Antibody compositions and methods of use thereof

Abstract

The present disclosure provides a pharmaceutical composition comprising an anti-PD-1 antibody and / or an anti-PD-L1 antibody, an anti-LAG-3 antibody, and an endoglycosidase hydrolase enzyme. In some aspects, the pharmaceutical compositions are formulated for subcutaneous delivery. Other aspects of the disclosure relate to methods of subcutaneously delivering the pharmaceutical compositions.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This PCT application claims the benefit of priority to U.S. Provisional Application No. 63 / 348,409, filed on June 2, 2022, U.S. Provisional Application No. 63 / 384,213, filed on November 17, 2022, and U.S. Provisional Application No. 63 / 505,467, filed on June 1, 2023, which are incorporated herein by reference in their entirety. References to electronically submitted sequence listings

[0002] The contents of the electronically submitted Sequence Listing (Name: 3338_301PC03_Seqlisting_ST26; Size: 491,182 bytes; Creation Date: June 1, 2023) are submitted with this application and are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure provides pharmaceutical compositions comprising antibodies and methods of using these pharmaceutical compositions to treat subjects having tumors. Background Art

[0004] Human cancers have numerous genetic and epigenetic alterations that generate novel antigens that are potentially recognizable by the immune system (Sjoblom et al., Science 2006; 314(5797): 268-274). The adaptive immune system, composed of T and B lymphocytes, has a powerful anti-cancer potential, with broad capabilities and precise specificity to respond to diverse tumor antigens. In addition, the immune system exhibits considerable plasticity and memory components. Successfully harnessing all of these properties of the adaptive immune system will make immunotherapy unique among all cancer treatment modalities.

[0005] Until recently, cancer immunotherapy has focused significant efforts on approaches to enhance antitumor immune responses through adoptive transfer of activated effector cells, immunization against relevant antigens, or delivery of nonspecific immune stimulants such as cytokines. However, over the past decade, significant efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapeutic approaches for treating cancer, including the development of antibodies that specifically bind to the programmed death-1 (PD-1) receptor and block the inhibitory PD-1 / PD-1 ligand pathway, such as nivolumab and pembrolizumab (formerly lambrolizumab; USAN Council USAN Council Statement, 2013) (Topalian et al., Curr. Opin. Immunol. 2012;24(2):207-212; Topalian et al., N. Engl. J. Med. 2012;366(26):2443-2454; Topalian et al., J. Clin. Oncol. 2014;32(10):1020-1030; Hamid et al., N. Engl. J. Med. 2013;369(2):134-144; Hamid and Carvajal, Expert Opin. Biol. Ther. 2013;13(6):847-861; McDermott and Atkins, Cancer Med. [Cancer Medicine] 2013; 2(5): 662-673).

[0006] Lymphocyte activation gene-3 (LAG-3; CD223) is a type I transmembrane protein that is expressed on the cell surface of activated CD4+ and CD8+ T cells, as well as NK and dendritic cell subsets (Triebel F et al., J. Exp. Med. 1990; 171: 1393-1405; Workman CJ et al., J. Immunol. 2009; 182(4): 1885-91). LAG-3 is closely related to CD4, a co-receptor for T helper cell activation. Both molecules have four extracellular Ig-like domains and bind to the class II major histocompatibility complex (MHC). In contrast to CD4, LAG-3 is only expressed on the cell surface of activated T cells, and its cleavage from the cell surface terminates LAG-3 signaling. LAG-3 can also be found as a soluble protein, but its function is unknown.

[0007] Current methods for delivering anti-PD-1 and anti-LAG-3 antibodies use regular intravenous administration by a clinician, typically in a clinic or hospital. The inconvenience and invasiveness of treatment can negatively impact the patient experience. Subcutaneous delivery could significantly improve the patient experience. There remains a need in the art for formulations comprising an anti-PD-1 or anti-PD-L1 antibody and an anti-LAG-3 antibody suitable for subcutaneous delivery to a patient. Summary of the Invention

[0008] Some aspects of the present disclosure relate to a pharmaceutical composition comprising (i) an antibody that specifically binds to PD-1 ("anti-PD-1 antibody") and / or an antibody that specifically binds to PD-L1 ("anti-PD-L1 antibody"), (ii) an antibody that specifically binds to LAG-3 ("anti-LAG-3 antibody"), and (iii) an endoglycosidase hydrolase.

[0009] In some aspects, the pharmaceutical composition further comprises an antioxidant. In some aspects, the antioxidant comprises a sacrificial antioxidant, a metal ion chelator, or both. In some aspects, the antioxidant is methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, or any combination thereof. In some aspects, the antioxidant comprises pentetic acid ("DTPA") or ethylenediaminetetraacetic acid ("EDTA").

[0010] In some aspects, the pharmaceutical composition comprises at least two antioxidants. In some aspects, the at least two antioxidants are selected from methionine, DTPA, and EDTA. In some aspects, the at least two antioxidants are (i) methionine and DTPA or (ii) methionine and EDTA.

[0011] In some aspects, the pharmaceutical composition comprises at least about 0.1 mM to at least about 100 mM or at least about 1 mM to about 20 mM methionine. In some aspects, the pharmaceutical composition comprises about 0.1 mM to about 100 mM, about 0.1 mM to about 90 mM, about 0.1 mM to about 80 mM, about 0.1 mM to about 70 mM, about 0.1 mM to about 60 mM, about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 10 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 10 mM, about 1 mM to about 20 mM, about 1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 10 mM, about 1 mM to about 20 mM, about 1 mM to about 3 ...30 mM, about 1 mM to about 20 mM, about 1 mM to about 10 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 10 mM, about 1 mM to about 20 mM, about 1 m About 1 mM to about 9 mM, about 1 mM to about 8 mM, about 1 mM to about 7 mM, about 1 mM to about 6 mM, about 1 mM to about 5 mM, about 2 mM to about 9 mM, about 3 mM to about 8 mM, about 4 mM to about 7 mM, about 4 mM to about 6 mM, about 4 mM to about 5 mM, about 5 mM to about 20 mM, about 5 mM to about 15 mM, about 5 mM to about 10 mM, about 5 mM to about 9 mM, about 5 mM to about 8 mM, about 5 mM to about 7 mM, or about 5 mM to about 6 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM, or at least about 20 mM methionine. In some aspects, the pharmaceutical composition comprises about 1 mM, about 1.5 mM, about 2 mM, about 2.5 mM, about 3 mM, about 3.5 mM, about 4 mM, about 4.5 mM, about 5 mM, about 5.5 mM, about 6 mM, about 6.5 mM, about 7 mM, about 7.5 mM, about 8 mM, about 8.5 mM, about 9 mM, about 9.5 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM In some aspects, the pharmaceutical composition comprises about 5mM methionine.

[0012] In some aspects, the pharmaceutical composition comprises at least about 1 μM to at least about 250 μM or at least about 5 μM to about 200 μM DTPA. In some aspects, the pharmaceutical composition comprises about 1 μM to about 250 μM, about 10 μM to about 200 μM, about 10 μM to about 175 μM, about 10 μM to about 150 μM, about 10 μM to about 125 μM, about 10 μM to about 100 μM, about 10 μM to about 75 μM, about 10 μM to about 70 μM, about 10 μM to about 60 μM, about 10 μM to about 50 μM, about 20 μM to about 100 μM, about 20 μM to about 75 μM, about 20 μM to about 70 μM, about 20 μM to about 60 μM, about 20 μM to about 50 μM, about 25 μM to about 100 μM, about 25 μM to about 75 μM, about 25 μM to about 50 μM, about 30 μM to about 100 μM, about 30 μM to about 75 μM, about 30 μM to about 70 μM, about 30 μM to about 60 μM, about 30 μM to about 50 μM, about 40 μM to about 100 μM, about 40 μM to about 75 μM, about 40 μM to about 70 μM, about 40 μM to about 60 μM, about 40 μM to about 50 μM, about 41 μM to about 59 μM, about 42 μM to about 58 μM, about 43 μM to about 57 μM, about 44 μM to about 56 μM, about 45 μM to about 55 μM, about 46 μM to about 54 μM, about 47 μM to about 53 μM, about 48 μM to about 52 μM, about 49 μM to about 51 μM, about 50 μM to about 100 μM, about 50 μM to about 75 μM, about 50 μM to about 70 μM, about 50 μM to about 60 μM DTPA. In some aspects, the pharmaceutical composition comprises at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 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 At least about 70 μM, at least about 75 μM, at least about 80 μM, at least about 85 μM, at least about 90 μM, at least about 95 μM, at least about 100 μM, at least about 110 μM, at least about 120 μM, at least about 130 μM, at least about 140 μM, at least about 150 μM, at least about 160 μM, at least about 170 μM, at least about 180 μM, at least about 190 μM, or at least about 200 μM DTPA.In some aspects, the pharmaceutical composition comprises about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 55 μM, about 60 μM, about 65 μM, about 70 μM, about 75 μM, about 80 μM, about 85 μM, about 90 μM, about 95 μM, about 100 μM, about 110 μM, about 120 μM, about 130 μM, about 140 μM, about 150 μM, about 160 μM, about 170 μM, about 180 μM, about 190 μM, about 200 μM, about 210 μM, about 220 μM, about 230 μM, about 240 μM, or about 250 μM DTPA. In some aspects, the pharmaceutical composition comprises about 50 μM DTPA.

[0013] In some aspects, the ratio of the anti-PD-1 antibody to the anti-LAG-3 antibody is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:16 In some aspects, the ratio of the anti-PD-1 antibody to the anti-LAG-3 antibody is about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, or about 2:1.

[0014] In some aspects, the pharmaceutical composition comprises an anti-PD-1 antibody or an anti-PD-1 antibody and an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL or at least about 20 mg / mL to at least about 200 mg / mL of the anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 10 mg / mL to about 500 mg / mL, about 10 mg / mL to about 450 mg / mL, about 10 mg / mL to about 400 mg / mL, about 10 mg / mL to about 350 mg / mL, about 10 mg / mL to about 300 mg / mL, about 10 mg / mL to about 250 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 190 mg / mL, about 10 mg / mL to about 180 mg / mL, about 10 mg / mL to about 170 mg / mL, about 10 mg / mL to about 160 mg / mL. mL, about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 140 mg / mL, about 10 mg / mL to about 130 mg / mL, about 10 mg / mL to about 120 mg / mL, about 10 mg / mL to about 110 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 85 mg / mL, about 10 mg / mL to about 80 mg / mL, about 20 mg / mL to about 500 mg / mL, about 20 mg / mL to about 450 mg / mL, about 20 mg / mL to about 40 0 mg / mL, about 20 mg / mL to about 350 mg / mL, about 20 mg / mL to about 300 mg / mL, about 20 mg / mL to about 250 mg / mL, about 20 mg / mL to about 200 mg / mL, about 20 mg / mL to about 190 mg / mL, about 20 mg / mL to about 180 mg / mL, about 20 mg / mL to about 170 mg / mL, about 20 mg / mL to about 160 mg / mL, about 20 mg / mL to about 150 mg / mL, about 20 mg / mL to about 140 mg / mL, about 20 mg / mL to about 130 mg / mL, about 20 mg / mL to about g / mL to about 120 mg / mL, about 20 mg / mL to about 110 mg / mL, about 20 mg / mL to about 100 mg / mL, about 20 mg / mL to about 90 mg / mL, about 20 mg / mL to about 85 mg / mL, about 20 mg / mL to about 80 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 190 mg / mL, about 50 mg / mL to about 180 mg / mL, about 50 mg / mL to about 170 mg / mL, about 50 mg / mL to about 160 mg / mL, about 50 mg / mL to about 150 mg / mL,About 50 mg / mL to about 140 mg / mL, about 50 mg / mL to about 130 mg / mL, about 50 mg / mL to about 120 mg / mL, about 50 mg / mL to about 110 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 90 mg / mL, about 50 mg / mL to about 85 mg / mL, about 50 mg / mL to about 80 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 150 mg / mL, about 150 mg / mL to about 200 mg / mL, about 135 mg / mL to about 180 mg / mL, about 100 mg / mL to about 130 mg / mL, or about 108 mg / mL to about 132 mg / mL of the anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL, at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL of the anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 108 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 132 mg / mL. mL, about 135 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL,About 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL of the anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 80 mg / mL of the anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about The present invention also provides an embodiment of the present invention relates to an anti-PD-1 antibody of the present invention. The present invention further comprises: a first-line treatment of an anti-PD-1 antibody comprising ... In some aspects, the pharmaceutical composition comprises about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5. mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg,about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, 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, 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, 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 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080mg, About 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg of the anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 960 mg of the anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises about 1200 mg of the anti-PD-1 antibody.

[0015] In some aspects, the pharmaceutical composition comprises at least about 3 mg / mL to at least about 200 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises about 1 mg / mL to about 500 mg / mL, about 1 mg / mL to about 450 mg / mL, about 1 mg / mL to about 400 mg / mL, about 1 mg / mL to about 350 mg / mL, about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 150 mg / mL, about 1 mg / mL to about 140 mg / mL, about 1 mg / mL to about 130 mg / mL, about 1 mg / mL to about 120 mg / mL, about 1 mg / mL to about 110 mg / mL, about 1 mg / mL to about 150 mg / mL, about 1 mg / mL to about 160 mg / mL, about 1 mg / mL to about 170 mg / mL, about 1 mg / mL to about 180 mg / mL, about 1 mg / mL to about 190 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 250 mg / mL, about about 100 mg / mL, about 1 mg / mL to about 90 mg / mL, about 1 mg / mL to about 80 mg / mL, about 1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 60 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 45 mg / mL, about 1 mg / mL to about 40 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 29 mg / mL, about 1 mg / mL to about 28 mg / mL, about 1 mg / mL to about 27 mg / mL, about 1 mg / mL to about 26 mg / mL, about 1 mg / mL to about about 25 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 15 mg / mL, about 1 mg / mL to about 10 mg / mL, or about 1 mg / mL to about 5 mg / mL, about 3 mg / mL to about 200 mg / mL, about 5 mg / mL to about 250 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 150 mg / mL, about 5 mg / mL to about 140 mg / mL, about 5 mg / mL to about 130 mg / mL, about 5 mg / mL to about 120 mg / mL, about 5 mg / mL to about 110 mg / mL, about 5 mg / mL to about 100 mg / mL , about 5 mg / mL to about 90 mg / mL, about 5 mg / mL to about 80 mg / mL, about 5 mg / mL to about 70 mg / mL, about 5 mg / mL to about 60 mg / mL, about 5 mg / mL to about 50 mg / mL, about 5 mg / mL to about 45 mg / mL, about 5 mg / mL to about 40 mg / mL, about 5 mg / mL to about 35 mg / mL, about 5 mg / mL to about 30 mg / mL, about 5 mg / mL to about 29 mg / mL, about 5 mg / mL to about 28 mg / mL, about 5 mg / mL to about 27 mg / mL, about 5 mg / mL to about 26 mg / mL, about 5 mg / mL to about 25 mg / mL,from about 5 mg / mL to about 20 mg / mL, from about 5 mg / mL to about 15 mg / mL, from about 5 mg / mL to about 10 mg / mL, from about 10 mg / mL to about 100 mg / mL, from about 10 mg / mL to about 90 mg / mL, from about 10 mg / mL to about 80 mg / mL, from about 10 mg / mL to about 70 mg / mL, from about 10 mg / mL to about 60 mg / mL, from about 10 mg / mL to about 50 mg / mL, from about 10 mg / mL to about 45 mg / mL, from about 10 mg / mL to about 40 mg / mL, from about 10 mg / mL to about 35 mg / mL, from about 10 mg / mL to about 30 mg / mL, from about 10 mg / mL to about 29 mg / mL, from about 10 mg / mL to about 28 mg / mL, from about 10 mg / mL to about 27 mg / mL, from about 10 mg / mL to about 26 mg / mL

[0014] In some embodiments, the anti-LAG-3 antibody is present in an amount of about 10 mg / mL to about 25 mg / mL, about 10 mg / mL to about 20 mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 45 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 35 mg / mL, about 20 mg / mL to about 30 mg / mL, about 20 mg / mL to about 29 mg / mL, about 20 mg / mL to about 28 mg / mL, about 20 mg / mL to about 27 mg / mL, about 20 mg / mL to about 26 mg / mL, about 20 mg / mL to about 25 mg / mL, about 25 mg / mL to about 30 mg / mL, about 25 mg / mL to about 29 mg / mL, about 25 mg / mL to about 28 mg / mL, or about 25 mg / mL to about 27 mg / mL. In some aspects, the pharmaceutical composition comprises at least about 3 mg / mL, at least about 3.3 mg / mL, at least about 4 mg / mL, at least about 5 mg / mL, at least about 6 mg / mL, at least about 7 mg / mL, at least about 8 mg / mL, at least about 9 mg / mL, at least about 10 mg / mL, at least about 13 mg / mL, at least about 15 mg / mL, at least about 18 mg / mL, at least about 20 mg / mL, at least about 23 mg / mL, at least about 25 mg / mL, at least about 26 mg / mL, at least about 27 mg / mL, at least about 28 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,In some aspects, the pharmaceutical composition comprises at least about 190 mg / mL, or at least about 200 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 3.3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 13 mg / mL, about 13.35 mg / mL, about 15 mg / mL, about 18 mg / mL, about 20 mg / mL, about 23 mg / mL, about 25 mg / mL, about 26 mg / mL, about 26.7 mg / mL, about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 108 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 132 mg / mL L, about 135 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL In some aspects, the pharmaceutical composition comprises about 13.3 mg / mL, about 13.35 mg / mL, about 26 mg / mL, about 26.7 mg / mL, about 40 mg / mL, or about 80 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises about 26.7 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises about 0.25 mg to about 2000 mg,about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2 In some embodiments, the anti-LAG-3 antibody is administered in an amount of about 1000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, 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, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg,About 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg 0mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, about 1080mg, about 1100mg, about 1140mg, about 1180mg, about 1200mg, about 1240mg, about 1280mg, about 1300mg, about 1 In some aspects, the pharmaceutical composition comprises about 320 mg of the anti-LAG-3 antibody.

[0016] In some aspects, the pharmaceutical composition comprises at least about 5 units ("U") to at least about 100,000 U of the endoglycosidase hydrolase. In some aspects, the pharmaceutical composition comprises about 50 U to about 100,000 U, about 500 U to about 100,000 U, about 1,000 U to about 100,000 U, about 5,000 U to about 100,000 U, about 10,000 U to about 100,000 U, about 15,000 U to about 100,000 U, about 20,000 U to about 100,000 U, about 500U to about 50,000U, about 1,000U to about 50,000U, about 5,000U to about 50,000U, about 10,000U to about 50,000U, about 15,000U to about 50,000U, about 20,000U to about 50,000U, about 15,000U to about 45,000U, about 16,000U to about 40,000U, about 1 7,000 U to about 35,000 U, about 18,000 U to about 30,000 U, about 19,000 U to about 29,000 U, about 19,000 U to about 28,000 U, about 19,000 U to about 27,000 U, about 19,000 U to about 26,000 U, about 19,000 U to about 25,000 U, about 19,000 U to about 24,000 U The endoglycosidase hydrolase comprises about 1,000 U to about 2,000 U of the present invention, about 1,000 U to about 2,000 U of the present invention, about 1,000 U to about 2,000 U of the present invention, about 1,000 U to about 2,000 U of the present invention, about 1,000 U to about 2,000 U of the present invention, about 1,000 U to about 2,000 U of the present invention, about 1,000 U to about 2,000 U of the present invention, In some aspects, the pharmaceutical composition comprises at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, ​​at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about At least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U, at least about 80,000 U, at least about 90,000 U, or at least about 100,000 U of the endoglycosidase hydrolase.In some aspects, the pharmaceutical composition comprises about 50 U, about 100 U, about 150 U, about 200 U, about 250 U, about 300 U, about 400 U, about 500 U, about 600 U, about 700 U, about 800 U, about 900 U, about 1000 U, about 1500 U, about 2000 U, about 2500 U, about 3000 U, about 4000 U, about 5000 U, about 10,000 U, about 15,000 U, about 20,000 U, about 24,000 U. In some aspects, the pharmaceutical composition comprises at least about 20,000U or about 24,000U of this endoglycosidase hydrolase. In some aspects, the pharmaceutical composition comprises at least about 500U / mL to at least about 5000U / mL of this endoglycosidase hydrolase.In some aspects, the pharmaceutical composition comprises about 50 U / mL to about 10,000 U / mL, about 100 U / mL to about 9500 U / mL, about 150 U / mL to about 9000 U / mL, about 200 U / mL to about 8500 U / mL, about 250 U / mL to about 8000 U / mL, about 300 U / mL to about 7500 U / mL, about 350 U / mL to about 7000 U / mL, about 400 U / mL to about 6500 U / mL, or about 500 U / mL to about 8000 U / mL. U / mL, about 450 U / mL to about 6000 U / mL, about 500 U / mL to about 5500 U / mL, about 550 U / mL to about 5000 U / mL, about 600 U / mL to about 4500 U / mL, about 650 U / mL to about 4000 U / mL, about 700 U / mL to about 3500 U / mL, about 750 U / mL to about 3000 U / mL, about 800 U / mL to about 2500 U / mL, about 900 U / mL to about 1500 U / mL, about 1200 U / mL to about 1500 U / mL, about 1400 U / mL to about 1600 U / mL, about 1500 U / mL to about 1600 U / mL, about 1600 U / mL to about 1700 U / mL, about 1800 U / mL to about 1900 U / mL, about 1900 U / mL to about 2000 U / mL, about 18 ... / mL to about 2500 U / mL, about 1000 U / mL to about 2500 U / mL, about 1500 U / mL to about 2500 U / mL, about 1600 U / mL to about 2500 U / mL, about 1700 U / mL to about 2500 U / mL, about 1800 U / mL to about 2500 U / mL, about 1900 U / mL to about 2500 U / mL, about 2000 U / mL to about 2500 U / mL, about 21 ...200 U / mL to about 2500 U / mL, about 2300 U / mL to about 2500 U / mL, about 2400 U / mL to about 2500 U / mL, about 2500 U / mL to about 2500 U / mL, about 2600 U / mL to about 2500 U / mL, about 2700 U / mL to about 2500 U / mL, about 2800 U / mL to about 2500 U / mL, about 2900 U / mL to about 2500 U / mL, about In some aspects, the pharmaceutical composition comprises at least about 50 U / mL of this endoglycosidase hydrolase. In some aspects, the pharmaceutical composition comprises at least about 1500 U / mL, at least about 1600 U / mL, at least about 1700 U / mL, at least about 1800 U / mL, at least about 1900 U / mL, at least about 2000 U / mL, at least about 2100 U / mL, at least about 2200 U / mL, at least about 2300 U / mL, at least about 2400 μM, at least about 2500 μM, at least about 3000 μM, at least about 3500 μM, at least about 4000 μM, at least about 4500 U / mL, or at least about 5000 U / mL of the endoglycosidase hydrolase.In some aspects, the pharmaceutical composition comprises about 50 U / mL, about 100 U / mL, about 150 U / mL, about 200 U / mL, about 250 U / mL, about 300 U / mL, about 350 U / mL, about 400 U / mL, about 450 U / mL, about 500 U / mL, about 550 U / mL, about 600 U / mL, about 650 U / mL, about 700 U / mL, about 750 U / mL, about 800 U / mL, about 850 U / mL, about 900 U / mL, about 950 U / mL, about 1000 U / mL, about 1100 U / mL, about 1200 U / mL, about 1300 U / mL, about 1400 U / mL, about 1500 U / mL, about 1600 U / mL , about 1700 U / mL, about 1800 U / mL, about 1900 U / mL, about 2000 U / mL, about 2100 U / mL, about 2200 U / mL, about 2300 U / mL, about 2400 U / mL, about 2500 U / mL, about 3000 U / mL, about 3500 U / mL, about 4000 U / mL, about 4500 U / mL, about 5000 U / mL, about 5500 U / mL, about 6000 U / mL, about 6500 U / mL, about 7000 U / mL, about 7500 U / mL, about 8000 U / mL, about 8500 U / mL, about 9000 U / mL, about 9500 U / mL, or about 10,000 U / mL of the endoglycosidase hydrolase. In some aspects, the pharmaceutical composition comprises about 2000 U / mL of the endoglycosidase hydrolase.

[0017] In some aspects, the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosamine beta (1-4) or (1-3) linkage. In some aspects, the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to amino acids 36-490 of SEQ ID NO: 1.

[0018] In some aspects, the endoglycosidase hydrolase comprises a hyaluronidase. In some aspects, the endoglycosidase hydrolase comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants and any isoforms thereof.

[0019] In some aspects, the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising: (i) one or more amino acid substitutions in the alpha helical region, (ii) one or more amino acid substitutions in the linker region, (iii) a deletion of one or more N-terminal and / or C-terminal amino acids, or (iv) any combination of (i)-(iii), the wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20: i. comprises one or more amino acid substitutions in the alpha helical region, the linker region, or both the alpha helical region and the linker region relative to wild-type rHuPH20; ii. lacks one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids relative to wild-type rHuPH20; or iii. comprises both (i) and (ii).

[0020] In some aspects, the pharmaceutical composition further comprises a tension regulator and / or a stabilizer. In some aspects, the tension regulator and / or stabilizer comprises sugar, amino acid, polyol, salt or a combination thereof. In some aspects, the tension regulator and / or stabilizer comprises sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine or any combination thereof. In some aspects, the tension regulator comprises sucrose. In some aspects, the pharmaceutical composition comprises at least about 10mM to at least about 500mM sucrose. In some aspects, the pharmaceutical composition comprises about 1 mM to about 500 mM, about 1 mM to about 400 mM, about 1 mM to about 350 mM, about 1 mM to about 300 mM, about 1 mM to about 250 mM, about 10 mM to about 400 mM, about 10 mM to about 350 mM, about 10 mM to about 300 mM, about 10 mM to about 250 mM, about 50 mM to about 400 mM, about 50 mM to about 350 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 100 mM to about 400 mM, about 100 mM to about 350 mM, about 100 mM to about 300 mM, about 100 mM to about 250 mM, about 100 mM to about or about 350 mM to about 400 mM sucrose.In some aspects, the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM. , at least about 260mM, at least about 270mM, at least about 280mM, at least about 290mM, at least about 300mM, at least about 310mM, at least about 320mM, at least about 330mM, at least about 340mM, at least about 350mM, at least about 360mM, at least about 370mM, at least about 380mM, at least about 390mM, at least about 400mM, at least about 410mM, at least about 420mM, at least about 430mM, at least about 440mM, at least about 450mM, at least about 460mM, at least about 470mM, at least about 480mM, at least about 490mM, or at least about 500mM sucrose. In some aspects, the pharmaceutical composition comprises about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, about 250 mM In some aspects, the pharmaceutical composition comprises about 250mM sucrose.

[0021] In some aspects, the pharmaceutical composition further comprises a buffer. In some aspects, the buffer is histidine, succinate, tromethamine, sodium phosphate, sodium acetate, sodium citrate, or any combination thereof. In some aspects, the buffer comprises histidine. In some aspects, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises about 1 mM to about 100 mM, about 1 mM to about 90 mM, about 1 mM to about 80 mM, about 1 mM to about 75 mM, about 1 mM to about 70 mM, about 1 mM to about 65 mM, about 1 mM to about 60 mM, about 1 mM to about 55 mM, about 1 mM to about 50 mM, about 1 mM to about 45 mM, about 1 mM to about 40 mM, about 1 mM to about 35 mM, about 1 mM to about 30 mM, about 1 mM to about 25 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 10 mM, about 1 mM to about 5 mM, about 5 mM to about 10 mM. 0mM, about 5mM to about 90mM, about 5mM to about 80mM, about 5mM to about 75mM, about 5mM to about 70mM, about 5mM to about 65mM, about 5mM to about 60mM, about 5mM to about 55mM, about 5mM to about 50mM, about 5mM to about 45mM, about 5mM to about 40mM, about 5mM to about 35mM, about 5mM to about 30mM, about 5mM to about 25mM, about 5mM to about 20mM, about 5mM to about 15mM, about 5mM to about 10mM, about 10mM to about 100mM, about 10mM to about 90mM, about 10mM to about 80mM, about 10mM M to about 75mM, about 10mM to about 70mM, about 10mM to about 65mM, about 10mM to about 60mM, about 10mM to about 55mM, about 10mM to about 50mM, about 10mM to about 45mM, about 10mM to about 40mM, about 10mM to about 35mM, about 10mM to about 30mM, about 10mM to about 25mM, about 10mM to about 20mM, about 10mM to about 15mM, about 15mM to about 100mM, about 15mM to about 90mM, about 15mM to about 80mM, about 15mM to about 75mM, about 15mM to about 70mM, about 15mM to about 6 15mM, about 15mM to about 20mM, about 16mM to about 24mM, about 17mM to about 23mM, about 18mM to about 22mM, about 19mM to about 21mM, about 20mM to about 100mM, about 20mM to about 90mM, about 20mM to about 80mM, about 20mM to about 75mM, about 20mM to about 70mM,From about 20 mM to about 65 mM, from about 20 mM to about 60 mM, from about 20 mM to about 55 mM, from about 20 mM to about 50 mM, from about 20 mM to about 45 mM, from about 20 mM to about 40 mM, from about 20 mM to about 35 mM, from about 20 mM to about 30 mM, from about 20 mM to about 25 mM, from about 25 mM to about 100 mM, from about 30 mM to about 100 mM, from about 35 mM to about 100 mM, from about 40 mM to about 100 mM, from about 45 mM to about 100 mM, or from about 50 mM to about 100 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 90 mM, or about 100 mM histidine. In some aspects, the pharmaceutical composition comprises about 20 mM histidine.

[0022] In some aspects, the pharmaceutical composition further comprises a surfactant. In some aspects, the surfactant is polysorbate 20, polysorbate 80, or poloxamer 188. In some aspects, the surfactant comprises polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises about 0.001% to about 1% w / v, about 0.001% w / v to about 0.9% w / v, about 0.001% w / v to about 0.8% w / v, about 0.001% w / v to about 0.7% w / v, about 0.001% w / v to about 0.6% w / v, about 0.001% w / v to about 0.5% w / v, about 0.001% w / v to about 0.4% w / v, about 0.001% w / v to about 0.3% w / v, about 0.001% w / v to about 0.2% w / v, about 0.001% w / v to about 0.1% w / v, about 0.001% w / v to about 0.09% w / v, about 0.001% w / v to about 0.08% w / v, about 0.001% w / v to about 0.07% w / v, about 0.001% w / v to about 0.06% w / v, about 0.001% w / v to about 0.05% w / v, about 0.01% w / v to about 0.9% w / v, about 0.01% w / v to about 0.8% w / v, about 0.01% w / v to about 0.7% w / v, about 0.01% w / v to about 0.6% w / v, about 0.01% w / v to about 0.5% w / v, about 0.01% w / v to about 0.4% w / v, about 0.01% w / v to about 0.3% w / v, about 0.01% w / v to about 0.2% w / v, about 0.01% w / v to about 0.1% w / v, about 0.01% w / v to about 0.09% w / v, about 0.01% w / v to about 0.08% w / v, about 0.01% w / v to about 0.07% w / v , about 0.01% w / v to about 0.06% w / v, about 0.01% w / v to about 0.05% w / v, about 0.02% w / v to about 0.1% w / v, about 0.02% w / v to about 0.09% w / v, about 0.02% w / v to about 0.08% w / v, about 0.02% w / v to about 0.07% w / v, about 0.02% w / v to about 0.06% w / v, about 0.02% w / v to about 0.05% w / v, about 0.03% w / v to about 0.1% w / v, about 0.0.03% w / v to about 0.09% w / v, about 0.03% w / v to about 0.08% w / v, about 0.03% w / v to about 0.07% w / v, about 0.03% w / v to about 0.06% w / v, about 0.03% w / v to about 0.05% w / v, about 0.04% w / v to about 0.1% w / v, about 0.04% w / v to about 0.09% w / v, about 0.04% w / v to about 0.08% w / v, about 0.0 4% w / v to about 0.07% w / v, about 0.04% w / v to about 0.06% w / v, about 0.04% w / v to about 0.05%, about 0.05% w / v to about 0.1% w / v, about 0.05% w / v to about 0.09% w / v, about 0.05% w / v to about 0.08% w / v, about 0.05% w / v to about 0.07% w / v, or about 0.05% w / v to about 0.06% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises about 0.001% w / v, 0.002% w / v, 0.003% w / v, 0.004% w / v, 0.005% w / v, 0.006% w / v, 0.007% w / v, 0.008% w / v, 0.009% w / v, 0.01% w / v, about 0.02% w / v, about 0.03% w / v, about 0.04% w / v, about 0.05% w / v, about 0.06% w / v, about 0.07% w / v, about 0.08% w / v, about 0.09% w / v, about 0.1% w / v, about 0.2% w / v, about 0.3% w / v, about 0.4% w / v, about 0.5% w / v, about 0.6% w / v, about 0.7% w / v, about 0.8% w / v, about 0.9% w / v, or about 1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises about 0.05% w / v polysorbate 80.

