Antibody composition and method for using the same

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. In some embodiments, the pharmaceutical composition is formulated for subcutaneous delivery. Other embodiments of the present disclosure relate to methods of subcutaneously delivering the pharmaceutical composition.

Description

Technical Field

[0001] Cross - Reference to Related Applications This PCT application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 348,409, filed on June 2, 2022, U.S. Provisional Patent Application No. 63 / 384,213, filed on November 17, 2022, and U.S. Provisional Patent Application No. 63 / 505,467, filed on June 1, 2023, the entire contents of which are incorporated herein by reference.

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

[0003] The present disclosure provides a pharmaceutical composition comprising an antibody and a method of using the same to treat a subject afflicted with a tumor.

Background Art

[0004] Human cancers have numerous genetic and epigenetic changes and generate neoantigens that are potentially recognizable by the immune system (Non - Patent Document 1). The adaptive immune system, composed of T lymphocytes and B lymphocytes, has a broad ability to respond to diverse tumor antigens and excellent specificity, and has a strong anti - cancer ability. Furthermore, the immune system exhibits considerable plasticity and a memory component. By fully exploiting all of these attributes of the adaptive immune system, immunotherapy becomes unique among all cancer therapies.

[0005] Until recently, cancer immunotherapy has focused substantial efforts on approaches to enhance the anti-tumor immune response by adoptive transfer of activated effector cells, immunization against relevant antigens, or provision of non-specific immunostimulants such as cytokines. However, in the past decade, intensive efforts to develop specific immune checkpoint pathway inhibitors have begun to provide new immunotherapy 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-ligand pathway, such as nivolumab and pembrolizumab (previously ramucirumab; Non-Patent Document 2) (Non-Patent Documents 3, 4, 5, 6, 7, 8).

[0006] Lymphocyte activation gene 3 (LAG-3; CD223) is a type I transmembrane protein expressed on the cell surface of activated CD4+ and CD8+ T cells, as well as subsets of NK cells and dendritic cells (Non-Patent Documents 9, 10). LAG-3 is closely related to CD4, which is a co-receptor for T helper cell activation. Both molecules have four extracellular Ig-like domains and bind to major histocompatibility complex (MHC) class II. In contrast to CD4, LAG-3 is expressed only 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.

Prior Art Documents

Non-Patent Documents

[0007]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

[0008] Current methods of delivering anti-PD-1 antibodies and anti-LAG-3 antibodies use regular intravenous administration, which is often administered by clinicians in clinics or hospitals in many cases. The inconvenience and invasiveness of treatment can have an adverse impact on the patient experience. Subcutaneous delivery could significantly improve the patient experience. There is still a need in the art for formulations containing anti-PD-1 antibodies or anti-PD-L1 antibodies and anti-LAG-3 antibodies suitable for subcutaneous delivery to patients. [Means for Solving the Problems]

[0009] 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.

[0010] 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”).

[0011] 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.

[0012] In some embodiments, 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 of methionine. In some embodiments, 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 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 of methionine. In some embodiments, the pharmaceutical composition comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM or at least about 20 mM of methionine.In some embodiments, the pharmaceutical composition comprises methionine at 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 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. In some embodiments, the pharmaceutical composition comprises about 5 mM of methionine.

[0013] In some embodiments, the pharmaceutical composition comprises DTPA in an amount of at least about 1 μM to at least about 250 μM or at least about 5 μM to about 200 μM. In some embodiments, the pharmaceutical composition comprises DTPA in an amount of 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. In some embodiments, 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 70 μM, at least about 75 μM, at least about 80 μM, at least about 85 μM, at least about 90 μM, at least about 95 μM, at least about 100 μM, at least about 110 μM, at least about 120 μM, at least about 130 μM, at least about 140 μM, at least about 150 μM, at least about 160 μM, at least about 170 μM, at least about 180 μM, at least about 190 μM or at least about 200 μM of DTPA.In some embodiments, the pharmaceutical composition comprises DTPA at 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. In some embodiments, the pharmaceutical composition comprises about 50 μM of DTPA.

[0014] In some embodiments, 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. In some embodiments, 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.

[0015] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody or an anti-PD-1 antibody and an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody 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. In some embodiments, the pharmaceutical composition is 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, from about 10 mg / mL to about 140 mg / mL, from about 10 mg / mL to about 130 mg / mL, from about 10 mg / mL to about 120 mg / mL, from about 10 mg / mL to about 110 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 85 mg / mL, from about 10 mg / mL to about 80 mg / mL, from about 20 mg / mL to about 500 mg / mL, from about 20 mg / mL to about 450 mg / mL, from about 20 mg / mL to about 400 mg / mL, from about 20 mg / mL to about 350 mg / mL, from about 20 mg / mL to about 300 mg / mL, from about 20 mg / mL to about 250 mg / mL, from about 20 mg / mL to about 200 mg / mL, from about 20 mg / mL to about 190 mg / mL, from about 20 mg / mL to about 180 mg / mL, from about 20 mg / mL to about 170 mg / mL, from about 20 mg / mL to about 160 mg / mL, from about 20 mg / mL to about 150 mg / mL, from about 20 mg / mL to about 140 mg / mL, from about 20 mg / mL to about 130 mg / mL, from about 20 mg / mL to about 120 mg / mL, from about 20 mg / mL to about 110 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 90 mg / mL, from about 20 mg / mL to about 85 mg / mL, from about 20 mg / mL to about 80 mg / mL, from about 50 mg / mL to about 200 mg / mL, from about 50 mg / mL to about 190 mg / mL, from about 50 mg / mL to about 180 mg / mL, from about 50 mg / mL to about 170 mg / mL, from about 50 mg / mL to about 160 mg / mL,It contains an anti-PD-1 antibody at 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. In some embodiments, the pharmaceutical composition contains an anti-PD-1 antibody at 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. In some embodiments, the pharmaceutical composition contains an anti-PD-1 antibody at 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, about 200 mg / mL, about 210 mg / mL, about 220 mg / mL, about 230 mg / mL, about 240 mg / mL, about 250 mg / mL,It contains an anti-PD-1 antibody at 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. In some embodiments, the pharmaceutical composition contains an anti-PD-1 antibody at about 80 mg / mL. In some embodiments, the pharmaceutical composition contains an anti-PD-1 antibody at 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, 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. In some embodiments, the pharmaceutical composition contains 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 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 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 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,It contains about 1900 mg, about 1940 mg, about 1980 mg or about 2000 mg of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition contains about 960 mg of the anti-PD-1 antibody. In some embodiments, the pharmaceutical composition contains about 1200 mg of the anti-PD-1 antibody.,

[0016] In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody at at least about 3 mg / mL to at least about 200 mg / mL. In some embodiments, the pharmaceutical composition is from about 1 mg / mL to about 500 mg / mL, from about 1 mg / mL to about 450 mg / mL, from about 1 mg / mL to about 400 mg / mL, from about 1 mg / mL to about 350 mg / mL, from about 1 mg / mL to about 300 mg / mL, from about 1 mg / mL to about 250 mg / mL, from about 1 mg / mL to about 200 mg / mL, from about 1 mg / mL to about 150 mg / mL, from about 1 mg / mL to about 140 mg / mL, from about 1 mg / mL to about 130 mg / mL, from about 1 mg / mL to about 120 mg / mL, from about 1 mg / mL to about 110 mg / mL, from about 1 mg / mL to about 100 mg / mL, from about 1 mg / mL to about 90 mg / mL, from about 1 mg / mL to about 80 mg / mL, from about 1 mg / mL to about 70 mg / mL, from about 1 mg / mL to about 60 mg / mL, from about 1 mg / mL to about 50 mg / mL, from about 1 mg / mL to about 45 mg / mL, from about 1 mg / mL to about 40 mg / mL, from about 1 mg / mL to about 35 mg / mL, from about 1 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 29 mg / mL, from about 1 mg / mL to about 28 mg / mL, from about 1 mg / mL to about 27 mg / mL, from about 1 mg / mL to about 26 mg / mL, from about 1 mg / mL to about 25 mg / mL, from about 1 mg / mL to about 20 mg / mL, from about 1 mg / mL to about 15 mg / mL, from about 1 mg / mL to about 10 mg / mL or from about 1 mg / mL to about 5 mg / mL, from about 3 mg / mL to about 200 mg / mL, from about 5 mg / mL to about 250 mg / mL, from about 5 mg / mL to about 200 mg / mL, from about 5 mg / mL to about 150 mg / mL, from about 5 mg / mL to about 140 mg / mL, from about 5 mg / mL to about 130 mg / mL, from about 5 mg / mL to about 120 mg / mL, from about 5 mg / mL to about 110 mg / mL, from about 5 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 90 mg / mL, from about 5 mg / mL to about 80 mg / mL, from about 5 mg / mL to about 70 mg / mL, from about 5 mg / mL to about 60 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 45 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 35 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 29 mg / mL, from about 5 mg / mL to about 28 mg / mL, from about 5 mg / mL to about 27 mg / mL, from about 5 mg / mL to about 26 mg / mL,Comprising an anti-LAG-3 antibody at 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, 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 embodiments, the pharmaceutical composition is 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,It comprises an anti-LAG-3 antibody at 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. In some embodiments, the pharmaceutical composition is at 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, 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 an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition is at about 13.3 mg / mL,It contains an anti-LAG-3 antibody at about 13.35 mg / mL, about 26 mg / mL, about 26.7 mg / mL, about 40 mg / mL, or about 80 mg / mL. In some embodiments, the pharmaceutical composition contains an anti-LAG-3 antibody at about 26.7 mg / mL. In some embodiments, the pharmaceutical composition contains an anti-LAG-3 antibody at 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, 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. In some embodiments, the pharmaceutical composition contains 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,Comprising an anti-LAG-3 antibody of 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 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 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. In some embodiments, the pharmaceutical composition comprises about 320 mg of the anti-LAG-3 antibody.,

[0017] In some embodiments, the pharmaceutical composition comprises at least about 5 units ("U") to at least about 100,000 U of an endoglycosidase hydrolase. In some embodiments, 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 500 U to about 50,000 U, about 1,000 U to about 50,000 U, about 5,000 U to about 50,000 U, about 10,000 U to about 50,000 U, about 15,000 U to about 50,000 U, about 20,000 U to about 50,000 U, about 15,000 U to about 45,000 U, about 16,000 U to about 40,000 U, about 17,000 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, about 19,000 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.In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase of at least about 5 U, at least about 10 U, at least about 20 U, at least about 30 U, at least about 40 U, at least about 50 U, at least about 75 U, at least about 100 U, at least about 200 U, at least about 300 U, at least about 400 U, at least about 500 U, at least about 750 U, at least about 1000 U, at least about 2000 U, at least about 3000 U, at least about 4000 U, at least about 5000 U, at least about 6000 U, at least about 7000 U, at least about 8000 U, at least about 9000 U, at least about 10,000 U, at least about 20,000 U, at least about 30,000 U, at least about 40,000 U, at least about 50,000 U, at least about 60,000 U, at least about 70,000 U, at least about 80,000 U, at least about 90,000 U or at least about 100,000 U. In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase of 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. In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase of about 20,000 U or about 24,000 U. In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase of at least about 500 U / mL to at least about 5000 U / mL.In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase at 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, 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 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, 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. In some embodiments, the pharmaceutical composition comprises at least about 50 U / mL of an endoglycosidase hydrolase. In some embodiments, the pharmaceutical composition comprises at least about 1500 U / mL, at least about 1600 U / mL, at least about 1700 U / mL, at least about 1800 U / mL, at least about 1900 U / mL, at least about 2000 U / mL, at least about 2100 U / mL, at least about 2200 U / mL, at least about 2300 U / mL, at least about 2400 μM, at least about 2500 μM, at least about 3000 μM, at least about 3500 μM, at least about 4000 μM, at least about 4500 U / mL or at least about 5000 U / mL of an endoglycosidase hydrolase.In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase at 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. In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase at about 2000 U / mL.

[0018] In some embodiments, the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosaminide β(1-4) or (1-3) bond. In some embodiments, the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4 or HYALPS1. In some embodiments, 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.

[0019] In some embodiments, the endoglycosidase hydrolase includes hyaluronidase. In some embodiments, the endoglycosidase hydrolase includes a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant thereof, and any isoform.

[0020] In some embodiments, the endoglycosidase hydrolase includes rHuPH20 or a fragment thereof. In some embodiments, the endoglycosidase hydrolase includes a modified hyaluronidase that includes one or more amino acid substitutions relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase includes a modified hyaluronidase that includes (i) one or more amino acid substitutions in the α-helix 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) relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase includes a modified rHuPH20, and the modified rHuPH20 includes: i. one or more amino acid substitutions in the α-helix region, the linker region, or both the α-helix region and the linker region relative to wild-type rHuPH20; ii. a deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids relative to wild-type rHuPH20; or iii. both (i) and (ii).

[0021] In some embodiments, the pharmaceutical composition further comprises an isotonicity adjusting agent and / or a stabilizer. In some embodiments, the isotonicity adjusting agent and / or the stabilizer comprises a sugar, an amino acid, a polyol, a salt, or a combination thereof. In some embodiments, the isotonicity adjusting agent and / or the stabilizer comprises sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, or any combination thereof. In some embodiments, the isotonicity adjusting agent comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM of sucrose. In some embodiments, the pharmaceutical composition comprises from about 1 mM to about 500 mM, from about 1 mM to about 400 mM, from about 1 mM to about 350 mM, from about 1 mM to about 300 mM, from about 1 mM to about 250 mM, from about 10 mM to about 400 mM, from about 10 mM to about 350 mM, from about 10 mM to about 300 mM, from about 10 mM to about 250 mM, from about 50 mM to about 400 mM, from about 50 mM to about 350 mM, from about 50 mM to about 300 mM, from about 50 mM to about 250 mM, from about 100 mM to about 400 mM, from about 100 mM to about 350 mM, from about 100 mM to about 300 mM, from about 100 mM to about 250 mM, from about 100 mM to about 200 mM, from about 100 mM to about 150 mM, from about 150 mM to about 400 mM, from about 150 mM to about 350 mM, from about 150 mM to about 300 mM, from about 150 mM to about 250 mM, from about 150 mM to about 200 mM, from about 200 mM to about 400 mM, from about 200 mM to about 350 mM, from about 200 mM to about 300 mM, from about 200 mM to about 250 mM, from about 250 mM to about 400 mM, from about 250 mM to about 350 mM, from about 250 mM to about 300 mM, from about 300 mM to about 400 mM, from about 300 mM to about 350 mM, or from about 350 mM to about 400 mM of sucrose.In some embodiments, the pharmaceutical composition comprises sucrose at at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM or at least about 500 mM. In some embodiments, the pharmaceutical composition comprises sucrose at 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 or about 500 mM.In some embodiments, the pharmaceutical composition comprises about 250 mM sucrose.

