Subcutaneous administration of PD1 / PD-L1 antibody

Abstract

The disclosure provides a pharmaceutical composition comprising an anti-PD-1 antibody or an anti-PD-L1 antibody formulated for subcutaneous delivery, the pharmaceutical composition further comprising an endoglycosidase hydrolase enzyme, for example, hyaluronidase.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Application Nos. 63 / 131,240, filed December 28, 2020, 63 / 150,420, filed February 17, 2021, and 63 / 184,082, filed May 4, 2021, each of which is incorporated by reference herein in its entirety.

[0002] Reference to sequence listings submitted electronically via EFS-WEB The contents of the electronically submitted sequence listing (Name: 3338_225PC03_Seqlisting_ST25.txt, Size: 1,011,316 bytes, and Creation Date: December 27, 2021) are incorporated herein by reference in their entirety.

[0003] Field of Disclosure The present disclosure provides methods for treating a subject afflicted with a tumor using checkpoint inhibitors, e.g., immunotherapy. [Background technology]

[0004] Human cancers have numerous genetic and epigenetic changes that result in neoantigens that can potentially be recognized by the immune system (Sjoblom et al., Science (2006) 314(5797):268-274). The adaptive immune system, composed of T and B lymphocytes, has potent anti-cancer capabilities and possesses a broad ability and exquisite specificity to respond to diverse tumor antigens. Furthermore, the immune system exhibits considerable plasticity and memory components. Successfully utilizing all these attributes of the adaptive immune system is believed to make immunotherapy unparalleled among all cancer treatment modalities.

[0005] Until recently, cancer immunotherapy has focused substantial efforts on approaches that enhance antitumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or the provision of nonspecific immune stimulants such as cytokines. However, over the past decade, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to lead to new immunotherapeutic approaches for treating cancer. This includes the development of antibodies, e.g., 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). Summary of the Invention [Problem to be solved by the invention]

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

[0007] Certain embodiments of the present disclosure are directed to methods of treating a subject in need thereof, comprising subcutaneously administering to the subject a dose of a pharmaceutical composition comprising: (i) an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction between PD-1 and PD-L1 (an "anti-PD-1 antibody" or "anti-PD-L1 antibody," respectively); and (ii) an endoglycosidase hydrolase enzyme, wherein the dose comprises one or more subcutaneous unit doses, and the dose comprises at least about 300 mg to at least about 2400 mg of the anti-PD-1 antibody or anti-PD-L1 antibody.

[0008] In some embodiments, the dose comprises two or more subcutaneous unit doses, and the two or more subcutaneous unit doses are administered simultaneously or sequentially. In some embodiments, the two or more subcutaneous unit doses are administered sequentially, and each of the two or more subcutaneous unit doses is administered within about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 9 hours, about 12 hours, about 18 hours, or about 24 hours between the subcutaneous unit doses. In some embodiments, the doses are administered about every 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, or 8 weeks.

[0009] In some embodiments, the antibody comprises an anti-PD-1 antibody. In some embodiments, the dose of the antibody is about 250 mg to about 600 mg administered about every week. In some embodiments, the dose of the antibody is about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg administered about every week. In some embodiments, the antibody dose is about 300 mg administered about every week. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 300 mg. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 300 mg in a total dose volume of about 2 mL.

[0010] In some embodiments, the dose of 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. In some embodiments, (i) the two subcutaneous unit doses are administered to the same body site of the subject, or (ii) at least two of the three subcutaneous unit doses are administered to the same body site of the subject.

[0011] In some embodiments, the antibody dose is about 300 mg to about 900 mg administered about every two weeks. In some embodiments, the antibody dose is about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, about 900 mg, about 910 mg, about 920 mg, about 930 mg, about 940 mg, about 950 mg, about 960 mg, about 970 mg, about 980 mg, about 990 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about The antibody dose is about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg. In some embodiments, the antibody dose is about 600 mg administered about every two weeks. In some embodiments, the antibody dose comprises a single subcutaneous unit dose.

[0012] In some embodiments, the antibody dose comprises two, three, or at least four subcutaneous unit doses. In some embodiments, the antibody dose comprises two subcutaneous unit doses, each of the two subcutaneous unit doses comprising about 300 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least two of the subcutaneous unit doses are administered to the same body site of the subject.

[0013] In some embodiments, the antibody dose is about 900 mg to about 1500 mg administered about every four weeks. In some embodiments, the antibody dose is about 900, about 950, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg, about 1510 mg, about 1520 mg, about 1530 mg, about 1540 mg, about 1550 mg, about 1560 mg, about 1570 mg The antibody dose is about 1200 mg administered about every four weeks. In some embodiments, the antibody dose comprises a single subcutaneous unit dose.

[0014] In some embodiments, the antibody dose comprises two, three, four, six, or at least eight subcutaneous unit doses. In some embodiments, the antibody dose comprises four subcutaneous unit doses, each of the four subcutaneous unit doses comprising about 300 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses comprises about 300 mg of antibody in a total volume of more than 2 mL. In some embodiments, at least two of the subcutaneous unit doses are administered to the same body site of the subject. In some embodiments, two, three, four, six, or at least eight subcutaneous unit doses are administered on the same day.

[0015] In some embodiments, the antibody comprises an anti-PD-L1 antibody. In some embodiments, the antibody dose is about 900 mg to about 1800 mg of antibody administered about every two weeks. In some embodiments, the antibody dose is about 900, about 950, about 1000, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg, about 1510 mg, about 1520 mg, about 1530 mg, about 1540 mg, about 1550 0 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, or about 1500 mg. In some embodiments, the antibody dose is about 1200 mg about every two weeks. In some embodiments, the dose comprises a single subcutaneous unit dose of about 1200 mg in a total administration volume of greater than about 5 mL.

[0016] In some embodiments, the dose comprises two, three, four, six, or at least eight subcutaneous unit doses. In some embodiments, the antibody dose comprises four subcutaneous unit doses, each of the four subcutaneous unit doses comprising about 300 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses comprises about 300 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least two of the subcutaneous unit doses are administered to the same body site of the subject. In some embodiments, two, three, four, six, or at least eight subcutaneous unit doses are administered on the same day.

[0017] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the endoglycosidase hydrolase enzyme are administered together. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the endoglycosidase hydrolase enzyme are administered simultaneously. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the endoglycosidase hydrolase enzyme are administered sequentially.

[0018] In some embodiments, the pharmaceutical composition is administered at a dose of at least about 1,000 units to at least about 30,000 units of the endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition is administered at a dose of at least about 1,000 units, at least about 1,500 units, at least about 2,000 units, at least about 2,500 units, at least about 3,000 units, at least about 3,500 units, at least about 4,000 units, at least about 4,500 units, at least about 5,000 units, at least about 6,000 units, at least about 7,000 units, at least about 8,000 units, at least about 9,000 units, at least about 10,000 units, at least about 11,000 units, at least about 12,000 units, at least about 13,000 units, at least about 14,000 units, at least about In some embodiments, the pharmaceutical composition is administered at a dose of about 15,000 units, at least about 16,000 units, at least about 17,000 units, at least about 18,000 units, at least about 19,000 units, at least about 20,000 units, at least about 21,000 units, at least about 22,000 units, at least about 23,000 units, at least about 24,000 units, at least about 25,000 units, at least about 26,000 units, at least about 27,000 units, at least about 28,000 units, at least about 29,000 units, or at least about 30,000 units of the endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition is administered at a dose of about 4000 units of the endoglycosidase hydrolase enzyme.

[0019] In some embodiments, the pharmaceutical composition is administered about once every week at a dose of (i) about 300 mg of antibody and (ii) about 4000 units of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition is administered about once every two weeks at a dose of (i) about 600 mg of antibody and (ii) about 8000 units of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition is administered about once every four weeks at a dose of (i) about 1200 mg of antibody and (ii) about 20,000 units of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition is administered about once every two weeks at a dose of (i) about 1200 mg of antibody and (ii) about 8000 units of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition is administered at a dose of (i) about 1800 mg of antibody, and (ii) about 12,000 units of the endoglycosidase hydrolase enzyme, about once every three weeks.

[0020] 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. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to amino acids 36-490 of SEQ ID NO: 1. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant and any isoform thereof, hi some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0021] In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the alpha-helical region relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase, wherein one or more N-terminal and / or C-terminal amino acids are deleted compared to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, wherein the modified rHuPH20 comprises: i. one or more amino acid substitutions within the alpha-helical region, within the linker region, or in both the alpha-helical region and the linker region, compared to wild-type rHuPH20; ii. one or more deletions of the N-terminal amino acids, one or more deletions of the C-terminal amino acids, or one or more deletions of the N-terminal amino acids and one or more C-terminal amino acids, compared to wild-type rHuPH20; or iii. both (i) and (ii).

[0022] In some embodiments, the anti-PD-1 antibody comprises an antibody selected from the group consisting of nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplimab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, and 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.

[0023] In some embodiments, 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.

[0024] In some embodiments, the subject is afflicted with cancer, including squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-refractory prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, gastric cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, and fallopian tube cancer. , endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, childhood solid tumors, ureteral cancer, renal pelvis cancer, central nervous system neoplasm (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers including those induced by asbestos, virus-associated or virus-derived cancers (e.g., human papillomavirus (HPV-associated or HPV-derived tumors)), and any combination thereof.

[0025] In some embodiments, the pharmaceutical composition is administered using an autoinjector. In some embodiments, the pharmaceutical composition is administered using a wearable pump.

[0026] In some embodiments, the pharmaceutical composition is administered to the subject by subcutaneous infusion for less than about 10 minutes, hi some embodiments, the pharmaceutical composition is administered to the subject by subcutaneous infusion for less than about 5 minutes.

[0027] 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 mM to about 20 mM methionine. In some embodiments, the at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine. In some embodiments, the at least two antioxidants comprise about 5 mM methionine.

[0028] In some embodiments, the at least two antioxidants include at least about 10 μM to about 200 μM DTPA. In some embodiments, the at least two antioxidants comprise at least about 10 μM, at least about 15 μM, at least about 20 μM, at least about 25 μM, at least about 30 μM, at least about 35 μM, at least about 40 μM, at least about 45 μM, at least about 50 μM, at least about 55 μM, at least about 60 μM, at least about 65 μM, at least about 70 μM, at least about 75 μM, at least about 80 μM, at least about 85 μM, at least about 90 μM, at least about 95 μM, at least about 100 μM, at least about 110 μM, at least about 120 μM, at least about 130 μM, at least about 140 μM, at least about 150 μM, at least about 160 μM, at least about 170 μM, at least about 180 μM, at least about 190 μM, or at least about 200 μM DTPA. In some embodiments, the at least two antioxidants include about 50 μM DTPA.

[0029] In some embodiments, the pharmaceutical composition further comprises a tonicity adjusting agent and / or stabilizer. In some embodiments, the tonicity adjusting agent and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof. In some embodiments, the tonicity adjusting agent and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, and any combination thereof. In some embodiments, the tonicity adjusting agent comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, at least about 500 mM, at least about 510 mM, at least about 520 mM, at least about 530 mM, at least about 540 mM, at least about 550 mM, at least about 560 mM, at least about 570 mM In some embodiments, the pharmaceutical composition comprises about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, or at least about 500 mM sucrose. In some embodiments, the pharmaceutical composition comprises about 250 mM sucrose.

[0030] In some embodiments, the pharmaceutical composition further comprises a buffering agent. In some embodiments, the buffering agent is selected from histidine, succinate, tromethamine, sodium phosphate, sodium acetate, and sodium citrate. In some embodiments, the buffering agent comprises histidine. In some embodiments, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM histidine. In some embodiments, the pharmaceutical composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine. In some embodiments, the pharmaceutical composition comprises about 20 mM histidine.

[0031] In some embodiments, the pharmaceutical composition further comprises a surfactant. In some embodiments, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In some embodiments, the surfactant comprises polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v of polysorbate 80. In some embodiments, the pharmaceutical composition comprises about 0.05% w / v of polysorbate 80.

[0032] In some embodiments, the pharmaceutical composition comprises: (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM L-histidine, (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.

[0033] In some embodiments, the pharmaceutical composition comprises: (a) about 120 mg / mL of an anti-PD-1 antibody; (b) about 20 mM L-histidine; (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.

[0034] In some embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an anti-PD-1 antibody; (b) about 20 mM L-histidine; (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.

[0035] In some embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an anti-PD-1 antibody; (b) about 20 mM L-histidine; (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.

[0036] In some embodiments, the pharmaceutical composition is comprised at a pH of about 5.2 to about 6.8. In some embodiments, the pharmaceutical composition is comprised at a pH of about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8. In some embodiments, the pharmaceutical composition is comprised at a pH of about 6.0.

[0037] Certain embodiments of the present disclosure are directed to pharmaceutical compositions for use in any of the methods disclosed herein, including (i) an antibody that specifically binds to PD-1 (an "anti-PD-1 antibody"), (ii) an endoglycosidase hydrolase enzyme, and (iii) at least two antioxidants.

[0038] In some embodiments, the pharmaceutical composition comprises at least about 50 U / mL to at least about 5000 U / mL of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition comprises at least about 50 U / mL, at least about 100 U / mL, at least about 150 U / mL, at least about 200 U / mL, at least about 250 U / mL, at least about 300 U / mL, at least about 350 U / mL, at least about 400 U / mL, at least about 450 U / mL, at least about 500 U / mL, at least about 750 U / mL, at least about 1000 U / mL, at least about 1500 U / mL, at least about 2000 U / mL, at least about 2500 U / mL, at least about 30 ... U / mL, at least about 3500 U / mL, at least about 4000 U / mL, at least about 4500 U / mL, at least about 5000 U / mL, at least about 5500 U / mL, at least about 6000 U / mL, at least about 6500 U / mL, at least about 7000 U / mL, at least about 7500 U / mL, at least about 8000 U / mL, at least about 8500 U / mL, at least about 9000 U / mL, at least about 9500 U / mL, or at least about 10,000 U / mL of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition comprises at least about 500 U / mL of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition comprises at least about 1000 U / mL of endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition comprises at least about 2000 U / mL of endoglycosidase hydrolase enzyme.

[0039] 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. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to amino acids 36-490 of SEQ ID NO: 1. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant and any isoform thereof, hi some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof.

[0040] In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the alpha-helical region relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase, wherein one or more N-terminal and / or C-terminal amino acids are deleted compared to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, wherein the modified rHuPH20 comprises (i) one or more amino acid substitutions within the α-helical region, within the linker region, or both the α-helical region and the linker region, compared to wild-type rHuPH20; (ii) one or more deletions of the N-terminal amino acids, one or more deletions of the C-terminal amino acids, or one or more deletions of the N-terminal amino acids and one or more C-terminal amino acids, or (iii) both (i) and (ii).

[0041] 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 mM to about 20 mM methionine. In some embodiments, the at least two antioxidants comprise at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine. In some embodiments, the at least two antioxidants comprise about 5 mM methionine.

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

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

[0044] In some embodiments, the pharmaceutical composition further comprises a tonicity adjusting agent and / or stabilizer. In some embodiments, the tonicity adjusting agent and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof. In some embodiments, the tonicity adjusting agent and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, and any combination thereof. In some embodiments, the tonicity adjusting agent comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, at least about 500 mM, at least about 510 mM, at least about 520 mM, at least about 530 mM, at least about 540 mM, at least about 550 mM, at least about 560 mM, at least about 570 mM In some embodiments, the pharmaceutical composition comprises about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, or at least about 500 mM sucrose. In some embodiments, the pharmaceutical composition comprises about 250 mM sucrose.

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

[0046] In some embodiments, the pharmaceutical composition further comprises a surfactant. In some embodiments, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In some embodiments, the surfactant comprises polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v of polysorbate 80. In some embodiments, the pharmaceutical composition comprises about 0.05% w / v of polysorbate 80.

[0047] In some embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20.

[0048] In some embodiments, the pharmaceutical composition comprises: (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20.

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

[0050] Certain aspects of the present disclosure are directed to unit doses comprising any of the pharmaceutical compositions disclosed herein.

[0051] Certain embodiments of the present disclosure are directed to a unit dose comprising: (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM L-histidine, (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.

[0052] Certain embodiments of the present disclosure are directed to a unit dose comprising: (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM L-histidine, (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.

[0053] In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent. In some embodiments, the second therapeutic agent is an antibody. In some embodiments, the second therapeutic agent is a checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is an anti-CTLA-4 antibody, an anti-LAG-3 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-TIM3 antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA antibody, an anti-CD137 antibody, an anti-KIR antibody, an anti-TGFβ antibody, an anti-IL-10 antibody, an anti-IL-8 antibody, an anti-B7-H4 antibody, an anti-Fas ligand antibody, an anti-CXCR4 antibody, an anti-mesothelin antibody, an anti-CD27 antibody, an anti-GITR antibody, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises a third therapeutic agent. In some embodiments, the second therapeutic agent, the third therapeutic agent, or both comprise IL-2 (e.g., bempegaldesleukin) or IL12-Fc (e.g., BMS-986415).

[0054] Certain aspects of the present disclosure are directed to a vial containing any of the pharmaceutical compositions disclosed herein or any of the unit doses disclosed herein.

[0055] In some aspects, the vial is an autoinjector. Certain aspects of the present disclosure are directed to an autoinjector comprising any of the pharmaceutical compositions disclosed herein or any of the unit doses disclosed herein.

[0056] In some aspects, the vial is a wearable pump. Certain aspects of the present disclosure are directed to a wearable pump comprising any of the pharmaceutical compositions disclosed herein or any of the unit doses disclosed herein. [Brief explanation of the drawings]

[0057] [Figure 1] 1 presents a graphical representation of data regarding the osmolality and viscosity of nivolumab subcutaneous (SC) injection formulations as a function of sucrose concentration in the formulation according to Example 1. The X-axis represents sucrose concentration in mM, and the Y-axis represents formulation osmolality in mOsm / kg. The filled circles and solid line represent osmolality values, and the Xs and dashed line represent viscosity values.

[0058] [Figure 2] 2 presents a graphical representation of data regarding the effect of adding 75 mM arginine on the viscosity of nivolumab subcutaneous (SC) injection formulations according to Example 1. The X-axis represents protein concentration in mg / mL, and the Y-axis represents viscosity in cP at 20° C. Filled squares represent samples with added arginine, and filled diamonds represent samples without added arginine.

[0059] [Figure 3] Figure 3 is a schematic diagram of a study aimed at evaluating the safety and efficacy of various doses of an anti-PD-1 antibody (e.g., nivolumab) administered subcutaneously alone or in combination with hyaluronidase (e.g., rHuPH20).

[0060] [Figure 4] Figure 4 is a line graph of the predictive check of the SC / IV combined PPK model for nivolumab administration. Individual dots represent observed data. Lines represent the 5th, 50th, and 95th percentiles of the observed data, respectively. Shaded areas represent the 90% CIs based on simulations for the 5th (lowest trend line), 50th (middle trend line), and 95th (highest trend line) percentiles of the predicted data. Conc = concentration, Nivo = nivolumab, Pred-Corr = predictive correction.

[0061] [Figure 5]Figures 5A-5C are box plots illustrating predicted geometric mean ratios (SC / IV) for Cavgd28 (Figure 5A), Cmind28 (Figure 5B), and Cmax1 (Figure 5C) exposure by tumor type: CRC = colorectal cancer, HCC = hepatocellular carcinoma, Mel = melanoma, NSCLC = non-small cell lung cancer, and RCC = renal cell carcinoma.

[0062] [Figure 6] FIG. 6 is a schematic diagram of a study aimed at evaluating the safety and efficacy of 1200 mg nivolumab administered subcutaneously once every 4 weeks in combination with hyaluronidase (e.g., rHuPH20) compared to 3 mg / kg nivolumab administered IV once every 2 weeks.

[0063] [Figure 7] Figure 7 is a boxplot illustrating the distribution of nivolumab Cmind28 across doses and body weight for 3 mg / kg nivolumab IV once every 2 weeks, 10 mg / kg nivolumab IV once every 2 weeks, and 1200 mg nivolumab subcutaneously once every 4 weeks.

[0064] [Figure 8] Figures 8A-8C are box plots illustrating the observed distribution of Cavg (Figure 8A), Ctau (Figure 8B), and Cmax (Figure 8C) by body weight observed after subcutaneous delivery of 720 mg, 960 mg, or 1200 mg of nivolumab with rHuPH20. Dashed lines indicate 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).

[0065] [Figure 9]Figures 9A-9B show tumor-infiltrating lymphocyte CD8 expression (Figure 9A) and PD-L1 tumor expression (Figure 9B) 14 days after the first subcutaneous dose of nivolumab and rHuPH20 (Parts A, B, and D) for 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).

[0066] [Figure 10] Figure 10 is a graphical representation of the effect of headspace nitrogen and air on % HMW species for Nivo by SEC after combined metal, peroxide, and light stress with 30°C heat stress in Study 1. RT / light is continuous light stress, while the other light stress conditions are for a 3-day period. Formulations 1 (air) and 6 (nitrogen) have 50 μM DTPA, 5 mM Met, and formulations 2 (air) and 7 (nitrogen) have 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, along with 2,000 U / mL rHuPH20.

[0067] [Figure 11] Figure 11 is a graphical representation of the effect of various stress conditions on % HMW species for Nivo by SEC after combined metal, peroxide, and light stress with 30°C heat stress in Study 1. RT / light is continuous light stress, while the other light stress conditions are for a 3-day period. 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, along with 2,000 U / mL rHuPH20.