[0023] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 26.7 mg / mL of the anti-LAG-3 antibody; and (c) about 0.0182 mg / mL rHuPH20.

[0024] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 26.7 mg / mL of the anti-LAG-3 antibody; and (c) about 2000 U / mL rHuPH20.

[0025] In some aspects, the pharmaceutical composition comprises (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the anti-LAG-3 antibody; and (c) about 0.0182 mg / mL rHuPH20.

[0026] In some aspects, the pharmaceutical composition comprises (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the anti-LAG-3 antibody; and (c) about 2000 U / mL rHuPH20.

[0027] In some aspects, the pharmaceutical composition comprises (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the anti-LAG-3 antibody; and (c) about 24,000 U rHuPH20.

[0028] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 26.7 mg / mL of the 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 0.0182 mg / mL rHuPH20.

[0029] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 26.7 mg / mL of the 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.

[0030] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 13.35 mg / mL of the 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 0.0182 mg / mL rHuPH20.

[0031] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 13.35 mg / mL of the 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.

[0032] In some aspects, the pharmaceutical composition comprises (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the 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 0.0182 mg / mL rHuPH20.

[0033] In some aspects, the pharmaceutical composition comprises (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the 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.

[0034] In some aspects, the pharmaceutical composition comprises (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the 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 24,000 U rHuPH20.

[0035] In some aspects, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplizumab, toripalizumab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, sasanlimab, BI 754091, SSI-361, or any combination thereof. In some aspects, the anti-PD-1 antibody comprises nivolumab. In some aspects, the anti-PD-1 antibody comprises pembrolizumab. In some aspects, the anti-PD-1 antibody comprises: (a) a heavy chain variable region having the CDR1, CDR2, and CDR3 domains of the amino acid sequence of SEQ ID NO: 79, and a light chain variable region having the amino acid sequence of SEQ ID NO: 80; (b) a heavy chain variable region CDR1, CDR2, and CDR3 comprising the amino acid sequences of SEQ ID NO: 81, SEQ ID NO: 82, and SEQ ID NO: 83, respectively, and a light chain variable region CDR1, CDR2, and CDR3 comprising the sequences of SEQ ID NO: 84, SEQ ID NO: 85, and SEQ ID NO: 86, respectively; (c) heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 79 and 80, respectively; or (d) a heavy chain and light chain comprising the amino acid sequences of SEQ ID NOs: 77 and 78, respectively.

[0036] In some aspects, the anti-LAG-3 antibody comprises relalizumab, IMP731, GSK2831781, humanized BAP050, LAG-525, MK-4280, REGN3767, aLAG3(0414), aLAG3(0416), TSR-033, TSR-075, Sym022, FS-118, XmAb841, MGD013, BI754111, P13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or any combination thereof. In some aspects, the anti-LAG-3 antibody comprises relalizumab. In some aspects, the anti-LAG-3 antibody comprises: (a) a heavy chain variable region having the CDR1, CDR2, and CDR3 domains of the amino acid sequence of SEQ ID NO:3, and a light chain variable region having the CDR1, CDR2, and CDR3 domains of the amino acid sequence of SEQ ID NO:4; (b) a heavy chain variable region having the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively, and a light chain variable region having the CDR1, CDR2, and CDR3 sequences of SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively; (c) heavy and light chain variable regions having the amino acid sequences of SEQ ID NOs:3 and 4, respectively; (d) heavy and light chains having the amino acid sequences of SEQ ID NOs:1 and 2, respectively; or (e) heavy and light chains having the amino acid sequences of SEQ ID NOs:21 and 2, respectively.

[0037] In some aspects, the anti-PD-1 antibody comprises nivolumab and the anti-LAG-3 antibody comprises relalizumab.

[0038] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL nivolumab; (b) about 26.7 mg / mL relalizumab; (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 0.0182 mg / mL rHuPH20.

[0039] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL nivolumab; (b) about 26.7 mg / mL relalizumab; (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.

[0040] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL nivolumab; (b) about 13.35 mg / mL relalizumab; (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 0.0182 mg / mL rHuPH20.

[0041] In some aspects, the pharmaceutical composition comprises (a) about 80 mg / mL nivolumab; (b) about 13.35 mg / mL relalizumab; (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.

[0042] In some aspects, the pharmaceutical composition comprises (a) about 1200 mg nivolumab; (b) about 400 mg relalizumab; (c) about 8.68 mg histidine; (d) about 11.8 mg histidine HCl H2O; (e) about 479 mg sucrose; (f) about 2.80 mg polysorbate 80; (g) about 0.110 mg pentetic acid; (h) about 4.18 mg methionine; (i) about 0.102 mg rHuPH20; wherein (a)-(h) are reconstituted in water to a final volume of at least about 15 mL.

[0043] In some aspects, the pharmaceutical composition comprises (a) about 960 mg nivolumab; (b) about 320 mg relalizumab; (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 0.0182 mg / mL rHuPH20.

[0044] In some aspects, the pharmaceutical composition comprises (a) about 960 mg nivolumab; (b) about 320 mg relalizumab; (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.

[0045] In some aspects, the pharmaceutical composition comprises (a) about 960 mg nivolumab; (b) about 320 mg relalizumab; (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 24,000 U rHuPH20.

[0046] In some aspects, the pharmaceutical composition comprises a pH of about 5.2 to about 6.8. In some aspects, the pharmaceutical composition comprises a pH of about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.8. In some aspects, the pharmaceutical composition comprises a pH of about 5.8.

[0047] In some aspects, the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or any combination thereof.

[0048] In some aspects, the pharmaceutical composition further comprises another therapeutic agent. In some aspects, the other therapeutic agent comprises an antibody. In some aspects, the other therapeutic agent comprises a checkpoint inhibitor. In some aspects, the other therapeutic agent comprises an anti-CTLA-4 antibody, an anti-TIM3 antibody, an anti-TIGIT antibody, an anti-NKG2a antibody, an anti-OX40 antibody, an anti-ICOS antibody, an anti-MICA antibody, an anti-CD137 antibody, an anti-KIR antibody, an anti-TGFβ antibody, an anti-IL-10 antibody, an anti-IL-8 antibody, an anti-B7-H4 antibody, an anti-Fas ligand antibody, an anti-CXCR4 antibody, an anti-mesothelin antibody, an anti-CD27 antibody, an anti-GITR antibody, an anti-CCR8 antibody, an anti-ILT4 antibody, or any combination thereof.

[0049] Some aspects of the present disclosure relate to a vial comprising a pharmaceutical composition disclosed herein.

[0050] Some aspects of the present disclosure relate to a syringe comprising a pharmaceutical composition disclosed herein. In some aspects, the syringe further comprises a plunger.

[0051] Some aspects of the present disclosure relate to an autoinjector comprising a pharmaceutical composition disclosed herein.

[0052] Some aspects of the present disclosure relate to a wearable pump or wearable device comprising a pharmaceutical composition disclosed herein.

[0053] Some aspects of the present disclosure relate to a pen injector comprising a pharmaceutical composition disclosed herein.

[0054] Some aspects of the present disclosure relate to a method for treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of a pharmaceutical composition disclosed herein. In some aspects, the pharmaceutical composition is administered subcutaneously. In some aspects, the disease or condition is an infectious disease. In some aspects, the disease or condition is cancer. In some aspects, the cancer is 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, hepatoma, breast cancer, colon cancer, head and neck cancer, gastric cancer, germ cell tumors, pediatric sarcoma, sinonasal natural killer (sinonasal natural killer) killer), melanoma, bone cancer, skin cancer, uterine cancer, cancer of the anal region, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine system cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, solid tumors in children, ureteral cancer, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, tumor angiogenesis, spinal axis tumors, brain cancer, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers including asbestos-induced cancers, virus-related cancers or cancers of viral origin (e.g., human papillomavirus (HPV-associated or derived tumors)), or any combination thereof. In some aspects, the cancer is unresectable or metastatic melanoma. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] Figure 1A graphical representation of data relating osmolality and viscosity of a nivolumab subcutaneous (SC) injection formulation as a function of sucrose concentration in the formulation according to Example 1 is presented. The X-axis represents sucrose concentration in mM, and the Y-axis represents formulation osmolality in mOsm / kg. Solid circles and solid lines represent osmolality values, and solid X and dashed lines represent viscosity values.

[0056] Figure 2 A graphical representation of data is presented regarding the effect of adding 75 mM arginine on the viscosity of a nivolumab subcutaneous (SC) injection formulation according to Example 1. The X-axis represents protein concentration in mg / mL, and the Y-axis represents viscosity in cP at 20°C. Solid boxes represent samples containing added arginine, and solid diamonds represent samples without added arginine.

[0057] Figure 3 is a schematic diagram of a study designed to evaluate the safety and efficacy of various doses of subcutaneously administered anti-PD-1 antibodies (e.g., nivolumab), alone or in combination with a hyaluronidase (e.g., rHuPH20).

[0058] Figure 4 Figure 1 is a line graph illustrating the predictive performance of a combined SC / IV PPK model for nivolumab administration. Each dot represents observed data. Lines represent the 5th, 50th, and 95th percentiles of the observed data, respectively. Shaded areas represent simulation-based 90% CIs for the 5th (lowest trendline), 50th (middle trendline), and 95th (highest trendline) percentiles of the predicted data. Conc = concentration; Nivo = nivolumab; Pred-Corr = corrected prediction.

[0059] Figures 5A-5C Is to show Cavgd28( Figure 5A )、Cmind28( Figure 5B ) and Cmax1( Figure 5C ) by tumor type. CRC = colorectal cancer; HCC = hepatocellular carcinoma; Mel = melanoma; NSCLC = non-small cell lung cancer; and RCC = renal cell carcinoma.

[0060] Figure 6 Figure 2 is a schematic diagram of a study designed to evaluate the safety and efficacy of 1200 mg of nivolumab administered subcutaneously every 4 weeks in combination with a hyaluronidase (e.g., rHuPH20) compared to 3 mg / kg of nivolumab administered IV every 2 weeks.

[0061] Figure 7Figure 2 is a box plot showing the distribution of nivolumab Cmind28 at each dose and body weight for 3 mg / kg nivolumab administered IV every 2 weeks, 10 mg / kg nivolumab administered IV every 2 weeks, and 1200 mg nivolumab administered subcutaneously every 4 weeks.

[0062] Figures 8A-8C is a box plot showing the C observed after subcutaneous delivery of 720 mg, 960 mg, or 1200 mg of nivolumab and rHuPH20. avg ( Figure 8A ), C tau ( Figure 8B ), and C max ( Figure 8C The dotted line shows the geometric mean C for nivolumab 3 mg / kg IV Q2W (historical) avg ( Figure 8A ) and C tau ( Figure 8B ), and the geometric mean C of nivolumab 10 mg / kg IV Q2W (historical) max ( Figure 8C ).

[0063] Figures 9A-9B Figure 3. CD8 expression on tumor-infiltrating lymphocytes 14 days after the first subcutaneous dose of nivolumab and rHuPH20 (parts A, B, and D) in subjects with non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma (Mel), hepatocellular carcinoma (HCC), and microsatellite instability-high / mismatch repair-deficient colorectal cancer (MSI-H / dMMR CRC). Figure 9A ) and PD-L1 tumor expression ( Figure 9B ).

[0064] Figure 10 This is a graphical representation of the effect of headspace nitrogen and air on the % HMW species of Nivo by SEC following metal, peroxide, and light stress combined with 30°C heat stress in Study 1. RT / light was continuous light stress; the other light stress conditions lasted for 3 days. Formulations 1 (air) and 6 (nitrogen) contained: 50 μM DTPA, 5 mM Met; Formulations 2 (air) and 7 (nitrogen) contained: 0 μM DTPA, 0 mM Met. All formulations also contained 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80 (pH 6.0), and 2,000 U / mL rHuPH20.

[0065] Figure 11This figure shows the effect of various stress conditions on the % HMW species of Nivo by SEC following metal, peroxide, and light stress combined with 30°C heat stress in Study 1. RT / light is continuous light stress; the other light stress conditions lasted for 3 days. Formulation 1: 50 μM DTPA, 5 mM Met; Formulation 2: 0 μM DTPA, 0 mM Met; Formulation 3: 0 μM DTPA, 5 mM Met; Formulation 4: 50 μM DTPA, 0 mM Met; and Formulation 5: 100 μM EDTA, 5 mM Met. All formulations also contained 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80 (pH 6.0), and 2,000 U / mL rHuPH20.

[0066] Figure 12 This is a graphical representation of HMW formation in Study 1 under the presence of 0.5 ppm each of metals—iron, chromium, and copper—plus light (1000 lux at room temperature for 3 days plus 1 mM peroxide plus 30°C heat stress). Note: Formulations 1 (air) and 6 (nitrogen) completely overlap each other and have minimal HMW formation at 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 contained 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80 (pH 6.0), and 2,000 U / mL rHuPH20.

[0067] Figure 13 Figure 1 is a graphical representation of the % HMW in Study 1 after 3 months under various combinations of metals (0.5 ppm each of iron, chromium, and copper), light (1000 lux at room temperature for 3 days), and peroxide (1 mM peroxide) with heat stress at 30° C., divided by formulation composition with and without 5 mM Met, 50 μM DTPA, and 100 μM EDTA. All formulations also contained 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80 (pH 6.0), and 2,000 U / mL rHuPH20.

[0068] Figure 14This is a graphical representation of the % HMW in Study 1 after 3 months under various combinations of metals (0.5 ppm each of iron, chromium, and copper), light (1000 lux at room temperature for 3 days), and peroxide (1 mM peroxide), with 30°C heat stress included in the main effect statistical model. The graph is divided by the composition of the formulation with or without 5 mM Met and 50 μM DTPA. All formulations also contained 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80 (pH 6.0), and 2,000 U / mL rHuPH20.

[0069] Figure 15 Graph showing rHuPH20 enzyme activity after storage in Study 1 for 3 days at RT / dark followed by 30°C / dark [Control - Left], 3 days at RT / RL followed by 30°C / dark with metal and peroxide spikes [MPL - Middle], and at 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 contained 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80 (pH 6.0), and 2,000 U / mL rHuPH20.

[0070] Figures 16A-16F is a graphical representation of the distribution of formulations for Study 2. Formulations were varied within the maximum and minimum values ​​for excipients, with all other factors at the target composition: 120 mg / mL Nivo ( Figure 16A )、20mM histidine ( Figure 16C )、250mM sucrose, 50μM DTPA ( Figure 16D )、5mM Met( Figure 16E )、2,000U / mL rHPH20( Figure 16F )、0.05% w / v PS80 (pH 6.0) ( Figure 16B ).

[0071] Figure 17 Figure 2 is a graphical representation of high molecular weight species by SEC at various time points up to 6 months at 25°C, 35°C, and MPL and RT / RL stress conditions for 0-200 μM DTPA 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.

[0072] Figure 18 Figure 2 is a graphical representation of high molecular weight species by SEC at various time points 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. Composition includes: 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0.

[0073] Figure 19 Figure 2 is a graphical representation of high molecular weight species separated by SEC at various time points up to 6 months by formulation DTPA and Met concentration for Study 2. Composition includes: 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2000 U / mL rHuPH20, pH 6.0.

[0074] Figure 20 Figure 2 is a graphical representation of SEC % HMW versus methionine concentration for the three last sampled stress conditions, with a smooth curve trend estimate at 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 50 μM DTPA, 0.05% w / v PS80, 2000 U / mL rHuPH20 (pH 6.0).

[0075] Figures 21A-21C is 6 months at 25℃ ( Figure 21A ), 3 months at 35℃ ( Figure 21B ) and MPL stress for 3 months ( Figure 21C ) with the performance of the fit for a formulation containing 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 50 μM DTPA, 0.05% w / v PS80, 2000 U / mL rHuPH20 (pH 6.0).

[0076] Figures 22A-22B Under MPL conditions ( Figure 22A ) and 35℃ stress ( Figure 22B ) Graph showing the relationship between acidic species and time. Duplicate samples were obtained for formulations containing DTPA and Met, as well as formulations containing DTPA alone. Concentrations of 50 μM DTPA and 5 mM Met were used. The formulations used 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, and a pH of 6.0.

[0077] Figures 23A-23B Under MPL conditions ( Figure 23A ) and 35℃ stress ( Figure 23B ) Graph showing enzyme activity as a function of time. Duplicate samples were obtained for formulations with DTPA and Met, as well as formulations with DTPA alone. Concentrations of 50 μM DTPA and 5 mM Met were used. The formulations employed 120 mg / mL Nivo, 20 mM histidine, 250 mM sucrose, 0.05% w / v PS80, 2,000 U / mL rHuPH20, and a pH of 6.0.

[0078] Figures 24A-24B Under MPL conditions ( Figure 24A ) and 35℃ stress ( Figure 24B ) Graphical representation of PS80 levels as a function of time. Duplicate samples were obtained for formulations with DTPA and Met, as well as formulations with DTPA alone. Concentrations of 50 μM DTPA and 5 mM Met were used. The formulations employed 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 25A The middle graph shows a comparison between Study 1, Study 2, and Study 3 at the 3-month time point for high molecular weight species by SEC under MPL conditions, where fractionation was performed with and without 2,000 U / mL of rHuPH20 enzyme at various Met levels. Figure 25B Regression plot of high molecular weight species by SEC for Study 1, Study 2, and Study 3 as a function of Met at the 3-month time point under MPL conditions. Composition included 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 ).

[0080] Figure 26 It is a log that provides glycine, mannitol, sucrose, trehalose and succinate 10 Bar graphs showing comparisons of (kd), as indicated.

[0081] Figure 27 is a bar graph showing the average counts of the number of excipient molecules interacting with the nivolumab Fab group for glycine, sorbitol, trehalose, mannitol, and sucrose during the last 8 ns of the MD simulation, as indicated.

[0082] Figures 28A-28EIt is directed against the glycine on nivolumab Fab ( Figure 28A ), sorbitol ( Figure 28B ), mannitol ( Figure 28C ),sucrose( Figure 28D ) and trehalose ( Figure 28E ) . The Fab group is shown as a ribbon, the light binding pose is shown in ball and stick representation, and the tight binding pose is shown in space filling representation.

[0083] Figures 29A-29B The middle bar graph shows the interaction between the medium strength ( Figure 29A ) and strong binding interactions ( Figure 29B ) for each excipient (glycine, sorbitol, trehalose, mannitol, and sucrose). DETAILED DESCRIPTION

[0084] Current methods for delivering combination therapies comprising an anti-LAG-3 antibody and an anti-PD-1 and / or anti-PD-L1 antibody require regular intravenous administration by a clinician, typically in a clinic or hospital. This regimen often causes significant inconvenience to the patient, and the nature of the treatment itself may negatively impact the patient's experience. Subcutaneous delivery could greatly improve patient compliance, potentially allowing patients to receive this potentially lifesaving therapy in the comfort of their own homes. The present disclosure provides pharmaceutical compositions comprising (i) an antibody that specifically binds to PD-1 ("anti-PD-1 antibody"), (ii) an antibody that specifically binds to LAG-3 ("anti-LAG-3 antibody"), and (iii) an endoglycosidase hydrolase. Other aspects of the present disclosure provide pharmaceutical compositions comprising (i) an antibody that specifically binds to PD-L1 ("anti-PD-L1 antibody"), (ii) an anti-LAG-3 antibody, and (iii) an endoglycosidase hydrolase. Other aspects of the present disclosure provide pharmaceutical compositions comprising (i) an anti-PD-1 antibody, (ii) an anti-LAG-3 antibody, (iii) an anti-PD-L1 antibody, and (iv) an endoglycosidase hydrolase. I. Terminology

[0085] In order to make it easier to understand this disclosure, some terms are first defined. As used in this application, unless otherwise expressly provided herein, each of the following terms shall have the meaning set forth below. Additional definitions are set forth throughout this application.

[0086] It should be understood that any aspect described herein using the word "comprising" also provides other similar aspects described as "consisting of" and / or "consisting essentially of.

[0087] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure relates. For example, Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and Oxford Dictionary of Biochemistry And Molecular Biology, Revised Edition, 2000, Oxford University Press provide a general dictionary of many of the terms used in this disclosure for those of skill in the art.

[0088] Units, prefixes, and symbols are expressed in their International System of Units (SI) accepted form.

[0089] Numerical ranges are inclusive of the numbers defining the range.

[0090] 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 carboxyl orientation.

[0091] The headings provided herein are not limitations of the various aspects of the disclosure, which can be obtained by reference to the specification as a whole. Accordingly, the terms defined below are more fully defined by reference to the entire content of the specification.

[0092] "Administering" refers to the physical introduction of a therapeutic agent (e.g., a composition comprising a therapeutic agent, such as a pharmaceutical composition comprising an anti-LAG-3 antibody, an anti-PD-1 antibody, and / or an anti-PD-L1 antibody disclosed herein) into a subject using any of a variety of methods and delivery systems known to those skilled in the art. Administration can refer to any form of administration of a therapeutic agent, including intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration, such as by injection or infusion. The phrases "subcutaneous administration" and "subcutaneous injection" are used interchangeably and refer to a mode of administration in which the therapeutic agent is delivered beneath the skin of a subject, between the dermis and, for example, a muscle.

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

[0094] Administration can be performed, for example, once, 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 more than one unit dose.

[0095] As used herein, the term "dose" or "dosage" is defined as the amount of a therapeutic agent that can be administered at a given point. A dose can be an amount sufficient to achieve or at least partially achieve a desired effect, but this desired effect may be invisible or undetectable. A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent is any amount of the drug that promotes disease regression when used alone or in combination with another therapeutic agent, and the disease regression is visible as follows: disease symptom severity decreases, the frequency and duration of disease-free symptom periods increase, overall survival (the length of time a patient diagnosed with the disease still survives from the date of diagnosis or treatment commencement of a disease (such as cancer)) increases, or prevents damage or disability caused by the disease torture. The amount or dosage of a drug includes a "prophylactic effective amount" or "prophylactic effective dose," which is any amount of the drug that suppresses the development or recurrence of the disease when used alone or in combination with another therapeutic agent to a subject in a development disease or who is at risk of disease recurrence. The ability of therapeutic agents to promote disease regression or inhibit the development or recurrence of a disease can be assessed using a variety of methods known to skilled practitioners, such as during clinical trials in human subjects, in animal model systems for predicting efficacy in humans, or by measuring agent activity in in vitro assays. "Dosage" can include a single unit dose or multiple unit doses. In some aspects, dosage includes a single unit dose. In some aspects, dosage includes multiple unit doses.

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

[0097] As used herein, an "adverse event (AE)" is any unfavorable and generally unintentional 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 amplification of immune system cells (e.g., T cells) in response to treatment. A medical treatment may have one or more associated AEs, each of which may have the same or different severity. Reference to a method capable of "modifying adverse events" 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] "Antagonists" shall include, but are not limited to, any molecule that can block, reduce, or otherwise limit the interaction or activity of a target molecule (e.g., LAG-3, PD-1, or PD-L1). In some aspects, antagonists are antibodies. In other aspects, antagonists include small molecules. The terms "inhibitor" and "antagonist" are used interchangeably herein.

[0099] "Antibody" (Ab) shall include, but is not limited to, glycoprotein immunoglobulins or antigen-binding portions thereof, which specifically bind to an antigen and comprise at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each H chain comprises a heavy chain variable region (abbreviated herein as V H ) and the heavy chain constant region (abbreviated herein as C H The heavy chain constant region contains three constant domains C H1 、C H2 and C H3 The heavy chain may or may not have a C-terminal lysine. Each light chain comprises a light chain variable region (abbreviated herein as V L ) and a light chain constant region. The light chain constant region comprises a constant domain C L . V H and V LThe V domains can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FRs). H and V L It comprises three CDRs and four FRs, which are arranged in the following order from amino terminus to carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3 and FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. Unless otherwise specified herein, the amino acids in the variable region are numbered using the Kabat numbering system, and the amino acids in the constant region are numbered using the EU system. 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. Therefore, the term "anti-PD-1 antibody" includes, for example, complete antibodies with two heavy chains and two light chains that specifically bind to PD-1 and antigen-binding portions of complete antibodies. Non-limiting examples of antigen-binding portions are shown elsewhere herein. Immunoglobulins can be derived from any commonly known isotype, including but not limited to IgA, secretory IgA, IgG and IgM. IgG subclasses are also well known to those skilled in the art, including but 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, for example, naturally occurring antibodies and non-naturally occurring antibodies; monoclonal antibodies and polyclonal antibodies; chimeric antibodies and humanized antibodies; human antibodies or non-human antibodies; fully synthetic antibodies; single-chain antibodies; monospecific antibodies; bispecific antibodies; and multispecific antibodies. Non-human antibodies can be humanized by recombinant methods to reduce their immunogenicity in humans. In the absence of explicit instructions, and unless the context indicates otherwise, the term "antibody" also includes the antigen-binding fragment or antigen-binding portion of any of the above-mentioned immunoglobulins, and includes monovalent and bivalent fragments or portions, as well as single-chain antibodies that retain the ability to specifically bind to the antigen bound by the whole immunoglobulin.

[0100] In some aspects, the “antibodies” disclosed herein are capable of binding to more than one antigen, such as “multispecific” antibodies or “bispecific” antibodies. As used herein, “bispecific” antibodies are antibodies that can specifically bind to two antigens, wherein the first antigen and the second antigen are the same or different. As used herein, “multispecific” antibodies are capable of specifically binding to more than one antigen, such as at least two (i.e., “bispecific” antibodies), at least three (i.e., “trispecific” antibodies), at least four, at least five, or at least six antigens. Various multispecific antibodies are known and can be used in the compositions and / or methods disclosed herein, including but not limited to bispecific antibodies that bind to PD-1 and a second target, bispecific antibodies that bind to PD-L1 and a second target, and bispecific antibodies that bind to LAG-3 and a second target. In some aspects, bispecific antibodies bind to PD-1 and LAG-3. In some aspects, bispecific antibodies bind to PD-L1 and LAG-3. In some aspects, multispecific antibodies are T cell-dependent bispecific antibodies.

[0101] In some aspects, the “antibodies” of the disclosure are engineered to be activated at a target site, such as a “probody.” In some aspects, the antibody (e.g., probody) is proteolytically cleaved at a target tissue (e.g., a tumor).

[0102] An "isolated antibody" is an antibody that is substantially free of other antibodies with different antigenic specificities (e.g., an isolated antibody that specifically binds to PD-1 is substantially free of antibodies that specifically bind to antigens other than PD-1). However, an isolated antibody that specifically binds to an antigen may have cross-reactivity with other antigens, such as an antibody that binds to an antigen from one species may have cross-reactivity with that antigen from a different species (e.g., an antibody that specifically binds to PD-1 may have cross-reactivity with 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 that are substantially identical in primary sequence and that exhibit a single binding specificity and affinity for a particular epitope. A monoclonal antibody is an example of an isolated antibody. Monoclonal antibodies can be produced by hybridoma, recombinant, transgenic technology, or other techniques known to those skilled in the art.

[0104] "HuMAb" refers to an antibody with a variable region, wherein the framework region and CDR region are derived from human germline immunoglobulin sequences. In addition, if the antibody comprises a constant region, the constant region is also 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 mutations in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which the CDR sequences derived from the germline of another mammalian species (e.g., mouse) have been transplanted onto human framework sequences. The terms "human antibody" and "fully human antibody" are used synonymously.

[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 are replaced by corresponding amino acids derived from human immunoglobulins. In one aspect of the humanized form of an antibody, some, most, or all of the amino acids outside the CDRs have been replaced by amino acids from human immunoglobulins, while some, most, or all of the amino acids within one or more CDRs are unchanged. Minor additions, deletions, insertions, substitutions, or modifications of amino acids are permitted as long as they do not eliminate the ability of the antibody to bind to a specific antigen. A "humanized antibody" retains antigenic specificity similar to that of the original antibody.

[0106] A "chimeric antibody" refers to an antibody in which the variable region is derived from one species and the constant region is derived from another species, eg, an antibody in which the variable region is derived from a mouse antibody and the 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, an anti-PD-L1 antibody specifically binds to PD-L1, and an anti-LAG-3 antibody specifically binds to LAG-3.

[0108] An “antigen-binding portion” (also referred to as an “antigen-binding fragment”) of an antibody refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen bound by the intact antibody. It has been demonstrated that fragments of full-length antibodies can perform the antigen-binding function of an antibody. Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody (e.g., an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-LAG-3 antibody described herein) include (i) Fab fragments (fragments from papain cleavage) or fragments consisting of V L 、V H (ii) a F(ab')2 fragment (fragment resulting from pepsin cleavage) or a similar bivalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) a fragment consisting of V Hand CH1 domains; (iv) a V fragment consisting of a single arm of the antibody L and V H Fv fragment composed of structural domains, (v) consists of V H single domain antibody (dAb) fragments (Ward et al., (1989) Nature 341:544-546); (vi) isolated complementarity determining regions (CDRs), (vii) a combination of two or more isolated CDRs, optionally linked by a synthetic linker, (viii) a dAb consisting of two V domains linked by a hinge. H domains (dual affinity retargeting antibodies (DARTs)); and (ix) dual variable domain immunoglobulins. In addition, although the two domains V L and V H are encoded by separate genes, but they can be linked using recombinant methods via synthetic linkers that enable them to be prepared as a single protein chain, where V L and V H The regions pair to form monovalent molecules (called 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] The term "cancer" refers to a broad category of diseases characterized by the uncontrolled growth of abnormal cells in the body. Unregulated cell division and growth lead to the formation of malignant tumors, which can invade nearby tissues and spread to distant parts of the body through the lymphatic system or bloodstream.

[0110] As used herein, the term "tumor" refers to any mass of tissue resulting from excessive cell growth or proliferation, whether benign (non-cancerous) or malignant (cancerous), including precancerous lesions.

[0111] The term "immunotherapy" refers to the treatment of a subject having a disease or at risk of contracting a disease or recurrence of a disease by methods that involve inducing, enhancing, suppressing, or otherwise altering an immune response.