[0022] In some embodiments, the pharmaceutical composition further comprises a buffer. In some embodiments, the buffer is histidine, succinate, tromethamine, sodium phosphate, sodium acetate, sodium citrate, or any combination thereof. In some embodiments, the buffer comprises histidine. In some embodiments, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM of histidine. In some embodiments, the pharmaceutical composition comprises from about 1 mM to about 100 mM, from about 1 mM to about 90 mM, from about 1 mM to about 80 mM, from about 1 mM to about 75 mM, from about 1 mM to about 70 mM, from about 1 mM to about 65 mM, from about 1 mM to about 60 mM, from about 1 mM to about 55 mM, from about 1 mM to about 50 mM, from about 1 mM to about 45 mM, from about 1 mM to about 40 mM, from about 1 mM to about 35 mM, from about 1 mM to about 30 mM, from about 1 mM to about 25 mM, from about 1 mM to about 20 mM, from about 1 mM to about 15 mM, from about 1 mM to about 10 mM, from about 1 mM to about 5 mM, from about 5 mM to about 100 mM, from about 5 mM to about 90 mM, from about 5 mM to about 80 mM, from about 5 mM to about 75 mM, from about 5 mM to about 70 mM, from about 5 mM to about 65 mM, from about 5 mM to about 60 mM, from about 5 mM to about 55 mM, from about 5 mM to about 50 mM, from about 5 mM to about 45 mM, from about 5 mM to about 40 mM, from about 5 mM to about 35 mM, from about 5 mM to about 30 mM, from about 5 mM to about 25 mM, from about 5 mM to about 20 mM, from about 5 mM to about 15 mM, from about 5 mM to about 10 mM, from about 10 mM to about 100 mM, from about 10 mM to about 90 mM, from about 10 mM to about 80 mM, from about 10 mM to about 75 mM, from about 10 mM to about 70 mM, from about 10 mM to about 65 mM, from about 10 mM to about 60 mM, from about 10 mM to about 55 mM, from about 10 mM to about 50 mM, from about 10 mM to about 45 mM, from about 10 mM to about 40 mM, from about 10 mM to about 35 mM, from about 10 mM to about 30 mM, from about 10 mM to about 25 mM, from about 10 mM to about 20 mM, from about 10 mM to about 15 mM, from about 15 mM to about 100 mM, from about 15 mM to about 90 mM, from about 15 mM to about 80 mM, from about 15 mM to about 75 mM, from about 15 mM to about 70 mM, from about 15 mM to about 65 mM, from about 15 mM to about 60 mM, from about 15 mM to about 55 mM, from about 15 mM to about 50 mM, from about 15 mM to about 45 mM, from about 15 mM to about 40 mM, from about 15 mM to about 35 mM, from about 15 mM to about 30 mM, from about 15 mM to about 25 mM, from about 15 mM to about 20 mM, from about 16 mM to about 24 mM, from about 17 mM to about 23 mM, from about 18 mM to about 22 mM, from about 19 mM to about 21 mM,It contains histidine in an amount of about 20 mM to about 100 mM, about 20 mM to about 90 mM, about 20 mM to about 80 mM, about 20 mM to about 75 mM, about 20 mM to about 70 mM, about 20 mM to about 65 mM, about 20 mM to about 60 mM, about 20 mM to about 55 mM, about 20 mM to about 50 mM, about 20 mM to about 45 mM, about 20 mM to about 40 mM, about 20 mM to about 35 mM, about 20 mM to about 30 mM, about 20 mM to about 25 mM, 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. In some embodiments, the pharmaceutical composition contains at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 30 mM, at least about 35 mM, at least about 40 mM, at least about 45 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM or at least about 100 mM of histidine. In some embodiments, the pharmaceutical composition contains 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 of histidine. In some embodiments, the pharmaceutical composition contains about 20 mM of histidine.,

[0023] In some embodiments, the pharmaceutical composition further comprises a surfactant. In some embodiments, the surfactant is polysorbate 20, polysorbate 80, or poloxamer 188. In some embodiments, the surfactant comprises polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% w / v to at least about 0.1% w / v of polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v, or at least about 0.1% w / v of polysorbate 80. In some embodiments, the pharmaceutical composition comprises from about 0.001% to about 1% w / v, from about 0.001% w / v to about 0.9% w / v, from about 0.001% w / v to about 0.8% w / v, from about 0.001% w / v to about 0.7% w / v, from about 0.001% w / v to about 0.6% w / v, from about 0.001% w / v to about 0.5% w / v, from about 0.001% w / v to about 0.4% w / v, from about 0.001% w / v to about 0.3% w / v, from about 0.001% w / v to about 0.2% w / v, from about 0.001% w / v to about 0.1% w / v, from about 0.001% w / v to about 0.09% w / v, from about 0.001% w / v to about 0.08% w / v, from about 0.001% w / v to about 0.07% w / v, from about 0.001% w / v to about 0.06% w / v, from about 0.001% w / v to about 0.05% w / v, from about 0.01% w / v to about 0.9% w / v, from about 0.01% w / v to about 0.8% w / v, from about 0.01% w / v to about 0.7% w / v, from about 0.01% w / v to about 0.6% w / v, from about 0.01% w / v to about 0.5% w / v, from about 0.01% w / v to about 0.4% w / v, from about 0.01% w / v to about 0.3% w / v, from about 0.01% w / v to about 0.2% w / v, from about 0.01% w / v to about 0.1% w / v, from about 0.01% w / v to about 0.09% w / v, from about 0.01% w / v to about 0.08% w / v, from about 0.01% w / v to about 0.07% w / v, from about 0.01% w / v to about 0.06% w / v, from about 0.01% w / v to about 0.05% w / v, from about 0.02% w / v to about 0.1% w / v, from about 0.02% w / v to about 0.09% w / v, from about 0.02% w / v to about 0.08% w / v, from 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 0.05% 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 of polysorbate 80. In some embodiments, 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 of polysorbate 80. In some embodiments, the pharmaceutical composition comprises about 0.05% w / v of polysorbate 80.

[0024] In some embodiments, 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; and (c) about 0.0182 mg / mL of rHuPH20.

[0025] In some embodiments, 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; and (c) about 2000 U / mL of rHuPH20.

[0026] In some embodiments, the pharmaceutical composition comprises: (a) about 960 mg of an anti-PD-1 antibody; (b) about 320 mg of an anti-LAG-3 antibody; and (c) about 0.0182 mg / mL of rHuPH20.

[0027] In some embodiments, the pharmaceutical composition comprises: (a) about 960 mg of an anti-PD-1 antibody; (b) about 320 mg of an anti-LAG-3 antibody; and (c) about 2000 U / mL of rHuPH20.

[0028] In some embodiments, the pharmaceutical composition comprises: (a) about 960 mg of an anti-PD-1 antibody; (b) about 320 mg of an anti-LAG-3 antibody; and (c) about 24,000 U of rHuPH20.

[0029] In some embodiments, 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 of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 0.0182 mg / mL of rHuPH20.

[0030] In some embodiments, 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 of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20.

[0031] In some embodiments, 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 of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 0.0182 mg / mL of rHuPH20.

[0032] In some embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL.

[0033] In some embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 960 mg; (b) an anti-LAG-3 antibody at about 320 mg; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0034] In some embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 960 mg; (b) an anti-LAG-3 antibody at about 320 mg; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL.

[0035] In some embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 960 mg; (b) an anti-LAG-3 antibody at about 320 mg; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 24,000 U.

[0036] In some embodiments, the anti-PD-1 antibody comprises nivolumab, pembrolizumab, PDR001, MEDI-0680, semaprilimab, toripalimab, tislelizumab, INCSHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, sasanalimab, BI754091, SSI-361, or any combination thereof. In some embodiments, the anti-PD-1 antibody comprises nivolumab. In some embodiments, the anti-PD-1 antibody comprises pembrolizumab. In some embodiments, the anti-PD-1 antibody comprises (a) the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 79 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence shown in SEQ ID NO: 80; (b) the 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 the 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) the heavy chain variable region and the light chain variable region comprising the amino acid sequences shown in SEQ ID NO: 79 and 80, respectively; or (d) the heavy chain and the light chain comprising the amino acid sequences shown in SEQ ID NO: 77 and 78, respectively.

[0037] In some embodiments, the anti-LAG-3 antibody comprises relatlimab, 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 embodiments, the anti-LAG-3 antibody comprises relatlimab. In some embodiments, the anti-LAG-3 antibody comprises (a) the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 3 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence shown in SEQ ID NO: 4; (b) the 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 the 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) the heavy chain variable region and the light chain variable region comprising the amino acid sequences shown in SEQ ID NO: 3 and 4, respectively; (d) the heavy chain and the light chain comprising the amino acid sequences shown in SEQ ID NO: 1 and 2, respectively; or (e) the heavy chain and the light chain comprising the amino acid sequences shown in SEQ ID NO: 21 and 2, respectively.

[0038] In some embodiments, the anti-PD-1 antibody comprises nivolumab, and the anti-LAG-3 antibody comprises relatlimab.

[0039] In some embodiments, the pharmaceutical composition comprises (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0040] In some embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL.

[0041] In some embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0042] In some embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL.

[0043] In some embodiments, the pharmaceutical composition comprises: (a) about 1200 mg of nivolumab; (b) about 400 mg of relatlimab; (c) about 8.68 mg of histidine; (d) about 11.8 mg of histidine HCl H2O; (e) about 479 mg of sucrose; (f) about 2.80 mg of polysorbate 80; (g) about 0.110 mg of pentetic acid; and (h) about 4.18 mg of methionine; (i) about 0.102 mg of rHuPH20, wherein (a)-(h) are reconstituted in at least about 15 mL of final volume in water.

[0044] In some embodiments, the pharmaceutical composition comprises: (a) about 960 mg of nivolumab; (b) about 320 mg of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 0.0182 mg / mL of rHuPH20.

[0045] In some embodiments, the pharmaceutical composition comprises: (a) about 960 mg of nivolumab; (b) about 320 mg of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20.

[0046] In some embodiments, the pharmaceutical composition comprises: (a) about 960 mg of nivolumab; (b) about 320 mg of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 24,000 U of rHuPH20.

[0047] In some embodiments, the pharmaceutical composition has a pH of about 5.2 to about 6.8. In some embodiments, the pharmaceutical composition has a pH of about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7 or about 6.8. In some embodiments, the pharmaceutical composition has a pH of about 5.8.

[0048] In some embodiments, the anti-PD-L1 antibody comprises BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO36, FAZ053, CK-301, or any combination thereof.

[0049] In some embodiments, the pharmaceutical composition further comprises an additional therapeutic agent. In some embodiments, the additional therapeutic agent comprises an antibody. In some embodiments, the additional therapeutic agent comprises a checkpoint inhibitor. In some embodiments, the additional 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.

[0050] Some embodiments of the present disclosure relate to vials containing the pharmaceutical compositions disclosed herein.

[0051] Some embodiments of the present disclosure relate to syringes containing the pharmaceutical compositions disclosed herein. In some embodiments, the syringe further comprises a plunger.

[0052] Some embodiments of the present disclosure relate to autoinjectors containing the pharmaceutical compositions disclosed herein.

[0053] Some embodiments of the present disclosure relate to wearable pumps or wearable devices containing the pharmaceutical compositions disclosed herein.

[0054] Some embodiments of the present disclosure relate to pen-type syringes containing the pharmaceutical compositions disclosed herein.

[0055] Some aspects of the present disclosure relate to a method of treating a disease or disorder 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 disorder is an infectious disease. In some aspects, the disease or disorder 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-resistant prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, liver cancer, breast cancer, colon cancer, head and neck cancer, gastric cancer, germ cell tumor, pediatric sarcoma, nasal natural killer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, pediatric solid tumor, ureteral cancer, renal pelvis cancer, central nervous system (CNS) neoplasm, primary CNS lymphoma, tumor angiogenesis, spinal cord axial tumor, brain tumor, brainstem glioma, pituitary adenoma, Kaposi sarcoma, epidermoid carcinoma, squamous cell cancer, environmentally induced cancer including those induced by asbestos, virus-related cancer or virus-originated cancer (e.g., human papillomavirus (HPV-related or originated tumors)) or any combination thereof. In some aspects, the cancer is unresectable or metastatic melanoma.

Brief Description of the Drawings

[0056]

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Modes for Carrying Out the Invention

[0057] Current methods of delivering combination therapies comprising an anti-LAG-3 antibody and an anti-PD-1 and / or anti-PD-L1 antibody often require regular intravenous administration, which is frequently administered by a clinician in a clinic or hospital in many cases. This regimen often causes great inconvenience to patients, and the nature of the treatment itself can have an adverse impact on the patient experience. Subcutaneous delivery can significantly improve patient compliance and potentially enable patients to receive this life-saving treatment in the comfort of their homes. The present disclosure provides a pharmaceutical composition 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. Other aspects of the present disclosure provide a pharmaceutical composition comprising (i) an antibody that specifically binds to PD-L1 (an "anti-PD-L1 antibody"), (ii) an anti-LAG-3 antibody, and (iii) an endoglycosidase hydrolase. Other aspects of the present disclosure provide a pharmaceutical composition comprising (i) an anti-PD-1 antibody, (ii) an anti-LAG-3 antibody, (iii) an anti-PD-L1 antibody, and (iv) an endoglycosidase hydrolase.

[0058] I. Terms To make the present disclosure more readily understandable, certain terms are first defined. As used herein, each of the following terms shall have the meaning set forth below, unless specifically provided otherwise in this specification. Additional definitions are provided throughout the present application.

[0059] When an aspect is described herein with the term "comprising", it is understood that other aspects that are otherwise similar and are described with the terms "consisting of" and / or "consisting essentially of" are also provided.

[0060] Unless otherwise defined, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry And Molecular Biology, Revised, 2000, Oxford University Press provide one of ordinary skill in the art with general dictionaries of many of the terms used in this disclosure.

[0061] Units, prefixes, and symbols are expressed in the form recognized by the International System of Units (SI).

[0062] Numeric ranges are inclusive of the numbers defining the range.

[0063] Unless otherwise indicated, nucleotide sequences are written left to right in the 5' to 3' direction. Amino acid sequences are written left to right in the amino to carboxy orientation.

[0064] The headings provided herein are not limitations of the various aspects of the disclosure that may be had by reference to the specification as a whole. Accordingly, the terms defined immediately below are defined more fully by reference to the specification as a whole.

[0065] "Administration" refers to the physical introduction of a therapeutic agent (e.g., a composition comprising a therapeutic agent, such as a pharmaceutical composition disclosed herein comprising an anti-LAG-3 antibody, an anti-PD-1 antibody, and / or an anti-PD-L1 antibody) to a subject using any of a variety of methods and delivery systems known to those of skill in the art. Administration can refer to any mode of administration of a therapeutic agent, including, for example, intravenous, intramuscular, subcutaneous, intraperitoneal, spinal, or other parenteral routes of administration by injection or infusion. The terms "subcutaneous administration" and "subcutaneous injection" are used interchangeably and refer to a mode of administration in which a therapeutic agent is delivered to a subject under the skin, between the dermis and, for example, muscle.

[0066] Subcutaneous administration can be achieved using any method. In some embodiments, subcutaneous administration is achieved using a short needle or a plurality of short needles. In some embodiments, at least one of the needle or 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, and less than about 1 / 2 inch. In some embodiments, at least one of the needle or needles is about 5 / 8 inch in length.

[0067] Administration can be carried out, for example, once, a plurality of times, and / or over a continuous period of one or more times. Thus, as used herein, administration can refer to a single unit dose or a plurality of unit doses.

[0068] As used herein, the terms "dosage" or "dose" are defined as the amount of a therapeutic agent that can be administered at a given time. A dosage or dose can be an amount sufficient to achieve or at least partially achieve a desired effect, although such a desired effect may be invisible or undetectable. A "therapeutically effective amount" or "therapeutically effective dose" of a drug or therapeutic agent, when used alone or in combination with another therapeutic agent, is a decrease in the severity of disease symptoms, an increase in the frequency and duration of periods without disease symptoms, an increase in overall survival (the length of time that a patient diagnosed with a disease such as cancer remains alive, starting from either the date of diagnosis or the date of initiation of treatment), or any amount of a drug that promotes regression of a disease as demonstrated by prevention of disability or impairment due to the suffering of the disease. The amount or dose of a drug includes a "prophylactically effective amount" or "prophylactically effective dose", which is any amount of a drug that inhibits the onset or recurrence of a disease when administered alone or in combination with another therapeutic agent to a subject at risk of developing the disease or at risk of suffering a recurrence of the disease. The ability of a therapeutic agent to promote regression of a disease or to inhibit the onset or recurrence of a disease can be evaluated using various methods available to those of skill in the art, such as in human subjects during clinical trials, in animal model systems that predict efficacy in humans, or by assaying the activity of the agent in in vitro assays. A "dosage" can include a single unit dose or multiple unit doses. In some embodiments, the dosage includes a single unit dose. In some embodiments, the dosage includes multiple unit doses.