[0068] [Figure 12] Figure 12 is a graphical representation of HMW formation under metals—0.5 ppm each of iron, chromium, and copper—+ light (1000 lux, room temperature for 3 days + 1 mM peroxide + 30°C heat stress) in Study 1. Note: Formulations 1 (air) and 6 (nitrogen) completely overlay each other and exhibit the least HMW formation for 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, pH 6.0, along with 2,000 U / mL rHuPH20.

[0069] [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 iron, chromium, and copper), light (1000 lux, 3 days at room temperature), and peroxide (1 mM peroxide) with 30°C heat stress, by formulation composition with and without 5 mM Met and 50 μM DTPA and 100 μM EDTA. All formulations also contain 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, pH 6.0, along with 2,000 U / mL rHuPH20.

[0070] [Figure 14]Figure 14 is a graphical representation of %HMW in Study 1 after 3 months under various combinations of 30°C heat stress with metals (0.5 ppm each iron, chromium, and copper), light (1000 lux, 3 days at room temperature), and peroxide (1 mM peroxide) included in the main effects statistical model. The graph is separated by formulation composition with and without 5 mM Met and 50 μM DTPA. All formulations 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.

[0071] [Figure 15] Figure 15 is a graphical representation of rHuPH20 enzyme activity in Study 1, stored at 30°C / dark after 3 days of RT / dark [control—left], 30°C / dark with metal and peroxide spikes after 3 days of RT / RL [MPL—center], and room temperature / room light [RT / light—right]. Formulations 1 (air) and 6 (nitrogen): 50 μM DTPA, 5 mM Met; Formulations 2 (air) and 7 (nitrogen): 0 μM DTPA, 0 mM Met; Formulation 3: 0 μM DTPA, 5 mM Met; Formulation 4: 50 μM DTPA, 0 mM Met. All formulations also contain 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.

[0072] [Figure 16] Figures 16A-16F are graphical representations of the distribution of formulations from Study 2. Formulations ranged from most to least excipient, with all other factors at the target composition: 120 mg / mL Nivo (Figure 16A), 20 mM His (Figure 16C), 250 mM sucrose, 50 μM DTPA (Figure 16D), 5 mM Met (Figure 16E), 2,000 U / mL rHPH20 (Figure 16F), 0.05% w / v PS80, pH 6.0 (Figure 16B).

[0073] [Figure 17]Figure 17 is a graphical representation of high molecular weight species by SEC at various time points for 0-200 μM DTPA at 25°C, 35°C, and MPL, and RT / RL stress conditions for up to 6 months for Study 2. 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.

[0074] [Figure 18] Figure 18 is a graphical representation of high molecular weight species by SEC at various time points for up to 6 months at 25°C, 35°C, and MPL, and RT / RL stress conditions, 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.

[0075] [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.

[0076] [Figure 20] FIG. 20 is a graphical representation of SEC %HMW versus methionine concentration at the last three sampled stress conditions with smooth curve trend estimates for 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.

[0077] [Figure 21]Figures 21A-21C are graphical representations of linear regression models for % total HMW as a function of Met level with fit performance for formulations 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, after 6 months at 25°C (Figure 21A), 3 months at 35°C (Figure 21B), and 3 months with MPL stress (Figure 21C).

[0078] [Figure 22] 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). Samples are duplicated for formulations with DTPA and Met, as well as formulations with DTPA only. DTPA is at 50 μM and Met is at 5 mM 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.

[0079] [Figure 23] Figures 23A-23B are graphical representations of enzyme activity as a function of time under MPL conditions (Figure 23A) and 35°C stress (Figure 23B). Samples are duplicated for formulations with DTPA and Met, as well as formulations with DTPA only. DTPA is at 50 μM and Met is at 5 mM 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.

[0080] [Figure 24]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). Samples are duplicated for formulations with DTPA and Met, as well as formulations with DTPA only. DTPA is at 50 μM and Met is at 5 mM 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.

[0081] [Figure 25-1] Figure 25A is a graphical representation illustrating a comparison across Studies 1, 2, and 3 of high molecular weight species by SEC at 3 months for MPL conditions with and without 2,000 U / mL rHuPH20 enzyme at various Met levels. Figure 25B is a regression plot across Studies 1, 2, and 3 of high molecular weight species by SEC at 3 months for MPL conditions as a function of Met. The composition includes 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 50 μM DTPA, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0 (Figures 25A-25B). [Figure 25-2] Same as above.

[0082] [Figure 26] FIG. 26 is a bar graph providing a comparison of log 10 (kd) for glycine, mannitol, sucrose, trehalose, and succinate, as indicated.

[0083] [Figure 27] FIG. 27 is a bar graph showing the average count of the number of excipient molecules interacting with the nivolumab Fab group during the last 8 ns of the MD simulation for glycine, sorbitol, trehalose, mannitol, and sucrose, as indicated.

[0084] [Figure 28]Figures 28A-28E are diagrams of the binding poses found for glycine (Figure 28A), sorbitol (Figure 28B), mannitol (Figure 28C), sucrose (Figure 28D), and trehalose (Figure 28E) on nivolumab Fab. Fab groups are displayed as ribbons, with light binding poses shown in ball-and-stick representation and strong binding poses shown in space-filling representation.

[0085] [Figure 29] 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 for medium strength interactions (FIG. 29A) and strong binding interactions (FIG. 29B). DETAILED DESCRIPTION OF THE INVENTION

[0086] Current methods of delivering anti-PD-1 antibodies and / or anti-PD-L1 antibodies require regular intravenous administration, often administered by a clinician in a clinic or hospital. This regimen often poses significant inconvenience to patients, and the nature of the treatment itself can adversely affect the patient experience. Subcutaneous delivery, for example, via the use of an autoinjector or wearable pump, could greatly improve patient compliance and, in some cases, may allow patients to receive this potentially life-saving therapy in the comfort of their own homes. The present disclosure provides methods of treating a subject in need thereof, comprising subcutaneously administering to the subject (i) a dose of a pharmaceutical composition comprising an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction between PD-1 and PD-L1 (an "anti-PD-1 antibody" or "anti-PD-L1 antibody," respectively). In some embodiments, the pharmaceutical composition further comprises (ii) an endoglycosidase hydrolase enzyme. In some embodiments, the dose comprises one or more subcutaneous unit doses.

[0087] In some embodiments, the pharmaceutical composition does not include an endoglycosidase hydrolase enzyme. In some embodiments, at least one of the subcutaneous unit doses has a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 3 mL, or less than about 2.5 mL). In certain embodiments, the dose comprises at least about 250 mg to at least about 2400 mg of antibody.

[0088] I. Terminology In order that this disclosure may be more readily understood, some specific terms are first defined. As used in this application, unless expressly defined otherwise herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0089] Whenever an embodiment is described herein using the word "comprising," it is understood that otherwise similar embodiments described using the terms "consisting of" and / or "consisting essentially of" are also provided.

[0090] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure pertains.For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press, The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press, and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press provide those skilled in the art with a general dictionary of many of the terms used in this disclosure.

[0091] Units, prefixes, and symbols are written in the format accepted by the International System of Units (SI). Numeric ranges are inclusive of the numbers defining the range. Unless otherwise indicated, nucleotide sequences are written left to right in 5' to 3' orientation. Amino acid sequences are written left to right in amino to carboxy orientation. The headings provided herein are not limiting of the various aspects of the disclosure, which may be had by reference to the specification in its entirety. Accordingly, the terms defined immediately below are more fully defined by reference to the specification in its entirety.

[0092] "Administering" refers to the physical introduction of a composition containing a therapeutic agent into a subject using any of a variety of methods and delivery systems known to those of skill in the art. Administration can refer to any form of administration for immunotherapy, e.g., an anti-PD-1 antibody or anti-PD-L1 antibody, including, for example, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other enteral routes of administration, 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 substance, e.g., a composition, including an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction between PD-1 and PD-L1, is delivered beneath the skin of a subject, between the dermis and, for example, the muscle.

[0093] Subcutaneous administration can be achieved by any method. In some embodiments, subcutaneous administration is achieved by using a short needle or multiple short needles. In some embodiments, the needle or at least one of the multiple needles is less than about 1 inch, less than about 7 / 8 inch, less than about 6 / 8 inch, less than about 5 / 8 inch, or less than about 1 / 2 inch. In some embodiments, the needle or at least one of the multiple needles is about 5 / 8 inch long.

[0094] Administration can be, for example, one time, multiple times, and / or over one or more extended periods of time. Thus, as used herein, administration can refer to a single unit dose or multiple unit doses.

[0095] As used herein, the term "dose" or "administration" is defined as the amount of a therapeutic agent that can be administered at a given time. A dose or administration amount may be sufficient to achieve or at least partially achieve a desired effect, although such a desired effect may not be visible or detectable. A "therapeutically effective amount" or "therapeutically effective dosage" of a drug or therapeutic agent is any amount of drug that, when used alone or in combination with another therapeutic agent, promotes disease regression as evidenced by a reduction in the severity of disease symptoms, an increase in the frequency and duration of disease symptom-free periods, an increase in overall survival (the length of time a patient diagnosed with a disease, such as cancer, is still alive from either the date of diagnosis or the date treatment begins), or the prevention of disability or disability due to disease suffering. The amount or dosage of a drug includes a "prophylactically effective amount" or "prophylactically effective dosage," which is any amount of drug that, when administered alone or in combination with another therapeutic agent to a subject at risk of developing or suffering from disease recurrence, inhibits the onset or recurrence of disease. The ability of a therapeutic agent to promote regression of disease or inhibit the onset or recurrence of disease can be assessed using a variety of methods available to those skilled in the art, for example, by assaying the activity of the agent in human subjects during clinical trials, in animal model systems predictive of efficacy in humans, or in in vitro assays. A "dose" can comprise a single unit dose or multiple unit doses. In some aspects, a dose comprises a single unit dose. In some aspects, a dose comprises multiple unit doses.

[0096] As used herein, a subcutaneous "unit dose" refers to a single amount of a substance delivered by subcutaneous injection, for example, from a single vial, a single autoinjector, and / or a single syringe. In some embodiments, multiple subcutaneous doses are administered to achieve a therapeutically effective dose. When multiple unit doses are administered, the individual unit doses can be administered simultaneously or sequentially. In some embodiments, each unit dose of a therapeutically effective dose is administered on the same day. Each unit dose can be administered to the same or different body sites. In some embodiments, a first unit dose is administered to a first body site, and a second unit dose is administered to a second body site. Any body site known in the art to be suitable for subcutaneous delivery can be used in the methods disclosed herein. In some embodiments, at least one subcutaneous unit dose of the dose is administered to a body site selected from the arm (e.g., the side or back of the upper arm), the abdomen, and the front of the thigh.

[0097] As used herein, an "adverse event" (AE) is any unfavorable, generally unintended, or undesirable sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, an adverse event may be associated with activation of the immune system or proliferation of immune system cells (e.g., T cells) in response to the treatment. A medical treatment may have one or more associated AEs, each of which may have the same or different levels of severity. Reference to a method that can "modify an adverse event" refers to a treatment regimen that reduces the incidence and / or severity of one or more AEs associated with the use of a different treatment regimen.

[0098] "Antibody" (Ab) is intended to include, but is not limited to, a glycoprotein immunoglobulin comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds that specifically binds to an antigen, or an antigen-binding portion thereof. Each H chain comprises a heavy chain variable region (referred to herein as V H The heavy chain constant region comprises three constant domains: C H1 , C H2 and CH3 Each light chain comprises a light chain variable region (referred to herein as V L The light chain constant region contains one constant domain, C L Includes V H Area and V L The regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs) interspersed with more conserved regions called framework regions (FRs). H and V L contains three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant region of the antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Thus, the term "anti-PD-1 antibody" includes complete antibodies having two heavy chains and two light chains that specifically bind to PD-1, as well as antigen-binding portions of complete antibodies. Non-limiting examples of antigen-binding portions are provided elsewhere herein.

[0099] Immunoglobulins can be derived from any of the commonly known isotypes, including, but not limited to, IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art and include, but are not limited to, human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to the antibody class or subclass (e.g., IgM or IgG1) encoded by the heavy chain constant region gene. The term "antibody" includes, by way of example, both naturally occurring and non-naturally occurring antibodies, monoclonal and polyclonal antibodies, chimeric and humanized antibodies, human or non-human antibodies, fully synthetic antibodies, and single-chain antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans. Unless explicitly stated and the context indicates otherwise, the term "antibody" also includes antigen-binding fragments or portions of any of the above immunoglobulins, including monovalent and bivalent fragments or portions, and single-chain antibodies.

[0100] In some embodiments, an "antibody" of the present disclosure is capable of binding to multiple antigens, e.g., a "multispecific" antibody. As used herein, a "bispecific" antibody is an antibody that can specifically bind to two antigens, where the first antigen and the second antigen are the same or different. As used herein, a "multispecific" antibody can specifically bind to multiple antigens, e.g., at least two (i.e., a "bispecific" antibody), at least three (i.e., a "trispecific" antibody), at least four, at least five, or at least six antigens. A variety of multispecific antibodies are known and can be used in the compositions and / or methods disclosed herein, including, but not limited to, bispecific antibodies that bind to PD-1 and a second target, and bispecific antibodies that bind to PD-L1 and a second target. In some embodiments, a multispecific antibody is a T cell-dependent bispecific antibody. In some embodiments, the multispecific antibody is an anti-FcRH5 / CD3 bispecific antibody that targets B-cell lineage markers, FcRH5, and CD3, e.g., for use in the treatment of multiple myeloma.

[0101] In some aspects, the "antibodies" of the present disclosure are engineered to be activated at the target site, e.g., are "probodies." In some aspects, antibodies, e.g., probodies, are proteolytically cleaved in the target tissue (e.g., tumor).

[0102] An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds 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 have cross-reactivity to other antigens, e.g., PD-1 molecules from different species. Furthermore, an isolated antibody may be substantially free of other cellular material and / or chemicals.

[0103] The term "monoclonal antibody" (mAb) refers to a non-naturally occurring preparation of antibody molecules of single molecular composition, i.e., antibody molecules which are essentially identical in their primary sequence and which display a single binding specificity and affinity for a particular epitope. A monoclonal antibody is an example of an isolated antibody. Monoclonal antibodies may be produced by hybridoma, recombinant, transgenic, or other techniques known to those skilled in the art.

[0104] A "human antibody" (HuMAb) refers to an antibody having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences. The terms "human antibody" and "fully human antibody" are used interchangeably.

[0105] A "humanized antibody" refers to an antibody in which some, most, or all of the amino acids outside the CDRs of a non-human antibody have been replaced with the corresponding amino acids from a human immunoglobulin. In one embodiment of a humanized form of an antibody, some, most, or all of the amino acids outside the CDRs have been replaced with amino acids from a human immunoglobulin, while some, most, or all of the amino acids within one or more CDRs remain unchanged. Small additions, deletions, insertions, substitutions, or modifications of amino acids are permitted as long as they do not destroy the antibody's ability to bind to a specific antigen. A "humanized antibody" retains antigen specificity similar to that of the original antibody.

[0106] A "chimeric antibody" refers to an antibody whose variable region is derived from one species and whose constant region is derived from another species, e.g., whose variable region is derived from a murine antibody and whose constant region is derived from a human antibody.

[0107] 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.

[0108] An "antigen-binding portion" (also called an "antigen-binding fragment") of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen bound by the whole antibody. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments included within the term "antigen-binding portion" of an antibody, such as the anti-PD-1 or anti-PD-L1 antibodies described herein, include (i) a Fab fragment (a fragment from papain cleavage) or a V L , V H (ii) an F(ab')2 fragment (a fragment resulting from pepsin cleavage) or an analogous bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) a V H and an Fd fragment consisting of the CH1 domain, (iv) a V of a single arm of an antibody L and V H Fv fragment consisting of domains, (v) V H (vi) isolated complementarity-determining regions (CDRs); and (vii) combinations of two or more isolated CDRs, optionally joined by a synthetic linker. Additionally, the two domains of the Fv fragment, V, are also included. L and V H are encoded by separate genes, they can be synthesized using recombinant methods L and V HThe regions may be connected by a synthetic linker that allows them to be produced as a single protein chain that pairs to form a monovalent molecule (known as a single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426, and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antigen-binding portions can be produced by recombinant DNA techniques or by enzymatic or chemical cleavage of intact immunoglobulins.

[0109] "Cancer" refers to a broad group of diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and proliferation leads to the formation of malignant tumors that can invade nearby tissues and metastasize to distant parts of the body via the lymphatic system or bloodstream.

[0110] The term "immunotherapy" refers to the treatment of a subject suffering from, or at risk of, a disease, or suffering from a recurrence of a disease by methods that involve inducing, enhancing, suppressing, or otherwise modifying the immune response. "Treatment" or "therapy" of a subject refers to any type of intervention or process performed on, or administration of an active agent to, a subject with the intent of reversing, alleviating, ameliorating, inhibiting, delaying, or preventing the onset, progression, onset, severity of symptoms, or recurrence of symptoms, complications, or conditions, or biochemical signs associated with a disease.

[0111] "Programmed death-1" (PD-1) refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is expressed primarily on activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, as well as analogs that share at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank accession number U64863.

[0112] "Programmed death-ligand-1" (PD-L1) is one of two cell surface glycoprotein ligands for PD-1 (the other is PD-L2), and downregulates T cell activation and cytokine secretion upon binding to PD-1. As used herein, the term "PD-L1" includes human PD-L1 (hPD-L1), variants, isoforms, and species homologs of hPD-L1, as well as analogs that share 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).

[0113] As used herein, "hyaluronidase" refers to an enzyme that can catalyze the cleavage of hyaluronan. Hyaluronan is a repeating polymer of N-acetyl-glucosamine and glucuronic acid that resides in the subcutaneous space and contributes to the soluble gel-like component of the skin's extracellular matrix, where it is restored by rapid turnover (resynthesis). In some embodiments, the hyaluronidase comprises rHuPH20, a glycosylated 447-amino acid single-chain polypeptide that depolymerizes hyaluronan locally in the subcutaneous space at the injection site of the skin. Depolymerization of hyaluronan by hyaluronidase is achieved by hydrolysis of the polysaccharide polymer. Depolymerization of hyaluronan results in a transient decrease in the viscosity of the gel-like phase of the extracellular matrix and an increase in hydraulic conductance, which facilitates the dispersion and absorption of co-administered therapeutic agents. Thus, hyaluronidases, such as rHuPH20, can improve the speed and ease of subcutaneous delivery of injectable biologics and drugs by acting as permeation enhancers. In certain embodiments, the hyaluronidase comprises ENHANZE™.

[0114] A "subject" includes any human or non-human animal. The term "non-human animal" includes, but is not limited to, vertebrates, such as non-human primates, sheep, dogs, and rodents, such as mice, rats, and guinea pigs. In a preferred embodiment, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0115] The use of the term "fixed dose" with respect to the methods and dosages of the present disclosure refers to a dose administered to a patient without regard to the patient's weight or body surface area (BSA). Thus, a fixed dose is not presented as a mg / kg dose, but rather as an absolute amount of an agent (e.g., an anti-PD-1 antibody). For example, a 60 kg person and a 100 kg person would receive the same dose of antibody (e.g., 240 mg of an anti-PD-1 antibody).

[0116] The term "weight-based dose" referred to herein means that the dose administered to a patient is calculated based on the patient's weight. For example, if a patient weighing 60 kg requires 3 mg / kg of anti-PD-1 antibody, the appropriate amount of anti-PD-1 antibody for administration (i.e., 180 mg) can be calculated and used.

[0117] By way of example, an "anti-cancer drug" promotes the regression of cancer in a subject. In some embodiments, a therapeutically effective amount of a drug promotes the regression of cancer to the point of eliminating the cancer. "Promoting cancer regression" means that administering a therapeutically effective amount of a drug, alone or in combination with an anti-tumor drug, results in a decrease in tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of disease symptom-free periods, or prevention of disability or incapacity due to disease affliction. Furthermore, the terms "effective" and "efficacy" with respect to treatment include both pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote the regression of cancer in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ, and / or organismal level resulting from the administration of a drug.

[0118] For example, in the treatment of tumors, a therapeutically effective amount of an anticancer drug preferably inhibits cell proliferation or tumor growth by at least about 20%, more preferably at least about 40%, even more preferably at least about 60%, and even more preferably at least about 80% relative to untreated subjects. In other preferred embodiments of the present disclosure, tumor regression can be observed and can continue for at least about 20 days, more preferably at least about 40 days, or even more preferably at least about 60 days. Despite these ultimate measures of therapeutic efficacy, the evaluation of immunotherapeutic agents must also take into account immune-related response patterns.

[0119] "Immune response" is understood in the art and generally refers to a biological response in a vertebrate to foreign substances or abnormal, e.g., cancerous, cells, which protects the organism from these substances 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 (including antibodies, cytokines, and complement) produced by any of these cells or the liver, resulting in the selective targeting, binding, damage, destruction, and / or removal from the vertebrate body of invading pathogens, pathogen-infected cells or tissues, cancerous or other abnormal cells, or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues. Immune responses include, for example, T cells, e.g., effector T cells, Th cells, CD4 + cells, CD8 + This includes the activation or inhibition of T cells, or Treg cells, or any other cells of the immune system, for example NK cells.