[0112] "Programmed death-1 (PD-1)" refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is primarily expressed on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. As used herein, the term "PD-1" includes human PD-1 (hPD-1), variants, isoforms, and species homologs of hPD-1, as well as analogs that share at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GenBank accession number U64863.

[0113] "Programmed death ligand-1 (PD-L1)" is one of the two cell surface glycoprotein ligands of PD-1 (the other is PD-L2), which downregulates T cell activation and cytokine secretion after 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, and analogs that have 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).

[0114] "LAG-3" refers to lymphocyte activation gene-3. The term "LAG-3" includes variants, isoforms, homologs, orthologs, and paralogs. For example, in some cases, antibodies specific for human LAG-3 protein may cross-react with LAG-3 proteins from species other than human. In other aspects, antibodies specific for human LAG-3 protein may be completely specific for human LAG-3 protein and exhibit no species or other types of cross-reactivity, or may cross-react with LAG-3 from certain other species but not all other species (e.g., cross-react with monkey LAG-3 but not mouse LAG-3). The term "human LAG-3" refers to the complete amino acid sequence of human LAG-3, such as the complete amino acid sequence of human LAG-3 having GenBank Accession No. NP_002277. The term "mouse LAG-3" refers to the complete amino acid sequence of mouse LAG-3, such as the complete amino acid sequence of mouse LAG-3 having GenBank Accession No. NP_032505. LAG-3 is also known in the art as CD223, for example. The human LAG-3 sequence can differ from the human LAG-3 of GenBank Accession No. NP_002277, for example, by having a conservative mutation or a mutation in a non-conserved region, and the LAG-3 has substantially the same biological function as the human LAG-3 of GenBank Accession No. NP_002277. For example, the biological function of human LAG-3 is having an epitope in the extracellular domain of LAG-3 that is specifically bound by an antibody of the disclosure, or the biological function of human LAG-3 is binding to an MHC class II molecule.

[0115] A specific human LAG-3 sequence will generally be at least about 90% identical in amino acid sequence to the human LAG-3 of GenBank Accession No. NP_002277 and contain amino acid residues that identify the amino acid sequence as human when compared to LAG-3 amino acid sequences of other species (e.g., mouse). In some cases, the human LAG-3 may be at least about 95%, or even at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identical in amino acid sequence to the LAG-3 of GenBank Accession No. NP_002277. In certain aspects, the human LAG-3 sequence will exhibit no more than 10 amino acid differences from the LAG-3 sequence of GenBank Accession No. NP_002277. In certain aspects, the human LAG-3 may exhibit no more than 5, or even no more than 4, 3, 2, or 1 amino acid differences from the LAG-3 sequence of GenBank Accession No. NP_002277.

[0116] As used herein, " hyaluronidase " refers to the enzyme that can catalyze hyaluronic acid cutting.Hyaluronic acid is the repeating polymer of N-acetyl-glucosamine and glucuronic acid, and it is present in the subcutaneous space and helps the soluble gel-like component of the extracellular matrix of skin, and by rapid turnover (resynthesis) recovery. In some aspects, hyaluronidase comprises rHuPH20, and it is 447 amino acid whose single-chain polypeptides of glycosylation of hyaluronic acid depolymerization topically at the skin injection site in the subcutaneous space.Hyaluronidase is completed by the hydrolysis of polysaccharide polymer to the depolymerization of hyaluronic acid.Hyaluronic depolymerization causes the instantaneous reduction of the viscosity of the gel-like phase of extracellular matrix and the increase of hydraulic conductivity, and this helps dispersion and the absorption of the therapeutic agent of co-administration.Therefore, hyaluronidase (for example rHuPH20) can be by serving as penetration enhancer and improve the speed and the easiness of subcutaneous delivery injectable biological preparation and medicine. In some aspects, hyaluronidase comprises ENHANZE.

[0117] "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 (e.g., mice, rats, and guinea pigs). In preferred aspects, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0118] The term "stable dose" is used with respect to the methods and doses of the present disclosure to refer to the dose administered to a patient regardless of the patient's weight or body surface area (BSA). Thus, a steady dose is not provided as a mg / kg dose, but rather as an absolute amount of an agent (e.g., an anti-PD-1 antibody or an anti-LAG-3 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).

[0119] The term "weight-based dose" as used herein means a dose calculated based on the patient's weight. For example, if a 60 kg patient requires 3 mg / kg of anti-PD-1 antibody, an appropriate amount of anti-PD-1 antibody (i.e., 180 mg) can be calculated and used for administration.

[0120] For example, "anticancer agent" promotes the regression of cancer in a subject. In some aspects, a therapeutically effective amount of a drug promotes the regression of cancer to the extent of eliminating cancer. "Promoting cancer regression" means administering a therapeutically effective amount of a drug alone or in combination with an antitumor agent to cause slowing of tumor growth or reduction of tumor size, tumor necrosis, reduction of the severity of at least one disease symptom, increase of the frequency and duration of the disease-free period, or prevention of damage or disability caused by disease torture. In addition, the terms "effective" and "effectiveness" for treatment include pharmacological effectiveness and physiological safety. Pharmacological effectiveness refers to the ability of a drug to promote the regression of a patient's cancer. Physiological safety refers to the toxicity level caused by the administration of a drug or other adverse physiological effects (adverse effects) at the cell, organ and / or organism level.

[0121] For example, for the treatment of tumors, a therapeutically effective amount of an anticancer agent preferably inhibits cell growth or tumor growth by at least about 20%, at least about 40%, at least about 60%, or at least about 80% relative to an untreated subject. In other aspects of the present disclosure, tumor regression can be observed and persists for a period of at least about 20 days, at least about 40 days, or at least about 60 days. Despite these ultimate measures of therapeutic effectiveness, the evaluation of immunotherapy drugs must also take into account immune-related response patterns.

[0122] "Immune response" is understood in the art and generally refers to a biological response in a vertebrate to a foreign agent or abnormality, such as a cancer cell, that protects the organism from these agents and the diseases caused by them. 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, which results in selective targeting, binding, damage, destruction, and / or removal of invading pathogens, cells or tissues infected with pathogens, cancer or other abnormal cells, or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues from the vertebrate body. The immune response includes, for example, activation or suppression of T cells, such as effector T cells, Th cells, CD4 T cells, and the like. + cells, CD8 + T cells or Treg cells, or any other cells that activate or suppress the immune system, such as NK cells.

[0123] An "immune-related response pattern" refers to a clinical response pattern typically observed in cancer patients treated with immunotherapeutics that produce antitumor effects by inducing a cancer-specific immune response or by modifying innate immune processes. This response pattern is characterized by a beneficial treatment effect following an initial increase in tumor burden or the appearance of new lesions, which, in the evaluation of traditional chemotherapeutics, would be classified as disease progression and would be synonymous with drug failure. Therefore, appropriate evaluation of immunotherapeutics may require long-term monitoring of the effects of these agents on the target disease.

[0124] As used herein, with respect to a formulation or drug product, the term "stable" is a formulation or drug product in which one or more antibodies or molecules substantially retain their physical and chemical stability and integrity upon storage. The stability of a formulation herein can be measured after a selected time period at a selected temperature. For example, aggregate formation or an increase in low molecular weight species are indicators of instability. Maintaining original transparency and / or color throughout the shelf life is also an indicator for monitoring stability. In some aspects, a "stable" drug product is one in which the increase in aggregation, as measured by an increase in the percentage of high molecular weight species (% HMW), is less than about 5%, and preferably less than about 3%, when the formulation is stored at 2°C-8°C for at least about one year.

[0125] As used herein, the terms "treat," "treating," and "therapy" refer to any type of intervention or process performed on a subject or administered to a subject with the goal of reversing, alleviating, ameliorating, inhibiting, slowing, or preventing the progression, development, severity, or recurrence of symptoms, complications, conditions, or biochemical markers associated with a disease, or enhancing overall survival. Treatment can be treatment of a subject with a disease or a subject without a disease (e.g., for prevention).

[0126] As used herein, "immuno-oncology" therapy or "IO" or "IO" therapy refers to a therapy that includes the use of an immune response to target and treat a subject's tumor. Therefore, as used herein, IO therapy is an anti-cancer therapy. In some aspects, IO therapy includes administering an antibody to a subject. In some aspects, IO therapy includes administering an immune cell, such as a T cell, such as a modified T cell, such as a T cell modified to express a chimeric antigen receptor or a specific T cell receptor, to a subject. In some aspects, IO therapy includes administering a therapeutic vaccine to a subject. In some aspects, IO therapy includes administering a cytokine or chemokine to a subject. In some aspects, IO therapy includes administering an interleukin to a subject. In some aspects, IO therapy includes administering an interferon to a subject. In some aspects, IO therapy includes administering a colony stimulating factor to a subject.

[0127] As used herein, the term "about weekly", "about every two weeks" or any other similar dosing interval term (for example, "about once a week" or "about once a week") means an approximate number. "About weekly" can include every seven days ± one day, i.e., every six days to every eight days. "About every two weeks" can include every fourteen days ± three days, i.e., every eleven days to every seventeen days. Similar approximations are applicable to, for example, about every three weeks, about every four weeks, about every five weeks, about every six weeks and about every twelve weeks. In some aspects, the dosing interval of about every six weeks or about every twelve weeks means that the first dose can be applied on any day of the first week, and then the next dose can be applied on any day of the sixth week or the twelfth week, respectively. In other aspects, the dosing interval of about every six weeks or about every twelve weeks means that the first dose is applied on a specific day (such as Monday) of the first week, and then the next dose is applied on the same day (i.e. Monday) of the sixth week or the twelfth week, respectively. When multiple subcutaneous unit doses are applied to reach a certain dose, the dosing interval refers to the time period between the first subcutaneous unit dose of the first effective dose and the first subcutaneous unit dose of the second effective dose. For example, where the method comprises administering a dose of about 600 mg administered about every two weeks, wherein the dose of the antibody comprises two subcutaneous unit doses, wherein each of the two subcutaneous unit doses contains about 300 mg of the antibody, the first subcutaneous unit dose of the first effective dose of the antibody of about 300 mg is administered on day 1, and the first subcutaneous unit dose of the second effective dose of the antibody of about 300 mg is administered on about day 14. In this example, the second unit dose of the first effective dose of the antibody of about 300 mg can be administered on day 1 or at any other time before administration of the first subcutaneous unit dose of the second effective dose of the antibody of about 300 mg.

[0128] As used herein, "a" or "an" should be understood to refer to "one or more" of any listed or enumerated component. For example, "nucleotide sequence" should be understood to refer to one or more nucleotide sequences. Therefore, the terms "a", "an", "one or more", and "at least one" are used interchangeably herein.

[0129] As used herein, the term "and / or" should be taken as a specific disclosure of each of the two specified features or components with or without the other. Thus, the term "and / or" as used herein in phrases such as "A and / or B" is intended to include "A and B," "A or B," "A" (alone), and "B" (alone). Similarly, the term "and / or" as used in phrases such as "A, B, and / or C" is intended to cover each of the following: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0130] The term "about" or "consisting essentially of..." refers to a value or composition that is within an acceptable error range for the 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 "consisting essentially of..." can mean within 1 or more than 1 standard deviations according to practice in the art. Alternatively, "about" or "consisting essentially of..." can mean a range of up to 10%. In addition, particularly for biological systems or processes, the term can mean up to an order of magnitude or up to 5 times the value. When a particular value or composition is provided in the application and claims, unless otherwise stated, the meaning of "about" or "consisting essentially of..." should be assumed to be within an acceptable error range for that particular value or composition.

[0131] As described herein, unless otherwise indicated, any concentration range, percentage range, ratio range, or integer range should be understood to include the value of any integer within the recited range, and where appropriate, fractions thereof (such as tenths and hundredths of integers).

[0132] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. that are physiologically compatible. Preferably, carriers for compositions containing antibodies are suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion), while carriers for compositions containing antibodies and / or cytokines are suitable for non-parenteral (e.g., oral) administration.

[0133] "Tumor-infiltrating inflammatory cells" or "tumor-associated inflammatory cells" are any type of cell that typically participates in the inflammatory response in a subject and infiltrates tumor tissue. These cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes, and dendritic cells.

[0134] The terms "LAG-3 positive" or "LAG-3 expression positive" in relation to LAG-3 expression refer to tumor tissue (e.g., a test tissue sample) that is scored as expressing LAG-3 based on the proportion (i.e., percentage) of immune cells (e.g., tumor-infiltrating lymphocytes, such as CD8+ T cells) that express LAG-3 (e.g., greater than or equal to 1% expression) or based on the proportion (i.e., percentage) of nucleated cells that express LAG-3 (i.e., the ratio of LAG-3-expressing immune cells to total nucleated cells, e.g., greater than or equal to 1% expression).

[0135] "LAG-3 negative" or "LAG-3 expression negative" refers to a tumor tissue (eg, a test tissue sample) that is not scored as expressing LAG-3 (eg, less than 1% LAG-3 expression).

[0136] The terms "PD-1 positive" or "PD-1 expression positive" in relation to PD-1 expression refer to tumor tissue (e.g., a test tissue sample) that is scored as expressing PD-1 based on the proportion (i.e., percentage) of immune cells (e.g., tumor-infiltrating lymphocytes, such as CD8+ T cells) that express PD-1 (e.g., greater than or equal to 1% expression) or based on the proportion (i.e., percentage) of nucleated cells that express PD-1 (i.e., the ratio of immune cells expressing PD-1 to total nucleated cells, e.g., greater than or equal to 1% expression).

[0137] "PD-1 negative" or "PD-1 expression negative" refers to a tumor tissue (eg, a test tissue sample) that is not scored as expressing PD-1 (eg, less than 1% PD-1 expression).

[0138] The terms "PD-L1 positive" or "PD-L1 expression positive" in relation to cell surface PD-L1 expression refer to tumor tissue (e.g., a test tissue sample) that is scored as expressing PD-L1 based on the proportion (i.e., percentage) of tumor cells expressing PD-L1 (e.g., greater than or equal to 1% expression) or based on the proportion (i.e., percentage) of nucleated cells expressing PD-L1 (i.e., the proportion of tumor cells expressing PD-L1 to total nucleated cells, e.g., greater than or equal to 1% expression).

[0139] The term "PD-L1 negative" or "PD-L1 expression negative" refers to tumor tissue (eg, a test tissue sample) that is not scored as expressing PD-L1 (eg, less than 1% expression).

[0140] Various aspects of the disclosure are described in more detail in the following subsections. II. Compositions of the Disclosure

[0141] Some aspects of the present disclosure relate to pharmaceutical compositions comprising (i) an antibody that specifically binds to PD-1 ("anti-PD-1 antibody") and / or an antibody that specifically binds to PD-L1 ("anti-PD-L1 antibody"), (ii) an antibody that specifically binds to LAG-3 ("anti-LAG-3 antibody"), and (iii) an endoglycosidase hydrolase.

[0142] Some aspects of the present disclosure relate to pharmaceutical compositions comprising (i) an antibody that specifically binds to PD-1 (an "anti-PD-1 antibody"), (ii) an antibody that specifically binds to LAG-3 (an "anti-LAG-3 antibody"), and (iii) an endoglycosidase hydrolase.

[0143] Some aspects of the present disclosure relate to pharmaceutical compositions comprising (i) an antibody that specifically binds to PD-L1 (an "anti-PD-L1 antibody"), (ii) an antibody that specifically binds to LAG-3 (an "anti-LAG-3 antibody"), and (iii) an endoglycosidase hydrolase.

[0144] Some aspects of the present disclosure relate to pharmaceutical compositions comprising (i) an anti-PD-1 antibody, (ii) an anti-LAG-3 antibody, (iii) an endoglycosidase hydrolase, and (iv) an anti-PD-L1 antibody.

[0145] In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody are the only antibodies in the pharmaceutical composition. In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody are the only active agents in the pharmaceutical composition.

[0146] In some aspects, the anti-PD-L1 antibody and the anti-LAG-3 antibody are the only antibodies in the pharmaceutical composition. In some aspects, the anti-PD-L1 antibody and the anti-LAG-3 antibody are the only active agents in the pharmaceutical composition.

[0147] In some aspects, the anti-PD-1 antibody, anti-PD-L1 antibody, and anti-LAG-3 antibody are the only antibodies in the pharmaceutical composition. In some aspects, the anti-PD-1 antibody, anti-PD-L1 antibody, and anti-LAG-3 antibody are the only active agents in the pharmaceutical composition.

[0148] In some aspects, the pharmaceutical composition is formulated for subcutaneous administration.

[0149] In some aspects, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0150] In some aspects, the pharmaceutical composition further comprises an antioxidant. In some aspects, the antioxidant prevents oxidation of formulation components and / or improves the stability of one or more antibodies. In some aspects, the pharmaceutical composition comprises at least two antioxidants.

[0151] In some aspects, the pharmaceutical composition comprises a tonicity modifier or stabilizer.

[0152] In some aspects, the pharmaceutical composition comprises a buffer.

[0153] In some aspects, the pharmaceutical composition comprises a surfactant. II.A. Anti-LAG-3 Antibodies

[0154] The anti-LAG-3 antibodies disclosed herein bind to human LAG-3. Any anti-LAG-3 antibody can be used in the pharmaceutical compositions and methods disclosed herein. Antibodies that bind to LAG-3 have been disclosed in International Publication No. WO / 2015 / 042246 and U.S. Publication Nos. 2014 / 0093511 and 2011 / 0150892, each of which is incorporated herein by reference in its entirety.

[0155] An exemplary LAG-3 antibody useful in the present disclosure is 25F7 (described in U.S. Publication No. 2011 / 0150892). Another exemplary LAG-3 antibody useful in the present disclosure is BMS-986016 (relalizumab). In some aspects, the anti-LAG-3 antibodies useful in the present disclosure can cross-compete with 25F7 or BMS-986016. In some aspects, the anti-LAG-3 antibodies useful in the present disclosure can bind to the same epitope as 25F7 or BMS-986016. In some aspects, the anti-LAG-3 antibodies comprise the six CDRs of 25F7 or BMS-986016.

[0156] Other art-recognized anti-LAG-3 antibodies that can be used in the methods and / or compositions of the present disclosure include IMP731 (H5L7BW) described in US 2011 / 007023, MK-4280 (28G-10, mavezilimab) described in WO 2016028672 and US Publication No. 2020 / 0055938, Burova E, et al., J. Immunother. Cancer (2016); 4(Suppl 1): P195 and REGN3767 (foramalizumab) described in U.S. Patent No. 10,358,495, humanized BAP050 described in WO2017 / 019894, GSK2831781, IMP-701 (LAG525; elaralizumab) described in U.S. Patent No. 10,711,060 and U.S. Publication No. 2020 / 0172617, aLAG3(0414), aLAG3(0416), Sym022, TSR-033, TSR-075, XmAb841 (formerly XmAb22841), MGD013 (tepolizumab), BI754111, FS118, P 13B02-30, AVA-017, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007 and ABL501.These and other anti-LAG-3 antibodies useful in the present invention can be found, for example, in US 10,188,730, WO 2016 / 028672, WO 2017 / 106129, WO2017 / 062888, WO2009 / 044273, WO2018 / 069500, WO2016 / 126858, WO2014 / 179664, WO2016 / 200782, WO2015 / 200119, WO20 17 / 019846、WO2017 / 198741、WO2017 / 220555、WO2017 / 220569、WO2018 / 071500、WO2017 / 015560、WO2017 / 025498、WO2017 / 087589、WO2017 / The contents of each of these references are incorporated by reference in their entirety.

[0157] Anti-LAG-3 antibodies useful in the methods and / or compositions of the present disclosure also include isolated antibodies that specifically bind to human LAG-3 and cross-compete for binding to human LAG-3 with any of the anti-LAG-3 antibodies disclosed herein (e.g., relalizumab). In some aspects, the anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein (e.g., relalizumab).

[0158] In some aspects, antibodies that cross-compete for binding to human LAG-3 or bind to the same epitope region as any of the anti-LAG-3 antibodies disclosed herein (e.g., relalizumab) are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric, engineered, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0159] The ability of an antibody to cross-compete for binding to an antigen indicates that the antibody binds to the same epitope region of the antigen and sterically hinders other cross-competing antibodies from binding to that specific epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of a reference antibody (e.g., relalizumab) due to binding to the same epitope region. Cross-competing antibodies can be easily identified based on their cross-competitive ability in standard binding assays, such as Biacore analysis, ELISA assays, or flow cytometry (see, e.g., WO 2013 / 173223).

[0160] Anti-LAG-3 antibodies useful in the methods and / or compositions of the present disclosure also include antigen-binding portions of any of the above-described full-length antibodies. It has been well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0161] In some aspects, the anti-LAG-3 antibody is a full-length antibody.

[0162] In some aspects, the anti-LAG-3 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody is a dual affinity retargeting antibody (DART), a DVD-Ig, or a bispecific antibody.

[0163] In some aspects, the anti-LAG-3 antibody is a multispecific antibody that specifically binds (i) LAG-3 and (ii) a second antigen, such as a bispecific antibody. In some aspects, the antibody is a multispecific antibody that specifically binds (i) LAG-3 and (ii) CD3, such as a bispecific antibody. In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody in the pharmaceutical composition are part of a bispecific antibody (e.g., a pharmaceutical composition comprising (i) a bispecific antibody that specifically binds PD-1 and LAG-3, and (ii) an endoglycosidase hydrolase).

[0164] In some aspects, the anti-LAG-3 antibody is a trispecific antibody. In some aspects, the antibody specifically binds to (i) LAG-3, (ii) a second antigen, and (iii) a third antigen. In some aspects, the second antigen and the third antigen are the same. In some aspects, the second antigen and the third antigen are different. In some aspects, the anti-PD-1 antibody and the anti-LAG-3 antibody in the pharmaceutical composition are part of a trispecific antibody (e.g., a pharmaceutical composition comprising (i) a trispecific antibody that specifically binds to PD-1, LAG-3, and a third antigen (e.g., CD3), and (ii) an endoglycosidase hydrolase).

[0165] In some aspects, the antigen-binding portion of the bispecific or trispecific antibody is a scFv, such as the scFv of relalizumab of the bispecific or trispecific antibody that specifically binds LAG-3.

[0166] The second or third antigen that specifically binds to the bispecific or trispecific antibody herein can be any antigen disclosed herein.

[0167] In some aspects, the anti-LAG-3 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0168] In some aspects, the anti-LAG-3 antibody is BMS-986016 (relalizumab), IMP731 (H5L7BW), MK4280 (28G-10, mavezilimab), REGN3767 (furanlizumab), GSK2831781, humanized BAP050, IMP-701 (LAG525, elalimumab), aLAG3 (0414), aLAG3 (0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tepolizumab), BI754111, FS118, P 13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or an antigen-binding portion thereof.

[0169] In some aspects, the anti-LAG-3 antibody is relalizumab.

[0170] In some aspects, the anti-LAG-3 antibody comprises the heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or heavy and light chains of relalizumab. In some aspects, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 3, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 4. In some aspects, the anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 5; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 6; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 7; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 8; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 9; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 10. In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 3 and 4, respectively. In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 1 and 2, respectively. In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 21 and 2, respectively.

[0171] In some aspects, the anti-LAG-3 antibody is MGD013 (Tepolizumab), which is a bispecific PD-1 x LAG-3 DART.

[0172] In some aspects, the anti-LAG-3 antibody comprises the heavy and light chain variable region CDRs and / or the heavy and light chain variable regions of tepolizumab.

[0173] In some aspects, the anti-LAG-3 antibody is REGN3767 (Fulimumab).

[0174] In some aspects, the anti-LAG-3 antibody comprises the heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or heavy and light chains of follimab. In some aspects, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence of SEQ ID NO: 25, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence of SEQ ID NO: 26. In some aspects, the anti-LAG-3 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 27; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 28; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 29; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 30; (e) a light chain variable region CDR2 comprising the amino acid sequence DAS; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 32. In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 25 and 26, respectively. In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 23 and 24, respectively.

[0175] In some aspects, the anti-LAG-3 antibody is LAG525 (elalimumab).

[0176] In some aspects, the anti-LAG-3 antibody comprises the heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or heavy and light chains of elarizumab. In some aspects, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence of SEQ ID NO: 47, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence of SEQ ID NO: 49. In some aspects, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence of SEQ ID NO: 48, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence of SEQ ID NO: 50. In some aspects, the anti-LAG-3 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 51; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 52; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 53; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 54; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 55; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 56. In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 47 and 49, respectively. In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 48 and 50, respectively. In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 43 and 45, respectively. In some aspects, the anti-LAG-3 antibody comprises heavy and light chains comprising the amino acid sequences set forth in SEQ ID NOs: 44 and 46, respectively.

[0177] In some aspects, the anti-LAG-3 antibody is MK4280 (mavezemalimab).

[0178] In some aspects, the anti-LAG-3 antibody comprises the heavy and light chain variable region CDRs, the heavy and light chain variable regions, and / or the heavy and light chains of mavezemalimab. In some aspects, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 69, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 70. In some aspects, the anti-LAG-3 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 71; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 72; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 73; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 74; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 75; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 76. In some aspects, the anti-LAG-3 antibody comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 69 and 70, respectively.

[0179] In some aspects, the pharmaceutical composition comprises at least about 1 mg / mL to at least about 500 mg / mL of an anti-LAG-3 antibody. In some aspects, at least about 1 mg / mL to at least about 400 mg / mL, at least about 1 mg / mL to at least about 300 mg / mL, at least about 1 mg / mL to at least about 250 mg / mL, at least about 1 mg / mL to at least about 200 mg / mL, at least about 1 mg / mL to at least about 150 mg / mL, at least about 1 mg / mL to at least about 140 mg / mL, at least about 1 mg / mL to at least about 130 mg / mL, at least about 1 mg / mL to at least about 120 mg / mL, at least about 1 mg / mL to at least about 110 mg / mL, at least about 1 mg / mL to at least about 100 mg / mL, at least about 1 mg / mL to at least about 90 mg / mL. In some aspects, the pharmaceutical composition comprises at least about 3 mg / mL to at least about 200 mg / mL of anti-LAG-3 antibody.

[0180] In some aspects, the pharmaceutical composition comprises at least about 1 mg / mL, at least about 2 mg / mL, at least about 3 mg / mL, at least about 3.3 mg / mL, at least about 4 mg / mL, at least about 5 mg / mL, at least about 6 mg / mL, at least about 7 mg / mL, at least about 8 mg / mL, at least about 9 mg / mL, at least about 10 mg / mL, at least about 13 mg / mL, at least about 15 mg / mL, at least about 18 mg / mL, at least about 20 mg / mL, at least about 23 mg / mL, at least about 25 mg / mL, at least about 26 mg / mL, at least about 27 mg / mL, at least about 28 mg / mL. In some embodiments, the present invention provides at least about 1 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-LAG-3 antibody.

[0181] In some aspects, the pharmaceutical composition comprises at least about 3 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 3.3 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 5 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 13 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises about 13.35 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 15 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 20 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 25 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 26 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises about 26.7 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 30 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 35 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 40 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 45 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 50 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 55 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 60 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 65 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 70 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 75 mg / mL of the anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 80 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 85 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 95 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 110 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 120 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 130 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 140 mg / mL of an anti-LAG-3 antibody.In some aspects, the pharmaceutical composition comprises at least about 150 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 160 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 170 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 180 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 190 mg / mL of an anti-LAG-3 antibody. In some aspects, the pharmaceutical composition comprises at least about 200 mg / mL of an anti-LAG-3 antibody.

[0182] In some aspects, a pharmaceutical composition as disclosed herein comprises at least about 1 mg / mL, at least about 2 mg / mL, at least about 3 mg / mL, at least about 3.3 mg / mL, at least about 4 mg / mL, at least about 5 mg / mL, at least about 6 mg / mL, at least about 7 mg / mL, at least about 8 mg / mL, at least about 9 mg / mL, at least about 10 mg / mL, at least about 13 mg / mL, at least about 15 mg / mL, at least about 18 mg / mL, at least about 20 mg / mL, at least about 23 mg / mL, at least about 25 mg / mL, at least about 26 mg / mL, at least about 27 mg / mL, at least about 28 mg / mL, at least about 30 mg / mL, at least about In some embodiments, the dosage of an anti-LAG-3 antibody as disclosed herein (e.g., relalizumab, tepolizumab, foramalizumab, elaralizumab, or mavezemalimab) is / are preferably at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL of an anti-LAG-3 antibody as disclosed herein (e.g., relalizumab, tepolizumab, foramalizumab, elaralizumab, or mavezemalimab).

[0183] In some aspects, a pharmaceutical composition as disclosed herein comprises about 1 mg / mL to about 500 mg / mL, about 1 mg / mL to about 450 mg / mL, about 1 mg / mL to about 400 mg / mL, about 1 mg / mL to about 350 mg / mL, about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 150 mg / mL, about 1 mg / mL to about 140 mg / mL, about 1 mg / mL to about 130 mg / mL, about 1 mg / mL to about 120 mg / mL, about 1 mg / mL to about 110 mg / mL, about 1 mg / mL to about 100 mg / mL, or about 1 mg / mL to about 150 mg / mL. g / mL, about 1 mg / mL to about 90 mg / mL, about 1 mg / mL to about 80 mg / mL, about 1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 60 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 45 mg / mL, about 1 mg / mL to about 40 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 29 mg / mL, about 1 mg / mL to about 28 mg / mL, about 1 mg / mL to about 27 mg / mL, about 1 mg / mL to about 26 mg / mL, about 1 mg / mL to about 25 mg / mL, about 1 mg / mL mL to about 20 mg / mL, about 1 mg / mL to about 15 mg / mL, about 1 mg / mL to about 10 mg / mL, or about 1 mg / mL to about 5 mg / mL, about 3 mg / mL to about 200 mg / mL, about 5 mg / mL to about 250 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 150 mg / mL, about 5 mg / mL to about 140 mg / mL, about 5 mg / mL to about 130 mg / mL, about 5 mg / mL to about 120 mg / mL, about 5 mg / mL to about 110 mg / mL, about 5 mg / mL to about 100 mg / mL, about 5 mg / mL to about 90 mg / mL, about 5 mg / mL L to about 80 mg / mL, about 5 mg / mL to about 70 mg / mL, about 5 mg / mL to about 60 mg / mL, about 5 mg / mL to about 50 mg / mL, about 5 mg / mL to about 45 mg / mL, about 5 mg / mL to about 40 mg / mL, about 5 mg / mL to about 35 mg / mL, about 5 mg / mL to about 30 mg / mL, about 5 mg / mL to about 29 mg / mL, about 5 mg / mL to about 28 mg / mL, about 5 mg / mL to about 27 mg / mL, about 5 mg / mL to about 26 mg / mL, about 5 mg / mL to about 25 mg / mL, about 5 mg / mL to about 20 mg / mL, about 5 mg / mL to about 15 mg / mL,about 5 mg / mL to about 10 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 45 mg / mL, about 10 mg / mL to about 40 mg / mL, about 10 mg / mL to about 35 mg / mL, about 10 mg / mL to about 30 mg / mL, about 10 mg / mL to about 29 mg / mL, about 10 mg / mL to about 28 mg / mL, about 10 mg / mL to about 27 mg / mL, about 10 mg / mL to about 26 mg / mL, about 10 mg / mL to about 25 mg / mL, about 10 mg / mL to about 20 mg / mL L, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 45 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 35 mg / mL, about 20 mg / mL to about 30 mg / mL, about 20 mg / mL to about 29 mg / mL, about 20 mg / mL to about 28 mg / mL, about 20 mg / mL to about 27 mg / mL, about 20 mg / mL to about 26 mg / mL, about 20 mg / mL to about 25 mg / mL, about 25 mg / mL to about 30 mg / mL, about 25 mg / mL to about 29 mg / mL, about 25 mg / mL to about 28 mg / mL, about 25 mg / mL to about 27 mg / mL of an anti-LAG-3 antibody as disclosed herein (e.g., relalizumab, tepolizumab, foramalizumab, elaralizumab, or mavezemalimab).