[0069] As used herein, a subcutaneous "unit dose" refers to a single amount of a substance delivered by subcutaneous injection, for example, from a single vial, a single autoinjector, and / or a single syringe. In some embodiments, multiple subcutaneous doses are administered to achieve a therapeutically effective dose. When administering multiple unit doses, the individual unit doses can be administered simultaneously or sequentially. In some embodiments, each unit dose of the therapeutically effective dose is administered on the same day. Each unit dose can be administered at the same body location or at different body locations. In some embodiments, a first unit dose is administered at a first body location and a second unit dose is administered at a second body location. Any body location known in the art to be suitable for subcutaneous delivery can be used in the methods disclosed herein. In some embodiments, at least one subcutaneous unit dose of the dose is administered at a body location selected from the lateral or dorsal aspect of the upper arm, the abdomen, and the anterior thigh.

[0070] An "adverse event" (AE), as used herein, is any undesirable, generally unintended or unwanted sign (including abnormal clinical laboratory findings), symptom, or disease associated with the use of a medical treatment. For example, an adverse event can be associated with activation of the immune system or an increase in immune system cells (e.g., T cells) in response to treatment. A medical treatment can be one that is associated with one or more related AEs, and each AE can exhibit the same or different severity levels. Reference to a "change in adverse events" means a treatment regimen that reduces the incidence and / or severity of one or more AEs associated with the use of different treatment regimens.

[0071] An "antagonist" includes, but is 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 embodiments, the antagonist is an antibody. In other embodiments, the antagonist includes small molecules. The terms "inhibitor" and "antagonist" are used interchangeably herein.

[0072] "Antibody" (Ab) includes, but is not limited to, glycoprotein immunoglobulins that specifically bind to an antigen and contain at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds or antigen-binding portions thereof. Each H chain includes a heavy chain variable region (abbreviated herein as V H and omitted) and a heavy chain constant region (abbreviated herein as C H and omitted). The heavy chain constant region includes 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 includes a light chain variable region (abbreviated herein as V L and omitted) and a light chain constant region. The light chain constant region includes one constant domain C L . The V H and V L regions can be further divided into hypervariable regions called complementarity-determining regions (CDRs) with more conserved regions called framework regions (FRs) interspersed therebetween. Each V H and V LIt contains three CDRs and four FRs, which are arranged in the following order from the amino terminus to the carboxy 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 of the variable regions are numbered using the Kabat numbering system, and the amino acids of the constant regions are numbered using the EU system. The constant region of an antibody can mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. Thus, the term "anti-PD-1 antibody" includes, for example, a full antibody having two heavy chains and two light chains that specifically bind to PD-1 and the antigen-binding portion of the full antibody. Non-limiting examples of the antigen-binding portion are shown elsewhere in this specification. The immunoglobulin can be derived from any of the generally known isotypes, including but not limited to IgA, secretory IgA, IgG, and IgM. IgG subclasses are also well known to those skilled in the art and include but are not limited to human IgG1, IgG2, IgG3, and IgG4. "Isotype" refers to an antibody class or subclass (e.g., IgM or IgG1) encoded by a heavy chain constant region gene. By way of example, the term "antibody" includes both naturally occurring and non-naturally occurring antibodies; monoclonal and polyclonal antibodies; chimeric and humanized antibodies; human 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. Unless explicitly stated otherwise and unless the context indicates otherwise, the term "antibody" includes any antigen-binding fragment or portion of the aforementioned immunoglobulins and also includes monovalent and divalent fragments or portions and single-chain antibodies that retain the ability to specifically bind to the antigen bound by the full immunoglobulin.

[0073] In some embodiments, the "antibodies" of the present disclosure are capable of binding to two or more antigens, such as "multispecific" antibodies or "bispecific" antibodies. As used herein, a "bispecific" antibody is an antibody that is capable of specifically binding to two antigens, and the first and second antigens may be the same or different. As used herein, a "multispecific" antibody is capable of specifically binding to two or more antigens, such as at least two (i.e., "bispecific" antibody), at least three (i.e., "trispecific" antibody), at least four, at least five, or at least six antigens. A variety of multispecific antibodies are known, 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, and can be used in the compositions and / or methods disclosed herein. In some embodiments, the bispecific antibody binds to PD-1 and LAG-3. In some embodiments, the bispecific antibody binds to PD-L1 and LAG-3. In some embodiments, the multispecific antibody is a T cell-dependent bispecific antibody.

[0074] In some embodiments, the "antibodies" of the present disclosure are engineered to be activated at a target site, such as a "probody". In some embodiments, the antibody, such as a probody, is proteolytically cleaved at the target tissue (e.g., tumor).

[0075] An "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds to PD-1 is substantially free of antibodies that specifically bind to antigens other than PD-1). However, an isolated antibody that specifically binds to an antigen can have cross-reactivity to other antigens, such as cross-reactivity to that antigen from different species (e.g., an antibody that specifically binds to PD-1 and has cross-reactivity to PD-1 molecules from different species). Moreover, an isolated antibody can be substantially free of other cellular materials and / or chemicals.

[0076] The term "monoclonal antibody" ("mAb") refers to a preparation of antibody molecules of single molecular composition, i.e., a non-naturally occurring preparation of antibody molecules that have essentially the same primary sequence and exhibit a single binding specificity and affinity for a particular epitope. Monoclonal antibodies are an example of isolated antibodies. Monoclonal antibodies can be produced by hybridoma, recombinant, transgenic, or other techniques known to those skilled in the art.

[0077] A "human" antibody (HuMAb) refers to an antibody having a variable region in which both the framework region and the CDR region are derived from human germline immunoglobulin sequences. Further, when the antibody includes 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 in vitro by random or site-directed mutagenesis or introduced in vivo by somatic mutations). However, as used herein, the term "human antibody" is intended to exclude antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, are grafted onto human framework sequences. The terms "human antibody" and "fully human antibody" are used synonymously.

[0078] A "humanized antibody" refers to an antibody in which some, most, or all of the amino acids outside the CDRs of a non-human antibody have been replaced with amino acids from the corresponding human immunoglobulin. In one aspect of a humanized form of an antibody, some, most, or all of the amino acids outside the CDRs have been replaced with amino acids from a human immunoglobulin, while some, most, or all of the amino acids within one or more CDRs have not changed. Minor additions, deletions, insertions, substitutions, or modifications of amino acids are tolerated as long as the ability of the antibody to bind to a particular antigen is not thereby rendered ineffective. A "humanized" antibody retains the same antigen specificity as the original antibody.

[0079] "Chimeric antibody" refers to an antibody in which the variable region is derived from a mouse antibody and the constant region is derived from a human antibody, or an antibody in which the variable region is derived from one species and the constant region is derived from another species.

[0080] "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.

[0081] The "antigen-binding portion" of an antibody (also referred to as the "antigen-binding fragment") refers to one or more fragments of an antibody that retain the ability to specifically bind to the antigen to which the whole antibody binds. It has been shown that the antigen-binding function of an antibody can be performed by fragments of the full-length antibody. Examples of binding fragments included within the term "antigen-binding portion" of an antibody, such as an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-LAG-3 antibody described herein, include (i) a Fab fragment (a fragment derived from papain cleavage) or a similar monovalent fragment consisting of V L , V H , LC, and CH1 domains, (ii) an F(ab’)2 fragment (a fragment derived from pepsin cleavage) or a similar divalent fragment containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) an Fd fragment consisting of a V H domain and a CH1 domain; (iv) an Fv fragment consisting of the V L domain and the V H domain of a single arm of the antibody, (v) a single domain antibody (dAb) fragment consisting of a V H domain (Ward et al., (1989) Nature 341:544-546); (vi) an isolated complementarity-determining region (CDR), (vii) a combination of two or more isolated CDRs that may be linked by a synthetic linker in some cases, (viii) a bispecific single domain antibody (dual-affinity retargeting antibody (DART)) consisting of two V H domains linked by a hinge; and (ix) a dual variable domain immunoglobulin. Further, the two domains V L and V Hare encoded by separate genes, which, using recombinant methods, can be joined together by synthetic linkers, and V L and V H regions pair to form a single protein chain that forms a monovalent molecule (known as a single-chain Fv (scFv); see, for example, 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 by the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those of skill 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.

[0082] "Cancer" refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal cells in the body. Uncontrolled cell division and growth lead to the formation of malignant tumors that can invade adjacent tissues and metastasize to distant parts of the body via the lymphatic system or bloodstream.

[0083] The term "tumor" as used herein refers to any mass of tissue caused by excessive cell growth or proliferation, whether benign (non-cancerous) or malignant (cancerous), including pre-cancerous lesions.

[0084] The term "immunotherapy" refers to the treatment of a subject suffering from, at risk of developing, or at risk of recurrence of a disease by methods that include inducing, enhancing, suppressing, or otherwise modifying an immune response.

[0085] "Programmed death-1" (PD-1) refers to an immunosuppressive receptor belonging to the CD28 family. PD-1 is mainly expressed on previously activated T cells in vivo and binds to two ligands, PD-L1 and PD-L2. The term "PD-1", as used herein, includes human PD-1 (hPD-1), variants, isoforms and species homologs of hPD-1, and analogs having at least one epitope common to hPD-1. The complete hPD-1 sequence can be referenced by GenBank accession number U64863.

[0086] "Programmed death ligand 1" (PD-L1) is one of the two cell surface glycoprotein ligands of PD-1 (the other being PD-L2), and downregulates T cell activation and cytokine secretion upon binding to PD-1. The term "PD-L1", as used herein, includes human PD-L1 (hPD-L1), variants, isoforms and species homologs of hPD-L1, and analogs having at least one epitope common to hPD-L1. The complete hPD-L1 sequence can be referenced by GenBank accession number Q9NZQ7. The human PD-L1 protein is encoded by the human CD274 gene (NCBI gene ID: 29126).

[0087] "LAG-3" refers to lymphocyte activation gene 3. The term "LAG-3" includes variants, isoforms, homologs, orthologs, and paralogs. For example, an antibody specific for the human LAG-3 protein may, in certain cases, cross-react with LAG-3 proteins from non-human species. In other embodiments, an antibody specific for the human LAG-3 protein may be completely specific for the human LAG-3 protein and exhibit no species cross-reactivity or other types of cross-reactivity, or it may cross-react with LAG-3 from certain other species but not with any other species (e.g., it cross-reacts with monkey LAG-3 but not with mouse LAG-3). The term "human LAG-3" refers to human sequence LAG-3, such as the complete amino acid sequence of human LAG-3 having GenBank accession number NP_002277. The term "mouse LAG-3" refers to mouse sequence LAG-3, such as the complete amino acid sequence of mouse LAG-3 having GenBank accession number NP_032505. LAG-3 is also known in the art as, for example, CD223. The human LAG-3 sequence may differ, for example, in having conserved mutations or mutations in non-conserved regions compared to human LAG-3 of GenBank accession number NP_002277, and LAG-3 has substantially the same biological function as human LAG-3 of GenBank accession number NP_002277. For example, the biological function of human LAG-3 is that the extracellular domain of LAG-3 has an epitope to which the antibodies of the present disclosure specifically bind, or the biological function of human LAG-3 is to bind to MHC class II molecules.

[0088] Certain human LAG-3 sequences will generally have an amino acid sequence that is at least about 90% identical to human LAG-3 with GenBank accession number NP_002277 and contain amino acid residues that identify the amino acid sequence as being human when compared to LAG-3 amino acid sequences of other species (e.g., mouse). In certain cases, human LAG-3 can have an amino acid sequence that is 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 to LAG-3 with GenBank accession number NP_002277. In certain embodiments, the human LAG-3 sequence will exhibit no more than 10 amino acid differences from the LAG-3 sequence of GenBank accession number NP_002277. In certain embodiments, human LAG-3 can exhibit no more than 5 amino acid differences or even no more than 4, 3, 2 or 1 amino acid differences from the LAG-3 sequence of GenBank accession number NP_00227.

[0089] As used herein, "hyaluronidase" refers to an enzyme capable of catalyzing the cleavage of hyaluronic acid. Hyaluronic acid is a repeating polymer of N-acetyl-glucosamine and glucuronic acid that is present in the subcutaneous space, contributes to the soluble gel-like component of the extracellular matrix of the skin, and is restored by rapid metabolic turnover (resynthesis). In some embodiments, hyaluronidase comprises rHuPH20, a glycosylated 447 amino acid single chain polypeptide that locally depolymerizes hyaluronic acid in the subcutaneous space at the site of injection in the skin. Depolymerization of hyaluronic acid by hyaluronidase is achieved by hydrolysis of the polysaccharide polymer. Depolymerization of hyaluronic acid results in a temporary decrease in the viscosity of the gel-like phase of the extracellular matrix and an increase in hydraulic conductance that facilitates the dispersion and absorption of co-administered therapeutic agents. Thus, hyaluronidase, such as rHuPH20, can improve the rate and ease of subcutaneous delivery of injectable biologic agents and drugs by acting as a permeation enhancer. In certain embodiments, hyaluronidase comprises ENHANZE.

[0090] "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, etc., and rodents such as mice, rats, and guinea pigs. In a preferred embodiment, the subject is a human. The terms "subject" and "patient" are used interchangeably herein.

[0091] The use of the term "flat dose" with respect to the methods and dosages of the present disclosure means a dose administered to a patient regardless of the patient's weight or body surface area (BSA). Thus, the flat dose is provided as an absolute amount of the drug (e.g., an anti-PD-1 antibody or an anti-LAG-3 antibody), rather than as a mg / kg dose. For example, a 60 kg person and a 100 kg person receive the same dose of antibody (e.g., 240 mg of anti-PD-1 antibody).

[0092] The term "weight-converted dose" when referred to herein means that the dose administered to a patient is 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.

[0093] By way of example, an "anticancer agent" promotes regression of cancer in a subject. In some embodiments, a therapeutically effective amount of a drug promotes cancer regression to the point of eliminating the cancer. "Promotion of cancer regression" means that by administering a therapeutically effective amount of a drug alone or in combination with an antineoplastic agent, a decrease in tumor growth or size, tumor necrosis, a decrease in the severity of at least one disease symptom, an increase in the frequency and duration of periods without disease symptoms, or prevention of disability or impairment due to disease pain is brought about. In addition, the terms "effective" and "efficacy" with respect to treatment include both pharmacological efficacy and physiological safety. Pharmacological efficacy refers to the ability of a drug to promote cancer regression in a patient. Physiological safety refers to the level of toxicity or other adverse physiological effects (adverse effects) at the cellular, organ, and / or organism level resulting from administration of the drug.

[0094] As an example of treating a tumor, a therapeutically effective amount of an anti-cancer 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% compared to an untreated subject. In other aspects of the present disclosure, tumor regression is observed over a period of at least about 20 days, at least about 40 days or at least about 60 days and can continue to regress. Despite these ultimate measures of therapeutic efficacy, the evaluation of immunotherapeutic agents must also consider immune-related response patterns.

[0095] An "immune response" is as understood in the art and generally refers to a biological response within a vertebrate to foreign or abnormal, e.g., cancerous cells, which response protects the organism from these agents and the diseases they cause. An 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 either these cells or the liver, resulting in the selective targeting, binding, damaging, destroying and / or elimination from the vertebrate body of invading pathogens, pathogen-infected cells or tissues, cancerous or other abnormal cells or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues. An immune reaction includes, for example, activation or inhibition of T cells, such as effector T cells, Th cells, CD4 + cells, CD8 + T cells or Treg cells or activation or inhibition of any other cell of the immune system, such as NK cells.