[0120] " Immune-related response pattern " refers to the clinical response pattern often observed in cancer patients who are treated with immunotherapeutic agents, which induce cancer-specific immune responses or modify natural immune processes to produce anti-tumor effects.This response pattern is characterized by an initial increase in tumor burden or the appearance of new lesions, which is classified as disease progression in the evaluation of traditional chemotherapy drugs, and is synonymous with drug failure, followed by a beneficial therapeutic effect.Therefore, proper evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on target diseases.

[0121] As used herein, the term "stable" with reference to a formulation or drug product means that the antibody or molecule therein essentially retains its physical and chemical stability and integrity upon storage. The stability of a formulation herein can be measured at a selected temperature and after a selected period of time. For example, aggregate formation or an increase in low molecular weight species are indicators of instability. Retention of original clarity and / or color throughout shelf life is also an indicator used to monitor stability. In some embodiments, a "stable" drug product is one in which the increase in aggregation, as measured by the increase in percentage of high molecular weight species (% HMW), is less than about 5%, preferably less than about 3%, when the formulation is stored at 2-8°C for at least about one year.

[0122] As used herein, the terms "treat," "treating," and "therapy" refer to any type of intervention or process performed on a subject, or the administration of an active agent to a subject, for the purpose of reversing, alleviating, ameliorating, inhibiting, or slowing or preventing the progression, onset, severity, or recurrence of symptoms, complications, conditions, or biochemical manifestations associated with a disease, or enhancing overall survival. Treatment can be of subjects with disease or subjects without disease (e.g., for prophylaxis).

[0123] The terms "about every week," "about every two weeks," or any other similar dosing interval term, as used herein, are intended to be approximations. "About every week" can include every 7 days ± 1 day, i.e., every 6 to 8 days. "About every two weeks" can include every 14 days ± 3 days, i.e., every 11 to 17 days. Similar approximations apply, for example, to about every 3 weeks, about every 4 weeks, about every 5 weeks, about every 6 weeks, and about every 12 weeks. In some embodiments, a dosing interval of about every 6 weeks or about every 12 weeks means that the first dose can be administered on any day in the first week, followed by the next dose on any day in the sixth or twelfth week, respectively. In other embodiments, a dosing interval of about every 6 weeks or about every 12 weeks means that the first dose is administered on a specific day (e.g., Monday) in the first week, followed by the next dose on the same day (i.e., Monday) in the sixth or twelfth week, respectively. When multiple subcutaneous unit doses are administered to reach a certain dose, the administration interval refers to the period between the administration of the first subcutaneous unit dose of the first effective dose and the administration of the first subcutaneous unit dose of the second effective dose. For example, if the method includes administering doses of about 600 mg administered approximately every two weeks, the antibody dose includes two subcutaneous unit doses, each containing about 300 mg of antibody, and the first subcutaneous unit dose of about 300 mg of the first effective dose of the antibody is administered on day 1, and the first subcutaneous unit dose of about 300 mg of the second effective dose of the antibody is administered on about day 14. In this example, the second unit dose of about 300 mg of the first effective dose of the antibody can be administered on day 1 or at any other time point before the administration of the first subcutaneous unit dose of about 300 mg of the second effective dose of the antibody.

[0124] The use of alternatives (e.g., "or") should be understood to mean either one, both, or any combination thereof of the alternatives. As used herein, the indefinite article "a" or "an" should be understood to refer to "one or more" of any named or listed components.

[0125] The terms "about" or "essentially comprising" refer to a value or composition that is within an acceptable error range of a particular value or composition as determined by one of ordinary skill in the art, which will depend in part on how the value or composition is measured or determined, i.e., the limitations of the measurement system. For example, "about" or "essentially comprising" can mean within one or more standard deviations, according to practice in the art. Alternatively, "about" or "essentially comprising" can mean a range of up to 10%. Furthermore, particularly with respect to biological systems or processes, the term can mean up to an order of magnitude or up to five times the value. When a particular value or composition is provided in this application and claims, unless otherwise specified, the meaning of "about" or "essentially comprising" should be assumed to be within an acceptable error range of that particular value or composition.

[0126] As described herein, any concentration range, percentage range, ratio range, or integer range, unless otherwise indicated, should be understood to include any integer value within the recited range, and, where appropriate, fractions thereof (such as integer tenths and hundredths).

[0127] Various aspects of the disclosure are described in further detail in the following subsections.

[0128] II. Method of Disclosure Some embodiments of the present disclosure are directed to methods of treating a subject in need thereof, comprising subcutaneously administering to the subject a dose of a pharmaceutical composition comprising: (i) an antibody that specifically binds to PD-1 or PD-L1 and inhibits the interaction between PD-1 and PD-L1 (an "anti-PD-1 antibody" or "anti-PD-L1 antibody," respectively). In some embodiments, the pharmaceutical composition comprises (ii) an endoglycosidase hydrolase enzyme. In some embodiments, the dose may be a therapeutically effective dose. In some embodiments, the dose comprises one or more subcutaneous unit doses. In some embodiments, the dose comprises at least about 300 mg to at least about 2400 mg of the anti-PD-1 antibody or anti-PD-L1 antibody.

[0129] In some embodiments, the pharmaceutical composition does not comprise an endoglycosidase hydrolase enzyme. In some embodiments, at least one of the subcutaneous unit doses has a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 3 mL, or less than about 2.5 mL). In certain embodiments, the therapeutically effective dose comprises at least about 250 mg to at least about 2400 mg of antibody. In some embodiments, the pharmaceutical composition does not comprise an enzyme that facilitates subcutaneous delivery. In certain embodiments, the pharmaceutical composition does not comprise hyaluronidase.

[0130] II.A. Administration In some embodiments, a therapeutically effective dose of an antibody comprises a single subcutaneous unit dose, e.g., the entire dose is administered as a single unit dose. In some embodiments, a therapeutically effective dose of an antibody comprises two or more subcutaneous unit doses, e.g., an effective unit dose is divided into two or more subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises at least two subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises at least three subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises at least four subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises at least five subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises at least six subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises at least seven subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises at least eight subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises at least nine subcutaneous unit doses. In some embodiments, a therapeutically effective dose of an antibody comprises 10 or more subcutaneous unit doses.

[0131] In some embodiments, each subcutaneous unit dose is administered on the same day. In some embodiments, one or more subcutaneous unit doses are administered on the first day, and one or more subcutaneous unit doses of the same therapeutically effective dose are administered on the second day. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered sequentially. In some embodiments, a first subcutaneous unit dose and a second subcutaneous unit dose of the same effective dose are administered sequentially, and the second subcutaneous unit dose is administered less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 45 minutes, less than about 60 minutes, less than about 75 minutes, less than about 90 minutes, less than about 2 hours, less than about 2.5 hours, less than about 3 hours, less than about 3.5 hours, less than about 4 hours, less than about 4.5 hours, less than about 5 hours, less than about 5.5 hours, less than about 6 hours, less than about 7 hours, less than about 8 hours, less than about 9 hours, less than about 12 hours, less than about 18 hours, or less than about 24 hours after the first subcutaneous unit dose. In some embodiments, two or more subcutaneous unit doses are subsequently administered, each of the two or more subcutaneous unit doses being administered within an interval of less than about 10 minutes, less than about 15 minutes, less than about 20 minutes, less than about 25 minutes, less than about 30 minutes, less than about 45 minutes, less than about 1 hour, less than about 2 hours, less than about 3 hours, less than about 4 hours, less than about 5 hours, less than about 6 hours, less than about 7 hours, less than about 8 hours, less than about 9 hours, less than about 10 hours, less than about 11 hours, less than about 12 hours, less than about 15 hours, less than about 18 hours, less than about 21 hours, or less than about 24 hours between the subcutaneous unit doses.

[0132] In some embodiments, one or more subcutaneous unit doses are administered to one or more body sites. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to the same body site. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site and a second body site, and the first body site is not the same as the second body site. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose is administered to a second body site, and the first body site is not the same as the second body site. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose and the fourth subcutaneous dose are administered to a second body site, and the first body site is not the same as the second body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, and the third subcutaneous unit dose is administered to a third body site, and the first body site, second body site, and third body site are different. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, and the fourth subcutaneous unit dose is administered to a fourth body site, and the first body site, second body site, third body site, and fourth body site are different.

[0133] As used herein, when at least two subcutaneous unit doses are administered to the same body part, the two subcutaneous doses can be administered to the exact same injection site or to nearby injection sites in the same body part.For example, the two subcutaneous doses that are administered to a single body part can both be administered to the right arm of subject.In this example, as long as both subcutaneous doses are administered to, for example, the right arm, both subcutaneous unit doses are administered to the same " body part " as used herein.

[0134] The therapeutically effective dose and / or subcutaneous dose can be administered subcutaneously using any method or device as disclosed herein. In some embodiments, the therapeutically effective dose and / or subcutaneous dose is administered using a syringe. In some embodiments, the therapeutically effective dose and / or subcutaneous dose is administered using an auto-injector. In some embodiments, the therapeutically effective dose and / or subcutaneous dose is administered using an injector pen. In some embodiments, the therapeutically effective dose and / or subcutaneous dose is administered using a wearable pump.

[0135] In some embodiments, the therapeutically effective dose and / or subcutaneous unit dose is administered by subcutaneous infusion over a period of less than about 30 minutes, less than about 25 minutes, less than about 20 minutes, less than about 15 minutes, less than about 14 minutes, less than about 13 minutes, less than about 12 minutes, less than about 11 minutes, less than about 10 minutes, less than about 9 minutes, less than about 8 minutes, less than about 7 minutes, less than about 6 minutes, less than about 5 minutes, less than about 4 minutes, less than about 3 minutes, or less than about 2 minutes. In some embodiments, the therapeutically effective dose and / or subcutaneous unit dose is administered by subcutaneous infusion over a period of less than about 90 seconds, less than about 75 seconds, less than about 60 seconds, less than about 45 seconds, less than about 30 seconds, less than about 15 seconds, or less than about 10 seconds. In some embodiments, the therapeutically effective dose and / or subcutaneous unit dose is administered by subcutaneous infusion over a period of less than about 15 minutes. In some embodiments, the therapeutically effective dose and / or subcutaneous unit dose is administered by subcutaneous infusion over a period of less than about 10 minutes. In some embodiments, the therapeutically effective dose and / or subcutaneous unit dose is administered by subcutaneous infusion over a period of less than about 5 minutes. In some embodiments, the therapeutically effective dose and / or subcutaneous dose is administered by subcutaneous infusion over a period of less than about 4 minutes. In some embodiments, the therapeutically effective dose and / or subcutaneous dose is administered by subcutaneous infusion over a period of less than about 3 minutes. In some embodiments, the therapeutically effective dose and / or subcutaneous unit dose is administered by subcutaneous infusion over a period of less than about 2 minutes.

[0136] II.A.1. Administration of Anti-PD-1 Antibodies In certain embodiments of the present disclosure, the antibody comprises an anti-PD-1 antibody. Any anti-PD-1 antibody can be used in the methods disclosed herein. In some embodiments, the anti-PD-1 antibody comprises nivolumab. In some embodiments, the anti-PD-1 antibody comprises pembrolizumab.

[0137] In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 250 mg to about 600 mg of antibody administered about every week. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 250 mg to about 550 mg, about 250 mg to about 500 mg, about 250 mg to about 450 mg, about 250 mg to about 400 mg, about 250 mg to about 350 mg, about 250 mg to about 300 mg, about 275 mg to about 400 mg, about 275 mg to about 375 mg, about 275 mg to about 350 mg, about 275 mg to about 325 mg, about 275 mg to about 300 mg, about 300 mg to about 600 mg, about 300 mg to about 550 mg, about 300 mg to about 400 mg, about 300 mg to about 450 mg, about 300 mg to about 400 mg, about 300 mg to about 350 mg, or about 300 mg to about 325 mg of antibody. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 250 mg to about 400 mg of antibody administered about every week. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 250 mg to about 350 mg of antibody administered about every week. In some embodiments, the dose of the antibody, e.g., an anti-PD-1 antibody (e.g., nivolumab), is about 275 mg to about 325 mg of antibody administered about every week.

[0138] In some embodiments, the dose of the antibody is about 250 mg, about 260 mg, about 270 mg, about 275 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 325 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 375 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, or The antibody dose is about 420 mg, about 425 mg, about 430 mg, about 440 mg, about 450 mg, about 460 mg, about 470 mg, about 475 mg, about 480 mg, about 490 mg, about 500 mg, about 510 mg, about 520 mg, about 525 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 575 mg, about 580 mg, about 590 mg, or about 600 mg. In certain embodiments, the antibody dose is about 250 mg administered about weekly. In certain embodiments, the antibody dose is about 275 mg administered about weekly. In certain embodiments, the antibody dose is about 300 mg administered about weekly. In certain embodiments, the antibody dose is about 325 mg administered about weekly. In certain embodiments, the dose of antibody is about 350 mg administered about every week.

[0139] In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 300 mg. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 300 mg in a total administration volume of about 2 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 300 mg in a total administration volume of more than about 2 mL. In some embodiments, the antibody dose comprises two subcutaneous unit doses, each of the two subcutaneous unit doses comprising about 150 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses comprises about 150 mg of antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, the two subcutaneous unit doses are administered to two different body sites of the subject.

[0140] In some embodiments, the dose comprises three subcutaneous unit doses, each of the three subcutaneous unit doses comprising about 100 mg of antibody. In some embodiments, at least one of the three subcutaneous unit doses comprises about 100 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the three subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose is administered to a second body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, and the third subcutaneous unit dose is administered to a third body site.

[0141] In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 300 mg to about 900 mg of antibody administered about every two weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 300 mg to about 850 mg, about 300 mg to about 800 mg, about 300 mg to about 750 mg, about 300 mg to about 700 mg, about 300 mg to about 650 mg, about 300 mg to about 600 mg, about 350 mg to about 900 mg, about 350 mg to about 850 mg, about 350 mg to about 800 mg, about 350 mg to about 750 mg, mg, about 350mg to about 700mg, about 350mg to about 650mg, about 350mg to about 600mg, about 400mg to about 900mg, about 400mg to about 850mg, about 400mg to about 800mg, about 400mg to about 750mg, about 400mg to about 700mg, about 400mg to about 650mg, about 400mg to about 600mg, about 450 to about 900mg, about 450 to about 850mg, about 450 to about 800mg, about 450mg g to about 750mg, about 450mg to about 700mg, about 450mg to about 650mg, about 450mg to about 600mg, about 500mg to about 900mg, about 500mg to about 850mg, about 500mg to about 800mg, about 500mg to about 700mg, about 500mg to about 650mg, about 500mg to about 600mg, about 550mg to about 900mg, about 550mg to about 850mg, about 550mg to about 800mg, about 550mg to about to about 750 mg, about 550 mg to about 700 mg, about 550 mg to about 650 mg, about 550 mg to about 600 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, about 600 mg to about 800 mg, about 600 mg to about 750 mg, about 600 mg to about 700 mg, about 600 mg to about 650 mg, about 575 mg to about 625 mg, about 575 mg to about 600 mg, or about 600 mg to about 625 mg of antibody. In some embodiments, the dose of antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 400 mg to about 800 mg of antibody administered about every two weeks. In some embodiments, the dose of the antibody, e.g., an anti-PD-1 antibody (e.g., nivolumab), is about 500 mg to about 700 mg of antibody administered about every two weeks.In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 550 mg to about 650 mg of antibody administered about every two weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 575 mg to about 625 mg of antibody administered about every two weeks.

[0142] In some embodiments, the dose of the antibody is about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, or about 670 mg administered about every two weeks. The antibody dose is about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg. In some embodiments, the antibody dose is about 500 mg administered about every two weeks. In some embodiments, the antibody dose is about 550 mg administered about every two weeks. In some embodiments, the antibody dose is about 575 mg administered about every two weeks. In some embodiments, the antibody dose is about 600 mg administered about every two weeks. In some embodiments, the antibody dose is about 625 mg administered about every two weeks. In some embodiments, the antibody dose is about 650 mg administered about every two weeks. In some embodiments, the antibody dose is about 700 mg administered about every two weeks.

[0143] In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg in a total dose volume of about 2 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg in a total dose volume of greater than about 2 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg in a total dose volume of greater than about 5 mL.

[0144] In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg in a total administration volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL).

[0145] In some embodiments, the antibody dose comprises two subcutaneous unit doses, each of which comprises about 300 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In certain embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of less than about 2 mL. In some embodiments, the two subcutaneous unit doses are administered to a single body site of the subject. In some embodiments, the two subcutaneous unit doses are administered to two different body sites of the subject.

[0146] In some embodiments, the approximately 600 mg dose of antibody comprises three subcutaneous unit doses. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody. In some embodiments, each of the three subcutaneous unit doses comprises approximately 200 mg of antibody. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of greater than about 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of greater than about 5 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the three subcutaneous unit doses are administered to at least two different body parts of the subject.In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body part, and the third subcutaneous unit dose is administered to a second body part.In some embodiments, the first subcutaneous unit dose is administered to a first body part, the second subcutaneous unit dose is administered to a second body part, and the third subcutaneous unit dose is administered to a third body part.

[0147] In some embodiments, the approximately 600 mg dose of antibody comprises at least four subcutaneous unit doses. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the four subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose and the fourth subcutaneous unit dose are administered to a second body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, and the fourth subcutaneous unit dose is administered to a fourth body site.

[0148] In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 900 mg to about 1500 mg of antibody administered about every 4 weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 900 mg to about 1450 mg, about 900 mg to about 1400 mg, about 900 mg to about 1350 mg, about 900 mg to about 1300 mg, about 900 mg to about 1250 mg, about 900 mg to about 1200 mg, about 950 mg to about 1500 mg, about 950 mg to about 1450 mg, about 950 mg to about 1400 mg, about 950 mg to about 1350 mg, about 950 mg to about 130 0 mg, about 950 mg to about 1250 mg, about 950 mg to about 1200 mg, about 1000 mg to about 1500 mg, about 1000 mg to about 1450 mg, about 1000 mg to about 1400 mg, about 1000 mg to about 1350 mg, about 1000 mg to about 1300 mg, about 1000 mg to about 1250 mg, about 1000 mg to about 1200 mg, about 1050 to about 1500 mg, about 1050 to about 1450 mg, about 1050 to about 1400 mg, about 1050 to about 1350 mg, about 1050 mg g to about 1300 mg, about 1050 mg to about 1250 mg, about 1050 mg to about 1200 mg, about 1100 mg to about 1500 mg, about 1100 mg to about 1450 mg, about 1100 mg to about 1400 mg, about 1100 mg to about 1350 mg, about 1100 mg to about 1300 mg, about 1100 mg to about 1250 mg, about 1100 mg to about 1200 mg, about 1150 mg to about 1500 mg, about 1150 mg to about 1450 mg, about 1150 mg to about 1400 mg, about 1150 mg to about 1350 mg, about 1150 mg to about 1300 mg, about 1150 mg to about 1250 mg, about 1150 mg to about 1200 mg, about 1200 mg to about 1500 mg, about 1200 mg to about 1450 mg, about 1200 mg to about 1400 mg, about 1200 mg to about 1350 mg, about 1200 mg to about 1300 mg, about 1200 mg to about 1250 mg, about 1175 mg to about 1225 mg, about 1175 mg to about 1200 mg, or about 1200 mg to about 1225 mg of antibody.In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 1000 mg to about 1400 mg of antibody administered about every four weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 1100 mg to about 1300 mg of antibody administered about every four weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody, is about 1150 mg to about 1250 mg of antibody administered about every four weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 1175 mg to about 1225 mg of antibody administered about every four weeks.

[0149] In some embodiments, the dose of the antibody is about 900 mg, about 950 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 1300 mg, about 1310 mg, about 1320 mg, about 1330 mg, about 1340 mg, about 1350 mg, about 1360 mg, about 1370 mg, about 1380 mg, about 1390 mg, about 1400 mg, about 1410 mg, about 1420 mg, about 1430 mg, about 1440 mg, about 1450 mg, about 1460 mg, about 1470 mg, about 1480 mg, about 1490 mg, about 1500 mg, about 1510 mg, about 1520 mg, about 1530 mg, about 1540 mg, about 1550 mg, about 1560 mg, about 1570 mg, about 1580 mg, about 1590 mg, about 1600 mg In some embodiments, the antibody dose is about 1100 mg administered about every four weeks. In some embodiments, the antibody dose is about 1150 mg administered about every four weeks. In some embodiments, the antibody dose is about 1175 mg administered about every four weeks. In some embodiments, the antibody dose is about 1200 mg administered about every four weeks. In some embodiments, the antibody dose is about 1225 mg administered about every four weeks. In some embodiments, the antibody dose is about 1250 mg administered about every four weeks. In some embodiments, the antibody dose is about 1300 mg administered about every four weeks.

[0150] In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg in a total dose volume of about 2 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg in a total dose volume of greater than about 2 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg in a total dose volume of greater than about 5 mL.

[0151] In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg in a total dosage volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL).

[0152] In some embodiments, the antibody dose comprises two, three, four, six, or at least eight subcutaneous unit doses. In some embodiments, the antibody dose comprises two subcutaneous unit doses, each of the two subcutaneous unit doses comprising about 600 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In certain embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of less than about 2 mL. In some embodiments, the two subcutaneous unit doses are administered to a single body site of the subject. In some embodiments, the two subcutaneous unit doses are administered to two different body sites of the subject.

