglycosidase hydrolase enzyme contains the rHuPH20 mature peptide (amino acids 36-490 of SEQ ID NO: 1).

[0506] [Table 2]

[0507] In some embodiments, the pharmaceutical composition comprises Halozyme Therapeutics' ENHANZE® drug delivery technology (see U.S. Patent No. 7,767,429, which is thereby incorporated herein by reference as a whole). ENHANZE® uses a co-formulation of an antibody and 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 recombinant human hyaluronidase enzyme, e.g., 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 injection site. Hyaluronan is a repeating polymer of N-acetylglucosamine and glucuronic acid, which contributes to the soluble gel-like components of the extracellular matrix of the skin. Depolymerization of hyaluronan by rHuPH20 results in a transient decrease in the viscosity of the gel-like phase of the extracellular matrix, as well as an increase in hydrodynamic conductivity, which facilitates the dispersion and absorption of the injected drug (see rHuPH20 IB). The use of rHuPH20 enables high-volume delivery (e.g., approximately 2 mL to 20 mL) for rapid SC injection, which may shorten dose-dosing 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 recovers to pre-injection levels within 24–48 hours after hyaluronidase injection. 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 on the PK of rHuPH20 (Halozyme study HALO-104-104) demonstrated that plasma concentrations of rHuPH20 rapidly decline with a very short t1 / 2 (≤10.4 minutes), and plasma concentrations become undetectable within 1.5 hours after the end of IV infusion for IV doses of 10,000 or 30,000 units of rHuPH20 (<0.03 ng / mL).

[0510] Subcutaneous administration of rHuPH20 is 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 administration of rHuPH20 alone, or co-administered with Ringer's lactate, saline, co-injected drugs (morphine, ceftriaxone, insulin, and insulin analogs), or biological products (immunoglobulin G [IgG] and adalimumab) is well-tolerated.

[0511] In some embodiments, the endoglycosidase hydrolase enzyme includes 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 fragments thereof. In some embodiments, the endoglycosidase hydrolase enzyme includes a modified hyaluronidase comprising one or more amino acid substitutions in the alpha-helix region compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase enzyme includes 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 fragments thereof. In some embodiments, the endoglycosidase hydrolase enzyme includes 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 fragments thereof.

[0512] In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, the modified rHuPH20 comprising one or more amino acid substitutions in the alpha-helix region, the linker region, or both the alpha-helix region and the linker region compared to wild-type rHuPH20. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, the modified rHuPH20 comprising 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 deletions compared 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-helix region, the linker region, or both the alpha-helix region and the linker region compared to wild-type rHuPH20; or, compared to wild-type rHuPH20, the modified rHuPH20 comprises one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids deletions.

[0513] Additional, non-limiting examples of endoglycosidase hydrolase enzymes can be found in EP3636752, which is thus incorporated herein by reference in its entirety.

[0514] In some embodiments, the endoglycosidase hydrolase enzyme is any polypeptide having endoglycosidase hydrolase enzyme activity as 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 thus incorporated herein by reference as a whole. In some embodiments, the endoglycosidase hydrolase enzyme is any polypeptide having endoglycosidase hydrolase enzyme activity disclosed in International Publications 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 thus incorporated herein by reference as a whole. In some embodiments, the endoglycosidase hydrolase enzyme contains 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 specified 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 Publications US2021155913A1 and / or US2021363270A1; and / or International Publications WO / 20 / 022791, WO / 20 / 197230, and / or WO / 21 / 150079; each of these is thus incorporated herein by reference as a whole. 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 specified in Sequence IDs 53-263. In some embodiments, the endoglycosidase hydrolase enzyme contains 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 the amino acid sequence specified in SEQ ID NO: 92. In some embodiments, the endoglycosidase hydrolase enzyme contains an amino acid sequence selected from the amino acid sequences specified in SEQ ID NOs: 53 to 263. In some embodiments, the endoglycosidase hydrolase enzyme contains the amino acid sequence specified in SEQ ID NO: 92. In some embodiments, the endoglycosidase hydrolase enzyme is HP46 (SEQ ID NO: 44 in International Publication WO / 20 / 197230).