[0096] "Immune-related response pattern" refers to the clinical response pattern often observed in cancer patients treated with immunotherapeutic agents that produce an antitumor effect by inducing a cancer-specific immune response or modifying the natural immune process. This response pattern is characterized by an initial increase in tumor burden or the appearance of new lesions followed by a beneficial therapeutic effect, which in the evaluation of traditional chemotherapeutic agents is classified as disease progression and is synonymous with drug failure. Therefore, the appropriate evaluation of immunotherapeutic agents may require long-term monitoring of the effects of these agents on the target disease.

[0097] As used herein, the term "stable" with respect to a formulation or drug product means that the antibody, antibody or molecule therein essentially retains its physical and chemical stability and integrity upon storage. The stability of the formulations herein can be measured at a selected temperature after a selected period. For example, aggregate formation or an increase in low molecular weight species is an indicator of instability. Retention of the original transparency and / or color over the shelf life is also an indicator utilized to monitor stability. In some embodiments, a "stable" formulation is one in which, when the formulation is stored at 2-8°C for at least about one year, the increase in aggregation measured by the increase in the percentage of high molecular weight species (%HMW) is less than about 5%, preferably less than about 3%.

[0098] As used herein, the terms "treat", "treating", "treatment" and "therapy" refer to any type of intervention or process performed on a subject for the purpose of reversing, alleviating, improving, inhibiting or slowing or preventing the progression, onset, severity or recurrence of symptoms, complications, conditions or biochemical markers associated with a disease or for the purpose of enhancing overall survival, or administering an active agent to a subject. Treatment can be of a subject having a disease or a subject not having a disease (e.g., for prevention).

[0099] As used herein, an "immuno-oncology" therapy or "I-O" or "IO" therapy refers to a therapy that involves using an immune response to target and treat a subject's tumor. Thus, as used herein, an I-O therapy is a type of anti-cancer therapy. In some embodiments, an I-O therapy involves administering an antibody to a subject. In some embodiments, an I-O therapy involves administering to a subject immune cells, such as T cells, such as modified T cells, such as T cells modified to express a chimeric antigen receptor or a specific T cell receptor. In some embodiments, an I-O therapy involves administering a therapeutic vaccine to a subject. In some embodiments, an I-O therapy involves administering a cytokine or chemokine to a subject. In some embodiments, an I-O therapy involves administering an interleukin to a subject. In some embodiments, an I-O therapy involves administering an interferon to a subject. In some embodiments, an I-O therapy involves administering a colony stimulating factor to a subject.

[0100] As used herein, the terms "about weekly", "about every two weeks", or any other similar dosing interval terms (e.g., "about once a week" or "about once per week") mean an approximate number. "For weekly" can include every 7 days ± 1 day, i.e., every 6 days to every 8 days. "For every two weeks" can include every 14 days ± 3 days, i.e., every 11 days to every 17 days. Similar approximations apply, for example, for about every three weeks, about every four weeks, about every five weeks, about every six weeks, and about every twelve weeks. In some embodiments, dosing intervals of about every six weeks or about every twelve weeks mean that the first dose can be administered on any day of the first week, and then the next dose can be administered on any day of the sixth or twelfth week, respectively. In other embodiments, dosing intervals of about every six weeks or about every twelve weeks mean that the first dose is administered on a specific day of the week (e.g., Monday) in the first week, and subsequently the next dose is administered on the same day of the week (i.e., Monday) in the sixth or twelfth week, respectively. When multiple subcutaneous unit doses are administered to reach a dose, the dosing interval refers to the period between the administration of the first subcutaneous unit dose of the first effective dose and the administration of the first subcutaneous unit dose of the second effective dose. For example, the method includes administering a dose of about 600 mg administered about every two weeks, the dose of the antibody includes two subcutaneous unit doses, each of the two subcutaneous unit doses includes about 300 mg of the antibody, the first subcutaneous unit dose of the antibody of the first effective dose of about 300 mg is administered on day 1, and the first subcutaneous unit dose of the antibody of the second effective dose of about 300 mg is administered on about day 14. In this example, the second unit dose of the first effective dose of about 300 mg of the antibody can be administered on day 1 or at any other time before the administration of the first subcutaneous unit dose of the second effective dose of about 300 mg of the antibody.

[0101] As used herein, it should be understood that "a" or "an" refers to "one or more" of the recited or listed components. For example, a "nucleotide sequence" is understood to represent one or more nucleotide sequences. Thus, the terms "a", "an", "one or more", and "at least one" can be used interchangeably herein.

[0102] When the term "and / or" is used herein, it should be construed as a specific disclosure with or without the other for each of the two specified features or components. Thus, when the term "and / or" is used in a phrase such as "A and / or B" herein, it 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 include each of the following aspects: 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).

[0103] The term "about" or "consisting essentially of" refers to a value or composition that is within the range of acceptable error for a particular value or composition as determined by one of ordinary skill in the art, and such error will in part depend on how the value or composition is measured or determined, i.e., on the limitations of the measuring system. For example, "about" or "consisting essentially of" can mean within one standard deviation or more than one standard deviation, in accordance with the conventions of the relevant art. Alternatively, "about" or "essentially" can mean within a range of up to 10%. Further, particularly with respect to biological systems or processes, these terms can mean up to one order of magnitude or up to five-fold of a value. When a particular value or composition is provided in the present application and the claims, unless otherwise specified, it must be assumed that the meaning of "about" or "consisting essentially of" is within the range of acceptable error for that particular value or composition.

[0104] When described herein, any range of concentrations, percentages, ratios, or integers is to be understood to include any integer value within the recited range and, where appropriate, fractions thereof (such as one-tenth and one-hundredth of an integer) unless otherwise indicated.

[0105] As used herein, "pharmaceutically acceptable carrier" includes any and all physiologically compatible solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic agents, absorption delaying agents, and the like. Preferably, the carrier of the composition containing an antibody is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion), and the carrier of the composition containing an antibody and / or cytokine is suitable for parenteral, e.g., oral administration.

[0106] "Tumor-infiltrating inflammatory cells" or "tumor-associated inflammatory cells" are any type of cells that are typically involved in the inflammatory response of a subject and infiltrate tumor tissue. Such cells include tumor-infiltrating lymphocytes (TILs), macrophages, monocytes, eosinophils, histiocytes, and dendritic cells.

[0107] With respect to LAG-3 expression, the terms "LAG-3 positive" or "LAG-3 expression positive" refer to a tumor tissue (e.g., a test tissue sample) that reaches a score of expressing LAG-3 based on the ratio (i.e., percentage) of immune cells expressing LAG-3 (e.g., tumor-infiltrating lymphocytes such as CD8+ T cells) (e.g., expression of 1% or more) or based on the ratio (i.e., percentage) of nucleated cells expressing LAG-3 (i.e., immune cells expressing LAG-3 as a ratio to total nucleated cells, e.g., expression of 1% or more).

[0108] "LAG-3 negative" or "LAG-3 expression negative" refers to a tumor tissue (e.g., a test tissue sample) that does not reach a score of expressing LAG-3 (e.g., LAG-3 expression of less than 1%).

[0109] The term "PD-1 positive" or "PD-1 expression positive" with respect to PD-1 expression refers to a tumor tissue (e.g., a test tissue sample) that is scored as expressing PD-1 based on the percentage of immune cells expressing PD-1 (e.g., tumor-infiltrating lymphocytes such as CD8+ T cells) (e.g., expression of 1% or more) or the percentage of nucleated cells expressing PD-1 (i.e., immune cells expressing PD-1 as a percentage of total nucleated cells, e.g., expression of 1% or more).

[0110] "PD-1 negative" or "PD-1 expression negative" refers to tumor tissue (e.g., a test tissue sample) that is not scored as expressing PD-1 (e.g., PD-1 expression of less than 1%).

[0111] The term "PD-L1 positive" or "PD-L1 expression positive" with respect to cell surface PD-L1 expression refers to tumor tissue (e.g., a test tissue sample) that is scored as expressing PD-L1 based on the percentage of tumor cells expressing PD-L1 (e.g., expression of 1% or more) or the percentage of nucleated cells expressing PD-L1 (i.e., tumor cells expressing PD-L1 as a percentage of all nucleated cells, e.g., expression of 1% or more).

[0112] The term "PD-L1 negative" or "PD-L1 expression negative" refers to tumor tissue (e.g., an examination tissue sample) that does not reach a score of expressing PD-L1 (e.g., expression of less than 1%).

[0113] Various aspects of the present disclosure are described in more detail in the following subsections.

[0114] II. Compositions of the Present Disclosure 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.

[0115] Some aspects of the present disclosure relate to 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] In some aspects, the anti-PD-1 antibody, 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-1 antibody, the anti-PD-L1 antibody, and the anti-LAG-3 antibody are the only active agents in the pharmaceutical composition.

[0121] In some aspects, the pharmaceutical composition is formulated for subcutaneous administration.

[0122] In some aspects, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0123] In some aspects, the pharmaceutical composition further comprises an antioxidant. In some aspects, the antioxidant prevents oxidation of the formulation components and / or improves the stability of one or more antibodies. In some aspects, the pharmaceutical composition comprises at least two antioxidants.

[0124] In some embodiments, the pharmaceutical composition comprises an isotonicity adjusting agent or a stabilizer.

[0125] In some embodiments, the pharmaceutical composition comprises a buffering agent.

[0126] In some embodiments, the pharmaceutical composition comprises a surfactant.

[0127] II.A. Anti-LAG-3 Antibodies The anti-LAG-3 antibodies of the present disclosure bind to human LAG-3. Any anti-LAG-3 antibody can be used in the pharmaceutical compositions and methods disclosed herein. Antibodies that bind to LAG-3 are described in WO 2015 / 042246 pamphlet, US 2014 / 0093511 specification, and US 2011 / 0150892 specification, each of which is incorporated herein by reference in its entirety.

[0128] Exemplary LAG-3 antibodies useful in the present disclosure are 25F7 (described in US 2011 / 0150892 specification). A further exemplary LAG-3 antibody useful in the present disclosure is BMS-986016 (relatlimab). In some embodiments, the anti-LAG-3 antibodies useful in the present disclosure cross-compete with 25F7 or BMS-986016. In some embodiments, the anti-LAG-3 antibodies useful in the present disclosure bind to the same epitope as 25F7 or BMS-986016. In some embodiments, the anti-LAG-3 antibody comprises the six CDRs of 25F7 or BMS-986016.

[0129] Other anti-LAG-3 antibodies recognized in the art that can be used in the methods and / or compositions of the present disclosure include IMP731 (H5L7BW) described in US Patent Application Publication No. 2011 / 007023, MK-4280 (28G-10, fabezelimab) described in International Publication No. 2016028672 pamphlet and US Patent Application Publication No. 2020 / 0055938, REGN3767 (fianlimab) described in Burova E, et al., J. Immunother. Cancer (2016); 4 (Supp. 1): P195 and US Patent No. 10,358,495, humanized BAP050 described in International Publication No. 2017 / 019894 pamphlet, GSK2831781, IMP-701 (LAG-525; yerramlimab) described in US Patent No. 10,711,060 and US Patent Application Publication No. 2020 / 0172617, aLAG3 (0414), aLAG3 (0416), Sym022, TSR-033, TSR-075, XmAb841 (former XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P13B02-30, AVA-017, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007 and ABL501.For these and other anti-LAG-3 antibodies useful in the claimed invention, reference can be made, for example, to U.S. Patent No. 10,188,730, International Publication No. WO 2016 / 028672, International Publication No. WO 2017 / 106129, International Publication No. WO 2017 / 062888, International Publication No. WO 2009 / 044273, International Publication No. WO 2018 / 069500, International Publication No. WO 2016 / 126858, International Publication No. WO 2014 / 179664, International Publication No. WO 2016 / 200782, International Publication No. WO 2015 / 200119, International Publication No. WO 2017 / 019846, International Publication No. WO 2017 / 198741, International Publication No. WO 2017 / 220555, International Publication No. WO 2017 / 220569, International Publication No. WO 2018 / 071500, International Publication No. WO 2017 / 015560, International Publication No. WO 2017 / 025498, International Publication No. WO 2017 / 087589, International Publication No. WO 2017 / 087901, International Publication No. WO 2018 / 083087, International Publication No. WO 2017 / 149143, International Publication No. WO 2017 / 219995, U.S. Patent Application Publication No. 2017 / 0260271, International Publication No. WO 2017 / 086367, International Publication No. WO 2017 / 086419, International Publication No. WO 2018 / 034227, International Publication No. WO 2018 / 185046, International Publication No. WO 2018 / 185043, International Publication No. WO 2018 / 217940, International Publication No. WO 19 / 011306, International Publication No. WO 2018 / 208868, International Publication No. WO 2014 / 140180, International Publication No. WO 2018 / 201096, International Publication No. WO 2018 / 204374, and International Publication No. WO 2019 / 018730. The contents of each of these references are hereby incorporated by reference in their entirety.

[0130] Anti-LAG-3 antibodies that can be used in the methods and / or compositions of the present disclosure include those that specifically bind to human LAG-3 and isolated antibodies that cross-compete with any of the anti-LAG-3 antibodies disclosed herein, such as relatlimab, with respect to binding to human LAG-3. In some embodiments, the anti-LAG-3 antibody binds to the same epitope as any of the anti-LAG-3 antibodies described herein, such as relatlimab.

[0131] In some embodiments, antibodies that cross-compete with any of the anti-LAG-3 antibodies disclosed herein, such as relatlimab, with respect to binding to human LAG-3, or that bind to the same epitope region as such antibodies, are monoclonal antibodies. For administration to a human subject, these cross-competing antibodies are chimeric antibodies, modified antibodies, or humanized or human antibodies. Such chimeric, modified, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0132] The ability of antibodies to cross-compete with respect to binding to an antigen indicates that such 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 thought to have very similar functional properties to a reference antibody, such as relatlimab, because they bind to the same epitope region. Cross-competing antibodies can be readily identified based on their ability to cross-compete in standard binding assays such as Biacore analysis, ELISA assays, or flow cytometry (see, for example, WO 2013 / 173223 pamphlet).

[0133] Anti-LAG-3 antibodies that can be used in the methods and / or compositions of the present disclosure also include antigen-binding portions of any of the above full-length antibodies. It has been well demonstrated that fragments of full-length antibodies can perform the antigen-binding function of the antibody.

[0134] In some embodiments, the anti-LAG-3 antibody is a full-length antibody.

[0135] In some embodiments, the anti-LAG-3 antibody is a monoclonal, human, humanized, chimeric or multispecific antibody. In some embodiments, the multispecific antibody is a dual-affinity retargeting antibody (DART), DVD-Ig or bispecific antibody.

[0136] In some embodiments, the anti-LAG-3 antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) LAG-3 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) LAG-3 and (ii) CD3. In some embodiments, the anti-PD-1 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-1 and LAG-3, and (ii) an endoglycosidase hydrolase).

[0137] In some embodiments, the anti-LAG-3 antibody is a trispecific antibody. In some embodiments, the antibody specifically binds to (i) LAG-3, (ii) a second antigen, and (iii) a third antigen. In some embodiments, the second antigen and the third antigen are the same. In some embodiments, the second antigen and the third antigen are different. In some embodiments, the anti-PD-1 antibody and the anti-LAG-3 antibody in the pharmaceutical composition are part of a trispecific antibody (e.g., the pharmaceutical composition) that specifically binds to (i) PD-1, LAG-3 and a third antigen (e.g., CD3), and (ii) an endoglycosidase hydrolase.