[0184] In some aspects, a pharmaceutical composition as disclosed herein comprises about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 3.3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 13 mg / mL, about 13.35 mg / mL, about 15 mg / mL, about 18 mg / mL, about 20 mg / mL, about 23 mg / mL, about 25 mg / mL, about 26 mg / mL, about 26.7 mg / mL, about 27 mg / mL, about 28 mg / mL. L, about 29 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 108 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 132 mg / mL, about 135 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL In some embodiments, the dosage form of the anti-LAG-3 antibody disclosed herein (e.g., relalizumab, tepolizumab, foramalizumab, elaralizumab, or mavezemalimab) is about 1, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL of an anti-LAG-3 antibody as disclosed herein (e.g., relalizumab, tepolizumab, foramalizumab, elaralizumab, or mavezemalimab) is about 1, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL of

[0185] In some aspects, a pharmaceutical composition as disclosed herein comprises about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 2000 mg. In some embodiments, the present invention provides an anti-LAG-3 antibody as disclosed herein (e.g., relalizumab, tepolizumab, foramalizumab, elaralizumab, or mavezemalimab) in an amount of about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg.

[0186] In some aspects, a pharmaceutical composition as disclosed herein comprises about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, 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 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg 0mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg,about 990mg, about 1000mg, about 1040mg, about 1080mg, about 1100mg, about 1140mg, about 1180mg, about 1200mg, about 1240mg, about 1280mg, about 1300mg, about 1340mg, about 1380mg, about 1400mg, about 1440mg, about 1480mg, about 1500mg, about 1540mg, about 1580mg, about 1 600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg of an anti-LAG-3 antibody as disclosed herein (e.g., relalizumab, tepolizumab, foramalizumab, elaralizumab, or mavezemalimab). II.B Anti-PD-1 Antibodies

[0187] In some aspects, the pharmaceutical composition comprises an antibody or antigen-binding portion thereof that specifically binds to PD-1 ("anti-PD-1 antibody"). Any anti-PD-1 antibody can be used in the compositions and methods described herein. Various human monoclonal antibodies that specifically bind to PD-1 with high affinity 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 shown to exhibit one or more of the following characteristics: (a) 1x10 -7 M or lower K D Binds to human PD-1 as determined by surface plasmon resonance using a Biacore biosensor system; (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 monkey 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 useful in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one, and in some aspects at least five, of the aforementioned characteristics.

[0188] Other anti-PD-1 monoclonal antibodies have been described, for example, in U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509, U.S. 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 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825 and WO 2017 / 133540, each of these documents is incorporated by reference in its entirety.

[0189] In some aspects, the anti-PD-1 antibody is nivolumab (also known as OPDIVO, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA, lambrolizumab, and MK-3475; see WO 2008 / 156712), PDR001 (Novartis; also known as spartalizumab; see WO 2015 / 112900 and U.S. Patent No. 9,683,048), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO 2012 / 145493), cemiplizumab (Regeneron; also known as LIBTAYO or REGN-2810; see WO 2015 / 112900 and U.S. Patent No. 9,683,048), 2015 / 112800 and U.S. Patent No. 9,987,500), JS001 (TAIZHOU JUNSHIPHARMA); also known as toripalimab; see Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), BGB-A317 (BeiGene; also known as tislelizumab; see WO 2015 / 35606 and US 2015 / 0079109), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or camrelizumab; see WO 2015 / 085847; Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), Liu et al., J. Hematol. Oncol. 10:136 (2017), TSR-042 (Tesaro Biopharmaceuticals; also known as ANB011 or dostarlimab; see WO 2014 / 179664), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals); also known as WBP3055; see Si-Yang Liu et al., J. Hematol. Oncol.[Journal of Hematology and Oncology] 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 [monoclonal antibodies] 10(2):183-203 (2018)), IBI308 (Innovent; also known as sintilimab; see WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825, and WO 2017 / 133540); sananlimab (Pfizer; also known as PF-06801591; US2016 / 0159905); BI 754091 (Boehringer Ingelheim; see Zettl M et al., Cancer. Res. (2018); 78(13 Suppl):Abstract 4558), SSI-361 (Lyvgen Biopharma Holdings Limited, US2018 / 0346569), or an antigen-binding portion thereof.

[0190] In one aspect, the anti-PD-1 antibody is nivolumab. Nivolumab is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively 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).

[0191] In some aspects, the anti-PD-1 antibody comprises the heavy chain and light chain variable region CDRs, heavy chain and light chain variable regions, and / or heavy chain and light chain of nivolumab. In some aspects, the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising the amino acid sequence shown in SEQ ID NO: 13, and the light chain variable region comprising the amino acid sequence shown in SEQ ID NO: 14. In some aspects, the antibody comprises a heavy chain complementary determining region (CDR) 1, CDR2, and CDR3 sequence, which comprises the amino acid sequence of the heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 13. In some aspects, the antibody comprises a light chain CDR1, CDR2, and CDR3 sequence, which comprises the amino acid sequence of the light chain CDR1, CDR2, and CDR3 of SEQ ID NO: 14. In some aspects, the anti-PD-1 antibody comprises a heavy chain variable region CDR1, CDR2, and CDR3 domain comprising the amino acid sequence of SEQ ID NO: 13, and a light chain variable region CDR1, CDR2, and CDR3 domain comprising the amino acid sequence of SEQ ID NO: 14. In some aspects, the anti-PD-1 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 15; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 16; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 17; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 18; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 19; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 20. In some aspects, the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the amino acid sequences of SEQ ID NOs: 11 and 12, respectively.

[0192] In another aspect, 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.

[0193] In some aspects, the anti-PD-1 antibody comprises the heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or heavy and light chains of pembrolizumab. In some aspects, the anti-PD-1 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence of SEQ ID NO: 79, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence of SEQ ID NO: 80. In some aspects, the anti-PD-1 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 81; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 82; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 83; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 84; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 85; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 86. In some aspects, the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 79 and 80, respectively. In some aspects, the anti-PD-1 antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 77 and 78, respectively.

[0194] In another aspect, the anti-PD-1 antibody is cemiplizumab (REGN2810). Cemiplizumab is described, for example, in WO 2015 / 112800 and U.S. Pat. No. 9,987,500.

[0195] In some aspects, the anti-PD-1 antibody comprises the heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or heavy and light chains of cemiplimab. In some aspects, the anti-PD-1 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence of SEQ ID NO: 35, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence of SEQ ID NO: 36. In some aspects, the anti-PD-1 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 37; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 38; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 39; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 40; (e) a light chain variable region CDR2 comprising the amino acid sequence AAS; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 42. In some aspects, the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 35 and 36, respectively. In some aspects, the anti-PD-1 antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 33 and 34, respectively.

[0196] In another aspect, the anti-PD-1 antibody is spartalizumab (PDR001). Spartalizumab is described, for example, in WO2015 / 112900 and U.S. Patent No. 9,683,048.

[0197] In some aspects, the anti-PD-1 antibody comprises the heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or heavy and light chains of spartalizumab. In some aspects, the anti-PD-1 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence of SEQ ID NO: 59, and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence of SEQ ID NO: 60. In some aspects, the anti-PD-1 antibody comprises (a) a heavy chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 61; (b) a heavy chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 62; (c) a heavy chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 63; (d) a light chain variable region CDR1 comprising the amino acid sequence of SEQ ID NO: 64; (e) a light chain variable region CDR2 comprising the amino acid sequence of SEQ ID NO: 65; and (f) a light chain variable region CDR3 comprising the amino acid sequence of SEQ ID NO: 66. In some aspects, the anti-PD-1 antibody comprises heavy and light chain variable regions comprising the amino acid sequences of SEQ ID NOs: 59 and 60, respectively. In some aspects, the anti-PD-1 antibody comprises heavy and light chains comprising the amino acid sequences of SEQ ID NOs: 57 and 58, respectively.

[0198] In another aspect, the anti-PD-1 antibody is sanskritizumab.

[0199] In some aspects, the anti-PD-1 antibody comprises the heavy and light chain variable region CDRs, the heavy and light chain variable regions, and / or the heavy and light chains of sanskritiumab.

[0200] In some aspects, any anti-PD-1 antibody as disclosed herein is combined with any anti-LAG-3 antibody as disclosed herein in any of the compositions and methods disclosed herein.

[0201] Anti-PD-1 antibodies that can be used in the compositions and methods of the present disclosure 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) for binding to human PD-1 (see, for example, U.S. Patent Nos. 8,008,449 and 8,779,105; WO 2013 / 173223). In some aspects, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein (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 other cross-competing antibodies from binding to that specific epitope region. It is expected that these cross-competing antibodies have very similar functional properties to the reference antibody (e.g., nivolumab) due to 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., WO 2013 / 173223).

[0202] In certain aspects, antibodies that cross-compete for binding to human PD-1 or bind to the same epitope region as any of the human PD-1 antibodies disclosed herein (e.g., nivolumab) are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0203] Anti-PD-1 antibodies useful in the compositions and methods of the present disclosure also include antigen-binding portions of the above-described full-length antibodies. It has been well documented that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0204] Anti-PD-1 antibodies suitable for use in the disclosed compositions and methods are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any composition or method disclosed herein, an anti-PD-1 "antibody" includes an antigen-binding portion or fragment that binds to the PD-1 receptor and exhibits functional properties similar to those of the intact antibody in inhibiting ligand binding and upregulating the immune system. In certain aspects, the anti-PD-1 antibody, or antigen-binding portion thereof, cross-competes with nivolumab for binding to human PD-1.

[0205] In some aspects, the anti-PD-1 antibody is a full-length antibody.

[0206] In some aspects, the anti-PD-1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody is a DART, a DVD-Ig, or a bispecific antibody.

[0207] In some aspects, the anti-PD-1 antibody is a bispecific antibody. In some aspects, the bispecific antibody specifically binds (i) PD-1 and (ii) a second antigen (e.g., TIGIT).

[0208] In some aspects, the pharmaceutical composition comprises a bispecific antibody or a 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., scFv of nivolumab). In some aspects, the second antigen binding portion is an antigen binding portion of any one of the antibodies disclosed herein. In some aspects, the second antigen binding portion is an antigen binding portion of an anti-LAG-3 antibody (e.g., relalizumab). In some aspects, the second antigen binding portion is an antigen binding portion of an anti-TIGIT antibody.

[0209] In some aspects, the anti-PD-1 antibody is a trispecific antibody. In some aspects, the trispecific antibody specifically binds (i) PD-1, (ii) a second antigen, and (iii) a third antigen. In some aspects, the second antigen and the third antigen are the same. In some aspects, the second antigen and the third antigen are different.

[0210] In some aspects, a 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).

[0211] In some aspects, the antigen-binding portion of the bispecific or trispecific antibody is a scFv, such as the scFv of nivolumab of the bispecific or trispecific antibody that specifically binds PD-1.

[0212] The second or third antigen that specifically binds to the bispecific or trispecific antibody herein can be any antigen disclosed herein.

[0213] In some aspects, the anti-PD-1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0214] In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of an anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL, at least about 10 mg / mL to at least about 400 mg / mL, at least about 10 mg / mL to at least about 300 mg / mL, at least about 10 mg / mL to at least about 250 mg / mL, at least about 10 mg / mL to at least about 200 mg / mL, at least about 10 mg / mL to at least about 190 mg / mL, at least about 10 mg / mL to at least about 180 mg / mL, at least about 10 mg / mL to at least about 170 mg / mL, at least about 10 mg / mL to at least about 160 mg / mL, at least about 10 mg / mL to at least about 150 mg / mL, at least about 20 mg / mL to at least about 500 mg / mL, at least about 20 mg / mL to at least about 400 mg / mL, at least about 20 mg / mL to at least about 300 mg / mL, at least about 20 mg / mL to at least about 250 mg / mL, to 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 In some aspects, the pharmaceutical composition comprises at least about 50 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 60 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 70 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 75 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 80 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 108 mg / mL of an anti-PD-1 antibody.In some aspects, the pharmaceutical composition comprises at least about 110 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 120 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 130 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 132 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 135 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 140 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 150 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 160 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 170 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 175 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 180 mg / mL of anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 190 mg / mL of the anti-PD-1 antibody. In some aspects, the pharmaceutical composition comprises at least about 200 mg / mL of the anti-PD-1 antibody.

[0215] In some aspects, a pharmaceutical composition as disclosed herein comprises at least about 10 mg / mL, at least about 15 mg / mL, at least about 20 mg / mL, at least about 25 mg / mL, at least about 30 mg / mL, at least about 35 mg / mL, at least about 40 mg / mL, at least about 45 mg / mL, at least about 50 mg / mL, at least about 55 mg / mL, at least about 60 mg / mL, at least about 65 mg / mL, at least about 70 mg / mL, at least about 75 mg / mL, at least about 80 mg / mL, at least about 85 mg / mL, at least about 90 mg / mL, at least about 95 mg / mL, at least about In some embodiments, the present invention provides an anti-PD-1 antibody as disclosed herein (e.g., nivolumab, pembrolizumab, cemiplizumab, or spartalizumab) at least about 100 mg / mL, at least about 108 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 132 mg / mL, at least about 135 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 175 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL of an anti-PD-1 antibody as disclosed herein (e.g., nivolumab, pembrolizumab, cemiplizumab, or spartalizumab).

[0216] In some aspects, a pharmaceutical composition as disclosed herein comprises about 10 mg / mL to about 500 mg / mL, about 10 mg / mL to about 450 mg / mL, about 10 mg / mL to about 400 mg / mL, about 10 mg / mL to about 350 mg / mL, about 10 mg / mL to about 300 mg / mL, about 10 mg / mL to about 250 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 190 mg / mL, about 10 mg / mL to about 180 mg / mL, about 10 mg / mL to about 170 mg / mL, about 10 mg / mL to about 160 mg / mL, about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 140 mg / mL, about 10 mg / mL to about 130 mg / mL, about 10 mg / mL to about 120 mg / mL, about 10 mg / mL to about 110 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 85 mg / mL, about 10 mg / mL to about 80 mg / mL, about 20 mg / mL to about 500 mg / mL, about 20 mg / mL to about 450 mg / mL, about 20 mg / mL to about 400 mg / mL, about 20 mg / mL to about 350 mg / mL, about 20 mg / mL to about 300 mg / mL, about 20 mg / mL to about 250 mg / mL, about 20 mg / mL to about 200 mg / mL, about 20 mg / mL to about 190 mg / mL, about 20 mg / mL to about 180 mg / mL, about 20 mg / mL to about 170 mg / mL, about 20 mg / mL to about 160 mg / mL, about 20 mg / mL to about 150 mg / mL, about 20 mg / mL to about 140 mg / mL, about 20 mg / mL to about 130 mg / mL, about 20 mg / mL to about 120 mg / mL, about 20 mg / mL to about 110 mg / mL, about 20 mg / mL to about 100 mg / mL, about 20 mg / mL to about 90 mg / mL, about 20 mg / mL to about 85 mg / mL g / mL, about 20 mg / mL to about 80 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 190 mg / mL, about 50 mg / mL to about 180 mg / mL, about 50 mg / mL to about 170 mg / mL, about 50 mg / mL to about 160 mg / mL, about 50 mg / mL to about 150 mg / mL, about 50 mg / mL to about 140 mg / mL, about 50 mg / mL to about 130 mg / mL, about 50 mg / mL to about 120 mg / mL, about 50 mg / mL to about 110 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 90 mg / mL,about 50 mg / mL to about 85 mg / mL, about 50 mg / mL to about 80 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 150 mg / mL, about 150 mg / mL to about 200 mg / mL, about 135 mg / mL to about 180 mg / mL, about 100 mg / mL to about 130 mg / mL, or about 108 mg / mL to about 132 mg / mL of an anti-PD-1 antibody as disclosed herein (e.g., nivolumab, pembrolizumab, cemiplimab, or spartalizumab).

[0217] In some aspects, a pharmaceutical composition as disclosed herein comprises about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL. / mL, about 95 mg / mL, about 100 mg / mL, about 108 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 132 mg / mL, about 135 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 In some embodiments, the dosage form of the anti-PD-1 antibody disclosed herein (e.g., nivolumab, pembrolizumab, cemiplizumab, or spartalizumab) is about 1 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL of an anti-PD-1 antibody as disclosed herein (e.g., nivolumab, pembrolizumab, cemiplizumab, or spartalizumab).

[0218] In some aspects, a pharmaceutical composition as disclosed herein comprises about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about or about 400 mg to about 1000 mg of an anti-PD-1 antibody as disclosed herein (e.g., nivolumab, pembrolizumab, cemiplizumab, or spartalizumab).

[0219] In some aspects, a pharmaceutical composition as disclosed herein comprises about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, 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 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg 0mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg,about 990mg, about 1000mg, about 1040mg, about 1080mg, about 1100mg, about 1140mg, about 1180mg, about 1200mg, about 1240mg, about 1280mg, about 1300mg, about 1340mg, about 1380mg, about 1400mg, about 1440mg, about 1480mg, about 1500mg, about 1540mg, about 1580mg g, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg of an anti-PD-1 antibody as disclosed herein (e.g., nivolumab, pembrolizumab, cemiprilizumab, or spartalizumab). In some aspects, the pharmaceutical composition as disclosed herein comprises relalizumab and an anti-PD-1 antibody as disclosed herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiprilizumab, or spartalizumab. In some aspects, the anti-PD-1 antibody is nivolumab.

[0220] In some aspects, a pharmaceutical composition as disclosed herein comprises mavezelimab and an anti-PD-1 antibody as disclosed herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplizumab, or spartalizumab. In some aspects, the anti-PD-1 antibody is pembrolizumab.

[0221] In some aspects, a pharmaceutical composition as disclosed herein comprises follizumab and an anti-PD-1 antibody as disclosed herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiprilimab, or spartalizumab. In some aspects, the anti-PD-1 antibody is cemiprilimab.

[0222] In some aspects, a pharmaceutical composition as disclosed herein comprises elalimumab and an anti-PD-1 antibody as disclosed herein. In some aspects, the anti-PD-1 antibody is nivolumab, pembrolizumab, cemiplizumab, or spartalizumab. In some aspects, the anti-PD-1 antibody is spartalizumab.

[0223] In some aspects, a pharmaceutical composition as disclosed herein comprises a ratio of an anti-PD-1 antibody (e.g., nivolumab) to an anti-LAG-3 antibody (e.g., relalizumab) of about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:15 1, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:1.

[0224] In some aspects, the pharmaceutical composition includes a ratio of about 6:1 of anti-PD-1 antibody (eg, nivolumab) to anti-LAG-3 antibody (eg, relalizumab).

[0225] In some aspects, the pharmaceutical composition includes a ratio of about 3:1 of anti-PD-1 antibody (eg, nivolumab) to anti-LAG-3 antibody (eg, relalizumab).

[0226] In some aspects, the pharmaceutical composition includes a ratio of about 1:1 of anti-PD-1 antibody (eg, nivolumab) to anti-LAG-3 antibody (eg, relalizumab).

[0227] In some aspects, the pharmaceutical composition includes a ratio of about 1:2 of anti-PD-1 antibody (eg, nivolumab) to anti-LAG-3 antibody (eg, relalizumab).

[0228] In some aspects, the pharmaceutical composition includes a ratio of anti-PD-1 antibody (eg, nivolumab) to anti-LAG-3 antibody (eg, relalizumab) of about 1:4.

[0229] In some aspects, the pharmaceutical composition comprises (i) about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab) and (ii) about 26.7 mg / mL of an anti-LAG-3 antibody (e.g., relalizumab).

[0230] In some aspects, the pharmaceutical composition comprises (i) about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab) and (ii) about 40 mg / mL of an anti-LAG-3 antibody (e.g., relalizumab).

[0231] In some aspects, the pharmaceutical composition comprises (i) about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab) and (ii) about 80 mg / mL of an anti-LAG-3 antibody (e.g., relalizumab).

[0232] In some aspects, the pharmaceutical composition comprises (i) about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab) and (ii) about 13.3 mg / mL of an anti-LAG-3 antibody (e.g., relalizumab).

[0233] In some aspects, the pharmaceutical composition comprises (i) about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab) and (ii) about 13.35 mg / mL of an anti-LAG-3 antibody (e.g., relalizumab).

[0234] In some aspects, the pharmaceutical composition comprises (i) about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab) and (ii) about 160 mg / mL of an anti-LAG-3 antibody (e.g., relalizumab).

[0235] In some aspects, the pharmaceutical composition comprises (i) about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab) and (ii) about 240 mg / mL of an anti-LAG-3 antibody (e.g., relalizumab).

[0236] In some aspects, the pharmaceutical composition comprises (i) about 1200 mg of an anti-PD-1 antibody (eg, nivolumab) and (ii) about 400 mg of an anti-LAG-3 antibody (eg, relalizumab).

[0237] In some aspects, the pharmaceutical composition comprises (i) about 960 mg of an anti-PD-1 antibody (eg, nivolumab) and (ii) about 320 mg of an anti-LAG-3 antibody (eg, relalizumab).

[0238] In some aspects, the anti-PD-1 antibody is administered once every 2, 3, 4, 5, 6, 7 or 8 weeks at a dose ranging from 0.1 mg / kg to 20.0 mg / kg body weight, for example, once every 2, 3 or 4 weeks at a dose of 0.1 mg / kg to 10.0 mg / kg body weight. In other aspects, the anti-PD-1 antibody is administered once every 2 weeks 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. In other aspects, the anti-PD-1 antibody is administered once every 3 weeks 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. In one aspect, the anti-PD-1 antibody is administered approximately once every 3 weeks at a dose of about 5 mg / kg body weight. In another aspect, the anti-PD-1 antibody (e.g., nivolumab) is administered at a dose of about 3 mg / kg body weight approximately once every 2 weeks. In other aspects, the anti-PD-1 antibody (e.g., pembrolizumab) is administered at a dose of about 2 mg / kg body weight approximately once every 3 weeks.

[0239] The anti-PD-1 antibodies useful for the present disclosure can be administered at a steady dose. In some aspects, the anti-PD-1 antibodies are administered at a steady 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 aspect, the anti-PD-1 antibody is administered at a steady-state dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, at least about 520 mg, at least about 540 mg, at least about 550 mg, at least about 560 mg, at least about 580 mg, at least about 600 mg, at least about 620 mg, at least about 640 mg, at least about 660 mg, at least about 680 mg, at least about 700 mg, or at least about 720 mg at a dosing interval of about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks. In another aspect, the anti-PD-1 antibody is administered at a steady dose of 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 at a dosing interval of about 1, 2, 3, or 4 weeks.

[0240] In some aspects, the anti-PD-1 antibody is administered at a steady dose of about 200 mg about once every 3 weeks. In other aspects, the anti-PD-1 antibody is administered at a steady dose of about 200 mg about once every 2 weeks. In other aspects, the anti-PD-1 antibody is administered at a steady dose of about 240 mg about once every 2 weeks. In certain aspects, the anti-PD-1 antibody is administered at a steady dose of about 480 mg about once every 4 weeks.

[0241] In some aspects, nivolumab is administered at a steady dose of about 240 mg approximately once every 2 weeks. In some aspects, nivolumab is administered at a steady dose of about 240 mg approximately once every 3 weeks. In some aspects, nivolumab is administered at a steady dose of about 360 mg approximately once every 3 weeks. In some aspects, nivolumab is administered at a steady dose of about 480 mg approximately once every 4 weeks. In some aspects, nivolumab is administered at a steady dose of about 720 mg approximately once every 6 weeks. In some aspects, nivolumab is administered at a steady dose of about 960 mg approximately once every 8 weeks.

[0242] In some aspects, pembrolizumab is administered at a steady-state dose of about 200 mg approximately once every 2 weeks. In some aspects, pembrolizumab is administered at a steady-state dose of about 200 mg approximately once every 3 weeks. In some aspects, pembrolizumab is administered at a steady-state dose of about 400 mg approximately once every 4 weeks.

[0243] In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL, at least about 10 mg / mL to at least about 400 mg / mL, at least about 10 mg / mL to at least about 300 mg / mL, at least about 10 mg / mL to at least about 250 mg / mL, at least about 10 mg / mL to at least about 200 mg / mL, at least about 10 mg / mL to at least about 190 mg / mL, at least about 10 mg / mL to at least about 180 mg / mL. 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 250 mg / mL, at least about 20 mg / mL to at least about 300 mg / mL mL to at least about 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, In some aspects, the pharmaceutical composition comprises at least about 50 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 60 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 70 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 75 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab).In some aspects, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 108 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 110 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 120 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 130 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 132 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 135 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 140 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 150 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 160 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 170 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 175 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 180 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 190 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some aspects, the pharmaceutical composition comprises at least about 200 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). II.C. Anti-PD-L1 Antibodies

[0244] Any anti-PD-L1 antibody can be used in the compositions and methods of the present disclosure. Examples of anti-PD-L1 antibodies that can be used in the compositions and methods of the present disclosure include the antibodies disclosed in U.S. Patent No. 9,580,507. The anti-PD-L1 human monoclonal antibody disclosed in U.S. Patent No. 9,580,507 has been shown to exhibit one or more of the following characteristics: (a) a 1x10 - 7 M or lower K DBinds to human PD-L1 as measured by surface plasmon resonance using a Biacore biosensor system; (b) increases T cell proliferation 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 an antibody response; and (f) reverses the effects of regulatory T cells on T cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies useful in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least one of the aforementioned characteristics, and in some aspects at least five.

[0245] In certain aspects, the anti-PD-L1 antibody is BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Pat. No. 7,943,743 and WO 2013 / 173223), atezolizumab (Roche; also known as TECENTRIQ; MPDL3280A, RG7446; see, e.g., U.S. Pat. No. 8,217,149; see also Herbst et al. (2013) J. Clin. Oncol. 31(Suppl):3000), durvalumab (AstraZeneca; also known as IMFINZI, MEDI-4736; see WO 2011 / 066389), avelumab (Pfizer; also known as BAVENCIO, MSB-0010718C; see WO 2013 / 079174), STI-1014 (Sorrento Pharmaceuticals; see WO 2013 / 181634), CX-072 (Cytomx; see WO 2016 / 149201), KN035 (3D Med / Alphamab; see Zhang et al., Cell Discov. 7:3 (March 2017)), LY3300054 (Eli Lilly Co.; see, e.g., WO 2017 / 034916), BGB-A333 (BeiGene; see Desai et al., JCO 36(15 Suppl):TPS3113 (2018)), ICO 36, FAZ053 (Novartis AG), and CK-301 (Checkpoint Pharmaceuticals; see, e.g., WO 2017 / 034916). Therapeutics); see Gorelik et al., AACR: Abstract 4606 (April 2016)) or comprising an antigen-binding portion thereof.

[0246] In certain aspects, the PD-L1 antibody is atezolizumab (TECENTRIQ). Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody.

[0247] In certain aspects, the PD-L1 antibody is durvalumab (IMFINZI). Durvalumab is a human IgG1κ monoclonal anti-PD-L1 antibody.

[0248] In certain aspects, the PD-L1 antibody is avelumab (BAVENCIO). Avelumab is a human IgG1λ monoclonal anti-PD-L1 antibody.

[0249] 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 aspects, 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 antigens indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder other cross-competing antibodies from binding to that specific epitope region. It is expected that these cross-competing antibodies have very similar functional properties to the reference antibodies (e.g., atezolizumab and / or avelumab) due to 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., WO 2013 / 173223).

[0250] In certain aspects, antibodies that cross-compete for binding to human PD-L1 or bind to the same epitope region as human PD-L1 antibodies (e.g., atezolizumab, durvalumab, and / or avelumab) are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0251] Anti-PD-L1 antibodies useful in the compositions and methods of the present disclosure also include antigen-binding portions of any of the above-described full-length antibodies. It has been well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0252] Anti-PD-L1 antibodies suitable for use in the disclosed compositions and methods are antibodies that bind to PD-L1 with high specificity and affinity, block PD-1 binding, and inhibit the immunosuppressive effects of the PD-1 signaling pathway. In any composition or method disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to PD-L1 and exhibits functional properties similar to those of the intact antibody in inhibiting receptor binding and upregulating the immune system. In certain aspects, the anti-PD-L1 antibody, or antigen-binding portion thereof, cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0253] The anti-PD-L1 antibodies useful in the present disclosure can be any PD-L1 antibody that specifically binds to PD-L1, such as antibodies that cross-compete with durvalumab, avelumab, or atezolizumab for binding to human PD-1, such as antibodies that bind to the same epitope as durvalumab, avelumab, or atezolizumab. In certain aspects, the anti-PD-L1 antibody is durvalumab. In other aspects, the anti-PD-L1 antibody is avelumab. In some aspects, the anti-PD-L1 antibody is atezolizumab.

[0254] In some aspects, any anti-PD-L1 antibody as disclosed herein is combined with any anti-LAG-3 antibody as disclosed herein in any of the compositions and methods disclosed herein.

[0255] In some aspects, any anti-PD-L1 antibody as disclosed herein is substituted for any anti-PD-1 antibody as disclosed herein in any of the compositions and methods disclosed herein.

[0256] In some aspects, any anti-PD-L1 antibody as disclosed herein is combined with any anti-LAG-3 antibody as disclosed herein and any anti-PD-1 antibody as disclosed herein in any of the compositions and methods disclosed herein.

[0257] In some aspects, the anti-PD-L1 antibody is a full-length antibody.

[0258] In some aspects, the anti-PD-L1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some aspects, the multispecific antibody is a DART, a DVD-Ig, or a bispecific antibody.

[0259] In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds (i) PD-L1 and (ii) a second antigen. In some aspects, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds (i) PD-L1 and (ii) CD3.

[0260] In some aspects, the anti-PD-L1 antibody and the anti-LAG-3 antibody in the pharmaceutical composition are part of a bispecific antibody (e.g., the pharmaceutical composition comprises (i) a bispecific antibody that specifically binds to PD-L1 and LAG-3, and (ii) an endoglycosidase hydrolase, or (i) a bispecific antibody that specifically binds to PD-L1 and LAG-3, (ii) an anti-PD-1 antibody, and (iii) an endoglycosidase hydrolase). In some aspects, the anti-PD-L1 antibody and the anti-PD-1 antibody in the pharmaceutical composition are part of a bispecific antibody (e.g., the pharmaceutical composition comprises (i) a bispecific antibody that specifically binds to PD-L1 and PD-1, (ii) an anti-LAG-3 antibody, and (iii) an endoglycosidase hydrolase).