[0153] In some embodiments, the approximately 1200 mg dose of antibody comprises three subcutaneous unit doses. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody. In some embodiments, each of the three subcutaneous unit doses comprises approximately 400 mg of antibody. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume greater than about 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume greater than about 5 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of approximately 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the three subcutaneous unit doses are administered to at least two different body parts of the subject.In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body part, and the third subcutaneous unit dose is administered to a second body part.In some embodiments, the first subcutaneous unit dose is administered to a first body part, the second subcutaneous unit dose is administered to a second body part, and the third subcutaneous unit dose is administered to a third body part.

[0154] In some embodiments, the approximately 1200 mg dose of antibody comprises four subcutaneous unit doses. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the four subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose and the fourth subcutaneous unit dose are administered to a second body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, and the fourth subcutaneous unit dose is administered to a fourth body site.

[0155] In some embodiments, the approximately 1200 mg dose of antibody comprises six subcutaneous unit doses. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the six subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first and second subcutaneous unit doses are administered to a first body site, the third and fourth subcutaneous unit doses are administered to a second body site, and the fifth and sixth subcutaneous unit doses are administered to a third body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, the fourth subcutaneous unit dose is administered to a fourth body site, the fifth subcutaneous unit dose is administered to a fifth body site, and the sixth subcutaneous unit dose is administered to a sixth body site.

[0156] In some embodiments, the approximately 1200 mg dose of antibody comprises at least eight subcutaneous unit doses. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the eight subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first and second subcutaneous unit doses are administered to a first body site, the third and fourth subcutaneous unit doses are administered to a second body site, the fifth and sixth subcutaneous unit doses are administered to a third body site, and the seventh and eighth subcutaneous unit doses are administered to a fourth body site.

[0157] In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 1800 mg to about 3000 mg of antibody administered about every 8 weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-1 antibody (e.g., nivolumab), is about 1800 mg to about 3000 mg of antibody administered about every 8 weeks. In some embodiments, the dose of the antibody is about 1900 mg, about 1950 mg, about 2000 mg, about 2010 mg, about 2020 mg, about 2030 mg, about 2040 mg, about 2050 mg, about 2060 mg, about 2070 mg, about 2080 mg, about 2090 mg, about 2100 mg, about 2110 mg, about 2120 mg, about 2130 mg, about 2140 mg, about 2150 mg, about 2160 mg, about 2170 mg, about 2180 mg, about 2190 mg, about 2200 mg, about 2210 mg, about 2220 mg, about 2230 mg, about 2240 mg, about 2250 mg, about 2260 mg, about 2270 mg, about 2280 mg, about 2290 mg, about 2300 mg, about 2310 mg, about 2320 mg, about 2330 mg, about 2340 mg, about 2350 mg, about 2360 mg, about 2370 mg, about 2380 mg, about 2390 mg, about 2400 mg, about 2410 mg, about 2420 mg, about 2430 mg, about 2440 mg, about 2450 mg, about 2460 mg, about 2470 mg, about 2480 mg, about 2490 mg, about 2500 mg, about 2510 mg, about 2520 mg, about 2530 mg, about 2540 mg, about 2550 mg, about 2560 mg, about 2570 mg, about 2580 mg, about 2590 mg, or about 2600 mg. In some embodiments, the antibody dose is about 2300 mg administered about every 4 weeks. In some embodiments, the antibody dose is about 2350 mg administered about every 4 weeks. In some embodiments, the antibody dose is about 2375 mg administered about every 4 weeks. In some embodiments, the antibody dose is about 2400 mg administered about every 4 weeks. In some embodiments, the antibody dose is about 2425 mg administered about every 4 weeks. In some embodiments, the antibody dose is about 2450 mg administered about every 4 weeks. In some embodiments, the antibody dose is about 2475 mg administered about every 4 weeks. In some embodiments, the antibody dose is about 2500 mg administered about every 4 weeks.

[0158] In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 2400 mg. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 2400 mg in a total dose volume of more than about 5 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 2400 mg in a total dose volume of about 5 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 2400 mg in a total dose volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL).

[0159] In some embodiments, the approximately 2400 mg dose of antibody comprises four subcutaneous unit doses. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the four subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose and the fourth subcutaneous unit dose are administered to a second body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, and the fourth subcutaneous unit dose is administered to a fourth body site.

[0160] In some embodiments, the approximately 2400 mg dose of antibody comprises six subcutaneous unit doses. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the six subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first and second subcutaneous unit doses are administered to a first body site, the third and fourth subcutaneous unit doses are administered to a second body site, and the fifth and sixth subcutaneous unit doses are administered to a third body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, the fourth subcutaneous unit dose is administered to a fourth body site, the fifth subcutaneous unit dose is administered to a fifth body site, and the sixth subcutaneous unit dose is administered to a sixth body site.

[0161] In some embodiments, the approximately 2400 mg dose of antibody comprises at least eight subcutaneous unit doses. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the eight subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first and second subcutaneous unit doses are administered to a first body site, the third and fourth subcutaneous unit doses are administered to a second body site, the fifth and sixth subcutaneous unit doses are administered to a third body site, and the seventh and eighth subcutaneous unit doses are administered to a fourth body site.

[0162] In some embodiments, the anti-PD-1 antibody comprises pembrolizumab, which is administered subcutaneously about once every week, about once every two weeks, about once every three weeks, or about once every four weeks. In some embodiments, about 100 mg to about 300 mg of pembrolizumab is administered subcutaneously about once every two weeks. In some embodiments, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg of pembrolizumab is administered subcutaneously about once every two weeks. In some embodiments, at least about 150 mg of pembrolizumab is administered subcutaneously once about every two weeks. In some embodiments, at least about 200 mg of pembrolizumab is administered subcutaneously once about every two weeks. In some embodiments, at least about 300 mg of pembrolizumab is administered subcutaneously once about every four weeks. In some embodiments, at least about 400 mg of pembrolizumab is administered subcutaneously once about every four weeks. In some embodiments, the dose of pembrolizumab is administered in a volume of at least about 2 mL to at least about 4 mL.

[0163] In some embodiments, the anti-PD-1 antibody comprises sasanlimab, which is administered subcutaneously about once every week, about once every two weeks, about once every three weeks, or about once every four weeks. In some embodiments, about 200 mg to about 400 mg of sasanlimab is administered subcutaneously about once every four weeks. In some embodiments, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, or about 400 mg of sasanlimab is administered subcutaneously about once every four weeks. In some embodiments, at least about 250 mg of sasanlimab is administered subcutaneously once about every 4 weeks. In some embodiments, at least about 200 mg of sasanlimab is administered subcutaneously once about every 4 weeks. In some embodiments, at least about 250 mg of sasanlimab is administered subcutaneously once about every 4 weeks. In some embodiments, at least about 300 mg of sasanlimab is administered subcutaneously once about every 4 weeks. In some embodiments, the dose of sasanlimab is administered in a single injection in a volume of at least about 2 mL. In some embodiments, the dose of sasanlimab is administered in at least three injections in a volume of at least about 6 mL.

[0164] In some embodiments, the anti-PD-1 antibody comprises KN035, which is administered subcutaneously about once every week, about once every two weeks, about once every three weeks, or about once every four weeks. In some embodiments, about 100 mg to about 200 mg of KN035 is administered subcutaneously about once every week. In some embodiments, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of KN035 is administered subcutaneously about once every week. In some embodiments, at least about 150 mg of KN035 is administered subcutaneously about once every week. In some embodiments, about 2.5 mg / kg of KN035 is administered subcutaneously about once every week. In some embodiments, about 200 mg to about 400 mg of KN035 is administered subcutaneously once about every three weeks. In some embodiments, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, or about 400 mg of KN035 is administered subcutaneously once about every three weeks. In some embodiments, at least about 300 mg of KN035 is administered subcutaneously once about every three weeks. In some embodiments, at least about 300 mg of KN035 is administered subcutaneously once about every four weeks. In some embodiments, at least about 400 mg of KN035 is administered subcutaneously about once every four weeks. In some embodiments, the dose of KN035 is administered in a volume of less than about 1 mL.

[0165] II.A.2. Anti-PD-L1 Antibody Administration In some embodiments of the present disclosure, the antibody comprises an anti-PD-L1 antibody. Any anti-PD-L1 antibody known in the art and / or disclosed herein can be used in the methods disclosed herein. In certain embodiments, the anti-PD-L1 antibody comprises atezolizumab. In certain embodiments, the anti-PD-L1 antibody comprises durvalumab. In certain embodiments, the anti-PD-L1 antibody comprises avelumab.

[0166] In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 300 mg to about 900 mg of antibody administered about every week. In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 300 mg to about 850 mg, about 300 mg to about 800 mg, about 300 mg to about 750 mg, about 300 mg to about 700 mg, about 300 mg to about 650 mg, about 300 mg to about 600 mg, about 350 mg to about 900 mg, about 350 mg to about 850 mg, about 350 mg to about 800 mg, about 350 mg to about 750 mg, about 350 mg to about 65 ...900 mg, about 350 mg to about 850 mg, about 350 mg to about 800 mg, about 350 mg to about 750 mg, about 350 mg to about 900 mg, about 350 mg to about 900 mg, about 350 mg to about 900 mg, about 350 mg to about 900 mg, about 350 mg to about 900 mg, about 350 mg to about 900 mg, about 350 mg to about 900 mg, about 350 mg to about mg to about 700mg, about 350mg to about 650mg, about 350mg to about 600mg, about 400mg to about 900mg, about 400mg to about 850mg, about 400mg to about 800mg, about 400mg to about 750mg, about 400mg to about 700mg, about 400mg to about 650mg, about 400mg to about 600mg, about 450 to about 900mg, about 450 to about 850mg, about 450 to about 800mg, about 450mg to about 7 50mg, about 450mg to about 700mg, about 450mg to about 650mg, about 450mg to about 600mg, about 500mg to about 900mg, about 500mg to about 850mg, about 500mg to about 800mg, about 500mg to about 700mg, about 500mg to about 650mg, about 500mg to about 600mg, about 550mg to about 900mg, about 550mg to about 850mg, about 550mg to about 800mg, about 550mg to about 750 mg, about 550 mg to about 700 mg, about 550 mg to about 650 mg, about 550 mg to about 600 mg, about 600 mg to about 900 mg, about 600 mg to about 850 mg, about 600 mg to about 800 mg, about 600 mg to about 750 mg, about 600 mg to about 700 mg, about 600 mg to about 650 mg, about 575 mg to about 625 mg, about 575 mg to about 600 mg, or about 600 mg to about 625 mg of antibody. In some embodiments, the dose of the antibody, e.g., the anti-PD-L1 antibody, is about 400 mg to about 800 mg of antibody administered about once a week. In some embodiments, the dose of the antibody, e.g., the anti-PD-L1 antibody, is about 500 mg to about 700 mg of antibody administered about once a week.In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 550 mg to about 650 mg of antibody administered about every week. In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 575 mg to about 625 mg of antibody administered about every week.

[0167] In some embodiments, the dose of the antibody is about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 510 mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560 mg, about 570 mg, about 580 mg, about 590 mg, about 600 mg, about 610 mg, about 620 mg, about 630 mg, about 640 mg, about 650 mg, about 660 mg, or about 670 mg administered about every week. The antibody dose is about 670 mg, about 680 mg, about 690 mg, about 700 mg, about 710 mg, about 720 mg, about 730 mg, about 740 mg, about 750 mg, about 760 mg, about 770 mg, about 780 mg, about 790 mg, about 800 mg, about 810 mg, about 820 mg, about 830 mg, about 840 mg, about 850 mg, about 860 mg, about 870 mg, about 880 mg, about 890 mg, or about 900 mg. In some embodiments, the antibody dose is about 500 mg administered about weekly. In some embodiments, the antibody dose is about 550 mg administered about weekly. In some embodiments, the antibody dose is about 575 mg administered about weekly. In some embodiments, the antibody dose is about 600 mg administered about weekly. In some embodiments, the antibody dose is about 625 mg administered about every week. In some embodiments, the antibody dose is about 650 mg administered about every week. In some embodiments, the antibody dose is about 700 mg administered about every week.

[0168] In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg in a total dose volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg in a total dose volume of about 2 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg in a total dose volume of about 5 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 600 mg in a total dose volume of more than about 5 mL.

[0169] In some embodiments, the antibody dose comprises two subcutaneous unit doses, each of which comprises about 300 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In certain embodiments, at least one of the two subcutaneous unit doses comprises about 300 mg of antibody in a total volume of less than about 2 mL. In some embodiments, the two subcutaneous unit doses are administered to a single body site of the subject. In some embodiments, the two subcutaneous unit doses are administered to two different body sites of the subject.

[0170] In some embodiments, the approximately 600 mg dose of antibody comprises three subcutaneous unit doses. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody. In some embodiments, each of the three subcutaneous unit doses comprises approximately 200 mg of antibody. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume greater than about 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume greater than about 5 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of approximately 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the three subcutaneous unit doses are administered to at least two different body parts of the subject.In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body part, and the third subcutaneous unit dose is administered to a second body part.In some embodiments, the first subcutaneous unit dose is administered to a first body part, the second subcutaneous unit dose is administered to a second body part, and the third subcutaneous unit dose is administered to a third body part.

[0171] In some embodiments, the approximately 600 mg dose of antibody comprises at least four subcutaneous unit doses. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the four subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose and the fourth subcutaneous unit dose are administered to a second body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, and the fourth subcutaneous unit dose is administered to a fourth body site.

[0172] In some embodiments, the dose of the antibody, e.g., the anti-PD-L1 antibody, is about 900 mg to about 1800 mg of antibody administered about every two weeks.In some embodiments, the dose of the antibody, e.g., an anti-PD-L1 antibody, is about 900 mg to about 1750 mg, about 900 mg to about 1700 mg, about 900 mg to about 1650 mg, about 900 mg to about 1600 mg, about 900 mg to about 1550 mg, about 900 mg to about 1500 mg, about 900 mg to about 1450 mg, about 900 mg to about 1400 mg, about 900 mg to about 1350 mg, about 900 mg to about 1300 mg, about 900 mg to about 1250 mg, about 900 mg to about 1200 mg, about 950 mg to about 150 0 mg, about 950 mg to about 1450 mg, about 950 mg to about 1400 mg, about 950 mg to about 1350 mg, about 950 mg to about 1300 mg, about 950 mg to about 1250 mg, about 950 mg to about 1200 mg, about 1000 mg to about 1500 mg, about 1000 mg to about 1450 mg, about 1000 mg to about 1400 mg, about 1000 mg to about 1350 mg, about 1000 mg to about 1300 mg, about 1000 mg to about 1250 mg, about 1000 mg to about 1200 mg, about 1050 to about 1500 mg, about 1050 to about 14 50 mg, about 1050 to about 1400 mg, about 1050 mg to about 1350 mg, about 1050 mg to about 1300 mg, about 1050 mg to about 1250 mg, about 1050 mg to about 1200 mg, about 1100 mg to about 1500 mg, about 1100 mg to about 1450 mg, about 1100 mg to about 1400 mg, about 1100 mg to about 1350 mg, about 1100 mg to about 1300 mg, about 1100 mg to about 1250 mg, about 1100 mg to about 1200 mg, about 1150 mg to about 1500 mg, about 1150 mg to about 1450 mg, about 11 The antibody is 50 mg to about 1400 mg, about 1150 mg to about 1350 mg, about 1150 mg to about 1300 mg, about 1150 mg to about 1250 mg, about 1150 mg to about 1200 mg, about 1200 mg to about 1500 mg, about 1200 mg to about 1450 mg, about 1200 mg to about 1400 mg, about 1200 mg to about 1350 mg, about 1200 mg to about 1300 mg, about 1200 mg to about 1250 mg, about 1175 mg to about 1225 mg, about 1175 mg to about 1200 mg, or about 1200 mg to about 1225 mg.In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 1000 mg to about 1400 mg of antibody administered about every two weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 1100 mg to about 1300 mg of antibody administered about every two weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 1150 mg to about 1250 mg of antibody administered about every two weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 1175 mg to about 1225 mg of antibody administered about every two weeks.

[0173] In some embodiments, the dose of the antibody is about 900 mg, about 950 mg, about 1000 mg, about 1010 mg, about 1020 mg, about 1030 mg, about 1040 mg, about 1050 mg, about 1060 mg, about 1070 mg, about 1080 mg, about 1090 mg, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, about 2000 mg, about 2010 mg, about 2020 mg, about 2030 mg, about 2040 mg, about 2050 mg, about 2060 mg, about 2070 mg, about 2080 mg, about 2090 mg, about 3000 mg, about 3100 mg, about 3110 mg, about 3120 mg, about 3130 mg, about 3140 mg, about 3150 mg, about 3160 mg, about 3170 mg, about 3180 mg, about 3190 mg, about 4000 mg, about 4100 mg, about 4110 mg, about 4120 mg, about 4130 mg, about 4140 mg, about 4150 mg, about 4160 mg, about 4170 mg, about 4180 mg In some embodiments, the antibody dose is about 1100 mg administered about every two weeks. In some embodiments, the antibody dose is about 1150 mg administered about every two weeks. In some embodiments, the antibody dose is about 1175 mg administered about every two weeks. In some embodiments, the antibody dose is about 1200 mg administered about every two weeks. In some embodiments, the antibody dose is about 1225 mg administered about every two weeks. In some embodiments, the antibody dose is about 1250 mg administered about every two weeks. In some embodiments, the antibody dose is about 1300 mg administered about every two weeks.

[0174] In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg in a total dose volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg in a total dose volume of about 2 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg in a total dose volume of about 5 mL. In some embodiments, the antibody dose comprises a single subcutaneous unit dose of about 1200 mg in a total dose volume of more than about 5 mL.

[0175] In some embodiments, the antibody dose comprises two, three, four, six, or at least eight subcutaneous unit doses. In some embodiments, the antibody dose comprises two subcutaneous unit doses, each of the two subcutaneous unit doses comprising about 600 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In certain embodiments, at least one of the two subcutaneous unit doses comprises about 600 mg of antibody in a total volume of less than about 2 mL. In some embodiments, the two subcutaneous unit doses are administered to a single body site of the subject. In some embodiments, the two subcutaneous unit doses are administered to two different body sites of the subject.

[0176] In some embodiments, the approximately 1200 mg dose of antibody comprises three subcutaneous unit doses. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody. In some embodiments, each of the three subcutaneous unit doses comprises approximately 400 mg of antibody. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume greater than about 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume greater than about 5 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of approximately 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the three subcutaneous unit doses are administered to at least two different body parts of the subject.In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body part, and the third subcutaneous unit dose is administered to a second body part.In some embodiments, the first subcutaneous unit dose is administered to a first body part, the second subcutaneous unit dose is administered to a second body part, and the third subcutaneous unit dose is administered to a third body part.

[0177] In some embodiments, the approximately 1200 mg dose of antibody comprises four subcutaneous unit doses. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the four subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose and the fourth subcutaneous unit dose are administered to a second body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, and the fourth subcutaneous unit dose is administered to a fourth body site.

[0178] In some embodiments, the approximately 1200 mg dose of antibody comprises six subcutaneous unit doses. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 200 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the six subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first and second subcutaneous unit doses are administered to a first body site, the third and fourth subcutaneous unit doses are administered to a second body site, and the fifth and sixth subcutaneous unit doses are administered to a third body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, the fourth subcutaneous unit dose is administered to a fourth body site, the fifth subcutaneous unit dose is administered to a fifth body site, and the sixth subcutaneous unit dose is administered to a sixth body site.

[0179] In some embodiments, the approximately 1200 mg dose of antibody comprises at least eight subcutaneous unit doses. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 150 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the eight subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first and second subcutaneous unit doses are administered to a first body site, the third and fourth subcutaneous unit doses are administered to a second body site, the fifth and sixth subcutaneous unit doses are administered to a third body site, and the seventh and eighth subcutaneous unit doses are administered to a fourth body site.

[0180] In some embodiments, two, three, four, six, or at least eight subcutaneous unit doses are administered on the same day.

[0181] In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 2100 mg to about 2700 mg of antibody administered about every 4 weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 2100 mg to about 2650 mg, about 2100 mg to about 2600 mg, about 2100 mg to about 2550 mg, about 2100 mg to about 2500 mg, about 2100 mg to about 2450 mg, about 2100 mg to about 2400 mg, about 2200 mg to about 2700 mg, about 2 ...50 mg, about 2100 mg to about 2550 mg, about 2100 mg to about 2500 mg, about 2100 mg to about 2450 mg, about 2100 mg to about 2400 mg, about 2200 mg to about 2700 mg, about 2200 mg to about 2650 mg, about 2100 mg to about 2450 mg, about 2100 mg to about 2400 mg, about 2200 mg to about 2700 mg, about 2200 mg to about 2650 mg, about 2100 mg to about 2650 mg, about 2100 mg About 2650mg, about 2200mg to about 2600mg, about 2200mg to about 2550mg, about 2200mg to about 2500mg, about 2200mg to about 2450mg, about 2200mg to about 2400mg, about 2300mg to about 2700mg, about 2300mg to about 2650mg, about 2300mg to about 2600mg, about 2300mg to about 2550mg, about 2300mg to about 2500 mg, about 2300 mg to about 2450 mg, about 2300 mg to about 2400 mg, about 2350 mg to about 2700 mg, about 2350 mg to about 2650 mg, about 2350 mg to about 2600 mg, about 2350 mg to about 2550 mg, about 2350 mg to about 2500 mg, about 2350 mg to about 2450 mg, about 2350 mg to about 2400 mg, about 2400 mg to about 2700 mg, about 2400 mg to about 2650 mg, about 2400 mg to about 2600 mg, about 2400 mg to about 2550 mg, about 2400 mg to about 2500 mg, about 2400 mg to about 2450 mg, about 2400 mg to about 2425 mg, about 2375 mg to about 2425 mg, or about 2375 mg to about 2400 mg of antibody. In some embodiments, the dose of the antibody, e.g., the anti-PD-L1 antibody, is about 2200 mg to about 2600 mg of antibody administered about every four weeks. In some embodiments, the dose of the antibody, e.g., the anti-PD-L1 antibody, is about 2300 mg to about 2500 mg of antibody administered about every four weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 2350 mg to about 2450 mg of antibody administered about every four weeks. In some embodiments, the dose of the antibody, e.g., anti-PD-L1 antibody, is about 2375 mg to about 2425 mg of antibody administered about every four weeks.