[0138] In some embodiments, the antigen-binding portion in the bispecific or trispecific antibody is a scFv, such as the scFv of relatlimab for a bispecific or trispecific antibody that specifically binds to LAG-3.

[0139] The second or third antigen specifically bound by the bispecific or trispecific antibody herein can be any antigen disclosed herein.

[0140] In some embodiments, the anti-LAG-3 antibody is an F(ab’)2 fragment, a Fab’ fragment, a Fab fragment, an Fv fragment, a scFv fragment, a dsFv fragment, a dAb fragment or a single-chain binding polypeptide.

[0141] In some embodiments, the anti-LAG-3 antibody is BMS-986016 (relatlimab), IMP731 (H5L7BW), MK4280 (28G-10, fabeslimab), REGN3767 (fianlimab), GSK2831781, humanized BAP050, IMP-701 (LAG525, yerramlimab), aLAG3 (0414), aLAG3 (0416), Sym022, TSR-033, TSR-075, XmAb841 (XmAb22841), MGD013 (tebotelimab), BI754111, FS118, P13B02-30, AVA-017, 25F7, AGEN1746, RO7247669, INCAGN02385, IBI-110, EMB-02, IBI-323, LBL-007, ABL501 or comprises an antigen-binding portion thereof.

[0142] In some embodiments, the anti-LAG-3 antibody is relatlimab.

[0143] In some embodiments, the anti-LAG-3 antibody comprises the CDRs of the heavy chain variable region and the light chain variable region, the heavy chain variable region and the light chain variable region, and / or the heavy and light chains of relatlimab. In some embodiments, 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 embodiments, the anti-LAG-3 antibody comprises: (a) heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 5; (b) heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 6; (c) heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 7; (d) light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 8; (e) light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 9; and (f) light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 3 and 4, respectively. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 2, respectively. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 21 and 2, respectively.

[0144] In some embodiments, the anti-LAG-3 antibody is MGD013 (tebotelimab), which is a bispecific PD-1×LAG-3 DART.

[0145] In some embodiments, the anti-LAG-3 antibody comprises the CDRs of the heavy chain variable region and the light chain variable region and / or the heavy chain variable region and the light chain variable region of tebotelimab.

[0146] In some embodiments, the anti-LAG-3 antibody is REGN3767 (fianlimab).

[0147] In some embodiments, the anti-LAG-3 antibody comprises heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or the heavy and light chains of fainlimab. In some embodiments, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 25 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence shown in SEQ ID NO: 26. In some embodiments, the anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence shown in SEQ ID NO: 27; (b) a heavy chain variable region CDR2 comprising the amino acid sequence shown in SEQ ID NO: 28; (c) a heavy chain variable region CDR3 comprising the amino acid sequence shown in SEQ ID NO: 29; (d) a light chain variable region CDR1 comprising the amino acid sequence shown in 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 shown in SEQ ID NO: 32. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences shown in SEQ ID NOs: 25 and 26, respectively. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the amino acid sequences shown in SEQ ID NOs: 23 and 24, respectively.

[0148] In some embodiments, the anti-LAG-3 antibody is LAG525 (relatlimab).

[0149] In some embodiments, the anti-LAG-3 antibody comprises the CDRs of the heavy chain variable region and the light chain variable region, the heavy chain variable region and the light chain variable region, and / or the heavy and light chains of relatlimab. In some embodiments, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 47 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence shown in SEQ ID NO: 49. In some embodiments, the anti-LAG-3 antibody comprises the CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 48 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence shown in SEQ ID NO: 50. In some embodiments, the anti-LAG-3 antibody comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence shown in SEQ ID NO: 51; (b) a heavy chain variable region CDR2 comprising the amino acid sequence shown in SEQ ID NO: 52; (c) a heavy chain variable region CDR3 comprising the amino acid sequence shown in SEQ ID NO: 53; (d) a light chain variable region CDR1 comprising the amino acid sequence shown in SEQ ID NO: 54; (e) a light chain variable region CDR2 comprising the amino acid sequence shown in SEQ ID NO: 55; and (f) a light chain variable region CDR3 comprising the amino acid sequence shown in SEQ ID NO: 56. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences shown in SEQ ID NOs: 47 and 49, respectively. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences shown in SEQ ID NOs: 48 and 50, respectively. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the amino acid sequences shown in SEQ ID NOs: 43 and 45, respectively. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain and a light chain comprising the amino acid sequences shown in SEQ ID NOs: 44 and 46, respectively.

[0150] In some embodiments, the anti-LAG-3 antibody is MK4280 (fabeslimab).

[0151] In some embodiments, the anti-LAG-3 antibody comprises heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or the heavy and light chains of faricimab. In some embodiments, 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 embodiments, the anti-LAG-3 antibody comprises: (a) heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 71; (b) heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 72; (c) heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 73; (d) light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 74; (e) light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 75; and (f) light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 76. In some embodiments, the anti-LAG-3 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 69 and 70, respectively.

[0152] In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody at least about 1 mg / mL to at least about 500 mg / mL. In some embodiments, 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, at least about 1 mg / mL to at least about 80 mg / mL, at least about 1 mg / mL to at least about 70 mg / mL, at least about 1 mg / mL to at least about 60 mg / mL, at least about 1 mg / mL to at least about 50 mg / mL, at least about 1 mg / mL to at least about 40 mg / mL, at least about 1 mg / mL to at least about 30 mg / mL, at least about 1 mg / mL to at least about 25 mg / mL, at least about 1 mg / mL to at least about 20 mg / mL, at least about 1 mg / mL to at least about 15 mg / mL, at least about 1 mg / mL to at least about 10 mg / mL or at least about 1 mg / mL to at least about 5 mg / mL of anti-Lag-3 antibody. In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody at least about 3 mg / mL to at least about 200 mg / mL.

[0153] In some embodiments, the pharmaceutical composition comprises an anti-LAG-3 antibody at 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 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.

[0154] In some embodiments, the pharmaceutical composition comprises at least about 3 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 3.3 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 5 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 10 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 13 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises about 13.35 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 15 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 20 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 25 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 26 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises about 26.7 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 30 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 35 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 40 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 45 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 50 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 55 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 60 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 65 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 70 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 75 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 80 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 85 mg / mL of an anti-LAG-3 antibody.In some embodiments, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 95 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 110 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 120 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 130 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 140 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 150 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 160 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 170 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 180 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 190 mg / mL of an anti-LAG-3 antibody. In some embodiments, the pharmaceutical composition comprises at least about 200 mg / mL of an anti-LAG-3 antibody.

[0155] In some embodiments, the pharmaceutical compositions disclosed herein comprise an anti-LAG-3 antibody (e.g., relatlimab, tebotelimab, ficlatlimab, yerramlimab, or fabeselimab) disclosed herein at 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 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.

[0156] In some embodiments, the pharmaceutical compositions disclosed herein are from about 1 mg / mL to about 500 mg / mL, from about 1 mg / mL to about 450 mg / mL, from about 1 mg / mL to about 400 mg / mL, from about 1 mg / mL to about 350 mg / mL, from about 1 mg / mL to about 300 mg / mL, from about 1 mg / mL to about 250 mg / mL, from about 1 mg / mL to about 200 mg / mL, from about 1 mg / mL to about 150 mg / mL, from about 1 mg / mL to about 140 mg / mL, from about 1 mg / mL to about 130 mg / mL, from about 1 mg / mL to about 120 mg / mL, from about 1 mg / mL to about 110 mg / mL, from about 1 mg / mL to about 100 mg / mL, from about 1 mg / mL to about 90 mg / mL, from about 1 mg / mL to about 80 mg / mL, from about 1 mg / mL to about 70 mg / mL, from about 1 mg / mL to about 60 mg / mL, from about 1 mg / mL to about 50 mg / mL, from about 1 mg / mL to about 45 mg / mL, from about 1 mg / mL to about 40 mg / mL, from about 1 mg / mL to about 35 mg / mL, from about 1 mg / mL to about 30 mg / mL, from about 1 mg / mL to about 29 mg / mL, from about 1 mg / mL to about 28 mg / mL, from about 1 mg / mL to about 27 mg / mL, from about 1 mg / mL to about 26 mg / mL, from about 1 mg / mL to about 25 mg / mL, from about 1 mg / mL to about 20 mg / mL, from about 1 mg / mL to about 15 mg / mL, from about 1 mg / mL to about 10 mg / mL or from about 1 mg / mL to about 5 mg / mL, from about 3 mg / mL to about 200 mg / mL, from about 5 mg / mL to about 250 mg / mL, from about 5 mg / mL to about 200 mg / mL, from about 5 mg / mL to about 150 mg / mL, from about 5 mg / mL to about 140 mg / mL, from about 5 mg / mL to about 130 mg / mL, from about 5 mg / mL to about 120 mg / mL, from about 5 mg / mL to about 110 mg / mL, from about 5 mg / mL to about 100 mg / mL, from about 5 mg / mL to about 90 mg / mL, from about 5 mg / mL to about 80 mg / mL, from about 5 mg / mL to about 70 mg / mL, from about 5 mg / mL to about 60 mg / mL, from about 5 mg / mL to about 50 mg / mL, from about 5 mg / mL to about 45 mg / mL, from about 5 mg / mL to about 40 mg / mL, from about 5 mg / mL to about 35 mg / mL, from about 5 mg / mL to about 30 mg / mL, from about 5 mg / mL to about 29 mg / mL, from about 5 mg / mL to about 28 mg / mL, from about 5 mg / mL to about 27 mg / mL, from about 5 mg / mL to about 26 mg / mL, from 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,Comprising an anti-LAG-3 antibody (e.g., relatlimab, tebotelimab, ficlatlimab, yerramlimab, or fabeselimab) at 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, 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.

[0157] In some embodiments, the pharmaceutical compositions disclosed herein comprise an anti-LAG-3 antibody (e.g., relatlimab, tebotelimab, ficlatlimab, yerramlimab, or fabeselimab) disclosed herein at 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, 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.

[0158] In some embodiments, the pharmaceutical compositions disclosed herein comprise 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 an anti-LAG-3 antibody disclosed herein (e.g., relatlimab, tebotelimab, fianlimab, yerramlimab or fabeselimab).

[0159] In some embodiments, the pharmaceutical compositions disclosed herein are 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 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 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,Comprising an anti-LAG-3 antibody disclosed herein at about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, 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 (for example, relatlimab, tebotelimab, ficlatlimab, yerramlimab or fabeselimab).

[0160] II.B Anti-PD-1 Antibodies In some embodiments, the pharmaceutical composition comprises an antibody that specifically binds to PD-1 (or an antigen-binding portion thereof) (an "anti-PD-1 antibody"). Any anti-PD-1 antibody can be used in the compositions and methods described herein. A variety of human monoclonal antibodies that specifically bind to PD-1 with high affinity are disclosed in U.S. Patent No. 8,008,449. The anti-PD-1 human antibodies disclosed in U.S. Patent No. 8,008,449 have been demonstrated to exhibit one or more of the following characteristics: (a) a K of 1 × 10 -7 M or less for human PD-1 as determined by surface plasmon resonance using a Biacore biosensor system Dbind by ; (b) do not substantially bind to human CD28, CTLA-4 or ICOS; (c) increase T cell proliferation in a mixed lymphocyte reaction (MLR) assay; (d) increase interferon-γ production in an MLR assay; (e) increase IL-2 secretion in an MLR assay; (f) bind to human PD-1 and cynomolgus PD-1; (g) inhibit the binding of PD-L1 and / or PD-L2 to PD-1; and (h) stimulate an antigen-specific memory response; (i) stimulate an antibody response; and (j) inhibit tumor cell growth in vivo. Anti-PD-1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-1 and exhibit at least one of the foregoing characteristics, and in some embodiments at least five.

[0161] For other anti-PD-1 monoclonal antibodies, see, for example, U.S. Patent Nos. 6,808,710, 7,488,802, 8,168,757, and 8,354,509; U.S. Patent Application Publication Nos. 2016 / 0272708, 2008 / 156712, 2015 / 112900, 2012 / 145493, 2015 / 112800, 2014 / 206107, 2015 / 35606, 2015 / 085847, 2014 / 179664, 2017 / 020291, 2017 / 020858, 2016 / 197367, 2017 / 024515, 2017 / 025051, 2017 / 123557, 2016 / 106159, 2014 / 194302, 2017 / 040790, 2017 / 133540, 2017 / 132827, 2017 / 024465, 2017 / 025016, 2017 / 106061, 2017 / 19846, 2017 / 024465, 2017 / 025016, 2017 / 132825, and 2017 / 133540 (each of which is incorporated by reference in its entirety).

[0162] In some embodiments, the anti-PD-1 antibody is nivolumab (also known as OPDIVO, 5C4, BMS-936558, MDX-1106, and ONO-4538), pembrolizumab (Merck; also known as KEYTRUDA, lambrolizumab, and MK-3475; see WO 2008 / 156712 pamphlet), PDR001 (Novartis; also known as spartalizumab; see WO 2015 / 112900 pamphlet and U.S. Pat. No. 9,683,048), MEDI-0680 (AstraZeneca; also known as AMP-514; see WO 2012 / 145493 pamphlet), cemiplimab (Regeneron; also known as LIBTAYO or REGN-2810; see WO 2015 / 112800 pamphlet and U.S. Pat. No. 9,987,500), JS001 (TAIZHOU JUNSHI PHARMA; also known as toripalimab; see Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), BGB-A317 (Beigene; also known as tislelizumab; see WO 2015 / 35606 pamphlet and U.S. Patent Application Publication No. 2015 / 0079109), INCSHR1210 (Jiangsu Hengrui Medicine; also known as SHR-1210 or camrelizumab; see WO 2015 / 085847 pamphlet, Si-Yang Liu et al., J. Hematol. Oncol. 10:136 (2017)), TSR-042 (Tesaro Biopharmaceutical; also known as ANB011 or dostarlimab; see WO 2014 / 179664 pamphlet), GLS-010 (Wuxi / Harbin Gloria Pharmaceuticals; also known as WBP3055; see Si-Yang Liu et al., J. Hematol. Oncol.See 10:136(2017), AM-0001 (Armo), STI-1110 (Sorrento Therapeutics; see International Publication No. WO 2014 / 194302), AGEN2034 (Agenus; see International Publication No. WO 2017 / 040790), MGA012 (Macrogenics; see International Publication No. WO 2017 / 19846), BCD-100 (Biocad; Kaplon et al., mAbs 10(2):183-203(2018)), IBI308 (Innovent; also known as sintilimab; see International Publication Nos. WO 2017 / 024465, WO 2017 / 025016, WO 2017 / 132825 and WO 2017 / 133540); sasanalimab (Pfizer; also known as PF-06801591; see U.S. Patent Application Publication No. 2016 / 0159905); BI754091 (Boehringer Ingelheim; Zettl M et al., Cancer Res. (2018); 78(13): abstract 4558), SSI-361 (Lyvgen Biopharma Holdings Limited, see U.S. Patent No. 2018 / 0346569) or an antigen-binding portion thereof.

[0163] In one aspect, the anti-PD-1 antibody is nivolumab. Nivolumab is a fully human IgG4 (S228P) PD-1 immune checkpoint inhibitor antibody that selectively prevents interaction with the PD-1 ligands (PD-L1 and PD-L2), thereby blocking downregulation of antitumor T cell function (U.S. Patent No. 8,008,449; Wang et al., 2014 Cancer Immunol Res. 2(9):846-56).