[0261] In some aspects, the anti-PD-L1 antibody is a trispecific antibody. In some aspects, the trispecific antibody specifically binds to (i) PD-L1, (ii) a second antigen, and (iii) a third antigen. In some aspects, the second antigen and the third antigen are the same. In some aspects, the second antigen and the third antigen are different. In some aspects, the anti-PD-L1 antibody and the anti-LAG-3 antibody in the pharmaceutical composition are part of a trispecific antibody (e.g., a pharmaceutical composition comprising (i) a trispecific antibody that specifically binds to PD-L1, LAG-3, and a third antigen, and (ii) an endoglycosidase hydrolase, or (i) a trispecific antibody that specifically binds to PD-L1, LAG-3, and a third antigen, (ii) an anti-PD-1 antibody, and (iii) an endoglycosidase hydrolase). In some aspects, the anti-PD-L1 antibody and the anti-PD-1 antibody in the pharmaceutical composition are part of a trispecific antibody (e.g., the pharmaceutical composition comprises (i) a trispecific antibody that specifically binds PD-L1, PD-1, and a third antigen, (ii) an anti-LAG-3 antibody, and (iii) an endoglycosidase hydrolase). In some aspects, the anti-PD-L1 antibody, the anti-LAG-3 antibody, and the anti-PD-1 antibody in the pharmaceutical composition are part of a trispecific antibody (e.g., the pharmaceutical composition comprises (i) a trispecific antibody that specifically binds PD-L1, LAG-3, and PD-1, and (ii) an endoglycosidase hydrolase).

[0262] In some aspects, the antigen binding portion of the bispecific or trispecific antibody is a scFV.

[0263] The second or third antigen that specifically binds to the bispecific or trispecific antibody herein can be any antigen disclosed herein.

[0264] In some aspects, the anti-PD-L1 antibody is a F(ab')2 fragment, a Fab' fragment, a Fab fragment, a Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0265] In some aspects, the anti-PD-L1 antibody is administered about once every 2, 3, 4, 5, 6, 7, or 8 weeks 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.

[0266] In some aspects, the anti-PD-L1 antibody is administered at a dose of about 15 mg / kg body weight approximately once every 3 weeks. In other aspects, the anti-PD-L1 antibody is administered at a dose of about 10 mg / kg body weight approximately once every 2 weeks.

[0267] In other aspects, the anti-PD-L1 antibodies useful in the present disclosure are steady-state doses. In some aspects, the anti-PD-L1 antibodies are administered at a steady-state 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 aspects, the anti-PD-L1 antibody is administered at a steady 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 about 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 at a dosing interval of about 1, 2, 3, or 4 weeks. In some aspects, the anti-PD-L1 antibody is administered at a steady dose of about 1200 mg about once every 3 weeks. In other aspects, the anti-PD-L1 antibody is administered at a steady dose of about 800 mg about once every 2 weeks. In other aspects, the anti-PD-L1 antibody is administered at a steady dose of about 840 mg about once every 2 weeks.

[0268] In some aspects, atezolizumab is administered at a steady-state dose of about 1200 mg approximately once every 3 weeks. In some aspects, atezolizumab is administered at a steady-state dose of about 800 mg approximately once every 2 weeks. In some aspects, atezolizumab is administered at a steady-state dose of about 840 mg approximately once every 2 weeks.

[0269] In some aspects, avelumab is administered at a steady dose of about 800 mg about once every 2 weeks.

[0270] In some aspects, durvalumab is administered at a dose of about 10 mg / kg approximately once every 2 weeks. In some aspects, durvalumab is administered at a steady-state dose of about 800 mg / kg approximately once every 2 weeks. In some aspects, durvalumab is administered at a steady-state dose of about 1200 mg / kg approximately once every 3 weeks.

[0271] In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 10 mg / mL to at least about 500 mg / mL, at least about 10 mg / mL to at least about 400 mg / mL, at least about 10 mg / mL to at least about 300 mg / mL, at least about 10 mg / mL to at least about 250 mg / mL, at least about 10 mg / mL to at least about 200 mg / mL, at least about 10 mg / mL to at least about 190 mg / mL, at least about 10 mg / mL to at least about 180 mg / mL, at least about 10 mg / mL to at least about 170 mg / mL, at least about 10 mg / mL to at least about 160 mg / mL, at least about 10 mg / mL to at least about 150 mg / mL, at least about 20 mg / mL to at least about 500 mg / mL, at least about 20 mg / mL to at least about 400 mg / mL, at least about 20 mg / mL to at least about 300 mg / mL, at least about 20 mg / mL to at least about 250 mg / mL, at least about 20 mg / mL to at least about 300 mg / mL, about 20 mg / mL to at least about 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 150 mg / mL, In some aspects, the pharmaceutical composition comprises at least about 50 mg / mL of anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 60 mg / mL of anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 70 mg / mL of anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 75 mg / mL of anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 80 mg / mL of anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 108 mg / mL of an anti-PD-L1 antibody.In some aspects, the pharmaceutical composition comprises at least about 110 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 120 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 130 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 132 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 135 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 140 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 150 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 160 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 170 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 175 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 180 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 190 mg / mL of an anti-PD-L1 antibody. In some aspects, the pharmaceutical composition comprises at least about 200 mg / mL of an anti-PD-L1 antibody.

[0272] In some aspects, a pharmaceutical composition as disclosed herein comprises at least about 10 mg / mL, at least about 15 mg / mL, at least about 20 mg / mL, at least about 25 mg / mL, at least about 30 mg / mL, at least about 35 mg / mL, at least about 40 mg / mL, at least about 45 mg / mL, at least about 50 mg / mL, at least about 55 mg / mL, at least about 60 mg / mL, at least about 65 mg / mL, at least about 70 mg / mL, at least about 75 mg / mL, at least about 80 mg / mL, at least about 85 mg / mL, at least about 90 mg / mL, at least about 95 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, at least about 200 mg / mL, at least about 210 mg / mL, at least about 220 mg / mL, at least about 230 mg / mL, at least about 240 mg / mL At least about 100 mg / mL, at least about 108 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 132 mg / mL, at least about 135 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 175 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL of an anti-PD-L1 antibody as disclosed herein (e.g., atezolizumab, durvalumab, or avelumab).

[0273] In some aspects, a pharmaceutical composition as disclosed herein comprises about 10 mg / mL to about 500 mg / mL, about 10 mg / mL to about 450 mg / mL, about 10 mg / mL to about 400 mg / mL, about 10 mg / mL to about 350 mg / mL, about 10 mg / mL to about 300 mg / mL, about 10 mg / mL to about 250 mg / mL, about 10 mg / mL to about 200 mg / mL, about 10 mg / mL to about 190 mg / mL, about 10 mg / mL to about 180 mg / mL, about 10 mg / mL to about 170 mg / mL, about 10 mg / mL to about 160 mg / mL, about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 140 mg / mL, about 10 mg / mL to about 130 mg / mL, about 10 mg / mL to about 120 mg / mL, about 10 mg / mL to about 110 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 85 mg / mL, about 10 mg / mL to about 80 mg / mL, about 20 mg / mL to about 500 mg / mL, about 20 mg / mL to about 450 mg / mL, about 20 mg / mL to about 400 mg / mL, about 20 mg / mL to about 350 mg / mL, about 20 mg / mL to about 300 mg / mL, about 20 mg / mL to about 250 mg / mL, about 20 mg / mL to about 200 mg / mL, about 20 mg / mL to about 190 mg / mL, about 20 mg / mL to about 180 mg / mL, about 20 mg / mL to about 170 mg / mL, about 20 mg / mL to about 160 mg / mL, about 20 mg / mL to about 150 mg / mL, about 20 mg / mL to about 140 mg / mL, about 20 mg / mL to about 130 mg / mL, about 20 mg / mL to about 120 mg / mL, about 20 mg / mL to about 110 mg / mL, about 20 mg / mL to about 100 mg / mL, about 20 mg / mL to about 90 mg / mL, about 20 mg / mL to about 85 mg / mL g / mL, about 20 mg / mL to about 80 mg / mL, about 50 mg / mL to about 200 mg / mL, about 520 mg / mL to about 190 mg / mL, about 50 mg / mL to about 180 mg / mL, about 50 mg / mL to about 170 mg / mL, about 50 mg / mL to about 160 mg / mL, about 50 mg / mL to about 150 mg / mL, about 50 mg / mL to about 140 mg / mL, about 50 mg / mL to about 130 mg / mL, about 50 mg / mL to about 120 mg / mL, about 50 mg / mL to about 110 mg / mL, about 50 mg / mL to about 100 mg / mL, about 50 mg / mL to about 90 mg / mL,about 50 mg / mL to about 85 mg / mL, about 50 mg / mL to about 80 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 150 mg / mL, about 150 mg / mL to about 200 mg / mL, about 135 mg / mL to about 180 mg / mL, about 100 mg / mL to about 130 mg / mL, or about 108 mg / mL to about 132 mg / mL of an anti-PD-L1 antibody as disclosed herein (e.g., atezolizumab, durvalumab, or avelumab).

[0274] In some aspects, a pharmaceutical composition as disclosed herein comprises about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 100 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL g / mL, about 95 mg / mL, about 100 mg / mL, about 108 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 132 mg / mL, about 135 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 190 mg / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about In some embodiments, the dosage form of the anti-PD-L1 antibody disclosed herein (e.g., atezolizumab, durvalumab, or avelumab) is preferably about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL of an anti-PD-L1 antibody as disclosed herein (e.g., atezolizumab, durvalumab, or avelumab).

[0275] In some aspects, a pharmaceutical composition as disclosed herein comprises about 0.25 mg to about 2000 mg, about 0.25 mg to about 1600 mg, about 0.25 mg to about 1200 mg, about 0.25 mg to about 800 mg, about 0.25 mg to about 400 mg, about 0.25 mg to about 100 mg, about 0.25 mg to about 50 mg, about 0.25 mg to about 40 mg, about 0.25 mg to about 30 mg, about 0.25 mg to about 20 mg, about 20 mg to about 2000 mg, about 20 mg to about 1600 mg, about 20 mg to about 1200 mg, about 20 mg to about 800 mg, about 20 mg to about 400 mg, about 20 mg to about 100 mg, about 100 mg to about 500 mg. to about 2000 mg, about 100 mg to about 1800 mg, about 100 mg to about 1600 mg, about 100 mg to about 1400 mg, about 100 mg to about 1200 mg, about 100 mg to about 1000 mg, about 100 mg to about 800 mg, about 100 mg to about 600 mg, about 100 mg to about 400 mg, about 400 mg to about 2000 mg, about 400 mg to about 1800 mg, about 400 mg to about 1600 mg, about 400 mg to about 1400 mg, about 400 mg to about 1200 mg, or about 400 mg to about 1000 mg of an anti-PD-L1 antibody as disclosed herein (e.g., atezolizumab, durvalumab, or avelumab).

[0276] In some aspects, a pharmaceutical composition as disclosed herein comprises about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, about 5 mg, about 5.25 mg, about 5.5 mg, about 5.75 mg, about 6 mg, about 6.25 mg, about 6.5 mg, about 6.75 mg, about 7 mg, about 7.25 mg, about 7.5 mg, about 7.75 mg, about 8 mg, about 8.25 mg, about 8.5 mg, about 8.75 mg, about 9 mg, about 9.25 mg, about 9.5 mg, about 9.75mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg, about 330mg , about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg, about 680mg, 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 1040 mg, about 1080 mg, about 1100 mg, about 1140 or about 2000 mg of an anti-PD-L1 antibody as disclosed herein (e.g., atezolizumab, durvalumab, or avelumab). II.D. Antioxidants

[0277] In some aspects, the pharmaceutical composition disclosed herein further comprises an antioxidant. Any antioxidant can be used in the pharmaceutical composition disclosed herein. In some aspects, the antioxidant is methionine, tryptophan and histidine, cysteine, ascorbic acid, glycine, pentetic acid (" DTPA ") or ethylenediaminetetraacetic acid (" EDTA "). In some aspects, the pharmaceutical composition comprises methionine.

[0278] In some aspects, the pharmaceutical composition comprises at least two antioxidants. In some aspects, at least one of the at least two antioxidants is a sacrificial antioxidant. Any sacrificial antioxidant can be used in the pharmaceutical composition and methods disclosed herein. In some aspects, the sacrificial antioxidant is methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine or other sacrificial agents. In some aspects, at least one of the at least two antioxidants comprises a metal ion chelator. Any metal ion chelator can be used in the pharmaceutical composition and methods disclosed herein. In some aspects, the metal ion chelator is pentetic acid ("DTPA") or EDTA. In some aspects, the at least two antioxidants are selected from methionine, DTPA and EDTA. In some aspects, the at least two antioxidants comprise methionine and EDTA. In some aspects, the at least two antioxidants comprise methionine and EDTA. In some aspects, the at least two antioxidants comprise methionine and pentetic acid (DTPA).

[0279] In some aspects, the pharmaceutical composition comprises at least about 0.1 mM to at least about 100 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 1 mM to at least about 20 mM, at least about 1 mM to at least about 15 mM, at least about 1 mM to at least about 10 mM, at least about 1 mM to at least about 5 mM, at least about 5 mM to at least about 20 mM, at least about 5 mM to at least about 15 mM, at least about 5 mM to at least about 10 mM, at least about 2 mM to at least about 9 mM, at least about 3 mM to at least about 8 mM, at least about 4 mM to at least about 7 mM, or at least about 4 mM to at least about 6 mM, at least about 4 mM to at least about 5 mM, at least about 5 mM to at least about 6 mM, at least about 5 mM to at least about 7 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, 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 aspects, the pharmaceutical composition comprises at least about 10 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 9 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 8 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 7 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 6 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 5 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 4 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 3 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 2 mM methionine. In some aspects, the pharmaceutical composition comprises at least about 1 mM methionine.

[0280] In some aspects, a pharmaceutical composition as disclosed herein comprises about 0.1 mM to about 100 mM, about 0.1 mM to about 90 mM, about 0.1 mM to about 80 mM, about 0.1 mM to about 70 mM, about 0.1 mM to about 60 mM, about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 10 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 10 mM. mM, about 1 mM to about 9 mM, about 1 mM to about 8 mM, about 1 mM to about 7 mM, about 1 mM to about 6 mM, about 1 mM to about 5 mM, about 2 mM to about 9 mM, about 3 mM to about 8 mM, about 4 mM to about 7 mM, about 4 mM to about 6 mM, about 4 mM to about 5 mM, about 5 mM to about 20 mM, about 5 mM to about 15 mM, about 5 mM to about 10 mM, about 5 mM to about 9 mM, about 5 mM to about 8 mM, about 5 mM to about 7 mM, or about 5 mM to about 6 mM methionine.

[0281] In some aspects, a pharmaceutical composition as disclosed herein comprises about 1 mM, about 1.5 mM, about 2 mM, about 2.5 mM, about 3 mM, about 3.5 mM, about 4 mM, about 4.5 mM, about 5 mM, about 5.5 mM, about 6 mM, about 6.5 mM, about 7 mM, about 7.5 mM, about 8 mM, about 8.5 mM, about 9 mM, about 9.5 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM, about 30 mM, about 31 mM, about 32 mM, about 33 mM, about 34 mM, about 35 mM, about 36 mM, about 37 mM, about 38 mM, about 39 mM, about 40 mM, about 41 mM, about 100 mM methionine.

[0282] In some aspects, the pharmaceutical composition comprises at least about 1 μM to at least about 250 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 10 μM to at least about 200 μM, at least about 10 μM to at least about 175 μM, at least about 10 μM to at least about 150 μM, at least about 10 μM to at least about 125 μM, at least about 10 μM to at least about 100 μM, at least about 10 μM to at least about 75 μM, at least about 10 μM to at least about 70 μM, at least about 10 μM to at least about 60 μM, at least about 10 μM to at least about 50 μM, at least about 20 μM to at least about 100 μM, at least about 20 μM to at least about 175 μM, at least about 10 μM to at least about 150 μM, at least about 10 μM to at least about 125 μM, at least about 10 μM to at least about 100 μM, at least about 10 μM to at least about 75 μM, at least about 10 μM to at least about 70 μM, at least about 10 μM to at least about 60 μM, at least about 10 μM to at least about 50 μM, at least about 25 μM to at least about 100 μM, at least about 2 5 μM to at least about 75 μM, at least about 25 μM to at least about 50 μM, at least about 30 μM to at least about 100 μM, at least about 30 μM to at least about 75 μM, at least about 30 μM to at least about 70 μM, at least about 30 μM to at least about 30 μM, at least about 30 μM to at least about 50 μM, at least about 40 μM to at least about 100 μM, at least about 40 μM to at least about 75 μM, at least about 40 μM to at least about 70 μM, at least about 40 μM to at least about 60 μM, at least about 40 μM to at least about 50 μM, at least about 50 μM to at least about 100 μM, at least about 50 μM to at least about 75 μM, at least about 50 μM to at least about 70 μM, or at least about 50 μM to at least about 60 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 1 μM, at least about 5 μM, at least about 10 μM, at least about 15 μM, at least about 20 μM, at least about 25 μM, at least about 30 μM, at least about 35 μM, at least about 40 μM, at least about 45 μM, at least about 50 μM, at least about 55 μM, at least about 60 μM, at least about 65 μM, at least about 70 μM, at least about 75 μM, at least about 80 μM, at least about 85 μM, at least about 90 μM, at least about 95 μM, 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 DTPA. In some aspects, the pharmaceutical composition comprises at least about 75 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 70 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 65 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 60 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 55 μM pentetic acid (DTPA).In some aspects, the pharmaceutical composition comprises at least about 50 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 45 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 40 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 35 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 30 μM pentetic acid (DTPA). In some aspects, the pharmaceutical composition comprises at least about 25 μM pentetic acid (DTPA).

[0283] In some aspects, the pharmaceutical compositions as disclosed herein comprise about 1 μM to about 250 μM, about 10 μM to about 200 μM, about 10 μM to about 175 μM, about 10 μM to about 150 μM, about 10 μM to about 125 μM, about 10 μM to about 100 μM, about 10 μM to about 75 μM, about 10 μM to about 70 μM, about 10 μM to about 60 μM, about 10 μM to about 50 μM, about 20 μM to about 100 μM, about 20 μM to about 75 μM, about 20 μM to about 70 μM, about 20 μM to about 60 μM, about 20 μM to about 50 μM, about 25 μM to about 100 μM, about 25 μM to about 75 μM, about 25 μM to about 50 μM, about 30 μM to about 100 μM, about 30 μM to about 75 μM,

[0014] In some embodiments, the present invention relates to pentetic acid (DTPA), wherein the present invention relates to pentetic acid (DTPA), wherein the present invention relates to pentetic acid (DTPA), wherein the present invention relates to pentetic acid (DTPA), wherein the present invention relates to pentetic acid (DTPA), wherein the present invention relates to pentetic acid (DTPA), wherein the present invention relates to pentetic acid (DTPA), wherein the present invention relates to pentetic acid (DTPA), wherein the present invention relates to pentetic acid (DTPA),

[0284] In some aspects, a pharmaceutical composition as disclosed herein comprises about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 55 μM, about 60 μM, about 65 μM, about 70 μM, about 75 μM, about 80 μM, about 85 μM, about 90 μM, about 95 μM, about 100 μM, about 110 μM, about 120 μM, about 130 μM, about 140 μM, about 150 μM, about 160 μM, about 170 μM, about 180 μM, about 190 μM, about 200 μM, about 210 μM, about 220 μM, about 230 μM, about 240 μM, or about 250 μM DTPA. II.E. Tonicity Adjusters / Stabilizers

[0285] In some aspects, the pharmaceutical composition disclosed herein further comprises a tension regulator and / or a stabilizer. Any tension regulator and / or any stabilizer can be used in the pharmaceutical composition disclosed herein. In some aspects, the tension regulator and / or stabilizer comprise sugar, amino acid, polyol, salt or any combination thereof. In some aspects, the tension regulator and / or stabilizer are sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, polyol, amino acid or salt.

[0286] In some aspects, the pharmaceutical composition comprises sucrose. In some aspects, the pharmaceutical composition comprises at least about 1 mM to at least about 500 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM, at least about 10 mM to at least about 400 mM, at least about 50 mM to at least about 400 mM, at least about 100 mM to at least about 400 mM, at least about 150 mM to at least about 400 mM, at least about 200 mM to at least about 400 mM, at least about 250 mM to at least about 400 mM, at least about 300 mM to at least about 400 mM, at least about 350 mM to at least about 400 mM, 0 mM to at least about 400 mM, at least about 50 mM to at least about 350 mM, at least about 100 mM to at least about 300 mM, at least about 100 mM to at least about 250 mM, at least about 100 mM to at least about 200 mM, at least about 100 mM to at least about 150 mM, at least about 200 mM to at least about 400 mM, at least about 200 mM to at least about 300 mM sucrose, or at least about 200 mM to at least about 250 mM. In some aspects, the pharmaceutical composition comprises at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM. In some aspects, the pharmaceutical composition comprises at least about 200mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 210mM ​​sucrose. In some aspects, the pharmaceutical composition comprises at least about 220 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 230 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 240 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 250 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 260 mM sucrose.In some aspects, the pharmaceutical composition comprises at least about 270 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 280 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 290 mM sucrose. In some aspects, the pharmaceutical composition comprises at least about 300 mM sucrose.

[0287] In some aspects, a pharmaceutical composition as disclosed herein comprises about 1 mM to about 500 mM, about 1 mM to about 400 mM, about 1 mM to about 350 mM, about 1 mM to about 300 mM, about 1 mM to about 250 mM, about 10 mM to about 400 mM, about 10 mM to about 350 mM, about 10 mM to about 300 mM, about 10 mM to about 250 mM, about 50 mM to about 400 mM, about 50 mM to about 350 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 100 mM to about 400 mM, about 100 mM to about 350 mM, about 100 mM to about 300 mM, about 100 mM to about 250 mM, or about 100 mM to about 200 mM, about 100 mM to about 150 mM, about 150 mM to about 400 mM, about 150 mM to about 350 mM, about 150 mM to about 300 mM, about 150 mM to about 250 mM, about 150 mM to about 200 mM, about 200 mM to about 400 mM, about 200 mM to about 350 mM, about 200 mM to about 300 mM, about 200 mM to about 250 mM, about 250 mM to about 400 mM, about 250 mM to about 350 mM, about 250 mM to about 300 mM, about 300 mM to about 400 mM, about 300 mM to about 350 mM, or about 350 mM to about 400 mM sucrose.

[0288] In some aspects, a pharmaceutical composition as disclosed herein comprises about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, about 250 mM, about 260 mM, about 270 mM, about 280 mM, about 290 mM, about 300 mM, about 310 mM, about 320 mM, about 330 mM, about 340 mM, about 350 mM, about 360 mM, about 370 mM, about 380 mM, about 390 mM, about 400 mM, about 410 mM, about 420 mM, about 430 mM, about 440 mM, about 450 mM, about 460 mM, about 470 mM, about 480 mM, about 490 mM, about 500 mM, about 510 mM, about 520 mM, about 530 mM, about 540 mM, about 550 mM, about 560 mM, about 570 mM, about 580 mM, about 590 mM, about 600 mM, about 490mM, or about 500mM sucrose. II.F. Buffers

[0289] In some aspects, the pharmaceutical compositions disclosed herein further comprise a buffer. In some aspects, the buffer is histidine, succinate, tromethamine, sodium phosphate, sodium acetate, or sodium citrate. In some aspects, the pharmaceutical composition comprises histidine. In some aspects, the pharmaceutical composition comprises citrate. In some aspects, the pharmaceutical composition comprises at least about 1 mM to at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM, at least about 10 mM to at least about 100 mM, at least about 15 mM to at least about 100 mM, at least about 20 mM to at least about 100 mM, at least about 25 mM to at least about 100 mM, at least about 30 mM to at least about 100 mM, at least about 35 mM to at least about 100 mM, at least about 40 mM to at least about 100 mM, at least about 50 mM to at least about 100 mM, at least about 60 mM to at least about 100 mM, at least about 70 mM to at least about 100 mM, at least about 80 mM to at least about 100 mM, at least about 90 mM to at least about 100 mM, at least about 100 mM to at least about 100 mM, at least about 15 mM to at least about 100 mM, at least about 1 At least about 45 mM to at least about 100 mM, at least about 50 mM to at least about 100 mM, at least about 10 mM to at least about 75 mM, at least about 10 mM to at least about 50 mM, at least about 10 mM to at least about 40 mM, at least about 10 mM to at least about 30 mM, at least about 15 mM to at least about 30 mM, at least about 10 mM to at least about 25 mM, or at least about 15 mM to at least about 25 mM histidine.

[0290] In some aspects, the pharmaceutical composition comprises at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 10 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 15 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 20 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 25 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 30 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 35 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 40 mM histidine. In some aspects, the pharmaceutical composition comprises at least about 45 mM histidine. In certain aspects, the pharmaceutical composition comprises at least about 50 mM histidine.

[0291] In some aspects, the pharmaceutical composition comprises about 1 mM to about 100 mM, about 1 mM to about 90 mM, about 1 mM to about 80 mM, about 1 mM to about 75 mM, about 1 mM to about 70 mM, about 1 mM to about 65 mM, about 1 mM to about 60 mM, about 1 mM to about 55 mM, about 1 mM to about 50 mM, about 1 mM to about 45 mM, about 1 mM to about 40 mM, about 1 mM to about 35 mM, about 1 mM to about 30 mM, about 1 mM to about 25 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 10 mM, about 1 mM to about 5 mM, about 5 mM to about 100 mM, about 5 mM to about 90 mM, about 5 mM to about 80 mM, about 5 mM to about 75mM, about 5mM to about 70mM, about 5mM to about 65mM, about 5mM to about 60mM, about 5mM to about 55mM, about 5mM to about 50mM, about 5mM to about 45mM, about 5mM to about 40mM, about 5mM to about 35mM, about 5mM to about 30mM, about 5mM to about 25mM, about 5mM to about 20mM, about 5mM to about 15mM, about 5mM to about 10mM, about 10mM to about 100mM, about 10mM to about 90mM, about 10mM to about 80mM, about 10mM to about 75mM, about 10mM to about 70mM, about 10mM to about 65mM, about 10mM to about 60mM, about 10mM to about 55mM , about 10mM to about 50mM, about 10mM to about 45mM, about 10mM to about 40mM, about 10mM to about 35mM, about 10mM to about 30mM, about 10mM to about 25mM, about 10mM to about 20mM, about 10mM to about 15mM, about 15mM to about 100mM, about 15mM to about 90mM, about 15mM to about 80mM, about 15mM to about 75mM, about 15mM to about 70mM, about 15mM to about 65mM, about 15mM to about 60mM, about 15mM to about 55mM, about 15mM to about 50mM, about 15mM to about 45mM, about 15mM to about 40mM, about 15mM to about 35mM, about 15mM about 20mM to about 30mM, about 15mM to about 25mM, about 15mM to about 20mM, about 16mM to about 24mM, about 17mM to about 23mM, about 18mM to about 22mM, about 19mM to about 21mM, about 20mM to about 100mM, about 20mM to about 90mM, about 20mM to about 80mM, about 20mM to about 75mM, about 20mM to about 70mM, about 20mM to about 65mM, about 20mM to about 60mM, about 20mM to about 55mM, about 20mM to about 50mM, about 20mM to about 45mM, about 20mM to about 40mM, about 20mM to about 35mM, about 20mM to about 30mM, about 20mM to about 25mM,About 25 mM to about 100 mM, about 30 mM to about 100 mM, about 35 mM to about 100 mM, about 40 mM to about 100 mM, about 45 mM to about 100 mM, or about 50 mM to about 100 mM histidine.

[0292] In some aspects, the pharmaceutical composition comprises about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 90 mM, or about 100 mM histidine.

[0293] In some aspects, the pharmaceutical composition comprises a pH of about 5.2 to about 6.8. In some aspects, the pH of the pharmaceutical composition is about 5.2. In some aspects, the pH of the pharmaceutical composition is about 5.3. In some aspects, the pH of the pharmaceutical composition is about 5.4. In some aspects, the pH of the pharmaceutical composition is about 5.5. In some aspects, the pH of the pharmaceutical composition is about 5.6. In some aspects, the pH of the pharmaceutical composition is about 5.7. In some aspects, the pH of the pharmaceutical composition is about 5.8. In some aspects, the pH of the pharmaceutical composition is about 5.9. In some aspects, the pH of the pharmaceutical composition is about 6.0. In some aspects, the pH of the pharmaceutical composition is about 6.1. In some aspects, the pH of the pharmaceutical composition is about 6.2. In some aspects, the pH of the pharmaceutical composition is about 6.3. In some aspects, the pH of the pharmaceutical composition is about 6.4. In some aspects, the pH of the pharmaceutical composition is about 6.5. In some aspects, the pH of the pharmaceutical composition is about 6.6. In some aspects, the pH of the pharmaceutical composition is about 6.7. In some aspects, the pH of the pharmaceutical composition is about 6.8. II.G. Surfactants

[0294] In some aspects, the pharmaceutical compositions disclosed herein further comprise a surfactant. Any surfactant can be used in the pharmaceutical compositions disclosed herein. In some aspects, the surfactant is polysorbate 20, polysorbate 80, or poloxamer 188. In certain aspects, the pharmaceutical composition comprises polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.001% to at least about 1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% to at least about 0.1%, at least about 0.02% to at least about 0.1%, at least about 0.03% to at least about 0.1%, at least about 0.04% to at least about 0.1%, at least about 0.05% to at least about 0.1%, at least about 0.01% to at least about 0.09%, at least about 0.01% to at least about 0.8%, at least about 0.01% to at least about 0.7%, at least about 0.01% to at least about 0.6%, at least about 0.01% to at least about 0.5%, at least about 0.02% to at least about 0.09%, at least about 0.03% to at least about 0.08%, at least about 0.04% to at least about 0.07%, or at least about 0.04% to at least about 0.06% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.01% to at least about 0.1% w / v polysorbate 80.

[0295] In some aspects, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.03% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.04% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.05% w / v polysorbate 80. In some aspects, the pharmaceutical composition comprises at least about 0.06% w / v polysorbate 80. In certain aspects, the pharmaceutical composition comprises at least about 0.07% w / v polysorbate 80.

[0296] In some aspects, the pharmaceutical composition comprises about 0.001% to about 1% w / v, about 0.001% w / v to about 0.9% w / v, about 0.001% w / v to about 0.8% w / v, about 0.001% w / v to about 0.7% w / v, about 0.001% w / v to about 0.6% w / v, about 0.001% w / v to about 0.5% w / v, about 0.001% w / v to about 0.4% w / v, about 0.001% w / v to about 0.3% w / v, about 0.001% w / v to about 0.2% w / v, about 0.001% w / v to about 0.1% w / v, about 0.001% w / v to about 0.09% w / v, about 0.001% w / v to about 0.08% w / v, about 0.001% w / v to about 0.07% w / v, about 0.001% w / v to about 0.06% w / v, about 0.001% w / v to about 0.05% w / v, about 0.01% w / v to about 0.9% w / v, about 0.01% w / v to about 0.8% w / v, about 0.01% w / v to about 0.7% w / v, about 0.01% w / v to about 0.6% w / v, about 0.01% w / v to about 0.5% w / v, about 0.01% w / v to about 0.4% w / v, about 0.01% w / v to about 0.3% w / v, about 0.01% w / v to about 0.2% w / v, about 0.01% w / v to about 0.1% w / v, about 0.01% w / v to about 0.09% w / v, about 0.01% w / v to about 0.08% w / v, about 0.01% w / v to about 0.07% w / v, about 0.01% w / v to about 0.06% w / v, about 0.01% w / v to about 0.05% w / v, about 0.02% w / v to about 0.1% w / v, about 0.02% w / v to about 0.09% w / v, about 0.02% w / v to about 0.08% w / v, about 0.02% w / v to about 0.07% w / v, about 0.02% w / v to about 0.06% w / v, about 0.02% w / v to about 0.05% w / v, about 0.03% w / v to about 0.1% w / v, about 0.03% w / v to about 0.09% w / v, about 0.03% w / v v to about 0.08% w / v, about 0.03% w / v to about 0.07% w / v, about 0.03% w / v to about 0.06% w / v, about 0.03% w / v to about 0.05% w / v, about 0.04% w / v to about 0.1% w / v, about 0.04% w / v to about 0.09% w / v, about 0.04% w / v to about 0.08% w / v, about 0.04% w / v to about 0.07% w / v, about 0.04% w / v to about 0.06% w / v, about 0.04% w / v to about 0.05%, about 0.05% w / v to about 0.1% w / v, about 0.05% w / v to about 0.09% w / v, about 0.05% w / v to about 0.08% w / v, about 0.00.05% w / v to about 0.07% w / v, or about 0.05% w / v to about 0.06% w / v polysorbate 80.