[0182] In some embodiments, the antibody dose is about 2100 mg, about 2150 mg, about 2200 mg, about 2250 mg, about 2300 mg, about 2350 mg, about 2400 mg, about 2450 mg, about 2500 mg, about 2550 mg, about 2600 mg, about 2650 mg, or about 2700 mg administered about every four weeks. In some embodiments, the antibody dose is about 2300 mg administered about every four weeks. In some embodiments, the antibody dose is about 2350 mg administered about every four weeks. In some embodiments, the antibody dose is about 2400 mg administered about every four weeks. In some embodiments, the antibody dose is about 2450 mg administered about every four weeks. In some embodiments, the antibody dose is about 2500 mg administered about every four weeks.

[0183] In some embodiments, the antibody dose comprises a single subcutaneous dose comprising about 2400 mg of antibody. In some embodiments, the single subcutaneous dose comprises about 2400 mg of antibody in a total volume of greater than about 2 mL. In some embodiments, the single subcutaneous unit dose comprises about 2400 mg of antibody in a total volume of greater than about 5 mL.

[0184] In some embodiments, the antibody dose comprises two, three, four, six, or at least eight subcutaneous unit doses. In some embodiments, the antibody dose comprises two subcutaneous unit doses, each of the two subcutaneous unit doses comprising about 1200 mg of antibody. In some embodiments, at least one of the two subcutaneous unit doses comprises about 1200 mg of antibody in a total volume of about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 1200 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 1200 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the two subcutaneous unit doses comprises about 1200 mg of antibody in a total volume of less than about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In certain embodiments, at least one of the two subcutaneous unit doses comprises about 1200 mg of antibody in a total volume of less than about 2 mL. In some embodiments, the two subcutaneous unit doses are administered to a single body site of the subject. In some embodiments, the two subcutaneous unit doses are administered to two different body sites of the subject.

[0185] In some embodiments, the approximately 2400 mg dose of antibody comprises three subcutaneous unit doses. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 800 mg of antibody. In some embodiments, each of the three subcutaneous unit doses comprises approximately 800 mg of antibody. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 800 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 800 mg of antibody in a total volume of greater than about 2 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 800 mg of antibody in a total volume of greater than about 5 mL. In some embodiments, at least one of the three subcutaneous unit doses comprises approximately 800 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the three subcutaneous unit doses are administered to at least two different body parts of the subject.In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body part, and the third subcutaneous unit dose is administered to a second body part.In some embodiments, the first subcutaneous unit dose is administered to a first body part, the second subcutaneous unit dose is administered to a second body part, and the third subcutaneous unit dose is administered to a third body part.

[0186] In some embodiments, the approximately 2400 mg dose of antibody comprises four subcutaneous unit doses. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the four subcutaneous unit doses comprises approximately 600 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the four subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first subcutaneous unit dose and the second subcutaneous unit dose are administered to a first body site, and the third subcutaneous unit dose and the fourth subcutaneous unit dose are administered to a second body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, and the fourth subcutaneous unit dose is administered to a fourth body site.

[0187] In some embodiments, the approximately 2400 mg dose of antibody comprises six subcutaneous unit doses. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the six subcutaneous unit doses comprises approximately 400 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the six subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first and second subcutaneous unit doses are administered to a first body site, the third and fourth subcutaneous unit doses are administered to a second body site, and the fifth and sixth subcutaneous unit doses are administered to a third body site. In some embodiments, the first subcutaneous unit dose is administered to a first body site, the second subcutaneous unit dose is administered to a second body site, the third subcutaneous unit dose is administered to a third body site, the fourth subcutaneous unit dose is administered to a fourth body site, the fifth subcutaneous unit dose is administered to a fifth body site, and the sixth subcutaneous unit dose is administered to a sixth body site.

[0188] In some embodiments, the approximately 2400 mg dose of antibody comprises at least eight subcutaneous unit doses. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of approximately 2 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of more than about 2 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of more than about 5 mL. In some embodiments, at least one of the eight subcutaneous unit doses comprises approximately 300 mg of antibody in a total volume of about 5 mL (e.g., less than about 4.5 mL, less than about 4.0 mL, less than about 3.5 mL, less than about 3.0 mL, less than about 2.5 mL, or less than about 2.0 mL). In some embodiments, at least two of the eight subcutaneous unit doses are administered to at least two different body sites of the subject. In some embodiments, the first and second subcutaneous unit doses are administered to a first body site, the third and fourth subcutaneous unit doses are administered to a second body site, the fifth and sixth subcutaneous unit doses are administered to a third body site, and the seventh and eighth subcutaneous unit doses are administered to a fourth body site.

[0189] In some embodiments, two, three, four, six, or at least eight subcutaneous unit doses are administered on the same day.

[0190] In some embodiments, the anti-PD-L1 antibody comprises atezolizumab, which is administered subcutaneously about once every week, about once every two weeks, about once every three weeks, or about once every four weeks. In some embodiments, about 1000 mg to about 1400 mg of atezolizumab is administered subcutaneously about once every two weeks. In some embodiments, about 1100 mg, about 1110 mg, about 1120 mg, about 1130 mg, about 1140 mg, about 1150 mg, about 1160 mg, about 1170 mg, about 1180 mg, about 1190 mg, about 1200 mg, about 1210 mg, about 1220 mg, about 1230 mg, about 1240 mg, about 1250 mg, about 1260 mg, about 1270 mg, about 1280 mg, about 1290 mg, or about 1300 mg of atezolizumab is administered subcutaneously once about every two weeks. In some embodiments, at least about 1200 mg of atezolizumab is administered subcutaneously once about every two weeks. In some embodiments, about 1700 mg to about 1900 mg of atezolizumab is administered subcutaneously once about every three weeks. In some embodiments, about 1700 mg, about 1710 mg, about 1720 mg, about 1730 mg, about 1740 mg, about 1750 mg, about 1760 mg, about 1770 mg, about 1780 mg, about 1790 mg, about 1800 mg, about 1810 mg, about 1820 mg, about 1830 mg, about 1840 mg, about 1850 mg, about 1860 mg, about 1870 mg, about 1880 mg, about 1890 mg, or about 1900 mg of atezolizumab is administered subcutaneously once about every three weeks. In some embodiments, at least about 1800 mg of atezolizumab is administered subcutaneously once about every three weeks. In some embodiments, the dose of atezolizumab is administered in a volume of at least about 2 mL to at least about 20 mL.

[0191] II.A.3. Administration of Endoglycosidase Hydrolase Enzymes In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase enzyme. Any endoglycosidase hydrolase enzyme can be used in the pharmaceutical compositions disclosed herein. In some embodiments, the endoglycosidase hydrolase enzyme cleaves hyaluronic acid at a hexosaminide β(1-4) or β(1-3) bond. In some embodiments, the endoglycosidase hydrolase enzyme comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1.

[0192] In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase. In some embodiments, the endoglycosidase hydrolase enzyme comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant and any isoform thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises rHuPH20 or a fragment thereof. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to amino acids 36-490 of SEQ ID NO:1. In some embodiments, the endoglycosidase hydrolase enzyme comprises the catalytic domain of rHuPH20 (UniProt ID No. P38567-1). In some embodiments, the endoglycosidase hydrolase enzyme comprises the rHuPH20 mature peptide (amino acids 36-490 of SEQ ID NO: 1A). [Table 1-1]

[0193] In some embodiments, subcutaneous injection is based on Halozyme Therapeutics' ENHANZE® drug delivery technology (see U.S. Patent No. 7,767,429, incorporated herein by reference in its entirety). ENHANZE® uses a co-formulation of an antibody with a recombinant human hyaluronidase enzyme (rHuPH20), eliminating traditional limitations on the volume of biologics and drugs that can be delivered subcutaneously due to the extracellular matrix (see U.S. Patent No. 7,767,429). In some embodiments, the pharmaceutical compositions of the present disclosure can further comprise a recombinant human hyaluronidase enzyme, e.g., rHuPH20.

[0194] Recombinant human hyaluronidase PH20 (rHuPH20, Halozyme Therapeutics Inc.) is a glycosylated 447-amino acid single-chain recombinant human polypeptide that depolymerizes hyaluronan locally in the subcutaneous (SC) space at the injection site. Hyaluronan is a repeating polymer of N-acetyl-glucosamine and glucuronic acid, which contributes to the soluble gel-like component of the skin's extracellular matrix. Depolymerization of hyaluronan by rHuPH20 results in a transient decrease in the viscosity of the gel-like phase of the extracellular matrix and an increase in hydraulic conductance, which facilitates the dispersion and absorption of injected drugs (see rHuPH20 IB). The use of rHuPH20 allows for the delivery of large volumes (e.g., approximately 2 mL to 20 mL) for rapid SC injection, which may shorten administration time, reduce dosing frequency, and potentially improve the PK profile of co-administered drugs, including improved absorption, increased bioavailability, shorter time to maximum concentration (Tmax), increased maximum concentration (Cmax), and reduced PK variability.

[0195] The half-life of rHuPH20 in the skin is less than 30 minutes, and the local permeability barrier in these tissues returns to pre-injection levels within 24 to 48 hours after injection of hyaluronidase. One study demonstrated that rHuPH20 was not detected systemically after subcutaneous administration of doses of 10,000 U and 30,000 U to healthy volunteers and patients. Another study of the PK of rHuPH20 (Halozyme Study HALO-104-104) demonstrated that plasma concentrations of rHuPH20 declined rapidly, with a very short t (≤10.4 minutes) and undetectable plasma concentrations (<0.03 ng / mL) within 1.5 hours after the end of IV infusion of 10,000 or 30,000 units of rHuPH20.

[0196] Subcutaneous injections of rHuPH20 are generally well tolerated in healthy participants, dehydrated pediatric participants, hospice and palliative care participants, participants with type 1 and type 2 diabetes, and participants with rheumatoid arthritis. Subcutaneous injections of rHuPH20 are well tolerated when administered alone or with lactated Ringer's, saline, co-infusion medications (morphine, ceftriaxone, insulin and insulin analogs), or biologics (immunoglobulin G [IgG] and adalimumab).

[0197] In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the alpha-helical region relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises an engineered hyaluronidase that comprises one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, and HYALPS1. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified hyaluronidase, wherein one or more N-terminal and / or C-terminal amino acids are deleted compared to a wild-type hyaluronidase, or a fragment thereof, selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1.

[0198] In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20 that comprises one or more amino acid substitutions in the α-helical region, in the linker region, or in both the α-helical region and the linker region relative to wild-type rHuPH20. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20 that comprises a deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids relative to wild-type rHuPH20. In some embodiments, the endoglycosidase hydrolase enzyme comprises a modified rHuPH20, wherein the modified rHuPH20 comprises one or more amino acid substitutions in the alpha-helical region, in the linker region, or in both the alpha-helical region and the linker region relative to wild-type rHuPH20, wherein the modified rHuPH20 comprises a deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids relative to wild-type rHuPH20.

[0199] Further non-limiting examples of endoglycosidase hydrolase enzymes are found in EP 3636752, which is incorporated herein by reference in its entirety.

[0200] In some embodiments, the endoglycosidase hydrolase enzyme is any polypeptide having endoglycosidase hydrolase enzyme activity disclosed in U.S. Patent Nos. 9,447,401; 10,865,400; 11,041,149; 11,066,656; 8,927,249; 9,284,543; 10,588,983; 10 / 328,130; and / or 9,993,529, each of which is incorporated by reference herein in its entirety. In some embodiments, the endoglycosidase hydrolase enzyme is any polypeptide having endoglycosidase hydrolase enzyme activity disclosed in International Publication Nos. WO / 13 / 102144, WO / 10 / 077297, WO / 15 / 003167, WO / 04 / 078140, WO / 09 / 128917, WO / 12 / 174478, and / or WO / 12 / 174480, each of which is incorporated by reference herein in its entirety. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 5-52. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 5-52.

[0201] In some embodiments, the endoglycosidase hydrolase enzyme is any polypeptide having endoglycosidase hydrolase enzyme activity disclosed in U.S. Patent Application Publication Nos. 2021155913A1 and / or 2021363270A1, and / or International Publication Nos. WO / 20 / 022791, WO / 20 / 197230, and / or WO / 21 / 150079, each of which is incorporated by reference in its entirety. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs:53-263. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the endoglycosidase hydrolase enzyme comprises an amino acid sequence selected from the amino acid sequences set forth in SEQ ID NOs: 53-263. In some embodiments, the endoglycosidase hydrolase enzyme comprises the amino acid sequence set forth in SEQ ID NO: 92. In some embodiments, the endoglycosidase hydrolase enzyme is HP46 (SEQ ID NO: 44 of International Publication WO / 20 / 197230).

[0202] In certain embodiments, the pharmaceutical compositions disclosed herein comprise hyaluronidase. In some embodiments, the pharmaceutical compositions comprise hyaluronidase at a concentration sufficient for administration of at least about 20,000 units of hyaluronidase. In some embodiments, the hyaluronidase is rHuPH20. In other embodiments, the pharmaceutical compositions do not comprise hyaluronidase.

[0203] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the endoglycosidase hydrolase enzyme (e.g., rHuPH20) are administered together. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the endoglycosidase hydrolase enzyme (e.g., rHuPH20) are administered simultaneously. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the endoglycosidase hydrolase enzyme (e.g., rHuPH20) are administered sequentially.

[0204] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the endoglycosidase hydrolase enzyme (e.g., rHuPH20) are present in a single pharmaceutical composition.

[0205] In some embodiments, the dose comprises at least about 5000 units to at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 5,000 Units, at least about 10,000 Units, at least about 15,000 Units, at least about 20,000 Units, at least about 25,000 Units, at least about 30,000 Units, at least about 35,000 Units, at least about 40,000 Units, at least about 45,000 Units, at least about 50,000 Units, at least about 55,000 Units, at least about 60,000 Units, at least about 65,000 Units, at least about 70,000 Units, at least about 75,000 Units, at least about 80,000 Units, at least about 85,000 Units, at least about 90,000 Units, at least about 95,000 Units, or at least about 100,000 Units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 20,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 30,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 40,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 50,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 60,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 70,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 80,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 90,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the dose comprises at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20).

[0206] It will be readily apparent to one of skill in the art that the amount of endoglycosidase hydrolase enzyme (e.g., rHuPH20) can be expressed in units or can be expressed in mg (or other weight-based units). For example, in some embodiments, a dose comprises an amount of endoglycosidase hydrolase enzyme (e.g., rHuPH20) expressed as at least about 500 U or at least about 0.00455 mg. In another example, in some embodiments, a dose comprises an amount of endoglycosidase hydrolase enzyme (e.g., rHuPH20) expressed as at least about 2000 U or at least about 0.0182 mg.

[0207] II.B. Anti-PD-1 Antibodies Useful for the Present Disclosure Anti-PD-1 antibodies known in the art can be used in the compositions and methods described herein. Various human monoclonal antibodies that specifically bind to PD-1 with high affinity are disclosed in U.S. Patent No. 8,008,449. The anti-PD-1 human antibodies disclosed in U.S. Patent No. 8,008,449 have been demonstrated to exhibit one or more of the following characteristics: (a) a PD-1 activity of 1×10 as determined by surface plasmon resonance using a Biacore biosensor system; -7 K below M D(b) does not substantially bind to human CD28, CTLA-4, or ICOS, (c) increases T-cell proliferation in a mixed lymphocyte reaction (MLR) assay, (d) increases interferon-γ production in an MLR assay, (e) increases IL-2 secretion in an MLR assay, (f) binds to human PD-1 and cynomolgus PD-1, (g) inhibits the binding of PD-L1 and / or PD-L2 to PD-1, (h) stimulates an antigen-specific memory response, (i) stimulates an antibody response, and (j) inhibits tumor cell growth in vivo. Anti-PD-1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some embodiments, at least five, of the foregoing characteristics.

[0208] Other anti-PD-1 monoclonal antibodies are described in, e.g., U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509, U.S. Patent Application Publication No. 2016 / 0272708, and PCT Publication Nos. WO 2012 / 145493, WO 2008 / 156712, WO 2015 / 112900, WO 2012 / 145493, WO 2015 / 112800, WO 2014 / 206107, WO 2015 / 35606, WO 2015 / 085847, WO 2014 / 179664, WO 2017 / 020291, WO 2017 / 020858, WO 2016 / 197367, WO 2017 / 024515, WO 2017 / 025051, WO 2017 / 123557, WO 2016 / 106159, WO 2014 / 194302, WO 2017 / 040790, WO 2017 / 133540, WO 2017 / 132827, WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 106061, WO 2017 / 19846, WO and WO 2017 / 133540, each of which is incorporated by reference in its entirety.

[0209] In some embodiments, the anti-PD-1 antibody is selected from the group consisting of nivolumab (also known as OPDIVO®, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA®, lambrolizumab, and MK-3475; see WO 2008 / 156712), PDR001 (Novartis; see WO 2015 / 112900), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO 2012 / 145493), cemiplimab (Regeneron; also known as REGN-2810; see WO 2015 / 112800), JS001 (TAIZHOU JUNSHI PHARMA; also known as toripalimab; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), BGB-A317 (Beigene; also known as tislelizumab; see WO 2015 / 35606 and U.S. Patent Application No. 2015 / 0079109), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210; WO 2015 / 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; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see WO 2014 / 194302), AGEN2034 (Agenus; see WO 2017 / 040790), MGA012 (Macrogenics; see WO 2017 / 19846), BCD-100 (Biocad; Kaplon et al., mAbs 10(2):183-203 (2018)), IBI308 (Innovent; see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540), and sasanlimab (PF-06801591).

[0210] In one embodiment, the anti-PD-1 antibody is nivolumab. Nivolumab is a fully human IgG4(S228P) PD-1 immune checkpoint inhibitor antibody that selectively blocks interaction with PD-1 ligands (PD-L1 and PD-L2), thereby blocking downregulation of anti-tumor T cell function (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56). The heavy and light chain variable regions of nivolumab are set forth in Table 1B (SEQ ID NOS: 2 and 3). In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 3. In some embodiments, the antibody comprises heavy chain complementarity-determining region (CDR) 1, CDR2, and CDR3 sequences comprising the heavy chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO: 2. In some embodiments, the antibody comprises light chain CDR1, CDR2, and CDR3 sequences comprising the light chain CDR1, CDR2, and CDR3 amino acid sequences of SEQ ID NO:3. [Table 1-2]

[0211] In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody directed against the human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1). Pembrolizumab is described, for example, in U.S. Patent Nos. 8,354,509 and 8,900,587.

[0212] Anti-PD-1 antibodies that can be used in the disclosed compositions and methods also include isolated antibodies that specifically bind to human PD-1 and cross-compete with any of the anti-PD-1 antibodies disclosed herein, e.g., nivolumab (see, e.g., U.S. Patent Nos. 8,008,449 and 8,779,105; WO 2013 / 173223), for binding to human PD-1. In some embodiments, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein, e.g., nivolumab. The ability of antibodies to cross-compete for binding to an antigen indicates that these monoclonal antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of the reference antibody, e.g., nivolumab, due to their binding to the same epitope region of PD-1. Cross-competing antibodies can be readily identified based on their ability to cross-compete with nivolumab in standard PD-1 binding assays, such as Biacore analysis, ELISA assays, or flow cytometry (see, e.g., WO2013 / 173223).

[0213] In certain embodiments, the antibody that cross-competes with the human PD-1 antibody nivolumab for binding to human PD-1 or binds to the same epitope region of the human PD-1 antibody nivolumab is a monoclonal antibody. These cross-competing antibodies for administration to human subjects are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric antibodies, engineered antibodies, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0214] The disclosed anti-PD-1 antibodies that can be used in the compositions and methods of the present disclosure also include antigen-binding portions of the above antibodies. It is well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0215] Anti-PD-1 antibodies suitable for use in the disclosed compositions and methods are those that bind to PD-1 with high specificity and affinity, block binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 "antibody" includes an antigen-binding portion or fragment that exhibits functional properties similar to a whole antibody in binding to the PD-1 receptor and inhibiting ligand binding to upregulate the immune system. In certain embodiments, the anti-PD-1 antibody or antigen-binding portion thereof cross-competes with nivolumab for binding to human PD-1.