[0164] In some embodiments, 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 nivolumab. In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 13 and a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the antibody comprises heavy chain complementarity determining regions (CDRs) 1, 2, and 3 comprising the amino acid sequences of heavy chain CDR1, CDR2, and CDR3 of SEQ ID NO: 13. In some embodiments, the antibody comprises light chain CDRs 1, 2, and 3 comprising the amino acid sequences of light chain CDR1, CDR2, and CDR3 of SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody comprises CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 13 and CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 14. In some embodiments, the anti-PD-1 antibody comprises: (a) heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 15; (b) heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 16; (c) heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 17; (d) light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 18; (e) light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 19; and (f) light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 20. In some embodiments, the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 11 and 12, respectively.

[0165] In another embodiment, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab is a humanized monoclonal IgG4 (S228P) antibody 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.

[0166] In some embodiments, the anti-PD-1 antibody comprises the CDRs of the heavy and light chain variable regions of pembrolizumab, the heavy and light chain variable regions, and / or the heavy and light chains. In some embodiments, the anti-PD-1 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: 79 and the CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence set forth in SEQ ID NO: 80. In some embodiments, the anti-PD-1 antibody comprises: (a) heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 81; (b) heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 82; (c) heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 83; (d) light chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 84; (e) light chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 85; and (f) light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 86. In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 79 and 80, respectively. In some embodiments, the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 77 and 78, respectively.

[0167] In another embodiment, the anti-PD-1 antibody is semiprismab (REGN2810). Semiprismab is described, for example, in WO 2015 / 112800 pamphlet and US Patent No. 9,987,500.

[0168] In some embodiments, the anti-PD-1 antibody comprises heavy chain variable region CDRs and light chain variable region CDRs, heavy chain variable regions and light chain variable regions, and / or semi-purified heavy chain variable regions and light chain variable regions. In some embodiments, the anti-PD-1 antibody comprises CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the amino acid sequence set forth in SEQ ID NO: 35 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the amino acid sequence set forth in SEQ ID NO: 36. In some embodiments, the anti-PD-1 antibody comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 37; (b) a heavy chain variable region CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 38; (c) a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 39; (d) a light chain variable region CDR1 comprising the amino acid sequence set forth in 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 set forth in SEQ ID NO: 42. In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 35 and 36, respectively. In some embodiments, the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the amino acid sequences set forth in SEQ ID NOs: 33 and 34, respectively.

[0169] In another embodiment, the anti-PD-1 antibody is spartalizumab (PDR001). Spartalizumab is described, for example, in WO 2015 / 112900 pamphlet and US Patent No. 9,683,048.

[0170] In some embodiments, the anti-PD-1 antibody comprises heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or the heavy and light chains of spartalizumab. In some embodiments, the anti-PD-1 antibody comprises CDR1, CDR2, and CDR3 domains of a heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 59 and CDR1, CDR2, and CDR3 domains of a light chain variable region having the amino acid sequence shown in SEQ ID NO: 60. In some embodiments, the anti-PD-1 antibody comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence shown in SEQ ID NO: 61; (b) a heavy chain variable region CDR2 comprising the amino acid sequence shown in SEQ ID NO: 62; (c) a heavy chain variable region CDR3 comprising the amino acid sequence shown in SEQ ID NO: 63; (d) a light chain variable region CDR1 comprising the amino acid sequence shown in SEQ ID NO: 64; (e) a light chain variable region CDR2 comprising the amino acid sequence shown in SEQ ID NO: 65; and (f) a light chain variable region CDR3 comprising the amino acid sequence shown in SEQ ID NO: 66. In some embodiments, the anti-PD-1 antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences shown in SEQ ID NOs: 59 and 60, respectively. In some embodiments, the anti-PD-1 antibody comprises a heavy chain and a light chain comprising the amino acid sequences shown in SEQ ID NOs: 57 and 58, respectively.

[0171] In another embodiment, the anti-PD-1 antibody is sasanlimab.

[0172] In some embodiments, the anti-PD-1 antibody comprises heavy and light chain variable region CDRs, heavy and light chain variable regions, and / or the heavy and light chains of sasanlimab.

[0173] In some embodiments, any anti-PD-1 antibody disclosed herein is combined with any anti-LAG-3 antibody disclosed herein in any composition and method disclosed herein.

[0174] Anti-PD-1 antibodies that can be used in the disclosed compositions and methods specifically bind to human PD-1 and also include isolated antibodies that cross-compete for binding to human PD-1 with any anti-PD-1 antibody disclosed herein, such as nivolumab (see, e.g., U.S. Patent Nos. 8,008,449 and 8,779,105; International Publication No. 2013 / 173223 pamphlet). In some embodiments, the anti-PD-1 antibody binds to the same epitope as any of the anti-PD-1 antibodies described herein, such as nivolumab. The ability of antibodies to cross-compete for antigen binding indicates that these monoclonal antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that specific epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of a reference antibody, such as nivolumab, due to their binding to the same epitope region of PD-1. Cross-competing antibodies can be readily identified based on their ability to cross-compete with nivolumab in standard PD-1 binding assays such as Biacore analysis, ELISA assay, or flow cytometry (see, e.g., International Publication No. 2013 / 173223 pamphlet).

[0175] In certain embodiments, antibodies that cross-compete for binding to human PD-1 with or bind to the same epitope region as any human PD-1 antibody disclosed herein, such as nivolumab, are monoclonal antibodies. For administration to human subjects, these cross-competing antibodies are chimeric antibodies, modified antibodies, or humanized or human antibodies. Such chimeric, modified, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0176] Anti-PD-1 antibodies that can be used in the compositions and methods of the present disclosure also include the antigen-binding portions of the full-length antibodies described above. It has been well demonstrated that fragments of full-length antibodies can perform the antigen-binding function of the antibody.

[0177] Anti-PD-1 antibodies suitable for use in the disclosed compositions and methods are antibodies that bind to PD-1 with high specificity and affinity, block the binding of PD-L1 and / or PD-L2, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-1 “antibody” includes an antigen-binding portion or fragment that binds to the PD-1 receptor, inhibits ligand binding, and exhibits functional properties similar to those of a full antibody in terms of upregulating the immune system. In certain embodiments, the anti-PD-1 antibody or its antigen-binding portion cross-competes with nivolumab for binding to human PD-1.

[0178] In some embodiments, the anti-PD-1 antibody is a full-length antibody.

[0179] In some embodiments, the anti-PD-1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody is a DART, a DVD-Ig, or a bispecific antibody.

[0180] In some embodiments, the anti-PD-1 antibody is a bispecific antibody. In some embodiments, the bispecific antibody specifically binds to (i) PD-1 and (ii) a second antigen (e.g., TIGIT).

[0181] In some embodiments, the pharmaceutical composition includes a bispecific or multispecific antibody that includes a first antigen-binding portion and a second antigen-binding portion, wherein the first antigen-binding portion includes an anti-PD-1 antigen-binding portion (e.g., the scFv of nivolumab). In some embodiments, the second antigen-binding portion is an antigen-binding portion of any one of the antibodies disclosed herein. In some embodiments, the second antigen-binding portion is an antigen-binding portion of an anti-LAG-3 antibody, such as relatlimab. In some embodiments, the second antigen-binding portion is an antigen-binding portion of an anti-TIGIT antibody.

[0182] In some embodiments, the anti-PD-1 antibody is a trispecific antibody. In some embodiments, the trispecific antibody specifically binds to (i) PD-1, (ii) a second antigen, and (iii) a third antigen. In some embodiments, the second antigen and the third antigen are the same. In some embodiments, the second antigen and the third antigen are different.

[0183] In some embodiments, the pharmaceutical composition comprises a multispecific antibody comprising a first antigen-binding portion, a second antigen-binding portion, and at least a third antigen-binding portion, wherein the first antigen-binding portion comprises an anti-PD-1 antigen-binding portion (e.g., the scFv of nivolumab).

[0184] In some embodiments, the antigen-binding portions in the bispecific or trispecific antibody are scFvs, e.g., the scFv of nivolumab in a bispecific or trispecific antibody that specifically binds to PD-1.

[0185] The second or third antigen specifically bound by the bispecific or trispecific antibody herein can be any antigen disclosed herein.

[0186] In some embodiments, the anti-PD-1 antibody is an F(ab’)2 fragment, a Fab’ fragment, a Fab fragment, an Fv fragment, an scFv fragment, a dsFv fragment, a dAb fragment, or a single-chain binding polypeptide.

[0187] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody at least about 10 mg / mL to at least about 500 mg / mL. In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody 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 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 135 mg / mL to at least about 180 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 130 mg / mL or at least about 108 mg / mL to at least about 132 mg / mL. In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody at least about 50 mg / mL. In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody at least about 60 mg / mL.In some embodiments, the pharmaceutical composition comprises at least about 70 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 75 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 80 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 110 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 120 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 130 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 132 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 140 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 150 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 160 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 170 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 175 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 180 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 190 mg / mL of an anti-PD-1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 200 mg / mL of an anti-PD-1 antibody.

[0188] In some embodiments, the pharmaceutical compositions disclosed herein comprise an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, semaprilumab, or spartalizumab) disclosed herein at 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 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.

[0189] In some embodiments, the pharmaceutical compositions disclosed herein are 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, from about 10 mg / mL to about 140 mg / mL, from about 10 mg / mL to about 130 mg / mL, from about 10 mg / mL to about 120 mg / mL, from about 10 mg / mL to about 110 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 85 mg / mL, from about 10 mg / mL to about 80 mg / mL, from about 20 mg / mL to about 500 mg / mL, from about 20 mg / mL to about 450 mg / mL, from about 20 mg / mL to about 400 mg / mL, from about 20 mg / mL to about 350 mg / mL, from about 20 mg / mL to about 300 mg / mL, from about 20 mg / mL to about 250 mg / mL, from about 20 mg / mL to about 200 mg / mL, from about 20 mg / mL to about 190 mg / mL, from about 20 mg / mL to about 180 mg / mL, from about 20 mg / mL to about 170 mg / mL, from about 20 mg / mL to about 160 mg / mL, from about 20 mg / mL to about 150 mg / mL, from about 20 mg / mL to about 140 mg / mL, from about 20 mg / mL to about 130 mg / mL, from about 20 mg / mL to about 120 mg / mL, from about 20 mg / mL to about 110 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 90 mg / mL, from about 20 mg / mL to about 85 mg / mL, from about 20 mg / mL to about 80 mg / mL, from about 50 mg / mL to about 200 mg / mL, from about 50 mg / mL to about 190 mg / mL, from about 50 mg / mL to about 180 mg / mL, from about 50 mg / mL to about 170 mg / mL, from about 50 mg / mL to about 160 mg / mL, from about 50 mg / mL to about 150 mg / mL, from about 50 mg / mL to about 140 mg / mL, from about 50 mg / mL to about 130 mg / mL, from about 50 mg / mL to about 120 mg / mL, from about 50 mg / mL to about 110 mg / mL, from about 50 mg / mL to about 100 mg / mL,Comprising an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, semaprilimab or spartalizumab) disclosed herein at 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.

[0190] In some embodiments, the pharmaceutical composition disclosed herein comprises an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, semaprilimab or spartalizumab) disclosed herein at 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, 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.

[0191] In some embodiments, the pharmaceutical compositions disclosed herein comprise 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 an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, cemiplimab or spartalizumab) disclosed herein.

[0192] In some embodiments, the pharmaceutical compositions disclosed herein are 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 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 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,Comprising from about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, 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 an anti-PD-1 antibody (e.g., nivolumab, pembrolizumab, semiprimab or spartalizumab) disclosed herein. In some embodiments, the pharmaceutical composition disclosed herein comprises relatorimab and an anti-PD-1 antibody disclosed herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab or spartalizumab. In some embodiments, the anti-PD-1 antibody is nivolumab.,

[0193] In some embodiments, the pharmaceutical composition disclosed herein comprises fabeselizumab and an anti-PD-1 antibody disclosed herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab or spartalizumab. In some embodiments, the anti-PD-1 antibody is pembrolizumab.

[0194] In some embodiments, the pharmaceutical composition disclosed herein comprises fieramilumab and an anti-PD-1 antibody disclosed herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab or spartalizumab. In some embodiments, the anti-PD-1 antibody is semiprimab.

[0195] In some embodiments, the pharmaceutical composition disclosed herein comprises yeramilumab and an anti-PD-1 antibody disclosed herein. In some embodiments, the anti-PD-1 antibody is nivolumab, pembrolizumab, semiprimab or spartalizumab. In some embodiments, the anti-PD-1 antibody is spartalizumab.

[0196] In some embodiments, the pharmaceutical compositions disclosed herein comprise an anti-PD-1 antibody (e.g., nivolumab) and an anti-LAG-3 antibody (e.g., relatlimab) in a ratio 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 1:120, 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.

[0197] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody (e.g., nivolumab) to anti-LAG-3 antibody (e.g., relatlimab) ratio of about 6:1.

[0198] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody (e.g., nivolumab) to anti-LAG-3 antibody (e.g., relatlimab) ratio of about 3:1.

[0199] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody (e.g., nivolumab) to anti-LAG-3 antibody (e.g., relatlimab) ratio of about 1:1.

[0200] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody (e.g., nivolumab) to anti-LAG-3 antibody (e.g., relatlimab) ratio of about 1:2.

[0201] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody (e.g., nivolumab) to anti-LAG-3 antibody (e.g., relatlimab) ratio of about 1:4.

[0202] In some embodiments, the pharmaceutical composition comprises (i) an anti-PD-1 antibody (e.g., nivolumab) at about 80 mg / mL and (ii) an anti-LAG-3 antibody (e.g., relatlimab) at about 26.7 mg / mL.

[0203] In some embodiments, the pharmaceutical composition comprises (i) an anti-PD-1 antibody (e.g., nivolumab) at about 80 mg / mL and (ii) an anti-LAG-3 antibody (e.g., relatlimab) at about 40 mg / mL.

[0204] In some embodiments, the pharmaceutical composition comprises (i) an anti-PD-1 antibody (e.g., nivolumab) at about 80 mg / mL and (ii) an anti-LAG-3 antibody (e.g., relatlimab) at about 80 mg / mL.

[0205] In some embodiments, the pharmaceutical composition comprises (i) an anti-PD-1 antibody (e.g., nivolumab) at about 80 mg / mL and (ii) an anti-LAG-3 antibody (e.g., relatlimab) at about 13.3 mg / mL.

[0206] In some embodiments, the pharmaceutical composition comprises (i) an anti-PD-1 antibody (e.g., nivolumab) at about 80 mg / mL and (ii) an anti-LAG-3 antibody (e.g., relatlimab) at about 13.35 mg / mL.

[0207] In some embodiments, the pharmaceutical composition comprises (i) an anti-PD-1 antibody (e.g., nivolumab) at about 80 mg / mL and (ii) an anti-LAG-3 antibody (e.g., relatlimab) at about 160 mg / mL.

[0208] In some embodiments, the pharmaceutical composition comprises (i) an anti-PD-1 antibody (e.g., nivolumab) at about 80 mg / mL and (ii) an anti-LAG-3 antibody (e.g., relatlimab) at about 240 mg / mL.

[0209] In some embodiments, the pharmaceutical composition comprises (i) an anti-PD-1 antibody (e.g., nivolumab) at about 1200 mg and (ii) an anti-LAG-3 antibody (e.g., relatlimab) at about 400 mg.

[0210] In some embodiments, the pharmaceutical composition comprises (i) about 960 mg of an anti-PD-1 antibody (e.g., nivolumab) and (ii) about 320 mg of an anti-LAG-3 antibody (e.g., relatlimab).