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

[0517] In some embodiments, the pharmaceutical composition contains at least about 50 units to at least about 48,000 units of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 50 U / mL to at least about 5,000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains 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, and less The pharmaceutical composition contains at least approximately 3500 U / mL, at least approximately 4000 U / mL, at least approximately 4500 U / mL, at least approximately 5000 U / mL, at least approximately 5500 U / mL, at least approximately 6000 U / mL, at least approximately 6500 U / mL, at least approximately 7000 U / mL, at least approximately 7500 U / mL, at least approximately 8000 U / mL, at least approximately 8500 U / mL, at least approximately 9000 U / mL, at least approximately 9500 U / mL, and at least approximately 10,000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least approximately 500 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least approximately 1000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 2000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 2500 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 3000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20).In some embodiments, the pharmaceutical composition contains at least about 3500 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 4000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 4500 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 5000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 6000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 7000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 8,000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 9,000 U / mL of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 10,000 U / mL of 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 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 endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition is 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 comprises 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 endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 20,000 units of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 30,000 units of endoglucosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 40,000 units of endoglucosidase hydrolase enzyme (e.g., rHuPH20).In some embodiments, the pharmaceutical composition contains at least about 50,000 units of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 60,000 units of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 70,000 units of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 80,000 units of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 90,000 units of endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition contains at least about 100,000 units of endoglycosidase hydrolase enzyme (e.g., rHuPH20).

[0519] It will be readily apparent to those skilled in the art that the amount of endoglucosidase hydrolase enzyme (e.g., rHuPH20) can be expressed in units or U / mL, or that the amount of endoglucosidase hydrolase enzyme (e.g., rHuPH20) can be expressed in mg / mL (or other weight-based units). For example, in some embodiments, the pharmaceutical composition contains an amount of endoglucosidase 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, the pharmaceutical composition contains an amount of endoglucosidase 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 its antigen-binding moiety (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 pentetate; (f) about 5 mM methionine; and (g) about 2000 U / mL rHuPH20. In a particular embodiment, the pharmaceutical composition comprises (a) about 120 mg / mL of nivolumab; (b) about 20 mM histidine; (c) about 250 mM sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM methionine; and (g) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of an antibody or its antigen-binding moiety (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 pentetate; (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 of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; and (g) about 0.0182 mg / mL of rHuPH20.

[0521] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an antibody or its antigen-binding moiety (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 pentetate; (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 nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; and (g) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an antibody or its antigen-binding moiety (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 pentetate; (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 of nivolumab; (b) about 20 mM of histidine; (c) about 250 mM of sucrose; (d) about 0.05% w / v of polysorbate 80; (e) about 50 μM of pentetic acid; (f) about 5 mM of methionine; and (g) about 0.0182 mg / mL of rHuPH20.

[0522] In certain embodiments, the unit dose described herein comprises (a) about 120 mg / mL of an antibody or its antigen-binding moiety (e.g., an...

Claims

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

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

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

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

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

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

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

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein 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 of methionine.

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

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

11. A pharmaceutical composition according to any one of claims 1 to 10, wherein 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 of DTPA.

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

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

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

15. A pharmaceutical composition according to any one of claims 1 to 14, comprising approximately 120 mg / mL or approximately 150 mg / mL of anti-PD-1 antibody.

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

17. At least about 5U, at least about 10U, at least about 20U, at least about 30U, at least about 40U, at least about 50U, at least about 75U, at least about 100U, at least about 200U, at least about 300U, at least about 400U, at least about 500U, at least about 750U, at least about 1000U, at least about 2000U, at least about 3000U, at least about 4000U, at least about 5000U, at least about 6000U, at least about 7000 A pharmaceutical composition according to any one of claims 1 to 16, comprising 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.

18. A pharmaceutical composition according to any one of claims 1 to 17, comprising approximately 20,000 U of endoglycosidase hydrolase enzyme.

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

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

21. A pharmaceutical composition according to any one of claims 1 to 20, comprising approximately 2000 U / mL of endoglycosidase hydrolase enzyme.

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

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

24. The pharmaceutical composition according to any one of claims 1 to 23, 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 with amino acids 36 to 490 of SEQ ID NO:

1.