[0216] In some embodiments, the anti-PD-1 antibody is administered at a dose ranging from 0.1 mg / kg to 20.0 mg / kg body weight once every 2, 3, 4, 5, 6, 7, or 8 weeks, e.g., at a dose ranging from 0.1 mg / kg to 10.0 mg / kg body weight once every 2, 3, or 4 weeks. In other embodiments, the anti-PD-1 antibody is administered at a dose of about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or 10 mg / kg body weight once every 2 weeks. In other embodiments, the anti-PD-1 antibody is administered at a dose of about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, or 10 mg / kg body weight once every three weeks. In one embodiment, the anti-PD-1 antibody is administered at a dose of about 5 mg / kg body weight once every three weeks. In another embodiment, the anti-PD-1 antibody, e.g., nivolumab, is administered at a dose of about 3 mg / kg body weight once every two weeks. In another embodiment, the anti-PD-1 antibody, e.g., pembrolizumab, is administered at a dose of about 2 mg / kg body weight once every three weeks.

[0217] Anti-PD-1 antibodies useful in the present disclosure can be administered as a fixed dose. In some embodiments, the anti-PD-1 antibody is administered in a fixed dose of about 100 to about 1000 mg, about 100 mg to about 900 mg, about 100 mg to about 800 mg, about 100 mg to about 700 mg, about 100 mg to about 600 mg, about 100 mg to about 500 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, or about 240 mg to about 480 mg. In one embodiment, the anti-PD-1 antibody is administered at a dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, at least about In another embodiment, the anti-PD-1 antibody is administered as a fixed dose of at least about 520 mg, at least about 540 mg, at least about 550 mg, at least about 560 mg, at least about 580 mg, at least about 600 mg, at least about 620 mg, at least about 640 mg, at least about 660 mg, at least about 680 mg, at least about 700 mg, or at least about 720 mg, at about 1-week, 2-week, 3-week, 4-week, 5-week, 6-week, 7-week, 8-week, 9-week, or 10-week intervals. In another embodiment, the anti-PD-1 antibody is administered as a fixed dose of about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, or about 200 mg to about 500 mg, at about 1-week, 2-week, 3-week, or 4-week intervals.

[0218] In some embodiments, the anti-PD-1 antibody is administered as a fixed dose of about 200 mg about once every three weeks. In other embodiments, the anti-PD-1 antibody is administered as a fixed dose of about 200 mg about once every two weeks. In other embodiments, the anti-PD-1 antibody is administered as a fixed dose of about 240 mg about once every two weeks. In certain embodiments, the anti-PD-1 antibody is administered as a fixed dose of about 480 mg about once every four weeks.

[0219] In some embodiments, nivolumab is administered at a fixed dose of about 240 mg once every two weeks. In some embodiments, nivolumab is administered at a fixed dose of about 240 mg once every three weeks. In other embodiments, nivolumab is administered at a fixed dose of about 360 mg once every three weeks. In some embodiments, nivolumab is administered at a fixed dose of about 480 mg once every four weeks. In some embodiments, nivolumab is administered at a fixed dose of about 720 mg once every six weeks. In some embodiments, nivolumab is administered at a fixed dose of about 960 mg once every eight weeks.

[0220] In some embodiments, pembrolizumab is administered at a fixed dose of about 200 mg once every two weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 200 mg once every three weeks. In some embodiments, pembrolizumab is administered at a fixed dose of about 400 mg once every four weeks.

[0221] In some embodiments, the pharmaceutical composition comprises a bispecific or multispecific antibody comprising a first antigen-binding portion and a second antigen-binding portion, wherein the first antigen-binding portion comprises an anti-PD-1 antigen-binding portion (e.g., an scFv of nivolumab). In some embodiments, the second antigen-binding portion is the antigen-binding portion of any one of the antibodies disclosed herein. In some embodiments, the second antigen-binding portion is the antigen-binding portion of an anti-LAG-3 antibody, e.g., leratolimab.

[0222] In some embodiments, the pharmaceutical composition comprises a multispecific antibody comprising a first antigen-binding portion, a second antigen-binding portion, and at least a third antigen-binding portion, wherein the first antigen-binding portion comprises an anti-PD-1 antigen-binding portion (e.g., an scFv of nivolumab).

[0223] II.C. Anti-PD-L1 Antibodies Useful in the Disclosure In certain embodiments, an anti-PD-L1 antibody is used in place of an anti-PD-1 antibody in any of the methods disclosed herein. Any anti-PD-L1 antibody can be used in the compositions and methods of the disclosure. Examples of anti-PD-L1 antibodies useful in the compositions and methods of the disclosure include those disclosed in U.S. Patent No. 9,580,507. The anti-PD-L1 human monoclonal antibody disclosed in U.S. Patent No. 9,580,507 has been demonstrated to exhibit one or more of the following characteristics: (a) a PD-L1 activity of 1 x 10 as determined by surface plasmon resonance using a Biacore biosensor system; -7 K below M D (b) binds to human PD-L1 in a mixed lymphocyte reaction (MLR) assay, (c) increases interferon-γ production in an MLR assay, (d) increases IL-2 secretion in an MLR assay, (e) stimulates antibody responses, and (f) reverses the effects of regulatory T cells on T cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one, and in some embodiments at least five, of the above characteristics.

[0224] In certain embodiments, the anti-PD-L1 antibody is selected from the group consisting of BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Patent No. 7,943,743 and WO2013 / 173223), atezolizumab (Roche; also known as TECENTRIQ®; MPDL3280A, RG7446; see, U.S. Patent No. 8,217,149; also see Herbst et al. (2013) J Clin Oncol 31(suppl):3000), durvalumab (AstraZeneca; IMFINZI™, also known as MEDI-4736; see WO2011 / 066389), avelumab (Pfizer; BAVENCIO®, 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 Co.; see, e.g., WO2017 / 034916), BGB-A333 (BeiGene; see Desai et al., JCO 36 (15suppl):TPS3113 (2018)), and CK-301 (Checkpoint Therapeutics; see Gorelik et al., AACR:Abstract 4606 (Apr 2016)).

[0225] In one particular embodiment, the PD-L1 antibody is atezolizumab (TECENTRIQ®). Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody.

[0226] In one particular embodiment, the PD-L1 antibody is durvalumab (IMFINZI™). Durvalumab is a human IgG1κ monoclonal anti-PD-L1 antibody.

[0227] In one particular embodiment, the PD-L1 antibody is avelumab (BAVENCIO®). Avelumab is a human IgG1 lambda monoclonal anti-PD-L1 antibody.

[0228] Anti-PD-L1 antibodies that can be used in the disclosed compositions and methods also include isolated antibodies that specifically bind to human PD-L1 and cross-compete with any of the anti-PD-L1 antibodies disclosed herein, e.g., atezolizumab, durvalumab, and / or avelumab, for binding to human PD-L1. 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 an antigen indicates that they bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have functional properties that are very similar 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-competing antibodies can be readily identified based on their ability to cross-compete with atezolizumab and / or avelumab in standard PD-L1 binding assays, such as Biacore analysis, ELISA assays, or flow cytometry (see, e.g., WO2013 / 173223).

[0229] In certain embodiments, antibodies that cross-compete with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1 or that bind to the same epitope region of human PD-L1 antibodies are monoclonal antibodies. These cross-competing antibodies for administration to human subjects are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0230] The anti-PD-L1 antibodies that can be used in the disclosed compositions and methods also include antigen-binding portions of the above antibodies. It is well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0231] Anti-PD-L1 antibodies suitable for use in the disclosed compositions and methods are those that bind to PD-L1 with high specificity and affinity, block PD-1 binding, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that exhibits functional properties similar to the whole antibody in binding to PD-L1 and inhibiting receptor binding to upregulate the immune system. In certain embodiments, the anti-PD-L1 antibody or antigen-binding portion thereof cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0232] Anti-PD-L1 antibodies useful in the present disclosure can be any PD-L1 antibody that specifically binds to PD-L1, for example, an antibody that cross-competes with durvalumab, avelumab, or atezolizumab for binding to human PD-1, for example, an antibody that binds to the same epitope as durvalumab, avelumab, or atezolizumab. In one particular embodiment, the anti-PD-L1 antibody is durvalumab. In another embodiment, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab.

[0233] In some embodiments, the anti-PD-L1 antibody is administered at a dose ranging from about 0.1 mg / kg to about 20.0 mg / kg body weight, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about 13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, or about 20 mg / kg, about once every 2, 3, 4, 5, 6, 7, or 8 weeks.

[0234] In some embodiments, the anti-PD-L1 antibody is administered at a dose of about 15 mg / kg body weight about once every three weeks. In other embodiments, the anti-PD-L1 antibody is administered at a dose of about 10 mg / kg body weight about once every two weeks.

[0235] In other embodiments, the anti-PD-L1 antibodies useful in the present disclosure are fixed dose. In some embodiments, the anti-PD-L1 antibodies are administered as a fixed dose of about 200 mg to about 1600 mg, about 200 mg to about 1500 mg, about 200 mg to about 1400 mg, about 200 mg to about 1300 mg, about 200 mg to about 1200 mg, about 200 mg to about 1100 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 700 mg to about 1300 mg, about 800 mg to about 1200 mg, about 700 mg to about 900 mg, or about 1100 mg to about 1300 mg. In some embodiments, the anti-PD-L1 antibody is administered as a fixed dose of at least about 240 mg, at least about 300 mg, at least about 320 mg, at least about 400 mg, at least about 480 mg, at least about 500 mg, at least about 560 mg, at least about 600 mg, at least about 640 mg, at least about 700 mg, at least 720 mg, at least about 800 mg, at least about 840 mg, at least about 880 mg, at least about 900 mg, at least 960 mg, at least about 1000 mg, at least about 1040 mg, at least about 1100 mg, at least about 1120 mg, at least about 1200 mg, at least about 1280 mg, at least about 1300 mg, at least about 1360 mg, or at least about 1400 mg, with a dosing interval of about 1 week, 2 weeks, 3 weeks, or 4 weeks. In some embodiments, the anti-PD-L1 antibody is administered as a fixed dose of about 1200 mg about once every three weeks. In other embodiments, the anti-PD-L1 antibody is administered as a fixed dose of about 800 mg about once every two weeks. In other embodiments, the anti-PD-L1 antibody is administered as a fixed dose of about 840 mg about once every two weeks.

[0236] In some embodiments, atezolizumab is administered at a fixed dose of about 1200 mg once every about three weeks. In some embodiments, atezolizumab is administered at a fixed dose of about 800 mg once every about two weeks. In some embodiments, atezolizumab is administered at a fixed dose of about 840 mg once every about two weeks.

[0237] In some embodiments, avelumab is administered as a fixed dose of about 800 mg once about every two weeks.

[0238] In some embodiments, durvalumab is administered at a dose of about 10 mg / kg about once every two weeks. In some embodiments, durvalumab is administered as a fixed dose of about 800 mg / kg about once every two weeks. In some embodiments, durvalumab is administered as a fixed dose of about 1200 mg / kg about once every three weeks.

[0239] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, specific for (i) PD-L1 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, specific for (i) PD-L1 and (ii) CD3.

[0240] II.D. Combination Therapy In some embodiments of the present disclosure, the methods disclosed herein include administering an anti-PD-1 antibody (or anti-PD-L1 antibody) in combination with an additional anti-cancer therapy. The additional anti-cancer therapy can include any therapy and / or any standard of care for treating a tumor in a subject, as disclosed herein. In some embodiments, the additional anti-cancer therapy includes surgery, radiation therapy, chemotherapy, immunotherapy, or any combination thereof. In some embodiments, the additional anti-cancer therapy includes chemotherapy, including any chemotherapy disclosed herein. In some embodiments, the additional anti-cancer therapy includes immunotherapy. In some embodiments, the additional anti-cancer therapy includes administration of an antibody or antigen-binding portion thereof that specifically binds to 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, or any combination thereof. In some embodiments, the additional anti-cancer therapy comprises administering IL-2 (e.g., a modified IL-2, e.g., a pegylated IL-2, e.g., bempegaldesleukin). In some embodiments, the second therapeutic agent, the third therapeutic agent, or both comprise IL12-Fc (e.g., BMS-986415).

[0241] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody is administered subcutaneously according to any method disclosed herein, and the additional anti-cancer therapy is administered by any suitable route known in the art. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody is administered subcutaneously according to any method disclosed herein, and the additional anti-cancer therapy is administered subcutaneously. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody is administered subcutaneously according to any method disclosed herein, and the additional anti-cancer therapy is administered intravenously. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the additional anti-cancer therapy are administered simultaneously. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the additional anti-cancer therapy are administered sequentially. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the additional anti-cancer therapy are administered on the same day. In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the additional anti-cancer therapy are administered on different days.

[0242] In some embodiments, the anti-PD-1 antibody or anti-PD-L1 antibody and the additional anti-cancer therapy, e.g., a checkpoint inhibitor, are combined in a single formulation.

[0243] In some embodiments, the method comprises administering a therapeutically effective amount of an anti-PD-1 antibody and an anti-CTLA-4 antibody, such as ipilimumab. In other embodiments, the method comprises administering a therapeutically effective amount of a composition comprising an anti-PD-1 antibody and an anti-CTLA-4 antibody. 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. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121, as well as International Publication Nos. WO 2012 / 122444, WO 2007 / 113648, WO 2016 / 196237, and WO 2000 / 037504, each of which is incorporated herein by reference in its entirety. In certain embodiments, the CTLA-4 antibody is selected from the group consisting of ipilimumab (also known as YERVOY®, MDX-010, 10D1; see U.S. Pat. No. 6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; see WO 2016 / 196237), and tremelimumab (AstraZeneca; also known as ticilimumab, CP-675,206; see WO 2000 / 037504 and Ribas, Update Cancer Ther. 2(3): 133-39 (2007)). In certain embodiments, the anti-CTLA-4 antibody is ipilimumab. In certain embodiments, the CTLA-4 antibody is tremelimumab. In certain embodiments, the CTLA-4 antibody is MK-1308. In a particular embodiment, the CTLA-4 antibody is AGEN-1884.

[0244] In some embodiments, the method comprises administering a therapeutically effective amount of an anti-PD-1 antibody and an anti-LAG-3 antibody. In other embodiments, the method comprises administering a therapeutically effective amount of a single formulation comprising an anti-PD-1 antibody and an anti-LAG-3 antibody, e.g., leratolimab. In some embodiments, the anti-LAG-3 antibody is leratolimab, e.g., BMS-986016, described in PCT / US13 / 48999, the teachings of which are incorporated herein by reference. In some embodiments, the anti-LAG-3 antibody cross-competes with leratolimab for binding to human LAG-3. In some embodiments, the anti-LAG-3 antibody binds to the same epitope as leratolimab. In some embodiments, the anti-LAG-3 antibody is a biosimilar of leratolimab. In some embodiments, the anti-LAG-3 antibody is LAG-525, MK-4280, REGN3767, TSR-033, TSR-075, Sym022, FS-118, or any combination thereof.

[0245] In some embodiments, the method comprises administering a therapeutically effective amount of an anti-PD-1 antibody or anti-PD-L1 antibody according to any method disclosed herein and administering chemotherapy. In some embodiments, the chemotherapy comprises a platinum-based therapy. In some embodiments, the platinum-based therapy comprises a platinum-based antineoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and any combination thereof. In certain embodiments, the platinum-based therapy comprises cisplatin. In one particular embodiment, the platinum-based therapy comprises carboplatin. In some embodiments, the chemotherapy comprises an anticancer agent selected from the group consisting of a platinum agent (e.g., cisplatin, carboplatin), a taxane (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel), vinorelbine, vinblastine, etoposide, pemetrexed, gemcitabine, bevacizumab (AVASTIN®), erlotinib (TARCEVA®), crizotinib (XALKORI®), cetuximab (ERBITUX®), and any combination thereof. In certain embodiments, the chemotherapy comprises a platinum-based doublet chemotherapy.

[0246] II.E. Tumor Certain embodiments of the present disclosure are directed to methods of treating a subject in need thereof, comprising subcutaneous delivery of an anti-PD-1 antibody or an anti-PD-L1 antibody. In some embodiments, the subject is afflicted with cancer (e.g., a tumor resulting from a cancer). In some embodiments, the tumor is selected from the group consisting of squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone refractory prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, gastric cancer, bladder cancer, hepatocellular carcinoma, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, sinus natural killer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube cancer, uterine The cancer may be from a cancer selected from the group consisting of endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, pediatric solid tumors, ureteral cancer, renal pelvis cancer, central nervous system neoplasm (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain cancer, brainstem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancer including asbestos-induced, virus-associated cancer or virus-derived cancer (e.g., human papillomavirus (HPV-associated or HPV-derived tumors)), and any combination thereof. In certain embodiments, the subject has undergone one, two, three, four, five, or more prior cancer treatments. In other embodiments, the subject is untreated. In certain embodiments, the subject has undergone and progressed with other cancer treatments. In certain embodiments, the prior cancer treatment included immunotherapy. In other embodiments, the prior cancer treatment included chemotherapy. In some embodiments, the tumor has recurred. In some embodiments, the tumor is metastatic. In other embodiments, the tumor is not metastatic. In some embodiments, the tumor is locally advanced.

[0247] In some embodiments, the subject has received a prior therapy to treat the tumor, and the tumor is relapsed or refractory. In certain embodiments, at least one prior therapy comprises standard therapy. In some embodiments, at least one prior therapy comprises surgery, radiation therapy, chemotherapy, immunotherapy, or any combination thereof. In some embodiments, at least one prior therapy comprises chemotherapy. In some embodiments, the subject has received a prior immuno-oncology (IO) therapy to treat the tumor, and the tumor is relapsed or refractory. In some embodiments, the subject has received two or more prior therapies to treat the tumor, and the subject is relapsed or refractory. In other embodiments, the subject has received either an anti-PD-1 antibody therapy or an anti-PD-L1 antibody therapy.

[0248] In some embodiments, the prior line therapy comprises chemotherapy. In some embodiments, the chemotherapy comprises a platinum-based therapy. In some embodiments, the platinum-based therapy comprises a platinum-based antineoplastic agent selected from the group consisting of cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin, and any combination thereof. In certain embodiments, the platinum-based therapy comprises cisplatin. In one particular embodiment, the platinum-based therapy comprises carboplatin.

[0249] In some embodiments, the at least one prior therapy is selected from therapies comprising administration of an anticancer agent selected from the group consisting of a platinum agent (e.g., cisplatin, carboplatin), a taxane (e.g., paclitaxel, albumin-bound paclitaxel, docetaxel), vinorelbine, vinblastine, etoposide, pemetrexed, gemcitabine, bevacizumab (AVASTIN®), erlotinib (TARCEVA®), crizotinib (XALKORI®), cetuximab (ERBITUX®), and any combination thereof. In certain embodiments, the at least one prior therapy comprises a platinum-based doublet chemotherapy.

[0250] In some embodiments, the subject has experienced disease progression after at least one prior therapy. In certain embodiments, the subject has received at least two prior therapies, at least three prior therapies, at least four prior therapies, or at least five prior therapies. In certain embodiments, the subject has received at least two prior therapies. In one embodiment, the subject has experienced disease progression after at least two prior therapies. In certain embodiments, the at least two prior therapies include a first prior therapy and a second prior therapy, and the subject has experienced disease progression after the first prior therapy and / or the second prior therapy, wherein the first prior therapy includes surgery, radiation therapy, chemotherapy, immunotherapy, or any combination thereof, and the second prior therapy includes surgery, radiation therapy, chemotherapy, immunotherapy, or any combination thereof. In some embodiments, the first prior therapy includes platinum-based doublet chemotherapy, and the second prior therapy includes single-agent chemotherapy. In some embodiments, the single-agent chemotherapy includes docetaxel.

[0251] In certain embodiments, the tumor is a PD-L1-positive tumor. As used herein, "PD-L1-positive" can be used interchangeably with "at least about 1% PD-L1 expression." PD-L1 expression can be measured by any method known in the art. In some embodiments, PD-L1 expression is measured by automated IHC. A PD-L1-positive tumor, therefore, can have at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100% of tumor cells express PD-L1, as measured by automated IHC. In certain embodiments, "PD-L1-positive" means that at least 100 cells express PD-L1 on their surface.

[0252] To assess PD-L1 expression, in one embodiment, a test tissue sample is obtained from a patient in need of a therapy disclosed herein. In another embodiment, assessing PD-L1 expression is accomplished without obtaining a test tissue sample. In some embodiments, selecting a suitable patient includes (i) providing a test tissue sample obtained from a patient with cancerous tissue, where the test tissue sample includes tumor cells and / or tumor-infiltrating inflammatory cells, and (ii) assessing the proportion of cells in the test tissue sample that express PD-L1 on their surface, based on assessing that the proportion of cells in the test tissue sample that express PD-L1 on their surface is higher than a predetermined threshold level.

[0253] It should be understood, however, that in any method involving measuring PD-L1 expression in a test tissue sample, the step involving providing a test tissue sample obtained from a patient is an optional step. It should also be understood that in certain embodiments, the "measuring" or "assessing" step to identify or determine the number or percentage of cells in the test tissue sample that express PD-L1 (e.g., expression of PD-L1 on the cell surface) is performed by performing a modified method of assaying PD-L1 expression, e.g., a reverse transcriptase polymerase chain reaction (RT-PCR) assay or an IHC assay. In certain other embodiments, no modified method step is included, and PD-L1 expression is assessed, e.g., by reviewing a test result report from a laboratory. In certain embodiments, the method steps leading up to and including assessing PD-L1 expression provide an intermediate result that can be provided to a physician or other health care provider for use in selecting suitable candidates for anti-PD-1 antibodies or anti-PD-L1 antibody therapy. In certain embodiments, the step of providing the intermediate result is performed by a physician, or someone acting under the physician's direction. In other aspects, these steps are performed by an independent laboratory or by an independent party, eg, a laboratory technician.