[0211] In some embodiments, the anti-PD-1 antibody is administered once every 2, 3, 4, 5, 6, 7, or 8 weeks at a dose in the range of 0.1 mg / kg body weight to 20.0 mg / kg body weight, e.g., at a dose in the range of 0.1 mg / kg body weight to 10.0 mg / kg body weight, once every 2, 3, or 4 weeks. In other embodiments, 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 embodiments, 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 embodiment, the anti-PD-1 antibody is administered about once every 3 weeks at a dose of about 5 mg / kg body weight. In another embodiment, the anti-PD-1 antibody, e.g., nivolumab, is administered once every about 2 weeks at a dose of about 3 mg / kg body weight. In other embodiments, the anti-PD-1 antibody, e.g., pembrolizumab, is administered once every about 3 weeks at a dose of about 2 mg / kg body weight.

[0212] The anti-PD-1 antibodies useful in the present disclosure can be administered as a flat dose. In some embodiments, the anti-PD-1 antibody is administered at a flat dose of about 100 to about 1000 mg, about 100 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 from about 240 mg to about 480 mg. In one embodiment, the anti-PD-1 antibody is administered at a flat dose of at least about 200 mg, at least about 220 mg, at least about 240 mg, at least about 260 mg, at least about 280 mg, at least about 300 mg, at least about 320 mg, at least about 340 mg, at least about 360 mg, at least about 380 mg, at least about 400 mg, at least about 420 mg, at least about 440 mg, at least about 460 mg, at least about 480 mg, at least about 500 mg, at least about 520 mg, at least about 540 mg, at least about 550 mg, at least about 560 mg, at least about 580 mg, at least about 600 mg, at least about 620 mg, at least about 640 mg, at least about 660 mg, at least about 680 mg, at least about 700 mg or at least about 720 mg at dosing intervals of about 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks. In another embodiment, the anti-PD-1 antibody is administered at a flat dose of about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 200 mg to about 500 mg at dosing intervals of about 1, 2, 3 or 4 weeks.

[0213] In some embodiments, the anti-PD-1 antibody is administered at a flat dose of about 200 mg once every 3 weeks. In other embodiments, the anti-PD-1 antibody is administered at a flat dose of about 200 mg once every 2 weeks. In other embodiments, the anti-PD-1 antibody is administered at a flat dose of about 240 mg once every 2 weeks. In certain embodiments, the anti-PD-1 antibody is administered at a flat dose of about 480 mg once every 4 weeks.

[0214] In some embodiments, nivolumab is administered at a flat dose of about 240 mg once every about two weeks. In some embodiments, nivolumab is administered at a flat dose of about 240 mg once every about three weeks. In some embodiments, nivolumab is administered at a flat dose of about 360 mg once every about three weeks. In some embodiments, nivolumab is administered at a flat dose of about 480 mg once every about four weeks. In some embodiments, nivolumab is administered at a flat dose of about 720 mg once every about six weeks. In some embodiments, nivolumab is administered at a flat dose of about 960 mg once every about eight weeks.

[0215] In some embodiments, pembrolizumab is administered at a flat dose of about 200 mg once every about two weeks. In some embodiments, pembrolizumab is administered at a flat dose of about 200 mg once every about three weeks. In some embodiments, pembrolizumab is administered at a flat dose of about 400 mg once every about four weeks.

[0216] In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab) at at least about 10 mg / mL to at least about 500 mg / mL. In some embodiments, the pharmaceutical composition comprises an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab) at 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 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 135 mg / mL to at least about 180 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 130 mg / mL or at least about 108 mg / mL to at least about 132 mg / mL.In some embodiments, the pharmaceutical composition comprises at least about 50 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 60 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 70 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 75 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 80 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 110 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 120 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 130 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 132 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 140 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 150 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab).In some embodiments, the pharmaceutical composition comprises at least about 160 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 170 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 175 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 180 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 190 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab). In some embodiments, the pharmaceutical composition comprises at least about 200 mg / mL of an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab).

[0217] II.C. Anti-PD-L1 Antibodies Any anti-PD-L1 antibody can be used in the compositions and methods of the present disclosure. Examples of anti-PD-L1 antibodies useful in the compositions and methods of the present disclosure include the antibodies disclosed in U.S. Patent No. 9,580,507. The anti-PD-L1 human monoclonal antibodies disclosed in U.S. Patent No. 9,580,507 have been demonstrated to exhibit one or more of the following characteristics: (a) binds to human PD-L1 with a K -7 of 1×10 D M or less as determined 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 effect of regulatory T cells on T cell effector cells and / or dendritic cells. Anti-PD-L1 antibodies that can be used in the present disclosure include monoclonal antibodies that specifically bind to human PD-L1 and exhibit at least five of the aforementioned characteristics in some embodiments.

[0218] In certain embodiments, the anti-PD-L1 antibody is BMS-936559 (also known as 12A4, MDX-1105; see, e.g., U.S. Patent No. 7,943,743 and WO 2013 / 173223), atezolizumab (Roche; TECENTRIQ; also known as MPDL3280A, RG7446; see U.S. Patent No. 8,217,149; see also Herbst et al. (2013) J. Clin. Oncol. 31 (supra): 3000), durvalumab (AstraZeneca; IMFINZI, also known as MEDI-4736; see WO 2011 / 066389), avelumab (Pfizer; BAVENCIO, also known as MSB-0010718C; see WO 2013 / 079174), STI-1014 (Sorrento; see WO 2013 / 181634), CX-072 (Cytomx; see WO 2016 / 149201), KN035 (3D Med / Alphamab; 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 supra): TPS3113 (2018)), ICO 36, FAZ053 (Novartis) and CK-301 (Checkpoint Therapeutics); see also Gorelik et al., AACR: Abstract 4606 (Apr 2016)) or an antigen-binding portion thereof.

[0219] In certain embodiments, the PD-L1 antibody is atezolizumab (TECENTRIQ). Atezolizumab is a fully humanized IgG1 monoclonal anti-PD-L1 antibody.

[0220] In certain embodiments, the PD-L1 antibody is durvalumab (IMFINZI). Durvalumab is a human IgG1κ monoclonal anti-PD-L1 antibody.

[0221] In certain embodiments, the PD-L1 antibody is avelumab (BAVENCIO). Avelumab is a human IgG1λ monoclonal anti-PD-L1 antibody.

[0222] Anti-PD-L1 antibodies that can be used in the disclosed compositions and methods include isolated antibodies that specifically bind to human PD-L1 and cross-compete with any anti-PD-L1 antibody disclosed herein for binding to human PD-L1, such as atezolizumab, durvalumab, and / or avelumab. In some embodiments, the anti-PD-L1 antibody binds to the same epitope as any of the anti-PD-L1 antibodies described herein, such as atezolizumab, durvalumab, and / or avelumab. The ability of antibodies to cross-compete for antigen binding indicates that these antibodies bind to the same epitope region of the antigen and sterically hinder the binding of other cross-competing antibodies to that particular epitope region. These cross-competing antibodies are expected to have functional properties very similar to those of the reference antibodies, such as atezolizumab and / or avelumab, due to their binding to the same epitope region of PD-L1. Cross-competing antibodies can be readily identified based on their ability to cross-compete with atezolizumab and / or avelumab in standard PD-L1 binding assays such as Biacore analysis, ELISA assays, or flow cytometry (see, for example, WO 2013 / 173223).

[0223] In certain embodiments, an antibody that cross-competes with a human PD-L1 antibody for binding to human PD-L1, or that binds to the same epitope region of a human PD-L1 antibody as, for example, atezolizumab, durvalumab, and / or avelumab, is a monoclonal antibody. For administration to a human subject, these cross-competing antibodies are chimeric, modified, humanized, or human antibodies. Such chimeric, modified, humanized, or human monoclonal antibodies can be prepared and isolated by methods well known in the art.

[0224] The anti-PD-L1 antibodies that can be used in the compositions and methods of the present disclosure also include antigen-binding portions of any of the above full-length antibodies. It has been well demonstrated that fragments of full-length antibodies can perform the antigen-binding function of the antibody.

[0225] The anti-PD-L1 antibodies suitable for use in the disclosed compositions and methods are antibodies that bind to PD-L1 with high specificity and affinity, block the binding of PD-1, and inhibit the immunosuppressive effect of the PD-1 signaling pathway. In any of the compositions or methods disclosed herein, an anti-PD-L1 "antibody" includes an antigen-binding portion or fragment that binds to PD-L1, inhibits receptor binding, and exhibits functional properties similar to those of a full antibody in terms of upregulating the immune system. In certain embodiments, the anti-PD-L1 antibody or its antigen-binding portion cross-competes with atezolizumab, durvalumab, and / or avelumab for binding to human PD-L1.

[0226] The anti-PD-L1 antibodies useful in the present disclosure can be any PD-L1 antibody that specifically binds to PD-L1, such as an antibody that cross-competes with durvalumab, avelumab, or atezolizumab for binding to human PD-1, for example, an antibody that binds to the same epitope as durvalumab, avelumab, or atezolizumab. In certain embodiments, the anti-PD-L1 antibody is durvalumab. In other embodiments, the anti-PD-L1 antibody is avelumab. In some embodiments, the anti-PD-L1 antibody is atezolizumab.

[0227] In some embodiments, any anti-PD-L1 antibody disclosed herein is combined with any anti-LAG-3 antibody disclosed herein in any of the compositions and methods disclosed herein.

[0228] In some embodiments, any anti-PD-L1 antibody disclosed herein is replaced with any anti-PD-1 antibody disclosed herein in any of the compositions and methods disclosed herein.

[0229] In some embodiments, any anti-PD-L1 antibody disclosed herein is combined with any anti-LAG-3 antibody disclosed herein and any anti-PD-1 antibody disclosed herein in any of the compositions and methods disclosed herein.

[0230] In some embodiments, the anti-PD-L1 antibody is a full-length antibody.

[0231] In some embodiments, the anti-PD-L1 antibody is a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, or a multispecific antibody. In some embodiments, the multispecific antibody is a DART, a DVD-Ig, or a bispecific antibody.

[0232] In some embodiments, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) PD-L1 and (ii) a second antigen. In some embodiments, the antibody is a multispecific antibody, such as a bispecific antibody, that specifically binds to (i) PD-L1 and (ii) CD3.

[0233] In some embodiments, 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 embodiments, 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) that 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).

[0234] In some embodiments, the anti-PD-L1 antibody is a trispecific antibody. In some embodiments, the trispecific antibody specifically binds to (i) PD-L1, (ii) a second antigen, and (iii) a third antigen. In some embodiments, the second antigen and the third antigen are the same. In some embodiments, the second antigen and the third antigen are different. In some embodiments, the anti-PD-L1 antibody and the anti-LAG-3 antibody in the pharmaceutical composition are part of a trispecific antibody (e.g., the pharmaceutical composition comprises (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 embodiments, 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) that comprises (i) a trispecific antibody that specifically binds to PD-L1, PD-1, and a third antigen, (ii) an anti-LAG-3 antibody, and (iii) an endoglycosidase hydrolase). In some embodiments, 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 to PD-L1, LAG-3, and PD-1, and (ii) an endoglycosidase hydrolase).

[0235] In some embodiments, the antigen-binding portion in a bispecific or trispecific antibody is an scFv.

[0236] The second or third antigen specifically bound by the bispecific or trispecific antibody herein can be any antigen disclosed herein.

[0237] In some embodiments, the anti-PD-L1 antibody is an F(ab’)2 fragment, Fab’ fragment, Fab fragment, Fv fragment, scFv fragment, dsFv fragment, dAb fragment, or single-chain binding polypeptide.

[0238] In some embodiments, the anti-PD-L1 antibody is administered once every 2, 3, 4, 5, 6, 7, or 8 weeks at a dose in the range of 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.

[0239] In some embodiments, the anti-PD-L1 antibody is administered once every about 3 weeks at a dose of about 15 mg / kg body weight. In other embodiments, the anti-PD-L1 antibody is administered once every about 2 weeks at a dose of about 10 mg / kg body weight.

[0240] In other embodiments, the anti-PD-L1 antibodies useful in the present disclosure are administered at a flat dose. In some embodiments, the anti-PD-L1 antibody is administered at a flat dose of about 200 mg to about 1600 mg, about 200 mg to about 1500 mg, about 200 mg to about 1400 mg, about 200 mg to about 1300 mg, about 200 mg to about 1200 mg, about 200 mg to about 1100 mg, about 200 mg to about 1000 mg, about 200 mg to about 900 mg, about 200 mg to about 800 mg, about 200 mg to about 700 mg, about 200 mg to about 600 mg, about 700 mg to about 1300 mg, about 800 mg to about 1200 mg, about 700 mg to about 900 mg, or about 1100 mg to about 1300 mg. In some embodiments, the anti-PD-L1 antibody is administered at a flat dose of at least about 240 mg, at least about 300 mg, at least about 320 mg, at least about 400 mg, at least about 480 mg, at least about 500 mg, at least about 560 mg, at least about 600 mg, at least about 640 mg, at least about 700 mg, at least 720 mg, at least about 800 mg, at least about 840 mg, at least about 880 mg, at least about 900 mg, at least 960 mg, at least about 1000 mg, at least about 1040 mg, at least about 1100 mg, at least about 1120 mg, at least about 1200 mg, at least about 1280 mg, at least about 1300 mg, at least about 1360 mg, or at least about 1400 mg, with an administration interval of about 1, 2, 3, or 4 weeks. In some embodiments, the anti-PD-L1 antibody is administered once every 3 weeks at a flat dose of about 1200 mg. In other embodiments, the anti-PD-L1 antibody is administered once every 2 weeks at a flat dose of about 800 mg. In other embodiments, the anti-PD-L1 antibody is administered once every 2 weeks at a flat dose of about 840 mg.

[0241] In some embodiments, atezolizumab is administered once every 3 weeks at a flat dose of about 1200 mg. In some embodiments, atezolizumab is administered once every 2 weeks at a flat dose of about 800 mg. In some embodiments, atezolizumab is administered once every 2 weeks at a flat dose of about 840 mg.

[0242] In some embodiments, abelumab is administered as a flat dose of about 800 mg once every about two weeks.

[0243] In some embodiments, durvalumab is administered at a dose of about 10 mg / kg once every about two weeks. In some embodiments, durvalumab is administered as a flat dose of about 800 mg / kg once every about two weeks. In some embodiments, durvalumab is administered as a flat dose of about 1200 mg / kg once every about three weeks.

[0244] In some embodiments, the pharmaceutical composition comprises an anti-PD-L1 antibody at least about 10 mg / mL to at least about 500 mg / mL. In some embodiments, the pharmaceutical composition comprises an anti-PD-L1 antibody 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 200 mg / mL, at least about 20 mg / mL to at least about 190 mg / mL, at least about 20 mg / mL to at least about 180 mg / mL, at least about 20 mg / mL to at least about 170 mg / mL, at least about 20 mg / mL to at least about 160 mg / mL, at least about 20 mg / mL to at least about 150 mg / mL, at least about 50 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 135 mg / mL to at least about 180 mg / mL, at least about 100 mg / mL to at least about 200 mg / mL, at least about 150 mg / mL to at least about 200 mg / mL, at least about 100 mg / mL to at least about 130 mg / mL or at least about 108 mg / mL to at least about 132 mg / mL. In some embodiments, the pharmaceutical composition comprises an anti-PD-L1 antibody at least about 50 mg / mL. In some embodiments, the pharmaceutical composition comprises an anti-PD-L1 antibody at least about 60 mg / mL.In some embodiments, the pharmaceutical composition comprises at least about 70 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 75 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 80 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 90 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 100 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 108 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 110 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 120 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 130 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 132 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 135 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 140 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 150 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 160 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 170 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 175 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 180 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 190 mg / mL of an anti-PD-L1 antibody. In some embodiments, the pharmaceutical composition comprises at least about 200 mg / mL of an anti-PD-L1 antibody.