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

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

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

28. The pharmaceutical composition according to any one of claims 1 to 27, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase having 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.

29. A pharmaceutical composition according to any one of claims 1 to 28, wherein the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase, which, compared to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof, includes (ii) one or more amino acid substitutions in the alpha-helix region, (iii) one or more deletions of N-terminal and / or C-terminal amino acids, or (iv) any combination of (i) to (iii).

30. The endoglycosidase hydrolase enzyme contains a modified rHuPH20, and the modified rHuPH20 is i. One or more amino acid substitutions in the alpha-helix region, linker region, or both the alpha-helix region and 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) A pharmaceutical composition according to any one of claims 1 to 29, comprising:

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

32. The pharmaceutical composition according to claim 31, wherein the tension modifier and / or stabilizer comprises sugars, amino acids, polyols, salts, or a combination thereof.

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

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

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

36. At least approximately 10 mM, at least approximately 20 mM, at least approximately 30 mM, at least approximately 40 mM, at least approximately 50 mM, at least approximately 60 mM, at least approximately 70 mM, at least approximately 80 mM, at least approximately 90 mM, at least approximately 100 mM, at least approximately 110 mM, at least approximately 120 mM, at least approximately 130 mM, at least approximately 140 mM, at least approximately 150 mM, at least approximately 160 mM, at least approximately 170 mM, at least approximately 180 mM, at least approximately 190 mM, at least approximately 200 mM, at least approximately 210 mM, at least approximately 220 mM, at least approximately 230 mM, at least approximately 240 mM, at least approximately 250 mM, at least approximately 260 mM, at least approximately 270 mM A pharmaceutical composition according to any one of claims 1 to 35, comprising 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 of sucrose.

37. A pharmaceutical composition according to any one of claims 1 to 36, comprising approximately 250 mM sucrose.

38. A pharmaceutical composition according to any one of claims 1 to 37, further comprising a buffering agent.

39. The pharmaceutical composition according to claim 38, wherein the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate.

40. The pharmaceutical composition according to claim 38 or 39, wherein the buffering agent comprises histidine.

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

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

43. A pharmaceutical composition according to any one of claims 1 to 42, comprising approximately 20 mM histidine.

44. A pharmaceutical composition according to any one of claims 1 to 43, further comprising a surfactant.

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

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

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

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

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

50. (a) Approximately 120 mg / mL of anti-PD-1 antibody; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; and (g) Approximately 0.0182 mg / mL of rHuPH2 A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 49, comprising:

51. (a) Approximately 120 mg / mL of anti-PD-1 antibody; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; and (g) Approximately 2000 U / mL of rHuPH2O A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 49, comprising:

52. (a) Approximately 150 mg / mL of anti-PD-1 antibody; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; and (g) Approximately 0.0182 mg / mL of rHuPH2 A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 49, comprising:

53. (a) Approximately 150 mg / mL of anti-PD-1 antibody; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; and (g) Approximately 2000 U / mL of rHuPH2O A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 49, comprising:

54. The pharmaceutical composition according to any one of claims 1 to 53, wherein the anti-PD-1 antibody is selected from nivolumab, pembrolizumab, PDR001, MEDI-0680, semiprimab, tripalimab, tislerizumab, INCSHHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, sasanlimab, and any combination thereof.

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

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

57. (a) Nivolumab at approximately 120 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; and (g) Approximately 0.0182 mg / mL of rHuPH2 A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 55, comprising:

58. (a) Nivolumab at approximately 120 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; and (g) Approximately 2000 U / mL of rHuPH2O A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 55, comprising:

59. (a) Nivolumab at approximately 150 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; and (g) Approximately 0.0182 mg / mL of rHuPH2 A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 55, comprising:

60. (a) Nivolumab at approximately 150 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; and (g) Approximately 2000 U / mL of rHuPH2O A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 55, comprising:

61. (a) Approximately 672 mg of nivolumab; (b) Approximately 8.68 mg of histidine; (c) Approximately 11.8 mg of histidine HCl H2O; (d) Approximately 479 mg of sucrose; (e) Approximately 2.80 mg of polysorbate 80; (f) Approximately 0.110 mg of pentetate; (g) Approximately 4.18 mg of methionine; (h) Approximately 0.102 mg of rHuPH2O A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 55, comprising (a) to (h), wherein (a) to (h) are reconstituted in water to a final volume of at least about 5.6 mL.