[0297] In some aspects, the pharmaceutical composition comprises about 0.001% w / v, 0.002% w / v, 0.003% w / v, 0.004% w / v, 0.005% w / v, 0.006% w / v, 0.007% w / v, 0.008% w / v, 0.009% w / v, 0.01% w / v, about 0.02% w / v, about 0.03% w / v, about 0.04% w / v, about 0.05% w / v, about 0.06% w / v, about 0.07% w / v, about 0.08% w / v, about 0.09% w / v, about 0.1% w / v, about 0.2% w / v, about 0.3% w / v, about 0.4% w / v, about 0.5% w / v, about 0.6% w / v, about 0.7% w / v, about 0.8% w / v, about 0.9% w / v, or about 1% w / v polysorbate 80. II.H. Endoglycosidase hydrolase

[0298] Any endoglycosidase hydrolase can be used in the pharmaceutical compositions and methods disclosed herein. In some aspects, the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosamine β (1-4) or (1-3) bond. In some aspects, the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1.

[0299] In some aspects, the endoglycosidase hydrolase comprises a hyaluronidase. In some aspects, the endoglycosidase hydrolase comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants thereof, and any isoforms thereof. In some aspects, the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to amino acids 36-490 of SEQ ID NO: 87 shown in Table 1. In some aspects, the endoglycosidase hydrolase comprises the catalytic domain of rHuPH20 (UniProt ID No. P38567-1). In some aspects, the endoglycosidase hydrolase comprises the rHuPH20 mature peptide (amino acids 36-490 of SEQ ID NO: 87). Table 1: Amino acid sequence of rHuPH20 Signal peptide: underlined; mature protein: bold; propeptide: italic.

[0300] In some aspects, the pharmaceutical composition includes ENHANZE drug delivery technology from Halozyme Therapeutics (see U.S. Patent No. 7,767,429, which is incorporated herein by reference in its entirety). ENHANZE uses a co-formulation of an antibody with recombinant human hyaluronidase (rHuPH20), which eliminates traditional limitations on the volume of biologics and drugs that can be delivered subcutaneously due to the extracellular matrix (see U.S. Patent No. 7,767,429). In some aspects, the pharmaceutical composition of the present disclosure may further comprise a recombinant human hyaluronidase, such as rHuPH20.

[0301] Recombinant human hyaluronidase PH20 (rHuPH20, Aolozimei Medical Co., Ltd.) is a glycosylated 447 amino acid whose single-chain recombinant human polypeptide, which depolymerizes hyaluronic acid locally in subcutaneous (SC) space at the injection site. Hyaluronic acid is the repeating polymer of N-acetyl-glucosamine and glucuronic acid, and it helps the soluble gel-like components of the extracellular matrix of skin. The hyaluronic depolymerization by rHuPH20 causes the instantaneous reduction of the viscosity of the gel-like phase of the extracellular matrix and the increase of hydraulic conductivity, which helps the dispersion and absorption (referring to rHuPH20 1B) of the injected drug. The use of rHuPH20 makes it possible to send large volumes for fast SC injection (for example, about 2mL to 20mL), which can shorten the dosage application time, reduce the frequency of application, and makes it possible to improve the PK curve of co-administered drugs potentially, comprise the absorption of improvement, the bioavailability of increase, the time (Tmax) of accelerated maximum concentration, the maximum concentration (Cmax) of increase and the PK variability of reduction.

[0302] The half-life of rHuPH20 in the skin is <30 minutes, and the local permeability barrier in these tissues returns to pre-injection levels within 24 to 48 hours after injection of hyaluronidase. Studies have shown that rHuPH20 is not systemically detectable in healthy volunteers and patients after SC administration of doses of 10,000 U and 30,000 U. Another PK study of rHuPH20 (Halozyme study HALO-104-104) demonstrated that plasma concentrations of rHuPH20 decline rapidly, with a very short t1 / 2 (≤10.4 min), and plasma concentrations become undetectable (<0.03 ng / mL) within 1.5 hours after the end of IV infusion of an IV dose of 10,000 or 30,000 units of rHuPH20.

[0303] Subcutaneous rHuPH20 was 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 rHuPH20 was well tolerated alone or co-administered with lactated Ringer's solution, normal saline, co-injected medications (morphine, ceftriaxone, insulin and insulin analogs), or biologics (immunoglobulin G [IgG] and adalimumab).

[0304] In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the alpha helical region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the linker region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof. In some aspects, the endoglycosidase hydrolase comprises a modified hyaluronidase wherein one or more N-terminal and / or C-terminal amino acids are deleted relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof.

[0305] In some aspects, the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20 comprises one or more amino acid substitutions in the alpha helical region, the linker region, or both the alpha helical region and the linker region relative to wild-type rHuPH20. In some aspects, the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20 lacks 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 aspects, the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20 comprises one or more amino acid substitutions in the alpha helical region, the linker region, or both the alpha helical region and the linker region relative to wild-type rHuPH20; and wherein the modified rHuPH20 lacks 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.

[0306] Additional non-limiting examples of endoglycosidase hydrolases are found in EP 3636752, which is incorporated herein by reference in its entirety.

[0307] In some aspects, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in U.S. Pat. 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 herein incorporated by reference in its entirety. In some aspects, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in International Publication Nos. WO / 13 / 102144, WO / 10 / 077297, WO / 15 / 003167, WO / 04 / 078140, WO / 09 / 128917, WO / 12 / 174478, and / or WO / 12 / 174480, each of which is incorporated herein by reference in its entirety. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identity to an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOs: 88-136. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence selected from the group consisting of the amino acid sequences set forth in SEQ ID NOs: 88-136.

[0308] In some aspects, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in the following U.S. Patent Application Publication Nos.: US2021155913 A1 and / or US2021363270A1; and / or International Publication Nos. WO / 20 / 022791, WO / 20 / 197230, and / or WO / 21 / 150079; each of which is incorporated herein by reference in its entirety. In some aspects, the endoglycosidase hydrolase comprises 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% identity to an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NOs: 137-347. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% identity to the amino acid sequence shown in SEQ ID NO: 176. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence selected from the group consisting of the amino acid sequences shown in SEQ ID NO: 137-347. In some aspects, the endoglycosidase hydrolase comprises an amino acid sequence shown in SEQ ID NO: 176. In some aspects, the endoglycosidase hydrolase is HP46 (SEQ ID NO: 348, corresponding to SEQ ID NO: 44 of International Publication No. WO / 2020 / 197230).

[0309] In some aspects, the pharmaceutical composition disclosed herein comprises hyaluronidase. In some aspects, the pharmaceutical composition comprises the hyaluronidase of sufficient concentration to use the hyaluronidase of at least about 20,000 units. In some aspects, the pharmaceutical composition comprises the hyaluronidase of sufficient concentration to use the hyaluronidase of at least about 24,000 units. In some aspects, the pharmaceutical composition comprises the hyaluronidase of sufficient concentration to use the hyaluronidase of at least about 50,000 units. In some aspects, the pharmaceutical composition comprises the hyaluronidase of sufficient concentration to use the hyaluronidase of at least about 75,000 units. In some aspects, the pharmaceutical composition comprises the hyaluronidase of sufficient concentration to use the hyaluronidase of at least about 100,000 units. In some aspects, the hyaluronidase is rHuPH20. In other aspects, the pharmaceutical composition does not comprise hyaluronidase.

[0310] In some aspects, the pharmaceutical composition comprises at least about 50 units to at least about 48000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 50 units / mL (U / mL) to at least about 5000U / mL of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 50U / mL, at least about 100U / mL, at least about 150U / mL, at least about 200U / mL, at least about 250U / mL, at least about 300U / mL, at least about 350U / mL, at least about 400U / mL, at least about 450U / mL, at least about 500U / mL, at least about 750U / mL, at least about 1000U / mL, at least about 1500U / mL, at least about 2000U / mL, at least about 2500U / mL, at least about 3000U / mL In some respects, pharmaceutical composition comprises at least about 3500U / mL, at least about 4000U / mL, at least about 4500U / mL, at least about 5000U / mL, at least about 5500U / mL, at least about 6000U / mL, at least about 6500U / mL, at least about 7000U / mL, at least about 7500U / mL, at least about 8000U / mL, at least about 8500U / mL, at least about 9000U / mL, at least about 9500U / mL or at least about 10,000U / mL of endoglycosidase hydrolase (for example, rHuPH20).In some respects, pharmaceutical composition comprises at least about 500U / mL of endoglycosidase hydrolase (for example, rHuPH20).In some respects, pharmaceutical composition comprises at least about 1000U / mL of endoglycosidase hydrolase (for example, rHuPH20). In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) of at least about 2000U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) of at least about 2500U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) of at least about 3000U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) of at least about 3500U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) of at least about 4000U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) of at least about 4500U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) of at least about 5000U / mL. In some aspects, the pharmaceutical composition comprises at least about 6000 U / mL of an endoglycosidase hydrolase (eg, rHuPH20).In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) at least about 7000U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) at least about 8000U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) at least about 9000U / mL. In some respects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example, rHuPH20) at least about 10,000U / mL.

[0311] In some respects, the pharmaceutical composition comprises at least about 50 units to at least about 100,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some respects, the pharmaceutical composition comprises at least about 500 units to at least about 100,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 50 units, at least about 100 units, at least about 150 units, at least about 200 units, at least about 250 units, at least about 300 units, at least about 400 units, at least about 500 units, at least about 600 units, at least about 700 units, at least about 800 units, at least about 900 units, at least about 1000 units, at least about 1500 units, at least about 2000 units, at least about 2500 units, at least about 3000 units, at least about 4000 units, at least about 5000 units, at least about 10,000 units, at least about 15,000 units, at least about 20,000 units, In some aspects, the pharmaceutical composition comprises at least about 20,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 30,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 40,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 50,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 60,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 70,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 80,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 90,000 units of endoglycosidase hydrolase (e.g., rHuPH20). In some aspects, the pharmaceutical composition comprises at least about 100,000 units of an endoglycosidase hydrolase (eg, rHuPH20).

[0312] It is obvious to those of ordinary skill in the art that the amount of endoglycosidase hydrolase (for example, rHuPH20) can be represented with unit or U / mL, or the amount of endoglycosidase hydrolase (for example, rHuPH20) can be represented with mg / mL (or with other units based on weight).For example, in some aspects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example rHuPH20) that is expressed as at least about 500U / mL or at least about the amount of 0.00455mg / mL.In another example, in some aspects, pharmaceutical composition comprises the endoglycosidase hydrolase (for example rHuPH20) that is expressed as at least about 2000U / mL or at least about the amount of 0.0182mg / mL.

[0313] In some aspects, the pharmaceutical composition comprises about 50 units (U) to about 100,000 U, about 500 U to about 100,000 U, about 1000 U to about 100,000 U, about 5000 U to about 100,000 U, about 10,000 U to about 100,000 U, about 15,000 U to about 100,000 U, about 20,000 U to about 100,000 U, about 50 0U to about 50,000U, about 1000U to about 50,000U, about 5000U to about 50,000U, about 10,000U to about 50,000U, about 15,000U to about 50,000U, about 20,000U to about 50,000U, about 15,000U to about 45,000U, about 16,000U to about 40,000U, about 17,000U to about 35,000 U, about 18,000 U to about 30,000 U, about 19,000 U to about 29,000 U, about 19,000 U to about 28,000 U, about 19,000 U to about 27,000 U, about 19,000 U to about 26,000 U, about 19,000 U to about 25,000 U, about 19,000 U to about 24,000 U, about 19,000 U to about 26,000 U In some embodiments, the present invention provides an endoglycosidase hydrolase (e.g., rHuPH20) at a concentration of 0 U to about 23,000 U, about 19,000 U to about 22,000 U, about 19,000 U to about 21,000 U, about 20,000 U to about 28,000 U, about 21,000 U to about 27,000 U, about 22,000 U to about 26,000 U, or about 23,000 U to about 25,000 U of an endoglycosidase hydrolase (e.g., rHuPH20).

[0314] In some aspects, the pharmaceutical composition comprises about 50 U, about 100 U, about 150 U, about 200 U, about 250 U, about 300 U, about 400 U, about 500 U, about 600 U, about 700 U, about 800 U, about 900 U, about 1000 U, about 1500 U, about 2000 U, about 2500 U, about 3000 U, about 4000 U, about 5000 U, about 10,000 U, about 15,000 U, about 20,000 U, about 24,000 U, about 25 ,000 U, about 30,000 U, about 35,000 U, about 40,000 U, about 45,000 U, about 48,000 U, about 50,000 U, about 55,000 U, about 60,000 U, about 65,000 U, about 70,000 U, about 75,000 U, about 80,000 U, about 85,000 U, about 90,000 U, about 95,000 U, or about 100,000 U of an endoglycosidase hydrolase (e.g., rHuPH20).

[0315] In some aspects, the pharmaceutical composition comprises about 50 U / mL to about 10,000 U / mL, about 100 U / mL to about 9500 U / mL, about 150 U / mL to about 9000 U / mL, about 200 U / mL to about 8500 U / mL, about 250 U / mL to about 8000 U / mL, about 300 U / mL to about 7500 U / mL, about 350 U / mL to about 7000 U / mL, about 400 U / mL to about 6500 U / mL, or about 7500 U / mL. L, about 450 U / mL to about 6000 U / mL, about 500 U / mL to about 5500 U / mL, about 550 U / mL to about 5000 U / mL, about 600 U / mL to about 4500 U / mL, about 650 U / mL to about 4000 U / mL, about 700 U / mL to about 3500 U / mL, about 750 U / mL to about 3000 U / mL, about 800 U / mL to about 2500 U / mL, about 800 U / mL to about 2 500 U / mL, about 1000 U / mL to about 2500 U / mL, about 1500 U / mL to about 2500 U / mL, about 1600 U / mL to about 2500 U / mL, about 1700 U / mL to about 2500 U / mL, about 1800 U / mL to about 2500 U / mL, about 1900 U / mL to about 2500 U / mL, about 2000 U / mL to about 2500 U / mL, about 2100 U / mL to about 2500 U / mL, about 2500 U / mL to about 2500 U / mL, about 2600 U / mL to about 2500 U / mL, about 2700 U / mL to about 2500 U / mL, about 2800 U / mL to about 2500 U / mL, about 2900 U / mL to about 2500 U / mL, about 3000 U / mL to about 2500 U / mL, about 3100 U / mL to about 2500 U / mL, about 3200 U / mL to about 2500 U / mL, about 3300 U / mL to about 2500 U / mL, about 3400 U / mL to about 2500 U / mL, about 3500 U / mL to about 2500 U / mL, about In some embodiments, the present invention provides an endoglycosidase hydrolase (e.g., rHuPH20) at a concentration of about 1 U / mL, about 2200 U / mL to about 2500 U / mL, about 2300 U / mL to about 2500 U / mL, about 1500 U / mL to about 2500 U / mL, about 1600 U / mL to about 2400 U / mL, about 1700 U / mL to about 2300 U / mL, about 1800 U / mL to about 2200 U / mL, or about 1900 U / mL to about 2100 U / mL.

[0316] In some aspects, the pharmaceutical composition comprises about 50 U / mL, about 100 U / mL, about 150 U / mL, about 200 U / mL, about 250 U / mL, about 300 U / mL, about 350 U / mL, about 400 U / mL, about 450 U / mL, about 500 U / mL, about 550 U / mL, about 600 U / mL, about 650 U / mL, about 700 U / mL, about 750 U / mL, about 800 U / mL, about 850 U / mL, about 900 U / mL, about 950 U / mL, about 1000 U / mL, about 1100 U / mL, about 1200 U / mL, about 1300 U / mL, about 1400 U / mL, about 1500 U / mL, about 1600 U / mL, about 1700 U / mL, about In some embodiments, the present invention relates to an endoglycosidase hydrolase (e.g., rHuPH20) at about 100 U / mL, about 1800 U / mL, about 1900 U / mL, about 2000 U / mL, about 2100 U / mL, about 2200 U / mL, about 2300 U / mL, about 2400 U / mL, about 2500 U / mL, about 3000 U / mL, about 3500 U / mL, about 4000 U / mL, about 4500 U / mL, about 5000 U / mL, about 5500 U / mL, about 6000 U / mL, about 6500 U / mL, about 7000 U / mL, about 7500 U / mL, about 8000 U / mL, about 8500 U / mL, about 9000 U / mL, about 9500 U / mL, or about 10,000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20).

[0317] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 26.7 mg / mL of 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. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 26.7 mg / mL of relalizumab; (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.

[0318] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 26.7 mg / mL of 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 2400 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 26.7 mg / mL of relalizumab; (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 2400 U / mL rHuPH20.

[0319] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 26.7 mg / mL of 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 0.0182 mg / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 26.7 mg / mL of relalizumab; (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 0.0182 mg / mL rHuPH20.

[0320] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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.

[0321] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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 2400 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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 2400 U / mL rHuPH20.

[0322] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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 0.0182 mg / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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 0.0182 mg / mL rHuPH20.

[0323] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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.

[0324] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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 2400 U / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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 2400 U / mL rHuPH20.

[0325] In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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 0.0182 mg / mL rHuPH20. In certain aspects, the pharmaceutical composition comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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 0.0182 mg / mL rHuPH20.

[0326] In some aspects, the pharmaceutical composition comprises: (a) about 1200 mg nivolumab; (b) about 400 mg relalizumab; (c) about 8.68 mg histidine; (d) about 11.8 mg histidine HCl H2O; (e) about 479 mg sucrose; (f) about 2.80 mg polysorbate 80; (g) about 0.110 mg pentetic acid; (h) about 4.18 mg methionine; and (i) about 0.102 mg rHuPH20; wherein (a)-(h) are reconstituted in water to a final volume of at least about 15 mL. In some aspects, the pharmaceutical composition comprises: (a) about 1200 mg nivolumab; (b) about 200 mg relalizumab; (c) about 8.68 mg histidine; (d) about 11.8 mg histidine HCl H2O; (e) about 479 mg sucrose; (f) about 2.80 mg polysorbate 80; (g) about 0.110 mg pentetic acid; (h) about 4.18 mg methionine; and (i) about 0.102 mg rHuPH20; wherein (a)-(h) are reconstituted in water to a final volume of at least about 15 mL. In certain aspects, the pharmaceutical composition comprises: (a) about 960 mg of an anti-PD-1 antibody; (b) about 320 mg of 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. In certain aspects, the pharmaceutical composition comprises: (a) about 960 mg of nivolumab; (b) about 320 mg of relalizumab; (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.

[0327] In certain aspects, the pharmaceutical composition comprises: (a) about 960 mg of an anti-PD-1 antibody; (b) about 360 mg of 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. In certain aspects, the pharmaceutical composition comprises: (a) about 960 mg of nivolumab; (b) about 320 mg of relalizumab; (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 24,000 U / mL rHuPH20.

[0328] In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 26.7 mg / mL of 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. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 26.7 mg / mL of relalizumab; (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.

[0329] In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 26.7 mg / mL of 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 2400 U / mL rHuPH20. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 26.7 mg / mL of relalizumab; (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 2400 U / mL rHuPH20.

[0330] In certain aspects, a unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 26.7 mg / mL of 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 0.0182 mg / mL rHuPH20. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 26.7 mg / mL of relalizumab; (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 0.0182 mg / mL rHuPH20.

[0331] In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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.

[0332] In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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 2400 U / mL rHuPH20. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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 2400 U / mL rHuPH20.

[0333] In certain aspects, a unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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 0.0182 mg / mL rHuPH20. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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 0.0182 mg / mL rHuPH20.

[0334] In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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.

[0335] In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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 2400 U / mL rHuPH20. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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 2400 U / mL rHuPH20.

[0336] In certain aspects, a unit dose described herein comprises: (a) about 80 mg / mL of an anti-PD-1 antibody; (b) about 13.35 mg / mL of 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 0.0182 mg / mL rHuPH20. In certain aspects, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relalizumab; (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 0.0182 mg / mL rHuPH20.

[0337] In some aspects, the unit dose described herein comprises: (a) about 1200 mg nivolumab; (b) about 400 mg relalizumab; (c) about 8.68 mg histidine; (d) about 11.8 mg histidine HCl H2O; (e) about 479 mg sucrose; (f) about 2.80 mg polysorbate 80; (g) about 0.110 mg pentetic acid; (h) about 4.18 mg methionine; and (i) about 0.102 mg rHuPH20; wherein (a)-(h) are reconstituted in water to a final volume of at least about 15 mL. In some aspects, the unit dose described herein comprises: (a) about 1200 mg nivolumab; (b) about 200 mg relalizumab; (c) about 8.68 mg histidine; (d) about 11.8 mg histidine HCl H2O; (e) about 479 mg sucrose; (f) about 2.80 mg polysorbate 80; (g) about 0.110 mg pentetic acid; (h) about 4.18 mg methionine; and (i) about 0.102 mg rHuPH20; wherein (a)-(h) are reconstituted in water to a final volume of at least about 15 mL.

[0338] In certain aspects, the unit dose described herein comprises: (a) about 960 mg of an anti-PD-1 antibody; (b) about 320 mg of 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. In certain aspects, the pharmaceutical composition comprises: (a) about 960 mg of nivolumab; (b) about 320 mg of relalizumab; (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.

[0339] In certain aspects, the unit dose described herein comprises: (a) about 960 mg of an anti-PD-1 antibody; (b) about 360 mg of 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. In certain aspects, the pharmaceutical composition comprises: (a) about 960 mg of nivolumab; (b) about 320 mg of relalizumab; (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 24,000 U / mL rHuPH20. II.I. Additional Therapeutic Agents

[0340] In some aspects, the pharmaceutical compositions disclosed herein further comprise an additional therapeutic agent.

[0341] Other therapeutic agents may include any therapy and / or any standard of care therapy known in the art for treating a subject's tumor. In some aspects, other therapeutic agents include anticancer agents. In some aspects, anticancer agents include tyrosine kinase inhibitors, anti-angiogenic agents, checkpoint inhibitors, checkpoint stimulators, chemotherapeutic agents, immunotherapeutic agents, platinum agents, alkylating agents, taxanes, nucleoside analogs, antimetabolites, topoisomerase inhibitors, anthracyclines, vinca alkaloids, or any combination thereof.

[0342] In some aspects, the tyrosine kinase inhibitors include sorafenib (e.g., sorafenib tosylate, also known as NEXAVAR), lenvatinib (e.g., lenvatinib mesylate, also known as LENVIMA), regorafenib (e.g., STIVARGA), cabozantinib (e.g., cabozantinib S-malate, also known as CABOMETYX), sunitinib (e.g., sunitinib malate, also known as SUTENT), brivanib, linifanib, pemmetinib (also known as PEMAZYRE), everolimus (also known as AFINITOR or ZORTRESS), gefitinib (IRESSA, a small molecule TKI for EGFR), imatinib (e.g., imatinib mesylate), lapatinib (e.g., lapatinib ditosylate, also known as TY KERB), nilotinib (e.g., nilotinib hydrochloride, also known as TASIGNA), pazopanib (e.g., pazopanib hydrochloride, also known as VOTRIENT), temsirolimus (also known as TORISEL), erlotinib (e.g., erlotinib hydrochloride, also known as TARCEVA, a small molecule TKI for EGFR), afatinib (GILOTRIF, a small molecule TKI for EGFR), dacomitinib (VIZIMPRO, a small molecule TKI for EGFR), osimertinib (TAGRISSO, a small molecule TKI for EGFR), alectinib (ALECENSA, a small molecule TKI for ALK), ceritinib (ZYKADIA, a small molecule TKI for ALK and ROS-1), brigatinib ( (a small molecule TKI of ALK), crizotinib (XALKORI, a small molecule TKI of ALK and ROS-1), lorlatinib (LORBRENA, a small molecule TKI of ALK and ROS-1), entrectinib (ROZLYTREK, a small molecule TKI of ROS-1 and NTRK), dabrafenib (TAFINLAR, a small molecule TKI of BRAF), trametinib (MEKINIST, a small molecule TKI of BRAF), vemurafenib (ZELBORAF, a small molecule TKI of BRAF), larotrectinib (ROZLYTREK, a small molecule TKI of NTRK), or any combination thereof.

[0343] In some aspects, the anti-angiogenic agent includes vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase with Ig-like and EGF-like domains (Tie) receptor, hepatocyte growth factor (HGF), tyrosine protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimeric protein 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), an inhibitor of EGFR, or any combination thereof. In some aspects, the anti-angiogenic agent includes bevacizumab (also known as AVASTIN), ranibizumab (also known as LUCENTIS), ramucirumab (also known as CYRAMZA), aflibercept (also known as EYLEA or ZALTRAP), tanezumab, olaratumab (also known as LARTRUVO), nevacuzumab, AMG780, MEDI3617, vanucuzumab, rilotumumab, filatuzumab, TAK-701, onatuzumab, imatinib, or any combination thereof.

[0344] In some aspects, the checkpoint stimulators include B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, GITR, inducible T cell co-stimulator (ICOS), ICOS-L, OX40, OX40L, CD70, CD27, CD40, death receptor 3 (DR3), an agonist of CD28H, or any combination thereof.

[0345] In some aspects, the chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, a hormone or hormone modulator, a protein tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a proteasome inhibitor, other oncological agents, or any combination thereof.

[0346] In some aspects, the immunotherapeutic agent includes an antibody that specifically binds EGFR (e.g., cetuximab (ERBITUX)), ALK, ROS-1, NTRK, BRAF, ICOS, CD137 (4-1BB), CD134 (OX40), NKG2A, CD27, CD96, GITR, herpes virus entry mediator (HVEM), PD-1, PD-L1, CTLA-4, BTLA, TIM-3, A2aR, killer cell lectin-like receptor G1 (KLRG-1), natural killer cell receptor 2B4 (CD244), CD160, TIGIT, VISTA, KIR, TGFβ, IL-10, IL-8, B7-H4, Fas ligand, CSF1R, CXCR4, mesothelin, CEACAM-1, CD52, HER2, MICA, MICB, or any combination thereof.

[0347] In some aspects, the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (eg, triplatin tetranitrate), lipoplatin, phenanthreneplatin, or any combination thereof.

[0348] In some aspects, the alkylating agent comprises altretamine, bendamustine, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, ifosfamide, lomustine, mechlorethamine, melphalan, oxaliplatin, procarbazine, streptozocin, temozolomide, thiotepa, or any combination thereof.

[0349] In some aspects, the taxane includes paclitaxel, nab-paclitaxel, docetaxel, cabazitaxel, or any combination thereof.

[0350] In some aspects, the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, telbivudine, or any combination thereof.

[0351] In some aspects, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.

[0352] In some embodiments, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.

[0353] In some aspects, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.

[0354] In some aspects, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vinaminol, vinoreldine, vinbutine, or any combination thereof.

[0355] In some aspects, checkpoint inhibitors include cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors, T cell immunoglobulin and ITIM domain (TIGIT) inhibitors, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, TIM-1 inhibitors, TIM-4 inhibitors, B7-H3 inhibitors, B7-H4 inhibitors, B and T cell lymphocyte attenuator (BTLA) inhibitors, V-domain Ig suppressor of T cell activation (VISTA) inhibitors, indoleamine 2,3-dioxygenase (IDO) inhibitors, nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitors, killer cell immunoglobulin-like receptor (KIR) inhibitors, adenosine A2a receptor (A2aR) inhibitors, transforming growth factor beta (TGF-β) inhibitors. ) inhibitors, phosphoinositide 3-kinase (PI3K) inhibitors, CD47 inhibitors, CD48 inhibitors, CD73 inhibitors, CD113 inhibitors, sialic acid-binding immunoglobulin-like lectin-7 (SIGLEC-7) inhibitors, SIGLEC-9 inhibitors, SIGLEC-15 inhibitors, glucocorticoid-induced TNFR-related protein (GITR) inhibitors, galectin-1 inhibitors, galectin-9 inhibitors, carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1) inhibitors, G protein-coupled receptor 56 (GPR56) inhibitors, glycoprotein A repeat predominant (GARP) inhibitors, 2B4 inhibitors, programmed death-1 homolog (PD1H) inhibitors, leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitors, or any combination thereof.

[0356] In some aspects, other therapeutic agents include a second antibody. In some aspects, other therapeutic agents include antibodies that specifically bind to CTLA-4, 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 aspects, other therapeutic agents include IL-2 (for example, bempegaldesleukin). In some aspects, other therapeutic agents include IL12-Fc (for example, BMS-986415).

[0357] In some aspects, the additional therapeutic agent comprises an anti-CTLA-4 antibody. The anti-CTLA-4 antibody can be any antibody or antigen-binding portion thereof that binds to CTLA-4 and inhibits its activity. In some aspects, the anti-CTLA-4 antibody is any anti-CTLA-4 antibody disclosed herein. In some aspects, the additional therapeutic agent comprises tremelimumab. In some aspects, the additional therapeutic agent comprises ipilimumab.

[0358] In some aspects, additional therapeutic agents include anti-CD137 antibodies. Anti-CD137 antibodies can be any antibodies that bind to CD137 and inhibit its activity. In some aspects, anti-CD137 antibodies include any anti-CD137 antibodies disclosed herein. In some aspects, additional therapeutic agents include urelumab.

[0359] In some aspects, the additional therapeutic agent comprises an anti-KIR antibody. Anti-KIR antibodies include any antibody that binds to KIR and inhibits its activity. In some aspects, the anti-KIR antibody includes any anti-KIR antibody disclosed herein. In some aspects, the additional therapeutic agent comprises lirilumab.

[0360] In some aspects, the additional therapeutic agent comprises an anti-GITR antibody. The anti-GITR antibody can be any antibody that binds to GITR and inhibits its activity. In some aspects, the anti-GITR antibody includes any anti-GITR antibody disclosed herein. In some aspects, the additional therapeutic agent comprises MK4166. In some aspects, the additional therapeutic agent comprises TRX518. In some aspects, the pharmaceutical composition disclosed herein further comprises an anti-VISTA antibody.

[0361] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-CD96 antibody.

[0362] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-IL-8 antibody, such as -IL8.

[0363] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-TGFβ antibody.

[0364] In some aspects, the additional therapeutic agent comprises an anti-B7-H4 antibody. In certain aspects, the anti-B7-H4 antibody is an anti-B7-H4 disclosed in International Publication No. WO / 2009 / 073533.

[0365] In some aspects, the additional therapeutic agent comprises an anti-CD96 antibody. In some aspects, the additional therapeutic agent comprises an anti-TIM3 antibody. In some aspects, the additional therapeutic agent comprises an anti-VISTA antibody. In some aspects, the additional therapeutic agent comprises an anti-NKG2A antibody. In some aspects, the additional therapeutic agent comprises an anti-ICOS antibody. In some aspects, the additional therapeutic agent comprises an anti-OX40 antibody. In some aspects, the additional therapeutic agent comprises an anti-TIGIT antibody. In some aspects, the additional therapeutic agent comprises an anti-IL8 antibody, such as HUMAX-IL8 (BMS-986253). In some aspects, the additional therapeutic agent comprises an anti-TGFβ antibody.