[0254] In certain embodiments of any of the present methods, the proportion of cells expressing PD-L1 is assessed by performing an assay to determine the presence of PD-L1 RNA. In further embodiments, the presence of PD-L1 RNA is determined by RT-PCR, in situ hybridization, or RNase protection. In other embodiments, the proportion of cells expressing PD-L1 is assessed by performing an assay to determine the presence of PD-L1 polypeptide. In further embodiments, the presence of PD-L1 polypeptide is determined by immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), in vivo imaging, or flow cytometry. In some embodiments, PD-L1 expression is assayed by IHC. In other embodiments of all these methods, cell surface expression of PD-L1 is assayed using, for example, IHC or in vivo imaging.

[0255] Imaging technologies have provided important tools in cancer research and treatment. Recent advances in molecular imaging systems, including positron emission tomography (PET), single-photon emission computed tomography (SPECT), fluorescence reflectance imaging (FRI), fluorescence-mediated tomography (FMT), bioluminescence imaging (BLI), laser scanning confocal microscopy (LSCM), and multiphoton microscopy (MPM), herald the likely widespread use of these technologies in cancer research. Some of these molecular imaging systems not only allow clinicians to see where tumors are located in the body, but also allow them to visualize the expression and activity of specific molecules, cells, and biological processes that affect tumor behavior and / or responsiveness to therapeutic agents (Condeelis and Weissleder, "In vivo imaging in cancer," Cold Spring Harb. Perspect. Biol. 2(12):a003848 (2010)). ImmunoPET imaging combines the specificity of antibodies with the sensitivity and resolution of PET testing, making it particularly attractive for monitoring and assaying antigen expression in tissue samples (McCabe and Wu, "Positive progress in immunoPET—not just a coincidence," Cancer Biother. Radiopharm. 25(3):253-61 (2010); Olafsen et al., "ImmunoPET imaging of B-cell lymphoma using 124I-anti-CD20 scFv dimers (diabodies)," Protein Eng. Des. Sel. 23(4):243-9 (2010)). In certain embodiments of any of the present methods, PD-L1 expression is assayed by immunoPET imaging. In certain embodiments of any of the present methods, the proportion of cells in the test tissue sample that express PD-L1 is assessed by performing an assay to determine the presence of PD-L1 polypeptide on the surface of cells in the test tissue sample. In certain embodiments, the test tissue sample is an FFPE tissue sample.In other embodiments, the presence of a PD-L1 polypeptide is determined by an IHC assay. In further embodiments, the IHC assay is performed using an automated process. In some embodiments, the IHC assay is performed using an anti-PD-L1 monoclonal antibody that binds to a PD-L1 polypeptide.

[0256] In one embodiment of the method of the present invention, automated IHC methods are used to assay PD-L1 expression on the surface of cells in FFPE tissue specimens. The present disclosure provides methods for detecting the presence of human PD-L1 antigen in a test tissue sample or for quantifying the level of human PD-L1 antigen or the proportion of cells expressing the antigen in a sample, comprising contacting the test sample and a negative control sample with a monoclonal antibody that specifically binds to human PD-L1 under conditions that allow the formation of a complex between the antibody, or a portion thereof, and human PD-L1. In certain embodiments, the test tissue sample and the control tissue sample are FFPE samples. The formation of the complex is then detected, and a difference in complex formation between the test sample and the negative control sample indicates the presence of human PD-L1 antigen in the sample. Various methods can be used to quantify PD-L1 expression.

[0257] In one particular embodiment, the automated IHC method includes the steps of (a) deparaffinizing and rehydrating mounted tissue sections in an automated stainer, (b) using a decloaking chamber and pH 6 buffer to heat to 110°C for 10 minutes to retrieve antigens, (c) loading reagents into the automated stainer, and (d) running the automated stainer to neutralize endogenous peroxidase in the tissue specimen, block nonspecific protein binding sites on the slide, incubating the slide with a primary antibody, incubating with a post-primary blocking agent, incubating with NovoLink polymer, adding a chromogenic substrate to develop color, and counterstaining with hematoxylin.

[0258] To assess PD-L1 expression in tumor tissue samples, a pathologist examined membrane PD-L1 expression in each field under a microscope. + The number of tumor cells is counted, the percentage of cells that are positive is estimated in mind, and then averaged to obtain a final percentage. Differences in staining intensity are defined as 0 / negative, 1+ / weak, 2+ / moderate, and 3+ / strong. Typically, percentage values ​​are first assigned to buckets of 0 and 3+, followed by consideration of intermediate intensities of 1+ and 2+. For highly heterogeneous tissues, the specimen is divided into multiple zones, each of which is scored separately and then combined to obtain a single set of percentage values. The percentages of negative and positive cells for different staining intensities are determined from each region, and the median value is assigned to each zone. Final percentage values ​​are assigned to the tissue for each staining intensity category: negative, 1+, 2+, and 3+. The sum of all staining intensities must equal 100%. In one embodiment, the threshold number of cells that need to be PD-L1 positive is at least about 100 cells, at least about 125 cells, at least about 150 cells, at least about 175 cells, or at least about 200 cells. In certain embodiments, the threshold number of cells that need to be PD-L1 positive is at least about 100 cells.

[0259] Staining is also assessed in tumor-infiltrating inflammatory cells, such as macrophages and lymphocytes. In most cases, macrophages serve as an internal positive control, as staining is observed in the majority of macrophages. Although staining at 3+ intensity is not required, the absence of macrophage staining should be considered to rule out any technical failure. Macrophages and lymphocytes are evaluated for plasma membrane staining, and for all samples, only positive or negative results are recorded for each cell category. Staining is also characterized by the external / internal designation of tumor immune cells. "Internal" means that immune cells are located within the tumor tissue and / or on the border of the tumor area, without any physical intervening tumor cells. "External" means that immune cells are found in the periphery, associated with connective tissue or any associated adjacent tissue, without any physical connection to the tumor.

[0260] In certain embodiments of these scoring methods, samples are scored by two pathologists working independently, and then the scores are combined. In certain other embodiments, the identification of positive and negative cells is scored using appropriate software.

[0261] The histoscore (also written as H-score) is used as a more quantitative measure of IHC data. The histoscore is calculated as follows: Histoscore = [(% tumor × 1 (low intensity)) + (% tumor × 2 (moderate intensity)) + (% tumor × 3 (high intensity)]

[0262] To determine the Histoscore, a pathologist estimates the percentage of stained cells in each intensity category within a specimen. Because expression of most biomarkers is heterogeneous, the Histoscore is a more accurate representation of overall expression. Final Histoscores range from 0 (no expression) to 300 (maximal expression).

[0263] An alternative means of quantifying PD-L1 expression in test tissue sample IHC is to determine the adjusted inflammation score (AIS), which is defined as the density of inflammation multiplied by the percentage of PD-L1 expression by tumor-infiltrating inflammatory cells (Taube et al., "Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape," Sci. Transl. Med. 4(127):127ra37 (2012)).

[0264] III. Compositions of the Present Disclosure Pharmaceutical compositions comprising anti-PD-1 antibodies or anti-PD-L1 antibodies are also within the scope of the present 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 lacking two antioxidants or at least one antioxidant. Therapeutic agents of the present disclosure may be configured as compositions, such as pharmaceutical compositions containing an antibody and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, that are physiologically compatible. Preferably, carriers for antibody-containing compositions are suitable for intravenous, intramuscular, subcutaneous, rectal, spinal, or epidermal administration (e.g., by injection or infusion), while carriers for antibody- and / or cytokine-containing compositions are suitable for non-rectal, e.g., oral, administration. In certain embodiments, the pharmaceutical composition does not contain hyaluronidase.

[0265] 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 or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL, at least about 10 mg / mL to at least about 400 mg / mL, at least about 10 mg / mL to at least about 300 mg / mL, at least about 10 mg / mL to at least about 250 mg / mL, at least about 10 mg / mL to at least about 200 mg / mL, at least about 10 mg / mL to at least about 190 mg / mL, or at least about 10 mg / mL to at least about 180 mg / mL. / mL, at least about 10 mg / mL to at least about 170 mg / mL, at least about 10 mg / mL to at least about 160 mg / mL, at least about 10 mg / mL to at least about 150 mg / mL, at least about 20 mg / mL to at least about 500 mg / mL, at least about 20 mg / mL to at least about 400 mg / mL, at least about 20 mg / mL to at least about 300 mg / mL, at least about 20 mg / mL to at least about 250 mg / mL, at least about 20 mg / mL to at least about 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least or at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 135 mg / mL to at least about 180 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 130 mg / mL, or at least about 108 mg / mL to at least about 132 mg / mL of anti-PD-1 antibody or anti-PD-L1 antibody.In some embodiments, the pharmaceutical composition comprises at least about 50 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 60 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 70 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 75 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 80 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 90 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 100 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 110 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 120 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 130 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 132 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 140 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 150 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 160 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 170 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 175 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 180 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody.In some embodiments, the pharmaceutical composition comprises at least about 190 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 200 mg / mL of the anti-PD-1 antibody or anti-PD-L1 antibody.

[0266] III.A. Endoglycosidase Hydrolase Enzymes In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase enzyme. In some embodiments, the pharmaceutical composition comprises at least about 50 U / mL to at least about 48,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50 U / mL to at least about 5,000 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50 U / mL, at least about 100 U / mL, at least about 150 U / mL, at least about 200 U / mL, at least about 250 U / mL, at least about 300 U / mL, at least about 350 U / mL, at least about 400 U / mL, at least about 450 U / mL, at least about 500 U / mL, at least about 750 U / mL, at least about 1000 U / mL, at least about 1500 U / mL, at least about 2000 U / mL, at least about 2500 U / mL, at least about 30 ...0 U / mL, at least about 4500 U / mL, at least about 500 U / mL, at least about 6000 U / mL, at least about 6500 U / mL, at least about 7500 U / mL, at least about 1000 U / mL, at least about 1500 U / mL, at least about 2000 U / mL, at least about 2500 The pharmaceutical composition may comprise at least about 3500 U / mL, at least about 4000 U / mL, at least about 4500 U / mL, at least about 5000 U / mL, at least about 5500 U / mL, at least about 6000 U / mL, at least about 6500 U / mL, at least about 7000 U / mL, at least about 7500 U / mL, at least about 8000 U / mL, at least about 8500 U / mL, at least about 9000 U / mL, at least about 9500 U / mL, or at least about 10,000 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 500 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 1000 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 2000 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 2500 U / mL of an endoglycosidase hydrolase enzyme (e.g., rHuPH20).In some embodiments, the pharmaceutical composition comprises at least about 3000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 3500 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 4000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 4500 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 5000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 6000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 7000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 8000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 9000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 10,000 U / mL of the endoglycosidase hydrolase enzyme (e.g., rHuPH20).

[0267] In some embodiments, the pharmaceutical composition comprises at least about 50 units to at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50 units, at least about 100 units, at least about 150 units, at least about 200 units, at least about 250 units, at least about 300 units, at least about 400 units, at least about 500 units, at least about 600 units, at least about 700 units, at least about 800 units, at least about 900 units, at least about 1000 units, at least about 1500 units, at least about 2000 units, at least about 2500 units, at least about 3000 units, at least about 4000 units, at least about 5000 units, at least about 10,000 units, at least about 15,000 units, at least about 20,000 units, The pharmaceutical composition may comprise at least about 25,000 units, at least about 30,000 units, at least about 35,000 units, at least about 40,000 units, at least about 45,000 units, at least about 48,000 units, at least about 50,000 units, at least about 55,000 units, at least about 60,000 units, at least about 65,000 units, at least about 70,000 units, at least about 75,000 units, at least about 80,000 units, at least about 85,000 units, at least about 90,000 units, at least about 95,000 units, or at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 20,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 30,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 40,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 60,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20).In some embodiments, the pharmaceutical composition comprises at least about 70,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 80,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 90,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 100,000 units of an endoglycosidase hydrolase enzyme (e.g., rHuPH20).

[0268] It will be readily apparent to one of skill in the art that the amount of endoglycosidase hydrolase enzyme (e.g., rHuPH20) can be expressed in units or U / mL, or the amount of endoglycosidase hydrolase enzyme (e.g., rHuPH20) can be expressed in mg / mL (or other weight-based units). For example, in some embodiments, a pharmaceutical composition comprises an amount of endoglycosidase hydrolase enzyme (e.g., rHuPH20) expressed as at least about 500 U / mL or at least about 0.00455 mg / mL. In another example, in some embodiments, a pharmaceutical composition comprises an amount of endoglycosidase hydrolase enzyme (e.g., rHuPH20) expressed as at least about 2000 U / mL or at least about 0.0182 mg / mL.

[0269] In certain embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20. In certain 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 certain embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 0.0182 mg / mL of rHuPH20. In certain 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.

[0270] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20. 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) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, 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 histidine, (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.

[0271] In certain embodiments, a unit dose described herein comprises (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20. In certain embodiments, a unit dose described herein comprises (a) about 120 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20. In certain embodiments, a unit dose described herein comprises (a) about 120 mg / mL of an 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 certain embodiments, a unit dose described herein comprises (a) about 120 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 0.0182 mg / mL rHuPH20.

[0272] In certain embodiments, a unit dose described herein comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20. In certain embodiments, a unit dose described herein comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20. In certain embodiments, a unit dose described herein comprises (a) about 150 mg / mL of an 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 certain embodiments, a unit dose described herein comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 0.0182 mg / mL rHuPH20.

[0273] In certain embodiments, the pharmaceutical composition comprises (a) about 672 mg of nivolumab, (b) about 8.68 mg of L-histidine, (c) about 11.8 mg of histidine HCl HO, (d) about 479 mg of sucrose, (e) about 2.80 mg of polyisoscurvate 80, (f) about 0.110 mg of pentetic acid, (g) about 4.18 mg of methionine, and (h) about 0.102 mg of rHuPH20, wherein (a)-(h) are reconstituted in water to a final volume of at least about 5.6 mL.

[0274] III.B. Antioxidants In some embodiments, the pharmaceutical composition further comprises an antioxidant. Any antioxidant can be used in the pharmaceutical compositions disclosed herein. In some embodiments, the antioxidant is selected from methionine, tryptophan, and histidine, cysteine, ascorbic acid, glycine, pentetic acid (DTPA), and EDTA. In certain embodiments, the pharmaceutical composition comprises methionine. In some embodiments, the pharmaceutical composition comprises at least two antioxidants. In some embodiments, multiple antioxidants, e.g., two antioxidants, prevent oxidation of formulation components and / or improve antibody stability. In some embodiments, the at least two antioxidants comprise (i) methionine and EDTA, or (ii) methionine and pentetic acid (DTPA).

[0275] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody, methionine, and pentetic acid (DTPA). In some embodiments, the pharmaceutical composition comprises at least about 0.1 mM to at least about 100 mM methionine. In some embodiments, the pharmaceutical composition comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, or at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 10 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 9 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 8 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 7 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 6 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 5 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 4 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 3 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 2 mM methionine. In certain embodiments, the pharmaceutical composition comprises at least about 1 mM methionine.

[0276] In some embodiments, the pharmaceutical composition comprises at least about 1 mM to at least about 250 mM pentetic acid (DTPA). In some embodiments, the pharmaceutical composition comprises at least about 1 μM, at least about 5 μM, at least about 10 μM, at least about 15 μM, at least about 20 μM, at least about 25 μM, at least about 30 μM, at least about 35 μM, at least about 40 μM, at least about 45 μM, at least about 50 μM, at least about 55 μM, at least about 60 μM, at least about 65 μM, at least about 70 μM, at least about 75 μM, at least about 80 μM, at least about 85 μM, at least about 90 μM, at least about 95 μM, or 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 certain embodiments, the pharmaceutical composition comprises at least about 75 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 70 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 65 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 60 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 55 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 50 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 45 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 40 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 35 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 30 μM pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 25 μM pentetic acid (DTPA).

[0277] III.C. Tonicity Adjusters / Stabilizers In some embodiments, the pharmaceutical composition further comprises a tonicity adjusting agent and / or stabilizer. Any tonicity adjusting agent and / or any stabilizer can be used in the pharmaceutical compositions disclosed herein. In some embodiments, the tonicity adjusting agent and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or any combination thereof. In some embodiments, the tonicity adjusting agent and / or stabilizer is selected from the group consisting of sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, a polyol, an amino acid, and a salt.

[0278] In certain embodiments, the pharmaceutical composition comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 1 mM to at least about 500 mM sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 400 mM, at least about 50 mM to at least about 400 mM, at least about 100 mM to at least about 400 mM, at least about 150 mM to at least about 400 mM, at least about 200 mM to at least about 400 mM, at least about 250 mM to at least about 400 mM, at least about 300 mM to at least about 400 mM, at least about 350 mM to at least about 400 mM. , at least about 50 mM to at least about 350 mM, at least about 100 mM to at least about 300 mM, at least about 100 mM to at least about 250 mM, at least about 100 mM to at least about 200 mM, at least about 100 mM to at least about 150 mM, at least about 200 mM to at least about 400 mM, at least about 200 mM to at least about 300 mM, or at least about 200 mM to at least about 250 mM sucrose.In some embodiments, the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, at least about 500 mM, at least about 510 mM, at least about 520 mM, at least about 530 mM, at least about 540 mM, at least about 550 mM, at least about 560 mM, at least about 570 mM In certain embodiments, the pharmaceutical composition comprises at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, or at least about 500 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 200 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 210 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 220 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 230 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 240 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 250 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 260 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 270 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 280 mM sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 290 mM sucrose.In certain embodiments, the pharmaceutical composition comprises at least about 300 mM sucrose.

[0279] III.D. Buffers 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 certain embodiments, the pharmaceutical composition comprises histidine. In certain embodiments, the pharmaceutical composition comprises citrate. In some embodiments, the pharmaceutical composition comprises at least about 1 mM to at least about 100 mM of histidine. In some embodiments, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM, at least about 10 mM to at least about 100 mM, at least about 15 mM to at least about 100 mM, at least about 20 mM to at least about 100 mM, at least about 25 mM to at least about 100 mM, at least about 30 mM to at least about 100 mM, at least about 35 mM to at least about 100 mM, at least about 40 ... Contains 5 mM to at least about 100 mM, at least about 50 mM to at least about 100 mM, at least about 10 mM to at least about 75 mM, at least about 10 mM to at least about 50 mM, at least about 10 mM to at least about 40 mM, at least about 10 mM to at least about 30 mM, at least about 15 mM to at least about 30 mM, at least about 10 mM to at least about 25 mM, or at least about 15 mM to at least about 25 mM histidine.

[0280] In some embodiments, the pharmaceutical composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine. In certain embodiments, the pharmaceutical composition comprises at least about 10 mM histidine. In certain embodiments, the pharmaceutical composition comprises at least about 15 mM histidine. In certain embodiments, the pharmaceutical composition comprises at least about 20 mM histidine. In certain embodiments, the pharmaceutical composition comprises at least about 25 mM histidine. In certain embodiments, the pharmaceutical composition comprises at least about 30 mM histidine. In certain embodiments, the pharmaceutical composition comprises at least about 35 mM histidine. In certain embodiments, the pharmaceutical composition comprises at least about 40 mM histidine, hi certain embodiments, the pharmaceutical composition comprises at least about 45 mM histidine, hi certain embodiments, the pharmaceutical composition comprises at least about 50 mM histidine.

[0281] In some embodiments, the pharmaceutical composition has a pH of about 5.2 to about 6.8. In some embodiments, the pH of the pharmaceutical composition is about 5.2. In some embodiments, the pH of the pharmaceutical composition is about 5.3. In some embodiments, the pH of the pharmaceutical composition is about 5.4. In some embodiments, the pH of the pharmaceutical composition is about 5.5. In some embodiments, the pH of the pharmaceutical composition is about 5.6. In some embodiments, the pH of the pharmaceutical composition is about 5.7. In some embodiments, the pH of the pharmaceutical composition is about 5.8. In some embodiments, the pH of the pharmaceutical composition is about 5.9. In some embodiments, the pH of the pharmaceutical composition is about 6.0. In some embodiments, the pH of the pharmaceutical composition is about 6.1. In some embodiments, the pH of the pharmaceutical composition is about 6.2. In some embodiments, the pH of the pharmaceutical composition is about 6.3. In some embodiments, the pH of the pharmaceutical composition is about 6.4. In some embodiments, the pH of the pharmaceutical composition is about 6.5. In some embodiments, the pH of the pharmaceutical composition is about 6.6. In some embodiments, the pH of the pharmaceutical composition is about 6.7. In some embodiments, the pH of the pharmaceutical composition is about 6.8.