62. A pharmaceutical composition according to any one of claims 1 to 61, comprising a pH of approximately 5.2 to approximately 6.

8.

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

8.

64. A pharmaceutical composition according to any one of claims 1 to 63, comprising a pH of approximately 6.

0.

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

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

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

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

69. (a) Nivolumab at approximately 120 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; (g) rHuPH2O at approximately 2000 U / mL; and (h) Anti-CTLA-4 antibody A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 68, comprising:

70. (a) Nivolumab at approximately 150 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; (g) rHuPH2O at approximately 2000 U / mL; and (h) Anti-CTLA-4 antibody A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 68, comprising:

71. (a) Nivolumab at approximately 120 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; (g) rHuPH2O at approximately 2000 U / mL; and (h) Anti-LAG-3 antibody A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 68, comprising:

72. (a) Nivolumab at approximately 150 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; (g) rHuPH2O at approximately 2000 U / mL; and (h) Anti-LAG-3 antibody A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 68, comprising:

73. (a) Nivolumab at approximately 120 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; (g) rHuPH2O at approximately 2000 U / mL; and (h) Anti-TIM3 antibody A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 68, comprising:

74. (a) Nivolumab at approximately 150 mg / mL; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) Approximately 50 μM pentetate; (f) Approximately 5 mM methionine; (g) rHuPH2O at approximately 2000 U / mL; and (h) Anti-TIM3 antibody A pharmaceutical composition according to any one of claims 1 to 27 and 31 to 68, comprising:

75. A vial comprising the pharmaceutical composition according to any one of claims 1 to 74.

76. A syringe comprising the pharmaceutical composition according to any one of claims 1 to 74.

77. An automatic syringe comprising the pharmaceutical composition according to any one of claims 1 to 74.

78. A wearable pump comprising the pharmaceutical composition according to any one of claims 1 to 74.

79. The syringe according to claim 76, further comprising a plunger.

80. A method for treating a disease or disorder in a subject requiring the use of a pharmaceutical composition according to any one of claims 1 to 74, comprising administering a pharmaceutically effective amount of the composition to the subject.

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

82. The method according to claim 80 or 81, wherein the disease or disorder is an infectious disease.

83. The method according to claim 80 or 81, wherein the disease or disorder is cancer.

84. Cancers include squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, kidney cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, renal cell carcinoma (RCC), prostate cancer, hormone-resistant prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma pleomorphonosum, cervical cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, paranasal sinus natural killer cancer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, and vaginal cancer. The method according to claim 83, which is selected from carcinomas of the vulva, carcinomas of the esophagus, cancers of the small intestine, cancers of the endocrine system, cancers of the parathyroid gland, cancers of the adrenal gland, sarcomas of soft tissue, cancers of the urethra, cancers of the penis, cancers of the rectum, solid tumors of childhood, cancers of the ureter, carcinomas of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axial tumors, brain cancer, brainstem 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 virus origin [e.g., human papillomavirus (tumors associated with or originating from HPV)], and any combination thereof.

85. A method for treating a subject in need of such treatment, comprising subcutaneously administering an effective dose of a pharmaceutical composition containing an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction between PD-1 and PD-L1 ("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 contains at least about 250 mg to at least about 2400 mg of antibody.

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

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

88. The method according to claim 87, wherein two or more subcutaneous unit doses are administered subcutaneously, and each of the two or more subcutaneous unit doses is administered within an interval of approximately 10 minutes, 15 minutes, 20 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 9 hours, 12 hours, 18 hours, or 24 hours between the two or more subcutaneous unit doses.

89. The method according to any one of claims 1 to 88, wherein an effective dose is administered approximately every 1, 2, 3, or 4 weeks.

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

91. The method according to any one of claims 85 to 90, wherein the effective dose of the antibody is approximately 250 mg to approximately 600 mg of antibody administered on a nearly weekly basis.