[0366] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-Fas ligand antibody. In certain aspects, the anti-Fas ligand antibody is an anti-Fas ligand disclosed in International Publication No. WO / 2009 / 073533.

[0367] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-CXCR4 antibody. In certain aspects, the anti-CXCR4 antibody is an anti-CXCR4 disclosed in US Publication No. 2014 / 0322208 (eg, Ulocuplumab (BMS-936564)).

[0368] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-mesothelin antibody. In certain aspects, the anti-mesothelin antibody is an anti-mesothelin disclosed in US Pat. No. 8,399,623.

[0369] In some aspects, the pharmaceutical composition disclosed herein further comprises an anti-HER2 antibody. In certain aspects, the anti-HER2 antibody is Herceptin (Herceptin) (U.S. Patent number 5,821,337), trastuzumab or ado-trastuzumab emtansine (Kadcyla, such as WO / 2001 / 000244).

[0370] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-CD27 antibody. In some aspects, the anti-CD-27 antibody is Varlilumab (also known as "CDX-1127" and "1F5"), which is a human IgG1 antibody that is an agonist of human CD27, as disclosed, for example, in U.S. Patent No. 9,169,325.

[0371] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-CD73 antibody. In certain aspects, the anti-CD73 antibody is CD73.4.IgG2C219S.IgG1.1f.

[0372] In some aspects, the pharmaceutical composition disclosed herein further comprises an anti-MICA / B antibody. In certain aspects, the anti-MICA / B antibody is any antibody that specifically binds to human MICA / B, including but not limited to any anti-MICA / B antibody disclosed in International Publication No. WO 2019 / 183551, which is incorporated herein by reference in its entirety.

[0373] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-IL-10 antibody. In some aspects, the pharmaceutical compositions disclosed herein further comprise a long-acting IL-10 molecule. In some aspects, the long-acting IL-10 molecule comprises an IL-10-Fc fusion molecule. In some aspects, the long-acting IL-10 molecule comprises a PEGylated IL-10, such as AM0010 (ARMO BioSciences).

[0374] In some aspects, the pharmaceutical compositions disclosed herein further comprise an anti-IL-2 antibody. In some aspects, the pharmaceutical compositions disclosed herein further comprise a long-acting IL-2 molecule. In some aspects, the long-acting IL-2 comprises a pegylated IL-2, such as NKTR-214 (Nektar; see US 8,252,275, WO 12 / 065086, and WO 15 / 125159).

[0375] In some aspects, the pharmaceutical compositions disclosed herein comprise (i) an anti-PD-1 antibody (e.g., nivolumab), (ii) an anti-LAG-3 antibody (e.g., relalizumab), (iii) an endoglycosidase hydrolase, and (iv) an additional therapeutic agent. In some aspects, the additional therapeutic agent comprises a checkpoint inhibitor. In some aspects, the additional therapeutic agent comprises an antibody. In some aspects, the antibody specifically binds to a checkpoint protein. In some aspects, the antibody specifically binds to PD-L1, CTLA-4, TIGIT, TIM3, NKG2a, OX40, ICOS, MICA, CD137, KIR, TGFβ, IL-10, IL-8, B7-H4, Fas ligand, CXCR4, mesothelin, CD27, GITR, CCR8, ILT4, or any combination thereof. II.I.1. Anti-CTLA-4 Antibodies

[0376] In some aspects, the pharmaceutical compositions disclosed herein comprise (i) an anti-PD-1 antibody and / or an anti-PD-L1 antibody, (ii) an anti-LAG-3 antibody, (iii) an endoglycosidase hydrolase, and (iv) an antibody that specifically binds to CTLA-4 ("anti-CTLA-4 antibody"). Any anti-CTLA-4 antibody known in the art can be used in the compositions and methods of the present disclosure. In some aspects, the anti-CTLA-4 antibodies of the present invention bind to human CTLA-4, thereby disrupting the interaction of CTLA-4 with the human B7 receptor. Because the interaction of CTLA-4 with B7 transduces signals that cause the inactivation of T cells carrying the CTLA-4 receptor, the interruption of the interaction effectively induces, enhances, or prolongs the activation of such T cells, thereby inducing, enhancing, or prolonging an immune response.

[0377] Human monoclonal antibodies that specifically bind to CTLA-4 with high affinity are disclosed in U.S. Patent No. 6,984,720. Other anti-CTLA-4 monoclonal antibodies have been described, for example, in U.S. Patent Nos. 5,977,318, 6,051,227, 6,682,736, and 7,034,121, and International Publication Nos. WO 2012 / 122444, WO 2007 / 113648, WO 2016 / 196237, and WO 2000 / 037504, each of which is incorporated herein by reference in its entirety. The anti-CTLA-4 human monoclonal antibodies disclosed in U.S. Patent No. 6,984,720 have been shown to exhibit one or more of the following characteristics: (a) binding to CTLA-4 by at least about 10 7 M -1 , or about 10 9 M -1 , or about 10 10 M -1 to 10 11 M -1 or higher equilibrium association constant (K a ) specifically binds to human CTLA-4 as determined by Biacore analysis; (b) at least about 10 3 , about 10 4 or about 10 5 m -1 s -1 The kinetic association constant (k a ); (c) at least about 10 3 , about 10 4 or about 10 5 m -1 s -1 The kinetic dissociation constant (k d ); and (d) inhibiting the binding of CTLA-4 to B7-1 (CD80) and B7-2 (CD86). Anti-CTLA-4 antibodies useful in the present invention include monoclonal antibodies that specifically bind to human CTLA-4 and exhibit at least one, at least two, or at least three of the aforementioned characteristics.

[0378] In certain aspects, the CTLA-4 antibody is ipilimumab (also known as YERVOY, MDX-010, 10D1; see U.S. Patent No. 6,984,720), MK-1308 (Merck), AGEN-1884 (Aginas; see WO 2016 / 196237), or tremelimumab (AstraZeneca; also known as ticilimumab, CP-675,206; see WO 2000 / 037504 and Ribas, Update Cancer Ther. 2(3):133-39 (2007). In some aspects, the anti-CTLA-4 antibody is ipilimumab.

[0379] In some aspects, the anti-CTLA-4 antibody for use in the compositions and methods disclosed herein is ipilimumab, 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.

[0380] In some aspects, the anti-CTLA-4 antibody is tremelimumab.

[0381] In some aspects, the anti-CTLA-4 antibody is MK-1308.

[0382] In some aspects, the anti-CTLA-4 antibody is AGEN-1884.

[0383] In some aspects, the anti-CTLA-4 antibody is non-fucosylated or hypofucosylated. In some aspects, the anti-CTLA-4 antibody exhibits enhanced ADCC and / or ADCP activity. In some aspects, the anti-CTLA-4 antibody is BMS-986218, as described in PCT / US18 / 19868.

[0384] Anti-CTLA-4 antibodies useful 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 (e.g., ipilimumab and / or tremelimumab) for binding to human CTLA-4. In some aspects, the anti-CTLA-4 antibodies bind to the same epitope as any of the anti-CTLA-4 antibodies described herein (e.g., ipilimumab and / or tremelimumab). The ability of antibodies to cross-compete for binding to an antigen indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder other cross-competing antibodies from binding to that specific epitope region. These cross-competing antibodies are expected to have very similar functional properties to the reference antibodies (e.g., ipilimumab and / or tremelimumab) due to 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., WO 2013 / 173223).

[0385] In certain aspects, antibodies that cross-compete with ipilimumab and / or tremelimumab for binding to human CTLA-4 or to the same epitope region of human CTLA-4 are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, engineered antibodies, or humanized or human antibodies. Such chimeric, engineered, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0386] Anti-CTLA-4 antibodies useful in the compositions and methods of the disclosed invention also include antigen-binding portions of the above-described full-length antibodies. It has been well established that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.

[0387] Anti-CTLA-4 antibodies suitable for use in the disclosed methods or compositions are antibodies 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, an anti-CTLA-4 "antibody" includes an antigen-binding portion or fragment that binds to CTLA-4 and exhibits functional properties similar to those of the intact antibody in inhibiting the interaction of CTLA-4 with the human B7 receptor and upregulating the immune system. In certain aspects, the anti-CTLA-4 antibody, or antigen-binding portion thereof, cross-competes with ipilimumab and / or tremelimumab for binding to human CTLA-4.

[0388] In some aspects, the anti-CTLA-4 antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds (i) CTLA-4 and (ii) a second antigen. In some aspects, the anti-CTLA-4 antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds (i) CTLA-4 and (ii) CD3. II.I.2. Anti-CD137 Antibodies

[0389] In some aspects, the pharmaceutical compositions disclosed herein comprise (i) anti-PD-1 antibodies and / or anti-PD-L1 antibodies, (ii) anti-LAG-3 antibodies, (iii) endoglycosidase hydrolases, and (iv) anti-CD137 antibodies. Anti-CD137 antibodies specifically bind to and activate immune cells expressing CD137, thereby stimulating an immune response against tumor cells, particularly a cytotoxic T cell response. Antibodies that bind to CD137 have been disclosed in U.S. Publication No. 2005 / 0095244 and U.S. Patent Nos. 7,288,638, 6,887,673, 7,214,493, 6,303,121, 6,569,997, 6,905,685, 6,355,476, 6,362,325, 6,974,863, and 6,210,669.

[0390] In some aspects, the anti-CD137 antibody is Ulmer (BMS-663513), described in U.S. Patent No. 7,288,638 (20H4.9-IgG4 [10C7 or BMS-663513]). In some aspects, the anti-CD137 antibody is BMS-663031 (20H4.9-IgG1), described in U.S. Patent No. 7,288,638. In some aspects, the anti-CD137 antibody is 4E9 or BMS-554271, described in U.S. Patent No. 6,887,673. In some aspects, the anti-CD137 antibody is an antibody disclosed in the following U.S. Patent Nos. 7,214,493, 6,303,121, 6,569,997, 6,905,685, or 6,355,476. In some aspects, anti-CD137 antibodies are 1D8 or BMS-469492; 3H3 or BMS-469497; or 3E1, described in U.S. Patent No. 6,362,325. In some aspects, anti-CD137 antibodies are antibodies disclosed in issued U.S. Patent No. 6,974,863 (e.g., 53A2). In some aspects, anti-CD137 antibodies are antibodies disclosed in issued U.S. Patent No. 6,210,669 (e.g., 1D8, 3B8, or 3E1). In some aspects, antibody is Pfizer's PF-05082566 (PF-2566). In other aspects, anti-CD137 antibodies that can be used for the present invention compete with anti-CD137 antibodies disclosed herein. In some aspects, anti-CD137 antibodies bind to the same epitope as anti-CD137 antibodies disclosed herein. In other aspects, anti-CD137 antibodies that can be used for the present disclosure include six CDRs of anti-CD137 antibodies disclosed herein.

[0391] In some aspects, anti-CD137 antibodies are multispecific antibodies that specifically bind (i) CD137 and (ii) a second antigen, such as bispecific antibodies. In some aspect...

Claims

1. A pharmaceutical composition comprising (i) an antibody that specifically binds to PD-1 ("anti-PD-1 antibody") and / or an antibody that specifically binds to PD-L1 ("anti-PD-L1 antibody"), (ii) an antibody that specifically binds to LAG-3 ("anti-LAG-3 antibody"), and (iii) an endoglycosidase hydrolase.

2. The pharmaceutical composition of claim 1, further comprising an antioxidant.

3. The pharmaceutical composition of claim 2, wherein the antioxidant comprises a sacrificial antioxidant, a metal ion chelator, or both.

4. The pharmaceutical composition of claim 1 or 2, wherein the antioxidant is methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, or any combination thereof.

5. The pharmaceutical composition of any one of claims 1 to 4, wherein the antioxidant comprises pentetic acid ("DTPA") or ethylenediaminetetraacetic acid ("EDTA").

6. The pharmaceutical composition according to any one of claims 1 to 5, comprising at least two antioxidants.

7. The pharmaceutical composition of claim 6, wherein the at least two antioxidants are selected from methionine, DTPA and EDTA.

8. The pharmaceutical composition of claim 6 or 7, wherein the at least two antioxidants are (i) methionine and DTPA or (ii) methionine and EDTA.

9. The pharmaceutical composition of any one of claims 1 to 8, comprising at least about 0.1 mM to at least about 100 mM or at least about 1 mM to about 20 mM methionine.

10. The pharmaceutical composition of any one of claims 1 to 9, comprising about 0.1 mM to about 100 mM, about 0.1 mM to about 90 mM, about 0.1 mM to about 80 mM, about 0.1 mM to about 70 mM, about 0.1 mM to about 60 mM, about 0.1 mM to about 50 mM, about 0.1 mM to about 40 mM, about 0.1 mM to about 30 mM, about 0.1 mM to about 20 mM, about 0.1 mM to about 10 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM To about 10mM, about 1mM to about 9mM, about 1mM to about 8mM, about 1mM to about 7mM, about 1mM to about 6mM, about 1mM to about 5mM, about 2mM to about 9mM, about 3mM to about 8mM, about 4mM to about 7mM, about 4mM to about 6mM, about 4mM to about 5mM, about 5mM to about 20mM, about 5mM to about 15mM, about 5mM to about 10mM, about 5mM to about 9mM, about 5mM to about 8mM, about 5mM to about 7mM, or about 5mM to about 6mM methionine.

11. A pharmaceutical composition as described in any one of claims 1 to 10, comprising 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.

12. The pharmaceutical composition of any one of claims 1 to 11, comprising about 1 mM, about 1.5 mM, about 2 mM, about 2.5 mM, about 3 mM, about 3.5 mM, about 4 mM, about 4.5 mM, about 5 mM, about 5.5 mM, about 6 mM, about 6.5 mM, about 7 mM, about 7.5 mM, about 8 mM, about 8.5 mM, about 9 mM, about 9.5 mM, about 10 mM, about 11 mM, about 12 mM. In some embodiments, the present invention relates to about 100 mM methionine, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM, or about 100 mM methionine.

13. The pharmaceutical composition of any one of claims 1 to 12, comprising about 5 mM methionine.

14. The pharmaceutical composition of any one of claims 1 to 13, comprising at least about 1 μM to at least about 250 μM or at least about 5 μM to about 200 μM DTPA.

15. The pharmaceutical composition of any one of claims 1 to 14, comprising about 1 μM to about 250 μM, about 10 μM to about 200 μM, about 10 μM to about 175 μM, about 10 μM to about 150 μM, about 10 μM to about 125 μM, about 10 μM to about 100 μM, about 10 μM to about 75 μM, about 10 μM to about 70 μM, about 10 μM to about 60 μM, about 10 μM to about 50 μM, about 20 μM to about 100 μM, about 20 μM to about 75 μM, about 20 μM to about 70 μM, about 20 μM to about 60 μM, about 20 μM to about 50 μM, about 25 μM to about 100 μM, about 25 μM to about 75 μM, about 25 μM to about 50 μM, about 30 μM to about 100 μM, about 30 μM to about 75 μM, about 30 μM to about 70 μM, about 30 μM to about 60 μM, about 30 μM to about 50 μM, about 40 μM to about 100 μM, about 40 μM to about 75 μM, about 40 μM to about 70 μM, about 40 μM to about 60 μM, about 40 μM to about 50 μM, about 41 μM to about 59 μM, about 42 μM to about 58 μM, about 43 μM to about 57 μM, about 44 μM to about 56 μM, about 45 μM to about 55 μM, about 46 μM to about 54 μM, about 47 μM to about 53 μM, about 48 μM to about 52 μM, about 49 μM to about 51 μM, about 50 μM to about 100 μM, about 50 μM to about 75 μM, about 50 μM to about 70 μM, about 50 μM to about 60 μM DTPA.

16. The pharmaceutical composition of any one of claims 1 to 15, comprising at least about 5 μM, at least about 6 μM, at least about 7 μM, at least about 8 μM, at least about 9 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 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.

17. A pharmaceutical composition as described in any one of claims 1 to 16, comprising about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 35 μM, about 40 μM, about 45 μM, about 50 μM, about 55 μM, about 60 μM, about 65 μM, about 70 μM, about 75 μM, about 80 μM, about 85 μM, about 90 μM, about 95 μM, about 100 μM, about 110 μM, about 120 μM, about 130 μM, about 140 μM, about 150 μM, about 160 μM, about 170 μM, about 180 μM, about 190 μM, about 200 μM, about 210 μM, about 220 μM, about 230 μM, about 240 μM, or about 250 μM. DTPA.

18. The pharmaceutical composition of any one of claims 1 to 17, comprising about 50 μM DTPA.

19. The pharmaceutical composition of any one of claims 1 to 18, wherein the ratio of the anti-PD-1 antibody to the anti-LAG-3 antibody is about 1:1, about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 1:15, about 1:20, about 1:30, about 1:40, about 1:50, about 1:60, about 1:70, about 1:80, about 1:90, about 1:100, about 1:120, about 1:140, about 1:160, about 1:180, about 1:200, about 200:1, about 180:1, about 160:1, about 140:1, about 120:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 15:1, about 10:1, about 9:1, about 8:1, about 7:1, about 6:1, about 5:1, about 4:1, about 3:1, or about 2:

1.

20. The pharmaceutical composition of any one of claims 1 to 19, wherein the ratio of the anti-PD-1 antibody to the anti-LAG-3 antibody is about 1:1, about 2:1, about 3:1, about 4:1, about 5:1, about 6:1, or about 2:

1.

21. The pharmaceutical composition of any one of claims 1 to 20, comprising an anti-PD-1 antibody or an anti-PD-1 antibody and an anti-PD-L1 antibody.

22. The pharmaceutical composition of any one of claims 1 to 21, comprising at least about 10 mg / mL to at least about 500 mg / mL or at least about 20 mg / mL to at least about 200 mg / mL of the anti-PD-1 antibody.

23. The pharmaceutical composition of any one of claims 1 to 22, comprising from about 10 mg / mL to about 500 mg / mL, from about 10 mg / mL to about 450 mg / mL, from about 10 mg / mL to about 400 mg / mL, from about 10 mg / mL to about 350 mg / mL, from about 10 mg / mL to about 300 mg / mL, from about 10 mg / mL to about 250 mg / mL, from about 10 mg / mL to about 200 mg / mL, from about 10 mg / mL to about 190 mg / mL, from about 10 mg / mL to about 180 mg / mL, from about 10 mg / mL to about 170 mg / mL, from about 10 mg / mL to about 160 mg / mL, from about 10 mg / mL to about 150 mg / mL, about 10 mg / mL to about 140 mg / mL, about 10 mg / mL to about 130 mg / mL, about 10 mg / mL to about 120 mg / mL, about 10 mg / mL to about 110 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 85 mg / mL, about 10 mg / mL to about 80 mg / mL, about 20 mg / mL to about 500 mg / mL, about 20 mg / mL to about 450 mg / mL, about 20 mg / mL to about 400 mg / mL, about 20 mg / mL to about 350 mg / mL, about 20 mg / mL to about 300 mg / mL g / mL, about 20 mg / mL to about 250 mg / mL, about 20 mg / mL to about 200 mg / mL, about 20 mg / mL to about 190 mg / mL, about 20 mg / mL to about 180 mg / mL, about 20 mg / mL to about 170 mg / mL, about 20 mg / mL to about 160 mg / mL, about 20 mg / mL to about 150 mg / mL, about 20 mg / mL to about 140 mg / mL, about 20 mg / mL to about 130 mg / mL, about 20 mg / mL to about 120 mg / mL, about 20 mg / mL to about 110 mg / mL, about 20 mg / mL to about 100 mg / mL, about 20 mg / mL to about 90 mg / mL mL, about 20 mg / mL to about 85 mg / mL, about 20 mg / mL to about 80 mg / mL, about 50 mg / mL to about 200 mg / mL, about 50 mg / mL to about 190 mg / mL, about 50 mg / mL to about 180 mg / mL, about 50 mg / mL to about 170 mg / mL, about 50 mg / mL to about 160 mg / mL, about 50 mg / mL to about 150 mg / mL, about 50 mg / mL to about 140 mg / mL, about 50 mg / mL to about 130 mg / mL, about 50 mg / mL to about 120 mg / mL, about 50 mg / mL to about 110 mg / mL, about 50 mg / mL to about 100 mg / mL,About 50 mg / mL to about 90 mg / mL, about 50 mg / mL to about 85 mg / mL, about 50 mg / mL to about 80 mg / mL, about 100 mg / mL to about 200 mg / mL, about 100 mg / mL to about 150 mg / mL, about 150 mg / mL to about 200 mg / mL, about 135 mg / mL to about 180 mg / mL, about 100 mg / mL to about 130 mg / mL, or about 108 mg / mL to about 132 mg / mL of the anti-PD-1 antibody.

24. The pharmaceutical composition of any one of claims 1 to 23, comprising at least about 10 mg / mL, at least about 20 mg / mL, at least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL of the anti-PD-1 antibody.

25. The pharmaceutical composition of any one of claims 1 to 24, comprising about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 25 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL , about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 108 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 132 mg / mL, about 135 mg / mL, about 140 mg / mL, about 150 mg / mL, about 160 mg / mL, about 170 mg / mL, about 175 mg / mL, about 180 mg / mL, about 190 mg / mL g / mL, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL, about 260 mg / mL, about 270 mg / mL, about 280 mg / mL, about 290 mg / mL, about 300 mg / mL, about 310 mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL of the anti-PD-1 antibody.

26. The pharmaceutical composition of any one of claims 1 to 25, comprising about 80 mg / mL of the anti-PD-1 antibody.

27. The pharmaceutical composition of any one of claims 1 to 26, comprising from about 0.25 mg to about 2000 mg, from about 0.25 mg to about 1600 mg, from about 0.25 mg to about 1200 mg, from about 0.25 mg to about 800 mg, from about 0.25 mg to about 400 mg, from about 0.25 mg to about 100 mg, from about 0.25 mg to about 50 mg, from about 0.25 mg to about 40 mg, from about 0.25 mg to about 30 mg, from about 0.25 mg to about 20 mg, from about 20 mg to about 2000 mg, from about 20 mg to about 1600 mg, from about 20 mg to about 1200 mg, from about 20 mg to about 800 mg, from about 20 mg to about 400 mg, From about 20 mg to about 100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 400 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1200 mg, or from about 400 mg to about 1000 mg of the anti-PD-1 antibody.

28. A pharmaceutical composition as described in any one of claims 1 to 27, comprising about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7mg, about 7.25mg, about 7.5mg, about 7.75mg, about 8mg, about 8.25mg, about 8.5mg, about 8.75mg, about 9mg, about 9.25mg, about 9.5mg, about 9.75mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg g, about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670mg 0mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg , about 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg of the anti-PD-1 antibody. .

29. The pharmaceutical composition of any one of claims 1 to 28, comprising about 960 mg of the anti-PD-1 antibody.

30. The pharmaceutical composition of any one of claims 1 to 28, comprising about 1200 mg of the anti-PD-1 antibody.

31. The pharmaceutical composition of any one of claims 1 to 30, comprising at least about 3 mg / mL to at least about 200 mg / mL of the anti-LAG-3 antibody.

32. A pharmaceutical composition as described in any one of claims 1 to 31, comprising about 1 mg / mL to about 500 mg / mL, about 1 mg / mL to about 450 mg / mL, about 1 mg / mL to about 400 mg / mL, about 1 mg / mL to about 350 mg / mL, about 1 mg / mL to about 300 mg / mL, about 1 mg / mL to about 250 mg / mL, about 1 mg / mL to about 200 mg / mL, about 1 mg / mL to about 150 mg / mL, about 1 mg / mL to about 140 mg / mL, about 1 mg / mL to about 130 mg / mL, about 1 mg / mL to about 120 mg / mL, about 1 mg / mL to about 110 mg / mL, about 1 mg / mL to about 100 mg / mL, about 1 mg / mL to about 90 mg / mL, about 1 mg / mL to about 80 mg / mL, about 1 mg / mL to about 70 mg / mL, about 1 mg / mL to about 60 mg / mL, about 1 mg / mL to about 50 mg / mL, about 1 mg / mL to about 45 mg / mL, about 1 mg / mL to about 40 mg / mL, about 1 mg / mL to about 35 mg / mL, about 1 mg / mL to about 30 mg / mL, about 1 mg / mL to about 29 mg / mL, about 1 mg / mL to about 28 mg / mL, about 1 mg / mL to about 27 mg / mL, about 1 mg / mL to about 26 mg / mL, about 1 mg / mL to about In some embodiments, the present invention relates to a pharmaceutical composition comprising: a) about 1 mg / mL to about 25 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL to about 15 mg / mL, about 1 mg / mL to about 10 mg / mL, or about 1 mg / mL to about 5 mg / mL, about 3 mg / mL to about 200 mg / mL, about 5 mg / mL to about 250 mg / mL, about 5 mg / mL to about 200 mg / mL, about 5 mg / mL to about 150 mg / mL, about 5 mg / mL to about 140 mg / mL, about 5 mg / mL to about 130 mg / mL, about 5 mg / mL to about 120 mg / mL, about 5 mg / mL to about 110 mg / mL, about 5 mg / mL to about 100 mg / mL, about 5 mg / mL to about about 90 mg / mL, about 5 mg / mL to about 80 mg / mL, about 5 mg / mL to about 70 mg / mL, about 5 mg / mL to about 60 mg / mL, about 5 mg / mL to about 50 mg / mL, about 5 mg / mL to about 45 mg / mL, about 5 mg / mL to about 40 mg / mL, about 5 mg / mL to about 35 mg / mL, about 5 mg / mL to about 30 mg / mL, about 5 mg / mL to about 29 mg / mL, about 5 mg / mL to about 28 mg / mL, about 5 mg / mL to about 27 mg / mL, about 5 mg / mL to about 26 mg / mL, about 5 mg / mL to about 25 mg / mL, about 5 mg / mL to about 20 mg / mL,about 5 mg / mL to about 15 mg / mL, about 5 mg / mL to about 10 mg / mL, about 10 mg / mL to about 100 mg / mL, about 10 mg / mL to about 90 mg / mL, about 10 mg / mL to about 80 mg / mL, about 10 mg / mL to about 70 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 50 mg / mL, about 10 mg / mL to about 45 mg / mL, about 10 mg / mL to about 40 mg / mL, about 10 mg / mL to about 35 mg / mL, about 10 mg / mL to about 30 mg / mL, about 10 mg / mL to about 29 mg / mL, about 10 mg / mL to about 28 mg / mL, about 10 mg / mL to about 27 mg / mL, about 10 mg / mL to about 26 mg / mL, about 10 mg / mL to about mL to about 25 mg / mL, about 10 mg / mL to about 20 mg / mL, about 20 mg / mL to about 50 mg / mL, about 20 mg / mL to about 45 mg / mL, about 20 mg / mL to about 40 mg / mL, about 20 mg / mL to about 35 mg / mL, about 20 mg / mL to about 30 mg / mL, about 20 mg / mL to about 29 mg / mL, about 20 mg / mL to about 28 mg / mL, about 20 mg / mL to about 27 mg / mL, about 20 mg / mL to about 26 mg / mL, about 20 mg / mL to about 25 mg / mL, about 25 mg / mL to about 30 mg / mL, about 25 mg / mL to about 29 mg / mL, about 25 mg / mL to about 28 mg / mL, or about 25 mg / mL to about 27 mg / mL of the anti-LAG-3 antibody.

33. The pharmaceutical composition of any one of claims 1 to 32, comprising at least about 3 mg / mL, at least about 3.3 mg / mL, at least about 4 mg / mL, at least about 5 mg / mL, at least about 6 mg / mL, at least about 7 mg / mL, at least about 8 mg / mL, at least about 9 mg / mL, at least about 10 mg / mL, at least about 13 mg / mL, at least about 15 mg / mL, at least about 18 mg / mL, at least about 20 mg / mL, at least about 23 mg / mL, at least about 25 mg / mL, at least about 26 mg / mL, at least about 27 mg / mL, at least about 28 mg / mL, At least about 30 mg / mL, at least about 40 mg / mL, at least about 50 mg / mL, at least about 60 mg / mL, at least about 70 mg / mL, at least about 80 mg / mL, at least about 90 mg / mL, at least about 100 mg / mL, at least about 110 mg / mL, at least about 120 mg / mL, at least about 130 mg / mL, at least about 140 mg / mL, at least about 150 mg / mL, at least about 160 mg / mL, at least about 170 mg / mL, at least about 180 mg / mL, at least about 190 mg / mL, or at least about 200 mg / mL of the anti-LAG-3 antibody.

34. The pharmaceutical composition of any one of claims 1 to 33, comprising about 1 mg / mL, about 2 mg / mL, about 3 mg / mL, about 3.3 mg / mL, about 4 mg / mL, about 5 mg / mL, about 6 mg / mL, about 7 mg / mL, about 8 mg / mL, about 9 mg / mL, about 10 mg / mL, about 13 mg / mL, about 13.35 mg / mL, about 15 mg / mL, about 18 mg / mL, about 20 mg / mL, about 23 mg / mL, about 25 mg / mL, about 26 mg / mL, about 26.7 mg / mL , about 27 mg / mL, about 28 mg / mL, about 29 mg / mL, about 30 mg / mL, about 35 mg / mL, about 40 mg / mL, about 45 mg / mL, about 50 mg / mL, about 55 mg / mL, about 60 mg / mL, about 65 mg / mL, about 70 mg / mL, about 75 mg / mL, about 80 mg / mL, about 85 mg / mL, about 90 mg / mL, about 95 mg / mL, about 100 mg / mL, about 108 mg / mL, about 110 mg / mL, about 120 mg / mL, about 130 mg / mL, about 132mg / mL, about 135mg / mL, about 140mg / mL, about 150mg / mL, about 160mg / mL, about 170mg / mL, about 175mg / mL, about 180mg / mL, about 190mg / mL, about 200mg / mL, about 210mg / mL, about 220mg / mL, about 230mg / mL, about 240mg / mL, about 250mg / mL, about 260mg / mL, about 270mg / mL, about 280mg / mL, about 290mg / mL, about 300mg / mL, about 310mg / mL, about 320 mg / mL, about 330 mg / mL, about 340 mg / mL, about 350 mg / mL, about 360 mg / mL, about 370 mg / mL, about 380 mg / mL, about 390 mg / mL, about 400 mg / mL, about 410 mg / mL, about 420 mg / mL, about 430 mg / mL, about 440 mg / mL, about 450 mg / mL, about 460 mg / mL, about 470 mg / mL, about 480 mg / mL, about 490 mg / mL, or about 500 mg / mL of the anti-LAG-3 antibody.

35. The pharmaceutical composition of any one of claims 1 to 34, comprising about 13.3 mg / mL, about 13.35 mg / mL, about 26 mg / mL, about 26.7 mg / mL, about 40 mg / mL, or about 80 mg / mL of the anti-LAG-3 antibody.

36. The pharmaceutical composition of any one of claims 1 to 35, comprising about 26.7 mg / mL of the anti-LAG-3 antibody.

37. A pharmaceutical composition as described in any one of claims 1 to 36, comprising from about 0.25 mg to about 2000 mg, from about 0.25 mg to about 1600 mg, from about 0.25 mg to about 1200 mg, from about 0.25 mg to about 800 mg, from about 0.25 mg to about 400 mg, from about 0.25 mg to about 100 mg, from about 0.25 mg to about 50 mg, from about 0.25 mg to about 40 mg, from about 0.25 mg to about 30 mg, from about 0.25 mg to about 20 mg, from about 20 mg to about 2000 mg, from about 20 mg to about 1600 mg, from about 20 mg to about 1200 mg, from about 20 mg to about 800 mg, from about 20 mg to about 400 mg, From about 20 mg to about 100 mg, from about 100 mg to about 2000 mg, from about 100 mg to about 1800 mg, from about 100 mg to about 1600 mg, from about 100 mg to about 1400 mg, from about 100 mg to about 1200 mg, from about 100 mg to about 1000 mg, from about 100 mg to about 800 mg, from about 100 mg to about 600 mg, from about 100 mg to about 400 mg, from about 400 mg to about 2000 mg, from about 400 mg to about 1800 mg, from about 400 mg to about 1600 mg, from about 400 mg to about 1400 mg, from about 400 mg to about 1200 mg, or from about 400 mg to about 1000 mg of the anti-LAG-3 antibody.