[0282] III.E. Surfactants In some embodiments, the pharmaceutical composition further comprises a surfactant. Any surfactant can be used in the pharmaceutical compositions disclosed herein. In some embodiments, the surfactant is selected from the group consisting of polysorbate 20, polysorbate 80, and poloxamer 188. In certain embodiments, the pharmaceutical composition comprises polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.001% to at least about 1% w / v polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% to at least about 0.1%, at least about 0.02% to at least about 0.1%, at least about 0.03% to at least about 0.1%, at least about 0.04% to at least about 0.1%, at least about 0.05% to at least about 0.1%, at least about 0.01% to at least about 0.09%, at least about 0.01% to at least about 0.8%, at least about 0.01% to at least about 0.7%, at least about 0.01% to at least about 0.6%, at least about 0.01% to at least about 0.5%, at least about 0.02% to at least about 0.09%, at least about 0.03% to at least about 0.08%, at least about 0.04% to at least about 0.07%, or at least about 0.04% to at least about 0.06% w / v polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% to at least about 0.1% w / v polysorbate 80.

[0283] 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 certain embodiments, the pharmaceutical composition comprises at least about 0.03% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.04% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.05% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.06% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.07% w / v polysorbate 80.

[0284] In certain embodiments, the pharmaceutical composition comprises (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, and (f) about 5 mM methionine. In certain 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, and (f) about 5 mM methionine.

[0285] In some embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody, e.g., nivolumab; (b) a checkpoint inhibitor, e.g., an anti-CTLA-4 antibody; (c) about 20 mM histidine; (d) about 250 mM sucrose; (e) about 0.05% w / v polysorbate 80; (f) about 50 μM pentetic acid; and (g) about 5 mM methionine. In some embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody, e.g., nivolumab; (b) a checkpoint inhibitor, e.g., an anti-CTLA-4 antibody; (c) about 20 mM histidine; (d) about 250 mM sucrose; (e) about 0.05% w / v polysorbate 80; (f) about 50 μM pentetic acid; (g) about 5 mM methionine; and (h) about 2000 U / mL rHuPH20.

[0286] In some embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody, e.g., nivolumab; (b) a checkpoint inhibitor, e.g., an anti-LAG-3 antibody; (c) about 20 mM histidine; (d) about 250 mM sucrose; (e) about 0.05% w / v polysorbate 80; (f) about 50 μM pentetic acid; and (g) about 5 mM methionine. In some embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody, e.g., nivolumab; (b) a checkpoint inhibitor, e.g., an anti-LAG-3 antibody; (c) about 20 mM histidine; (d) about 250 mM sucrose; (e) about 0.05% w / v polysorbate 80; (f) about 50 μM pentetic acid; (g) about 5 mM methionine; and (h) about 2000 U / mL rHuPH20.

[0287] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, and (f) about 5 mM methionine. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, and (f) about 5 mM methionine. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20.

[0288] In certain embodiments, a unit dose described herein comprises (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, and (f) about 5 mM methionine. In certain embodiments, a unit dose described herein comprises (a) about 120 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20. In certain embodiments, a unit dose described herein comprises (a) about 120 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, and (f) about 5 mM methionine. In certain embodiments, a unit dose described herein comprises (a) about 120 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20.

[0289] In certain embodiments, a unit dose described herein comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, and (f) about 5 mM methionine. In certain embodiments, a unit dose described herein comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL of rHuPH20. In certain embodiments, a unit dose described herein comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, and (f) about 5 mM methionine. In certain embodiments, a unit dose described herein comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) about 2000 U / mL rHuPH20.

[0290] In certain embodiments, the pharmaceutical composition comprises (a) about 672 mg of nivolumab, (b) about 8.68 mg of L-histidine, (c) about 11.8 mg of histidine HCl HO, (d) about 479 mg of sucrose, (e) about 2.80 mg of polysorbate 80, (f) about 0.110 mg of pentetic acid, and (g) about 4.18 mg of methionine, wherein (a)-(g) are reconstituted in water (e.g., sterile water for injection, SWFI) to a final volume of at least about 5.6 mL.

[0291] III.F. Containers and Delivery Devices Some aspects of the present disclosure are directed to a vial containing a pharmaceutical composition disclosed herein. In some aspects, the vial contains a unit dose of the pharmaceutical composition. In some aspects, the vial contains (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM L-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 some aspects, the vial does not contain hyaluronidase.

[0292] In some embodiments, the vial is a syringe.Any syringe can be used in the compositions and methods disclosed herein.In some embodiments, the syringe comprises one or more mechanical elements that improve subcutaneous administration.

[0293] In some embodiments, the vial is an autoinjector. Typically, autoinjectors function by the patient simply applying pressure to the injection site, thereby actuating the needle and subsequent flow of medication. The pressure triggers activation of a needle shield that engages the needle and causes the device to inject the medication. Accordingly, some embodiments of the present disclosure are directed to an autoinjector comprising: (a) about 150 mg / mL of an anti-PD-1 antibody; (b) about 20 mM L-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 some embodiments, the autoinjector does not contain hyaluronidase.

[0294] In some embodiments, the vial is an injector pen. Standard injector pens require the patient to activate a push button, which activates the needle into the target injection site. Accordingly, some embodiments of the present disclosure are directed to an injector pen comprising: (a) about 150 mg / mL of an anti-PD-1 antibody; (b) about 20 mM L-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 some embodiments, the injector pen does not contain hyaluronidase.

[0295] In some embodiments, the vial is a wearable pump or a wearable device. In some embodiments, the wearable pump is a patch pump. Accordingly, some embodiments of the present disclosure are directed to a wearable pump comprising: (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM L-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 some embodiments, the wearable pump does not contain hyaluronidase.

[0296] Some embodiments of the present disclosure are directed to an autoinjector comprising: (a) about 150 mg / mL of an anti-PD-1 antibody; (b) about 20 mM L-histidine; (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.

[0297] In some embodiments, the vial is an injector pen. Standard injector pens require the patient to activate a push button, which activates a needle into the target injection site. Accordingly, some embodiments of the present disclosure are directed to an injector pen comprising: (a) about 150 mg / mL of an anti-PD-1 antibody; (b) about 20 mM L-histidine; (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.

[0298] In some embodiments, the vial is a wearable pump or a wearable device. In some embodiments, the wearable pump is a patch pump. Accordingly, some embodiments of the present disclosure are directed to a wearable pump comprising: (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM L-histidine, (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.

[0299] III.G. Additional Therapeutic Agents In some embodiments, the pharmaceutical composition further comprises a second therapeutic agent (e.g., an anti-PD-1 antibody and an additional therapeutic agent, or an anti-PD-L1 antibody and an additional therapeutic agent). In some embodiments, the pharmaceutical composition further comprises a third therapeutic agent. The additional therapeutic agent may include any therapy and / or any standard of care for treating a tumor in a subject, as disclosed herein. In some embodiments, the additional therapeutic agent comprises a second antibody. In some embodiments, the additional therapeutic agent comprises an antibody or antigen-binding portion thereof that specifically binds to 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, or any combination thereof. In some embodiments, the second therapeutic agent, the third therapeutic agent, or both comprise IL-2 (e.g., bempegaldesleukin). In some embodiments, the second therapeutic agent, the third therapeutic agent, or both, comprises IL12-Fc (e.g., BMS-986415).

[0300] In some embodiments, the antibody is a multispecific antibody. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody is a trispecific antibody. In some embodiments, the antibody specifically binds to (i) PD-1 and (ii) a second antigen. In some embodiments, the antibody specifically binds to (i) PD-1, (ii) a second antigen, and (iii) a third antigen. In some embodiments, the antibody specifically binds to (i) PD-L1 and (ii) a second antigen. In some embodiments, the antibody specifically binds to (i) PD-L1, (ii) a second antigen, and (iii) a third antigen. In some embodiments, the second antigen and the third antigen are the same. In some embodiments, the second antigen and the third antigen are different. In some embodiments, the second antigen is CD3.

[0301] In some embodiments, the antibody specifically binds to (i) TIGIT and (ii) an inhibitory receptor expressed on T cells, NK cells, or both. In some embodiments, the antibody specifically binds to (i) CD40 and (ii) CD20.

[0302] In some embodiments, the second antibody comprises an anti-CTLA-4 antibody. The anti-CTLA-4 antibody can be any antibody or antigen-binding portion thereof that binds to and inhibits the activity of CTLA-4. In some embodiments, the anti-CTLA-4 antibody is any anti-CTLA-4 antibody disclosed herein. In some embodiments, the second antibody comprises tremelimumab. In some embodiments, the second antibody comprises ipilimumab.

[0303] In some embodiments, the second antibody comprises an anti-LAG3 antibody. The anti-LAG3 antibody can be any antibody or antigen-binding portion thereof that binds to LAG-3 and inhibits its activity. In some embodiments, the anti-LAG3 antibody comprises any anti-LAG3 antibody disclosed herein. In some embodiments, the second antibody comprises 25F7.

[0304] In some embodiments, the second antibody comprises an anti-CD137 antibody. The anti-CD137 antibody can be any antibody or antigen-binding portion thereof that binds to CD137 and inhibits its activity. In some embodiments, the anti-CD137 antibody comprises any anti-CD137 antibody disclosed herein. In some embodiments, the second antibody comprises urelumab.

[0305] In some embodiments, the second antibody comprises an anti-KIR antibody. An anti-KIR antibody includes any antibody or antigen-binding portion thereof that binds to KIR and inhibits its activity. In some embodiments, the anti-KIR antibody includes any anti-KIR antibody disclosed herein. In some embodiments, the second antibody comprises lirilumab.

[0306] In some embodiments, the second antibody comprises an anti-GITR antibody. The anti-GITR antibody can be any antibody or antigen-binding portion thereof that binds to GITR and inhibits its activity. In some embodiments, the anti-GITR antibody comprises any anti-GITR antibody disclosed herein. In some embodiments, the second antibody comprises MK4166. In some embodiments, the second antibody comprises TRX518.

[0307] In some embodiments, the second antibody comprises an anti-CD96 antibody. In some embodiments, the second antibody comprises an anti-TIM3 antibody. In some embodiments, the second antibody comprises an anti-VISTA antibody. In some embodiments, the second antibody comprises an anti-NKG2a antibody. In some embodiments, the second antibody comprises an anti-ICOS antibody. In some embodiments, the second antibody comprises an anti-OX40 antibody. In some embodiments, the second antibody comprises an anti-IL8 antibody, e.g., HuMax®-IL8 (BMS-986253).

[0308] III.G.1. Anti-CTLA-4 antibody In some embodiments, the second antibody comprises an anti-CTLA-4 antibody. Anti-CTLA-4 antibodies known in the art can be used in the compositions and methods of the present disclosure. The anti-CTLA-4 antibodies of the present invention bind to human CTLA-4 and disrupt the interaction between CTLA-4 and human B7 receptor. Because the interaction between CTLA-4 and B7 transmits a signal that leads to the inactivation of T cells bearing the CTLA-4 receptor, disruption of the interaction effectively induces, enhances, or prolongs the activation of such T cells, thereby inducing, enhances, or prolongs an immune response.

[0309] 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. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121, as well as International Publication Nos. WO2012 / 122444, WO2007 / 113648, WO2016 / 196237, and WO2000 / 037504, each of which is incorporated herein by reference in its entirety. 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) a cytoplasmic affinity of at least about 10, as determined by Biacore analysis; 7 M -1 , or about 10 9 M -1 , or about 10 10M -1 ~10 11 M -1 or higher equilibrium binding constant (K a ), (b) specifically binds human CTLA-4 with a binding affinity reflected by at least about 10 3 , about 10 4 , or about 10 5 m -1 s -1 The dynamic association constant (k a ), (c) at least about 10 3 , about 10 4 , or about 10 5 m -1 s -1 The dynamic dissociation constant (k d ), and (d) inhibit the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4 antibodies useful in the present invention include monoclonal antibodies that specifically bind to human CTLA-4 and exhibit at least one, at least two, or at least three of the above characteristics.

[0310] In certain embodiments, the CTLA-4 antibody is selected from the group consisting of ipilimumab (also known as YERVOY®, MDX-010, 10D1; see U.S. Pat. No. 6,984,720), MK-1308 (Merck), AGEN-1884 (Agenus Inc.; see WO2016 / 196237), and tremelimumab (AstraZeneca; also known as ticilimumab, CP-675,206; see WO2000 / 037504 and Ribas, Update Cancer Ther. 2(3): 133-39 (2007)). In certain embodiments, the anti-CTLA-4 antibody is ipilimumab.

[0311] In certain embodiments, the CTLA-4 antibody is ipilimumab for use in the compositions and methods disclosed herein. Ipilimumab is a fully human IgG1 monoclonal antibody that blocks the binding of CTLA-4 to its B7 ligand, thereby stimulating T cell activation and improving overall survival (OS) in patients with advanced melanoma.

[0312] 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.

[0313] In some embodiments, the CTLA-4 antibody is non-fucosylated or hypofucosylated. In some embodiments, the CTLA-4 antibody exhibits enhanced ADCC and / or ADCP activity. In some embodiments, the CTLA-4 antibody is BMS-986218 as described in PCT / US18 / 19868.

[0314] Anti-CTLA-4 antibodies that can be used in the disclosed compositions and methods also include isolated antibodies that specifically bind to human CTLA-4 and cross-compete with any of the anti-CTLA-4 antibodies disclosed herein, such as ipilimumab and / or tremelimumab, for binding to human CTLA-4. In some embodiments, the anti-CTLA-4 antibody binds to the same epitope as any of the anti-CTLA-4 antibodies described herein, such as ipilimumab and / or tremelimumab. The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of the reference antibody, such as ipilimumab and / or tremelimumab, due to their binding to the same epitope region of CTLA-4. Cross-competing antibodies can be readily identified based on their ability to cross-compete with ipilimumab and / or tremelimumab in standard CTLA-4 binding assays, such as Biacore analysis, ELISA assays or flow cytometry (see, e.g., WO2013 / 173223).

[0315] 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 antibodies are monoclonal antibodies. These cross-competing antibodies for administration to human subjects are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric antibodies, engineered antibodies, humanized or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0316] Anti-CTLA-4 antibodies that can be used in the compositions and methods of the disclosed invention also include antigen-binding portions of the above antibodies. It is well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0317] In some embodiments, the anti-CTLA-4 antibody can be formulated as a single formulation with the anti-PD-1 antibody in any one of the formulations disclosed herein. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of the anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) the anti-CTLA-4 antibody. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, (g) an anti-CTLA-4 antibody, and (h) about 2000 U / mL of rHuPH20.

[0318] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) an anti-CTLA-4 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, (g) an anti-CTLA-4 antibody, and (h) about 2000 U / mL rHuPH20.

[0319] Anti-CTLA-4 antibodies suitable for use in the disclosed methods or compositions are those that bind to CTLA-4 with high specificity and affinity, block the activity of CTLA-4, and disrupt the interaction of CTLA-4 with the human B7 receptor. In any of the compositions or methods disclosed herein, the anti-CTLA-4 "antibody" includes an antigen-binding portion or fragment that exhibits functional properties similar to those of the whole antibody in binding to CTLA-4, inhibiting the interaction of CTLA-4 with the human B7 receptor, and upregulating the immune system. In certain embodiments, the anti-CTLA-4 antibody or antigen-binding portion thereof cross-competes with ipilimumab and / or tremelimumab for binding to human CTLA-4.

[0320] In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, specific for (i) CTLA-4 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, e.g., a bispecific antibody, specific for (i) CTLA-4 and (ii) CD3.

[0321] III.G.2. Anti-LAG-3 antibody In some embodiments, the second antibody comprises an anti-LAG-3 antibody, such as leratolimab. The anti-LAG-3 antibody of the present disclosure binds to human LAG-3. Antibodies that bind to LAG-3 are disclosed in International Publication No. WO2015 / 042246 and U.S. Patent Application Publication Nos. 2014 / 0093511 and 2011 / 0150892, each of which is incorporated herein by reference in its entirety.

[0322] An exemplary LAG-3 antibody useful in the present disclosure is 25F7 (described in U.S. Patent Application Publication No. 2011 / 0150892). An additional exemplary LAG-3 antibody useful in the present disclosure is BMS-986016 (relatolimab). In some embodiments, an anti-LAG-3 antibody useful in the present disclosure cross-competes with 25F7 or BMS-986016. In some embodiments, an anti-LAG-3 antibody useful in the present disclosure binds to the same epitope as 25F7 or BMS-986016. In some embodiments, an anti-LAG-3 antibody comprises the six CDRs of 25F7 or BMS-986016.

[0323] Other anti-LAG-3 antibodies known in the art that can be used in the methods and / or compositions of the disclosure include IMP731 (H5L7BW), described in U.S. Patent Application Publication No. 2011 / 007023, MK-4280 (28G-10, favezelimab), described in WO2016028672 and U.S. Patent Application Publication No. 2020 / 0055938, Burova E, et al., J. Immunother. Cancer (2016); 4(Supp. 1): P195 and REGN3767 (fianlimab), described in U.S. Pat. No. 10,358,495; humanized BAP050, described in WO2017 / 019894; GSK2831781; IMP-701 (LAG525; ayelamirimab), described in U.S. Pat. No. 10,711,060 and U.S. Patent Application Publication No. 2020 / 0172617; aLAG3(0414); These include LAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (formerly XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P13B02-30, AVA-017, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, and ABL501.These and other anti-LAG-3 antibodies useful in the claimed invention are described in, e.g., U.S. Pat. No. 10,188,730, WO2016 / 028672, WO2017 / 106129, WO2017 / 062888, WO2009 / 044273, WO2018 / 069500, WO2016 / 1268 58, WO2014 / 179664, WO2016 / 200782, WO2015 / 200119, WO2017 / 019846, WO2017 / 19 8741, WO2017 / 220555, WO2017 / 220569, WO2018 / 071500, WO2017 / 015560, WO2017 / 025498, WO2017 / 087589, WO2017 / 087901, WO2018 / 083087, WO2017 / 149143, WO20 17 / 219995, US2017 / 0260271, WO2017 / 086367, WO2017 / 086419, WO2018 / 034227, W and WO2019 / 018730, the contents of each of which are incorporated by reference in their entirety.

[0324] Anti-LAG-3 antibodies that can be used in the methods and / or compositions of the present disclosure also include isolated antibodies that specifically bind to human LAG-3 and cross-compete with any of the anti-LAG-3 antibodies disclosed herein, e.g., leratolimab, for binding to human LAG-3. In some embodiments, the anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein, e.g., leratolimab.

[0325] In some embodiments, any anti-LAG-3 antibody disclosed herein, such as relatolimab, that cross-competes with or binds to the same epitope region as any anti-LAG-3 antibody disclosed herein, such as relatolimab, is a monoclonal antibody. These cross-competing antibodies for administration to human subjects are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0326] The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that specific epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of the reference antibody, such as leratolimab, due to their binding to the same epitope region. Cross-competing antibodies can be easily identified based on their ability to cross-compete in standard binding assays, such as Biacore analysis, ELISA assays or flow cytometry (see, for example, WO2013 / 173223).

[0327] Anti-LAG-3 antibodies that can be used in the methods and / or compositions of the disclosure also include antigen-binding portions of any of the full-length antibodies described above. It is well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0328] In some embodiments, the anti-LAG-3 antibody is a full-length antibody.

[0329] In some embodiments, the anti-LAG-3 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody is a dual affinity retargeting antibody (DART), a DVD-Ig, or a bispecific antibody.

[0330] In some embodiments, the anti-LAG-3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0331] In some embodiments, the anti-LAG-3 antibody is selected from the group consisting of BMS-986016 (leratolimab), IMP731 (H5L7BW), MK4280 (28G-10, favezelimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, ayelamirimab), aLAG3(0414), aLAG3(0416), Sym022, TSR- 033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or comprising an antigen-binding portion thereof.

[0332] In some embodiments, the anti-LAG-3 antibody is leratolimab.

[0333] In some embodiments, the anti-LAG-3 antibody is MGD013 (tebotelimab), a bispecific PD-1 x LAG-3 DART.

[0334] In some embodiments, the anti-LAG-3 antibody is REGN3767 (fianlimab).

[0335] In some embodiments, the anti-LAG-3 antibody is LAG525 (aielamirimab).

[0336] In some embodiments, the anti-LAG-3 antibody is MK4280 (fabezelimab).

[0337] In some embodiments, the anti-LAG-3 antibody can be formulated with the anti-PD-1 antibody in any one of the formulations disclosed herein as a single formulation. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of the anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) the anti-LAG-3 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) leratolimab. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, (g) an anti-LAG-3 antibody, and (h) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL of an anti-PD-1 antibody, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, (g) leratolimab, and (h) about 2000 U / mL of rHuPH20.

[0338] In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) an anti-LAG-3 antibody. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, and (g) leratolimab. In certain embodiments, the pharmaceutical composition comprises: (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, (g) an anti-LAG-3 antibody, and (h) about 2000 U / mL rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) about 150 mg / mL nivolumab, (b) about 20 mM histidine, (c) about 250 mM sucrose, (d) about 0.05% w / v polysorbate 80, (e) about 50 μM pentetic acid, (f) about 5 mM methionine, (g) leratolimab, and (h) about 2000 U / mL rHuPH20.

[0339] An exemplary LAG-3 antibody useful in the present disclosure is 25F7 (described in U.S. Patent Application Publication No. 2011 / 0150892). An additional exemplary LAG-3 antibody useful in the present disclosure is BMS-986016. In one embodiment, an anti-LAG-3 antibody useful in the present compositions cross-competes with 25F7 or BMS-986016. In another embodiment, an anti-LAG-3 antibo...

Claims

[Claim 1] The invention described in the specification or drawings of this application.

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