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

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

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

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

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

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

98. The method according to claim 96 or 97, wherein (i) two subcutaneous unit doses are administered to two different physical sites of the subject, or (ii) at least two of three subcutaneous unit doses are administered to at least two different physical sites of the subject.

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

100. The effective dose of the copolymer is approximately 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, and 600 mg, administered approximately every two weeks. The method according to claim 99, wherein the amount is 80 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 830 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, or approximately 900 mg.

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

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

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

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

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

106. The method according to any one of claims 103 to 105, wherein at least two subcutaneous unit doses are administered to at least two different physical sites of the subject.

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

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

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

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

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

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

113. The method according to any one of claims 110 to 112, wherein at least two subcutaneous unit doses are administered to at least two different physical sites of the subject.

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

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

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

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

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

119. The method according to any one of claims 85 to 114, wherein the anti-PD-1 antibody comprises an antibody selected from the group consisting of nivolumab, pembrolizumab, PDR001, MEDI-0680, semiprimab, tripalimab, tislerizumab, INCSHHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, KN035, sasanlimab, and any combination thereof.

120. The method according to any one of claims 85 to 114, wherein the anti-PD-1 antibody cross-competes with nivolumab for binding to human PD-1.

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

122. The method according to claim 119, wherein the anti-PD-1 antibody comprises pembrolizumab.

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

124. The method according to any one of claims 85 to 123, wherein the subject is suffering from cancer.

125. Cancers include squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, kidney cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, renal cell carcinoma (RCC), prostate cancer, hormone-resistant prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma pleomorphonosum, cervical cancer, stomach cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, paranasal sinus natural killer cancer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube carcinoma, endometrial carcinoma, cervical carcinoma, and vaginal carcinoma. The method according to claim 124, selected from the group consisting of vulvar carcinoma, esophageal cancer, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, childhood solid tumors, ureteral cancer, renal pelvis carcinoma, central nervous system (CNS) neoplasms, primary CNS lymphoma, tumor angiogenesis, spinal axial tumor, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environment-induced cancer including asbestos-induced cancer, virus-associated cancer or cancer of virus origin [e.g., human papillomavirus (HPV-associated or derived tumors)], and any combination thereof.

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

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

128. The method according to any one of claims 85 to 127, wherein the pharmaceutical composition is administered to a subject by subcutaneous injection over a period of less than approximately 10 minutes.

129. The method according to any one of claims 85 to 128, wherein the pharmaceutical composition is administered to a subject by subcutaneous injection over a period of less than approximately five minutes.

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

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

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

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

134. The method according to any one of claims 130 to 133, wherein at least two antioxidants include 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 of methionine.

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

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

137. The method according to any one of claims 130 to 136, wherein at least two antioxidants include DTPA in an amount of 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.

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

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

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

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

142. The method according to any one of claims 85 to 141, wherein the pharmaceutical composition comprises an anti-PD-1 antibody in an amount of 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.

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

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

145. The method according to claim 144, wherein the tension modifier and / or stabilizer comprises sugars, amino acids, polyols, salts, or a combination thereof.

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

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

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

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

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

151. The method according to claim 150, wherein the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate.

152. The method according to claim 150 or 151, wherein the buffering agent comprises histidine.

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

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

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

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

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

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

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

160. Pharmaceutical compositions, (a) Approximately 150 mg / mL of anti-PD-1 antibody; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) about 50 μM pentetate; and (f) Approximately 5 mM methionine The method according to any one of claims 85 to 114, 119 to 122, and 124 to 159, including

161. Pharmaceutical compositions, (a) Approximately 120 mg / mL of anti-PD-1 antibody; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) about 50 μM pentetate; and (f) Approximately 5 mM methionine The method according to any one of claims 85 to 114, 119 to 122, and 124 to 159, including

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

8.

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

0.

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

165. (a) Approximately 150 mg / mL of anti-PD-1 antibody; (b) Histidine at approximately 20 mM; (c) Sucrose at approximately 250 mM; (d) Polysorbate 80 at approximately 0.05% w / v; (e) about 50 μM pentetate; and (f) Approximately 5 mM methionine Unit dose, including the unit dose.

166. An automatic syringe comprising the unit dose described in claim 165.

167. A wearable device comprising the unit dose described in claim 165.

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