38. A pharmaceutical composition as described in any one of claims 1 to 37, comprising about 0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5 mg, about 1.75 mg, about 2 mg, about 2.25 mg, about 2.5 mg, about 2.75 mg, about 3 mg, about 3.25 mg, about 3.5 mg, about 3.75 mg, about 4 mg, about 4.25 mg, about 4.5mg, about 4.75mg, about 5mg, about 5.25mg, about 5.5mg, about 5.75mg, about 6mg, about 6.25mg, about 6.5mg, about 6.75mg, about 7mg, about 7.25mg, about 7.5mg, about 7.75mg, about 8mg, about 8.25mg, about 8.5mg, about 8.75mg, about 9mg, about 9.25mg, about 9.5mg, about 9.75mg, about 10mg, about 15mg, about 20mg, about 25mg, about 30mg, about 35mg, about 40mg, about 45mg, about 50mg, about 60mg, about 70mg, about 80mg, about 90mg, about 100mg, about 110mg, about 120mg, about 130mg, about 140mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 210mg, about 220mg, about 230mg, about 240mg, about 250mg, about 260mg, about 270mg, about 280mg, about 290mg, about 300mg, about 310mg, about 320mg , about 330mg, about 340mg, about 350mg, about 360mg, about 370mg, about 380mg, about 390mg, about 400mg, about 410mg, about 420mg, about 430mg, about 440mg, about 450mg, about 460mg, about 470mg, about 480mg, about 490mg, about 500mg, about 510mg, about 520mg, about 530mg, about 540mg, about 550mg, about 560mg, about 570mg, about 580mg, about 590mg, about 600mg, about 610mg, about 620mg, about 630mg, about 640mg, about 650mg, about 660mg, about 670 mg, about 680mg, about 690mg, about 700mg, about 710mg, about 720mg, about 730mg, about 740mg, about 750mg, about 760mg, about 770mg, about 780mg, about 790mg, about 800mg, about 810mg, about 820mg, about 830mg, about 840mg, about 850mg, about 860mg, about 870mg, about 880mg, about 890mg, about 900mg, about 910mg, about 920mg, about 930mg, about 940mg, about 950mg, about 960mg, about 970mg, about 980mg, about 990mg, about 1000mg, about 1040mg, About 1080 mg, about 1100 mg, about 1140 mg, about 1180 mg, about 1200 mg, about 1240 mg, about 1280 mg, about 1300 mg, about 1340 mg, about 1380 mg, about 1400 mg, about 1440 mg, about 1480 mg, about 1500 mg, about 1540 mg, about 1580 mg, about 1600 mg, about 1640 mg, about 1680 mg, about 1700 mg, about 1740 mg, about 1780 mg, about 1800 mg, about 1840 mg, about 1880 mg, about 1900 mg, about 1940 mg, about 1980 mg, or about 2000 mg of the anti-LAG-3 antibody.

39. The pharmaceutical composition of any one of claims 1 to 38, comprising about 320 mg of the anti-LAG-3 antibody.

40. The pharmaceutical composition of any one of claims 1 to 39, comprising at least about 5 units ("U") to at least about 100,000 U of the endoglycosidase hydrolase.

41. The pharmaceutical composition of any one of claims 1 to 40, comprising about 50 U to about 100,000 U, about 500 U to about 100,000 U, about 1,000 U to about 100,000 U, about 5,000 U to about 100,000 U, about 10,000 U to about 100,000 U, about 15,000 U to about 100,000 U, about 20,000 U to about 100,000 U, 100,000U, about 500U to about 50,000U, about 1,000U to about 50,000U, about 5,000U to about 50,000U, about 10,000U to about 50,000U, about 15,000U to about 50,000U, about 20,000U to about 50,000U, about 15,000U to about 45,000U, about 16,000U to about 40, 000U, about 17,000U to about 35,000U, about 18,000U to about 30,000U, about 19,000U to about 29,000U, about 19,000U to about 28,000U, about 19,000U to about 27,000U, about 19,000U to about 26,000U, about 19,000U to about 25,000U, about 19,000U to about 24 ,000U, about 19,000U to about 23,000U, about 19,000U to about 22,000U, about 19,000U to about 21,000U, about 20,000U to about 28,000U, about 21,000U to about 27,000U, about 22,000U to about 26,000U, or about 23,000U to about 25,000U of the endoglycosidase hydrolase.

42. The pharmaceutical composition of any one of claims 1 to 41, comprising at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, ​​at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about In some embodiments, the present invention relates to an endoglycosidase hydrolase in an amount of at least about 5000 U, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U, at least about 80,000 U, at least about 90,000 U, or at least about 100,000 U of the endoglycosidase hydrolase.

43. A pharmaceutical composition as described in any one of claims 1 to 42, comprising about 50U, about 100U, about 150U, about 200U, about 250U, about 300U, about 400U, about 500U, about 600U, about 700U, about 800U, about 900U, about 1000U, about 1500U, about 2000U, about 2500U, about 3000U, about 4000U, about 5000U, about 10,000U, about 15,000U, about 20,000U , about 24,000 U, about 25,000 U, about 30,000 U, about 35,000 U, about 40,000 U, about 45,000 U, about 48,000 U, about 50,000 U, about 55,000 U, about 60,000 U, about 65,000 U, about 70,000 U, about 75,000 U, about 80,000 U, about 85,000 U, about 90,000 U, about 95,000 U, or about 100,000 U of the endoglycosidase hydrolase.

44. The pharmaceutical composition of any one of claims 1 to 43, comprising about 20,000 U or about 24,000 U of the endoglycosidase hydrolase.

45. The pharmaceutical composition of any one of claims 1 to 44, comprising at least about 500 U / mL to at least about 5000 U / mL of the endoglycosidase hydrolase.

46. ​​The pharmaceutical composition of any one of claims 1 to 45, comprising about 50 U / mL to about 10,000 U / mL, about 100 U / mL to about 9500 U / mL, about 150 U / mL to about 9000 U / mL, about 200 U / mL to about 8500 U / mL, about 250 U / mL to about 8000 U / mL, about 300 U / mL to about 7500 U / mL, about 350 U / mL to about 7000 U / mL, about 40 0 U / mL to about 6500 U / mL, about 450 U / mL to about 6000 U / mL, about 500 U / mL to about 5500 U / mL, about 550 U / mL to about 5000 U / mL, about 600 U / mL to about 4500 U / mL, about 650 U / mL to about 4000 U / mL, about 700 U / mL to about 3500 U / mL, about 750 U / mL to about 3000 U / mL, about 800 U / mL to about 2500 U / mL, about 1000 U / mL to about 3500 U / mL, about 1500 U / mL to about 3000 U / mL, about 1000 U / mL to about 2500 U / mL, about 1500 U / mL to about 3000 U / mL, about 1000 U / mL to about 2500 U / mL, about 1000 U / mL to about 3500 U / mL, about 1000 U / mL to about 3000 U / mL, about 1000 U / mL to about 2500 U / mL, about 1500 U / mL to about 3000 U / mL, about 1000 U / mL to about 25 ... L, about 900 U / mL to about 2500 U / mL, about 1000 U / mL to about 2500 U / mL, about 1500 U / mL to about 2500 U / mL, about 1600 U / mL to about 2500 U / mL, about 1700 U / mL to about 2500 U / mL, about 1800 U / mL to about 2500 U / mL, about 1900 U / mL to about 2500 U / mL, about 2000 U / mL to about 2500 U / mL, about 2100 U / mL to about 2500 U / mL U / mL to about 2500 U / mL, about 2200 U / mL to about 2500 U / mL, about 2300 U / mL to about 2500 U / mL, about 1500 U / mL to about 2500 U / mL, about 1600 U / mL to about 2400 U / mL, about 1700 U / mL to about 2300 U / mL, about 1800 U / mL to about 2200 U / mL, or about 1900 U / mL to about 2100 U / mL of the endoglycosidase hydrolase.

47. The pharmaceutical composition of any one of claims 1 to 46, comprising at least about 50 U / mL of the endoglycosidase hydrolase.

48. The pharmaceutical composition of any one of claims 1 to 47, comprising at least about 1500 U / mL, at least about 1600 U / mL, at least about 1700 U / mL, at least about 1800 U / mL, at least about 1900 U / mL, at least about 2000 U / mL, at least about 2100 U / mL, at least about 2200 U / mL, at least about 2300 U / mL, at least about 2400 μM, at least about 2500 μM, at least about 3000 μM, at least about 3500 μM, at least about 4000 μM, at least about 4500 U / mL, or at least about 5000 U / mL of the endoglycosidase hydrolase.

49. The pharmaceutical composition of any one of claims 1 to 48, comprising about 50 U / mL, about 100 U / mL, about 150 U / mL, about 200 U / mL, about 250 U / mL, about 300 U / mL, about 350 U / mL, about 400 U / mL, about 450 U / mL, about 500 U / mL, about 550 U / mL, about 600 U / mL, about 650 U / mL, about 700 U / mL, about 750 U / mL, about 800 U / mL, about 850 U / mL, about 900 U / mL, about 950 U / mL, about 1000 U / mL, about 1100 U / mL, about 1200 U / mL, about 1300 U / mL, about 1400 U / mL, about 1500 U / mL, about 1600 U / mL, about 1700 U / mL In some embodiments, the endoglycosidase hydrolase is at least about 100 U / mL, about 200 U / mL, about 2100 U / mL, about 2200 U / mL, about 2300 U / mL, about 2400 U / mL, about 2500 U / mL, about 3000 U / mL, about 3500 U / mL, about 4000 U / mL, about 4500 U / mL, about 5000 U / mL, about 5500 U / mL, about 6000 U / mL, about 6500 U / mL, about 7000 U / mL, about 7500 U / mL, about 8000 U / mL, about 8500 U / mL, about 9000 U / mL, about 9500 U / mL, or about 10,000 U / mL of the endoglycosidase hydrolase.

50. The pharmaceutical composition of any one of claims 1 to 49, comprising about 2000 U / mL of the endoglycosidase hydrolase.

51. The pharmaceutical composition of any one of claims 1 to 50, wherein the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosamine β (1-4) or (1-3) linkage.

52. The pharmaceutical composition of any one of claims 1 to 51, wherein the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4 or HYALPS1.

53. The pharmaceutical composition of any one of claims 1 to 52, wherein the endoglycosidase hydrolase comprises an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity to amino acids 36-490 of SEQ ID NO:

87.

54. The pharmaceutical composition of any one of claims 1 to 53, wherein the endoglycosidase hydrolase comprises a hyaluronidase.

55. The pharmaceutical composition of any one of claims 1 to 54, wherein the endoglycosidase hydrolase comprises a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants and any isoforms thereof.

56. The pharmaceutical composition of any one of claims 1 to 55, wherein the endoglycosidase hydrolase comprises rHuPH20 or a fragment thereof.

57. The pharmaceutical composition of any one of claims 1 to 56, wherein the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof.

58. A pharmaceutical composition as described in any of claims 1 to 57, wherein the endoglycosidase hydrolase comprises a modified hyaluronidase, which comprises: (i) one or more amino acid substitutions in the alpha helical region, (ii) one or more amino acid substitutions in the linker region, (iii) one or more N-terminal and / or C-terminal amino acid deletions, or (iv) any combination of (i)-(iii), relative to a wild-type hyaluronidase, the wild-type hyaluronidase being selected from the group consisting of: HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or a fragment thereof.

59. The pharmaceutical composition of any one of claims 1 to 58, wherein the endoglycosidase hydrolase comprises a modified rHuPH20, wherein the modified rHuPH20: i. comprising one or more amino acid substitutions in the alpha helical region, the linker region, or both the alpha helical region and the linker region relative to wild-type rHuPH20; ii. lacking one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids relative to wild-type rHuPH20; or iii. Includes both (i) and (ii).

60. The pharmaceutical composition of any one of claims 1 to 59, further comprising a tonicity modifier and / or a stabilizer.

61. The pharmaceutical composition of claim 60, wherein the tonicity modifier and / or stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof.

62. The pharmaceutical composition of claim 60 or 61, wherein the tonicity modifier and / or stabilizer comprises sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, or any combination thereof.

63. The pharmaceutical composition of any one of claims 60 to 62, wherein the tonicity adjuster comprises sucrose.

64. The pharmaceutical composition of any one of claims 1 to 63, comprising at least about 10 mM to at least about 500 mM sucrose.

65. A pharmaceutical composition as described in any one of claims 1 to 64, comprising about 1 mM to about 500 mM, about 1 mM to about 400 mM, about 1 mM to about 350 mM, about 1 mM to about 300 mM, about 1 mM to about 250 mM, about 10 mM to about 400 mM, about 10 mM to about 350 mM, about 10 mM to about 300 mM, about 10 mM to about 250 mM, about 50 mM to about 400 mM, about 50 mM to about 350 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 100 mM to about 400 mM, about 100 mM to about 350 mM, about 50 mM to about 300 mM, about 50 mM to about 250 mM, about 100 mM to about 400 mM, about 100 mM to about 350 mM, about 100 mM to about 300 mM, about 100 mM to about 250 mM. mM, about 150 mM to about 400 mM, about 150 mM to about 350 mM, about 150 mM to about 300 mM, about 150 mM to about 250 mM, about 150 mM to about 200 mM, about 200 mM to about 400 mM, about 200 mM to about 350 mM, about 200 mM to about 300 mM, about 200 mM to about 250 mM, about 250 mM to about 400 mM, about 250 mM to about 350 mM, about 250 mM to about 300 mM, about 300 mM to about 400 mM, about 300 mM to about 350 mM, or about 350 mM to about 400 mM sucrose.

66. The pharmaceutical composition of any one of claims 1 to 65, comprising at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, at least about At least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM, or at least about 500 mM sucrose.

67. The pharmaceutical composition of any one of claims 1 to 66, comprising about 10 mM, about 20 mM, about 30 mM, about 40 mM, about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM , about 250mM, about 260mM, about 270mM, about 280mM, about 290mM, about 300mM, about 310mM, about 320mM, about 330mM, about 340mM, about 350mM, about 360mM, about 370mM, about 380mM, about 390mM, about 400mM, about 410mM, about 420mM, about 430mM, about 440mM, about 450mM, about 460mM, about 470mM, about 480mM, about 490mM, or about 500mM sucrose.

68. A pharmaceutical composition as described in any one of claims 1 to 67, comprising about 250 mM sucrose.

69. The pharmaceutical composition of any one of claims 1 to 68, further comprising a buffer.

70. The pharmaceutical composition of claim 69, wherein the buffer is histidine, succinate, tromethamine, sodium phosphate, sodium acetate, sodium citrate, or any combination thereof.

71. The pharmaceutical composition of claim 69 or 70, wherein the buffer comprises histidine.

72. The pharmaceutical composition of any one of claims 1 to 71, comprising at least about 5 mM to at least about 100 mM histidine.

73. The pharmaceutical composition of any one of claims 1 to 72, comprising about 1 mM to about 100 mM, about 1 mM to about 90 mM, about 1 mM to about 80 mM, about 1 mM to about 75 mM, about 1 mM to about 70 mM, about 1 mM to about 65 mM, about 1 mM to about 60 mM, about 1 mM to about 55 mM, about 1 mM to about 50 mM, about 1 mM to about 45 mM, about 1 mM to about 40 mM, about 1 mM to about 35 mM, about 1 mM to about 30 mM, about 1 mM to about 25 mM, about 1 mM to about 20 mM, about 1 mM to about 15 mM, about 1 mM to about 10 mM, about 1 mM to about 5 mM, about 5 mM to about 100 mM, about 5 mM to about 90 mM , about 5mM to about 80mM, about 5mM to about 75mM, about 5mM to about 70mM, about 5mM to about 65mM, about 5mM to about 60mM, about 5mM to about 55mM, about 5mM to about 50mM, about 5mM to about 45mM, about 5mM to about 40mM, about 5mM to about 35mM, about 5mM to about 30mM, about 5mM to about 25mM, about 5mM to about 20mM, about 5mM to about 15mM, about 5mM to about 10mM, about 10mM to about 100mM, about 10mM to about 90mM, about 10mM to about 80mM, about 10mM to about 75mM, about 10mM to about 70mM, about 10mM to about 65mM, about 10mM to about 60 mM, about 10mM to about 55mM, about 10mM to about 50mM, about 10mM to about 45mM, about 10mM to about 40mM, about 10mM to about 35mM, about 10mM to about 30mM, about 10mM to about 25mM, about 10mM to about 20mM, about 10mM to about 15mM, about 15mM to about 100mM, about 15mM to about 90mM, about 15mM to about 80mM, about 15mM to about 75mM, about 15mM to about 70mM, about 15mM to about 65mM, about 15mM to about 60mM, about 15mM to about 55mM, about 15mM to about 50mM, about 15mM to about 45mM, about 15mM to about 40mM, about 15mM to about 55mM M to about 35mM, about 15mM to about 30mM, about 15mM to about 25mM, about 15mM to about 20mM, about 16mM to about 24mM, about 17mM to about 23mM, about 18mM to about 22mM, about 19mM to about 21mM, about 20mM to about 100mM, about 20mM to about 90mM, about 20mM to about 80mM, about 20mM to about 75mM, about 20mM to about 70mM, about 20mM to about 65mM, about 20mM to about 60mM, about 20mM to about 55mM, about 20mM to about 50mM, about 20mM to about 45mM, about 20mM to about 40mM, about 20mM to about 35mM, about 20mM to about 30mM,From about 20 mM to about 25 mM, from about 25 mM to about 100 mM, from about 30 mM to about 100 mM, from about 35 mM to about 100 mM, from about 40 mM to about 100 mM, from about 45 mM to about 100 mM, or from about 50 mM to about 100 mM histidine.

74. A pharmaceutical composition as described in any one of claims 1 to 73, comprising at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, or at least about 100 mM histidine.

75. A pharmaceutical composition as described in any one of claims 1 to 74, comprising about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 90 mM, or about 100 mM histidine.

76. The pharmaceutical composition of any one of claims 1 to 75, comprising about 20 mM histidine.

77. The pharmaceutical composition of any one of claims 1 to 76, further comprising a surfactant.

78. The pharmaceutical composition of claim 77, wherein the surfactant is polysorbate 20, polysorbate 80 or poloxamer 188.

79. The pharmaceutical composition of claim 77 or 78, wherein the surfactant comprises polysorbate 80.

80. The pharmaceutical composition of any one of claims 1 to 79, comprising at least about 0.01% w / v to at least about 0.1% w / v polysorbate 80.

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

82. The pharmaceutical composition of any one of claims 1 to 81, comprising about 0.001% to about 1% w / v, about 0.001% w / v to about 0.9% w / v, about 0.001% w / v to about 0.8% w / v, about 0.001% w / v to about 0.7% w / v, about 0.001% w / v to about 0.6% w / v, about 0.001% w / v to about 0.5% w / v, about 0.001% w / v to about 0.4% w / v, about 0.001% w / v to about 0.3% w / v, about 0.001% w / v to about 0.2% w / v, about 0.001% w / v to about 0.1% w / v, about 0.001% w / v to about 0.09% w / v, about 0.0 0.01% w / v to about 0.08% w / v, about 0.001% w / v to about 0.07% w / v, about 0.001% w / v to about 0.06% w / v, about 0.001% w / v to about 0.05% w / v, about 0.01% w / v to about 0.9% w / v, about 0.01% w / v to about 0.8% w / v, about 0.01% w / v to about 0.7% w / v, about 0.01% w / v to about 0.6% w / v, about 0.01% w / v to about 0.5% w / v, about 0.01% w / v to about 0.4% w / v, about 0.01% w / v to about 0.3% w / v, about 0.01% w / v to about 0.2% w / v, about 0.01% w / v to about 0.1% w / v w / v, about 0.01% w / v to about 0.09% w / v, about 0.01% w / v to about 0.08% w / v, about 0.01% w / v to about 0.07% w / v, about 0.01% w / v to about 0.06% w / v, about 0.01% w / v to about 0.05% w / v, about 0.02% w / v to about 0.1% w / v, about 0.02% w / v to about 0.09% w / v, about 0.02% w / v to about 0.08% w / v, about 0.02% w / v to about 0.07% w / v, about 0.02% w / v to about 0.06% w / v, about 0.02% w / v to about 0.05% w / v, about 0.03% w / v to about 0.1% w / v, about 0.03% w / v to about 0.09% w / v, about 0.03% w / v to about 0.08% w / v, about 0.03% w / v to about 0.07% w / v, about 0.03% w / v to about 0.06% w / v, about 0.03% w / v to about 0.05% w / v, about 0.04% w / v to about 0.1% w / v, about 0.04% w / v to about 0.09% w / v, about 0.04% w / v to about 0.08% w / v, about 0.04% w / v to about 0.07% w / v, about 0.04% w / v to about 0.06% w / v, about 0.04% w / v to about 0.05%, about 0.05% w / v to about 0.1% w / v, about 0.05% w / v to about 0.09% w / v, about 0.00.05% w / v to about 0.08% w / v, about 0.05% w / v to about 0.07% w / v, or about 0.05% w / v to about 0.06% w / v polysorbate 80.

83. The pharmaceutical composition of any one of claims 1 to 82, comprising about 0.001% w / v, 0.002% w / v, 0.003% w / v, 0.004% w / v, 0.005% w / v, 0.006% w / v, 0.007% w / v, 0.008% w / v, 0.009% w / v, 0.01% w / v, about 0.02% w / v, about 0.03% w / v, about 0.0 In some embodiments, the present invention relates to polysorbate 80 in an amount of about 0.4% w / v, about 0.05% w / v, about 0.06% w / v, about 0.07% w / v, about 0.08% w / v, about 0.09% w / v, about 0.1% w / v, about 0.2% w / v, about 0.3% w / v, about 0.4% w / v, about 0.5% w / v, about 0.6% w / v, about 0.7% w / v, about 0.8% w / v, about 0.9% w / v, or about 1% w / v polysorbate 80.

84. The pharmaceutical composition of any one of claims 1 to 83, comprising about 0.05% w / v polysorbate 80.

85. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 26.7 mg / mL of the anti-LAG-3 antibody; and (c) approximately 0.0182 mg / mL rHuPH20.

86. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 26.7 mg / mL of the anti-LAG-3 antibody; and (c) about 2000 U / mL rHuPH20.

87. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the anti-LAG-3 antibody; and (c) approximately 0.0182 mg / mL rHuPH20.

88. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the anti-LAG-3 antibody; and (c) about 2000 U / mL rHuPH20.

89. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the anti-LAG-3 antibody; and (c) about 24,000 U rHuPH20.

90. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 26.7 mg / mL of the 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) approximately 0.0182 mg / mL rHuPH20.

91. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 26.7 mg / mL of the 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.

92. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 13.35 mg / mL of the 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) approximately 0.0182 mg / mL rHuPH20.

93. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 80 mg / mL of the anti-PD-1 antibody; (b) about 13.35 mg / mL of the 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.

94. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the 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) approximately 0.0182 mg / mL rHuPH20.

95. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the 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.

96. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 84, comprising: (a) about 960 mg of the anti-PD-1 antibody; (b) about 320 mg of the 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 24,000 U rHuPH20.

97. The pharmaceutical composition of any one of claims 1 to 96, wherein the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001, MEDI-0680, cemiplizumab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, saxanthlimab, BI754091, SSI-361, or any combination thereof.

98. The pharmaceutical composition of any one of claims 1 to 97, wherein the anti-PD-1 antibody comprises nivolumab.

99. The pharmaceutical composition of any one of claims 1 to 98, wherein the anti-PD-1 antibody comprises pembrolizumab.

100. The pharmaceutical composition of any one of claims 1 to 96, wherein the anti-PD-1 antibody comprises: (a) CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the amino acid sequence of SEQ ID NO:79, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the amino acid sequence of SEQ ID NO:80; (b) heavy chain variable region CDR1, CDR2 and CDR3 comprising the amino acid sequences shown in SEQ ID NO:81, SEQ ID NO:82, and SEQ ID NO:83, respectively, and light chain variable region CDR1, CDR2 and CDR3 comprising the sequences shown in SEQ ID NO:84, SEQ ID NO:85, and SEQ ID NO:86, respectively; (c) heavy and light chain variable regions comprising the amino acid sequences shown in SEQ ID NOs: 79 and 80, respectively; or (d) a heavy chain and a light chain comprising the amino acid sequences shown in SEQ ID NOs: 77 and 78, respectively.

101. The pharmaceutical composition of any one of claims 1 to 100, wherein the anti-LAG-3 antibody comprises relalizumab, IMP731, GSK2831781, humanized BAP050, LAG-525, MK-4280, REGN3767, aLAG3(0414), aLAG3(0416), TSR-033, TSR-075, Sym022, FS-118, XmAb841, MGD013, BI754111, P13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501, or any combination thereof.

102. The pharmaceutical composition of any one of claims 1 to 101, wherein the anti-LAG-3 antibody comprises relalizumab.

103. The pharmaceutical composition of any one of claims 1 to 102, wherein the anti-LAG-3 antibody comprises: (a) CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO:3, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the amino acid sequence shown in SEQ ID NO:4; (b) heavy chain variable region CDR1, CDR2 and CDR3 comprising the amino acid sequences shown in SEQ ID NO:5, SEQ ID NO:6, and SEQ ID NO:7, respectively, and light chain variable region CDR1, CDR2 and CDR3 comprising the sequences shown in SEQ ID NO:8, SEQ ID NO:9, and SEQ ID NO:10, respectively; (c) heavy and light chain variable regions comprising the amino acid sequences shown in SEQ ID NOs: 3 and 4, respectively; (d) a heavy chain and a light chain comprising the amino acid sequences shown in SEQ ID NOs: 1 and 2, respectively; or (e) a heavy chain and a light chain comprising the amino acid sequences shown in SEQ ID NOs: 21 and 2, respectively.

104. The pharmaceutical composition of any one of claims 1 to 103, wherein the anti-PD-1 antibody comprises nivolumab, and the anti-LAG-3 antibody comprises relalizumab.

105. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 104, comprising: (a) approximately 80 mg / mL nivolumab; (b) about 26.7 mg / mL relalizumab; (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) approximately 0.0182 mg / mL rHuPH20.

106. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 104, comprising: (a) approximately 80 mg / mL nivolumab; (b) about 26.7 mg / mL relalizumab; (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.

107. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 104, comprising: (a) approximately 80 mg / mL nivolumab; (b) about 13.35 mg / mL relalizumab; (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) approximately 0.0182 mg / mL rHuPH20.

108. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 104, comprising: (a) approximately 80 mg / mL nivolumab; (b) about 13.35 mg / mL relalizumab; (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.

109. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 104, comprising: (a) approximately 1200 mg of nivolumab; (b) about 400 mg of relalizumab; (c) about 8.68 mg histidine; (d) about 11.8 mg histidine HCl H2O; (e) about 479 mg sucrose; (f) about 2.80 mg polysorbate 80; (g) about 0.110 mg pentetic acid; (h) about 4.18 mg methionine; (i) about 0.102 mg rHuPH20; Wherein (a)-(h) are reconstituted in water to a final volume of at least about 15 mL.

110. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 104, comprising: (a) approximately 960 mg of nivolumab; (b) approximately 320 mg of relalizumab; (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) approximately 0.0182 mg / mL rHuPH20.

111. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 104, comprising: (a) approximately 960 mg of nivolumab; (b) approximately 320 mg of relalizumab; (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.

112. A pharmaceutical composition as described in any one of claims 1 to 56 and 60 to 104, comprising: (a) approximately 960 mg of nivolumab; (b) about 320 mg mg / mL relalizumab; (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 24,000 U rHuPH20.

113. The pharmaceutical composition of any one of claims 1 to 112, comprising a pH of about 5.2 to about 6.

8.

114. The pharmaceutical composition of any one of claims 1 to 113, comprising a pH of about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, or about 6.

8.

115. The pharmaceutical composition of any one of claims 1 to 114, comprising a pH of about 5.

8.

116. The pharmaceutical composition of any one of claims 1-115, wherein the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO 36, FAZ053, CK-301, or any combination thereof.

117. The pharmaceutical composition of any one of claims 1 to 116, further comprising an additional therapeutic agent.

118. The pharmaceutical composition of claim 117, wherein the additional therapeutic agent comprises an antibody.

119. The pharmaceutical composition of claim 118, wherein the additional therapeutic agent comprises a checkpoint inhibitor.

120. A pharmaceutical composition as described in claim 118 or 119, wherein the additional therapeutic agent comprises anti-CTLA-4 antibody, anti-TIM3 antibody, anti-TIGIT antibody, anti-NKG2a antibody, anti-OX40 antibody, anti-ICOS antibody, anti-MICA antibody, anti-CD137 antibody, anti-KIR antibody, anti-TGFβ antibody, anti-IL-10 antibody, anti-IL-8 antibody, anti-B7-H4 antibody, anti-Fas ligand antibody, anti-CXCR4 antibody, anti-mesothelin antibody, anti-CD27 antibody, anti-GITR antibody, anti-CCR8 antibody, anti-ILT4 antibody, or any combination thereof.

121. A vial comprising the pharmaceutical composition of any one of claims 1 to 120.

122. A syringe comprising the pharmaceutical composition of any one of claims 1 to 120.

123. The syringe of claim 122, further comprising a plunger.

124. An automatic injector comprising the pharmaceutical composition of any one of claims 1 to 120.

125. A wearable pump or wearable device comprising the pharmaceutical composition of any one of claims 1 to 120.

126. A pen injector comprising the pharmaceutical composition of any one of claims 1 to 120.

127. A method of treating a disease or condition in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of the pharmaceutical composition of any one of claims 1 to 120.

128. The method of claim 127, wherein the pharmaceutical composition is administered subcutaneously.

129. The method of claim 127 or 128, wherein the disease or disorder is an infectious disease.

130. The method of claim 127 or 128, wherein the disease or disorder is cancer.

131. The method of claim 130, wherein the cancer is squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, renal cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-refractory prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, gastric cancer, bladder cancer, hepatoma, breast cancer, colon cancer, head and neck cancer, gastric cancer, germ cell tumors, pediatric sarcoma, sinonasal natural killer, melanoma, bone cancer, skin cancer of the uterus, cancer of the anal region, testicular cancer, cancer of the fallopian tubes, cancer of the endometrium, cancer of the cervix, cancer of the vagina, cancer of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the parathyroid glands, cancer of the adrenal glands, soft tissue sarcomas, cancer of the urethra, cancer of the penis, cancer of the rectum, solid tumors in children, cancer of the ureter, cancer of the renal pelvis, central nervous system (CNS) tumors, primary CNS lymphomas, tumor angiogenesis, spinal axis tumors, brain cancer, brain stem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermoid carcinoma, squamous cell carcinoma, environmentally induced cancers including cancers induced by asbestos, virus-related cancers or cancers of viral origin (e.g., human papillomavirus (HPV-related or derived tumors)), or any combination thereof.

132. The method of claim 130 or 131, wherein the cancer is unresectable or metastatic melanoma.

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