[0245] In some embodiments, the pharmaceutical compositions disclosed herein comprise an anti-PD-L1 antibody (e.g., atezolizumab, durvalumab, or avelumab) disclosed herein at 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 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.

[0246] In some embodiments, the pharmaceutical compositions disclosed herein are 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, from about 10 mg / mL to about 140 mg / mL, from about 10 mg / mL to about 130 mg / mL, from about 10 mg / mL to about 120 mg / mL, from about 10 mg / mL to about 110 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 85 mg / mL, from about 10 mg / mL to about 80 mg / mL, from about 20 mg / mL to about 500 mg / mL, from about 20 mg / mL to about 450 mg / mL, from about 20 mg / mL to about 400 mg / mL, from about 20 mg / mL to about 350 mg / mL, from about 20 mg / mL to about 300 mg / mL, from about 20 mg / mL to about 250 mg / mL, from about 20 mg / mL to about 200 mg / mL, from about 20 mg / mL to about 190 mg / mL, from about 20 mg / mL to about 180 mg / mL, from about 20 mg / mL to about 170 mg / mL, from about 20 mg / mL to about 160 mg / mL, from about 20 mg / mL to about 150 mg / mL, from about 20 mg / mL to about 140 mg / mL, from about 20 mg / mL to about 130 mg / mL, from about 20 mg / mL to about 120 mg / mL, from about 20 mg / mL to about 110 mg / mL, from about 20 mg / mL to about 100 mg / mL, from about 20 mg / mL to about 90 mg / mL, from about 20 mg / mL to about 85 mg / mL, from about 20 mg / mL to about 80 mg / mL, from about 50 mg / mL to about 200 mg / mL, from about 520 mg / mL to about 190 mg / mL, from about 50 mg / mL to about 180 mg / mL, from about 50 mg / mL to about 170 mg / mL, from about 50 mg / mL to about 160 mg / mL, from about 50 mg / mL to about 150 mg / mL, from about 50 mg / mL to about 140 mg / mL, from about 50 mg / mL to about 130 mg / mL, from about 50 mg / mL to about 120 mg / mL, from about 50 mg / mL to about 110 mg / mL, from about 50 mg / mL to about 100 mg / mL,Comprising an anti-PD-L1 antibody (e.g., atezolizumab, durvalumab or avelumab) disclosed herein at 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.

[0247] In some embodiments, the pharmaceutical composition disclosed herein comprises an anti-PD-L1 antibody (e.g., atezolizumab, durvalumab or avelumab) disclosed herein at 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, 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.

[0248] In some embodiments, the pharmaceutical compositions disclosed herein comprise 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 an anti-PD-L1 antibody (e.g., atezolizumab, durvalumab or avelumab) disclosed herein.

[0249] In some embodiments, the pharmaceutical compositions disclosed herein are 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 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 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,Comprising an anti-PD-L1 antibody (e.g., atezolizumab, durvalumab or avelumab) disclosed herein in an amount of about 980 mg, about 990 mg, about 1000 mg, about 1040 mg, 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.

[0250] II.D. Antioxidants In some embodiments, the pharmaceutical compositions disclosed herein further comprise an antioxidant. Any antioxidant can be used in the pharmaceutical compositions disclosed herein. In some embodiments, the antioxidant is methionine, tryptophan and histidine, cysteine, ascorbic acid, glycine, pentetic acid (“DTPA”) or ethylenediaminetetraacetic acid (“EDTA”). In certain embodiments, the pharmaceutical composition comprises methionine.

[0251] In some embodiments, the pharmaceutical composition comprises at least two antioxidants. In some embodiments, at least one of the at least two antioxidants is a sacrificial antioxidant. Any sacrificial antioxidant can be used in the pharmaceutical compositions and methods disclosed herein. In some embodiments, the sacrificial antioxidant is methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, or other sacrificial agents. In some embodiments, at least one of the at least two antioxidants comprises a metal ion chelating agent. Any metal ion chelating agent can be used in the pharmaceutical compositions and methods disclosed herein. In some embodiments, the metal ion chelating agent is pentetic acid (“DTPA”) or EDTA. In some embodiments, the at least two antioxidants are selected from methionine, DTPA, and EDTA. In some embodiments, the at least two antioxidants comprise methionine and EDTA. In some embodiments, the at least two antioxidants comprise methionine and pentetic acid (DTPA).

[0252] In some embodiments, the pharmaceutical composition comprises at least about 0.1 mM to at least about 100 mM of methionine. In some embodiments, 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 of methionine. In some embodiments, the pharmaceutical composition comprises at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 3.5 mM, at least about 4 mM, at least about 4.5 mM, at least about 5 mM, at least about 5.5 mM, at least about 6 mM, at least about 6.5 mM, at least about 7 mM, at least about 7.5 mM, at least about 8 mM, at least about 8.5 mM, at least about 9 mM, at least about 9.5 mM, at least about 10 mM, at least about 11 mM, at least about 12 mM, at least about 13 mM, at least about 14 mM, at least about 15 mM, at least about 16 mM, at least about 17 mM, at least about 18 mM, at least about 19 mM or at least about 20 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 10 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 9 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 8 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 7 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 6 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 5 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 4 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 3 mM of methionine.In certain embodiments, the pharmaceutical composition comprises at least about 2 mM of methionine. In certain embodiments, the pharmaceutical composition comprises at least about 1 mM of methionine.

[0253] In some embodiments, the pharmaceutical compositions disclosed herein comprise from about 0.1 mM to about 100 mM, from about 0.1 mM to about 90 mM, from about 0.1 mM to about 80 mM, from about 0.1 mM to about 70 mM, from about 0.1 mM to about 60 mM, from about 0.1 mM to about 50 mM, from about 0.1 mM to about 40 mM, from about 0.1 mM to about 30 mM, from about 0.1 mM to about 20 mM, from about 0.1 mM to about 10 mM, from about 1 mM to about 20 mM, from about 1 mM to about 15 mM, from about 1 mM to about 10 mM, from about 1 mM to about 9 mM, from about 1 mM to about 8 mM, from about 1 mM to about 7 mM, from about 1 mM to about 6 mM, from about 1 mM to about 5 mM, from about 2 mM to about 9 mM, from about 3 mM to about 8 mM, from about 4 mM to about 7 mM, from about 4 mM to about 6 mM, from about 4 mM to about 5 mM, from about 5 mM to about 20 mM, from about 5 mM to about 15 mM, from about 5 mM to about 10 mM, from about 5 mM to about 9 mM, from about 5 mM to about 8 mM, from about 5 mM to about 7 mM, or from about 5 mM to about 6 mM of methionine.

[0254] In some embodiments, the pharmaceutical compositions disclosed herein comprise 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 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 of methionine.

[0255] In some embodiments, the pharmaceutical composition comprises pentetic acid (DTPA) in an amount of at least about 1 μM to at least about 250 μM. In some embodiments, the pharmaceutical composition comprises pentetic acid (DTPA) in an amount of at least about 10 μM to at least about 200 μM, at least about 10 μM to at least about 175 μM, at least about 10 μM to at least about 150 μM, at least about 10 μM to at least about 125 μM, at least about 10 μM to at least about 100 μM, at least about 10 μM to at least about 75 μM, at least about 10 μM to at least about 70 μM, at least about 10 μM to at least about 60 μM, at least about 10 μM to at least about 50 μM, at least about 20 μM to at least about 100 μM, at least about 20 μM to at least about 75 μM, at least about 20 μM to at least about 70 μM, at least about 20 μM to at least about 60 μM, at least about 20 μM to at least about 50 μM, at least about 25 μM to at least about 100 μM, at least about 25 μM to at least about 75 μM, at least about 25 μM to at least about 50 μM, at least about 30 μM to at least about 100 μM, at least about 30 μM to at least about 75 μM, at least about 30 μM to at least about 70 μM, at least about 30 μM to at least about 30 μM, at least about 30 μM to at least about 50 μM, at least about 40 μM to at least about 100 μM, at least about 40 μM to at least about 75 μM, at least about 40 μM to at least about 70 μM, at least about 40 μM to at least about 60 μM, at least about 40 μM to at least about 50 μM, at least about 50 μM to at least about 100 μM, at least about 50 μM to at least about 75 μM, at least about 50 μM to at least about 70 μM, or at least about 50 μM to at least about 60 μM.In some embodiments, the pharmaceutical composition comprises DTPA at 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. In certain embodiments, the pharmaceutical composition comprises at least about 75 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 70 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 65 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 60 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 55 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 50 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 45 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 40 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 35 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 30 μM of pentetic acid (DTPA). In certain embodiments, the pharmaceutical composition comprises at least about 25 μM of pentetic acid (DTPA).

[0256] In some embodiments, the pharmaceutical compositions disclosed herein comprise pentetic acid (DTPA) in an amount of 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.

[0257] In some embodiments, the pharmaceutical compositions disclosed herein comprise DTPA in an amount of 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.

[0258] II.E. Isotonicity Adjusting Agent / Stabilizer In some embodiments, the pharmaceutical compositions disclosed herein further comprise an isotonicity adjusting agent and / or a stabilizer. Any isotonicity adjusting agent and / or any stabilizer can be used in the pharmaceutical compositions disclosed herein. In some embodiments, the isotonicity adjusting agent and / or the stabilizer comprise a sugar, an amino acid, a polyol, a salt, or any combination thereof. In some embodiments, the isotonicity adjusting agent and / or the stabilizer are sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, polyol, amino acid, or a salt.

[0259] In certain embodiments, the pharmaceutical composition comprises sucrose. In some embodiments, the pharmaceutical composition comprises at least about 1 mM to at least about 500 mM of sucrose. In some embodiments, the pharmaceutical composition comprises at least about 10 mM to at least about 500 mM, at least about 10 mM to at least about 400 mM, at least about 50 mM to at least about 400 mM, at least about 100 mM to at least about 400 mM, at least about 150 mM to at least about 400 mM, at least about 200 mM to at least about 400 mM, at least about 250 mM to at least about 400 mM, at least about 300 mM to at least about 400 mM, at least about 350 mM to at least about 400 mM, at least about 50 mM to at least about 350 mM, at least about 100 mM to at least about 300 mM, at least about 100 mM to at least about 250 mM, at least about 100 mM to at least about 200 mM, at least about 100 mM to at least about 150 mM, at least about 200 mM to at least about 400 mM, at least about 200 mM to at least about 300 mM, or at least about 200 mM to at least about 250 mM of sucrose.In some embodiments, the pharmaceutical composition comprises sucrose at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, at least about 50 mM, at least about 60 mM, at least about 70 mM, at least about 80 mM, at least about 90 mM, at least about 100 mM, at least about 110 mM, at least about 120 mM, at least about 130 mM, at least about 140 mM, at least about 150 mM, at least about 160 mM, at least about 170 mM, at least about 180 mM, at least about 190 mM, at least about 200 mM, at least about 210 mM, at least about 220 mM, at least about 230 mM, at least about 240 mM, at least about 250 mM, at least about 260 mM, at least about 270 mM, at least about 280 mM, at least about 290 mM, at least about 300 mM, at least about 310 mM, at least about 320 mM, at least about 330 mM, at least about 340 mM, at least about 350 mM, at least about 360 mM, at least about 370 mM, at least about 380 mM, at least about 390 mM, at least about 400 mM, at least about 410 mM, at least about 420 mM, at least about 430 mM, at least about 440 mM, at least about 450 mM, at least about 460 mM, at least about 470 mM, at least about 480 mM, at least about 490 mM or at least about 500 mM. In certain embodiments, the pharmaceutical composition comprises at least about 200 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 210 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 220 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 230 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 240 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 250 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 260 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 270 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 280 mM of sucrose. In certain embodiments, the pharmaceutical composition comprises at least about 290 mM of sucrose.In certain embodiments, the pharmaceutical composition comprises at least about 300 mM of sucrose.

[0260] In some embodiments, the pharmaceutical compositions disclosed herein comprise from about 1 mM to about 500 mM, from about 1 mM to about 400 mM, from about 1 mM to about 350 mM, from about 1 mM to about 300 mM, from about 1 mM to about 250 mM, from about 10 mM to about 400 mM, from about 10 mM to about 350 mM, from about 10 mM to about 300 mM, from about 10 mM to about 250 mM, from about 50 mM to about 400 mM, from about 50 mM to about 350 mM, from about 50 mM to about 300 mM, from about 50 mM to about 250 mM, from about 100 mM to about 400 mM, from about 100 mM to about 350 mM, from about 100 mM to about 300 mM, from about 100 mM to about 250 mM, from about 100 mM to about 200 mM, from about 100 mM to about 150 mM, from about 150 mM to about 400 mM, from about 150 mM to about 350 mM, from about 150 mM to about 300 mM, from about 150 mM to about 250 mM, from about 150 mM to about 200 mM, from about 200 mM to about 400 mM, from about 200 mM to about 350 mM, from about 200 mM to about 300 mM, from about 200 mM to about 250 mM, from about 250 mM to about 400 mM, from about 250 mM to about 350 mM, from about 250 mM to about 300 mM, from about 300 mM to about 400 mM, from about 300 mM to about 350 mM or from about 350 mM to about 400 mM of sucrose.

[0261] In some embodiments, the pharmaceutical compositions disclosed herein comprise 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 or about 500 mM of sucrose.

[0262] II.F. Buffer In some embodiments, the pharmaceutical compositions disclosed herein further comprise a buffer. In some embodiments, the buffer is histidine, succinate, tromethamine, sodium phosphate, sodium acetate or sodium citrate. In certain embodiments, the pharmaceutical composition comprises histidine. In certain embodiments, the pharmaceutical composition comprises citrate. In some embodiments, the pharmaceutical composition comprises at least about 1 mM to at least about 100 mM of histidine. In some embodiments, the pharmaceutical composition comprises at least about 5 mM to at least about 100 mM, at least about 10 mM to at least about 100 mM, at least about 15 mM to at least about 100 mM, at least about 20 mM to at least about 100 mM, at least about 25 mM to at least about 100 mM, at least about 30 mM to at least about 100 mM, at least about 35 mM to at least about 100 mM, at least about 40 mM to at least about 100 mM, at least about 45 mM to at least about 100 mM, at least about 50 mM to at least about 100 mM, at least about 10 mM to at least about 75 mM, at least about 10 mM to at least about 50 mM, at least about 10 mM to at least about 40 mM, at least about 10 mM to at least about 30 mM, at least about 15 mM to at least about 30 mM, at least about 10 mM to at least about 25 mM or at least about 15 mM to at least about 25 mM of histidine.

[0263] In some embodiments, the pharmaceutical composition comprises histidine at 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. In certain embodiments, the pharmaceutical composition comprises at least about 10 mM of histidine. In certain embodiments, the pharmaceutical composition comprises at least about 15 mM of histidine. In certain embodiments, the pharmaceutical composition comprises at least about 20 mM of histidine. In certain embodiments, the pharmaceutical composition comprises at least about 25 mM of histidine. In certain embodiments, the pharmaceutical composition comprises at least about 30 mM of histidine. In certain embodiments, the pharmaceutical composition comprises at least about 35 mM of histidine. In certain embodiments, the pharmaceutical composition comprises at least about 40 mM of histidine. In certain embodiments, the pharmaceutical composition comprises at least about 45 mM of histidine. In certain embodiments, the pharmaceutical composition comprises at least about 50 mM of histidine.

[0264] In some embodiments, the pharmaceutical composition is from about 1 mM to about 100 mM, from about 1 mM to about 90 mM, from about 1 mM to about 80 mM, from about 1 mM to about 75 mM, from about 1 mM to about 70 mM, from about 1 mM to about 65 mM, from about 1 mM to about 60 mM, from about 1 mM to about 55 mM, from about 1 mM to about 50 mM, from about 1 mM to about 45 mM, from about 1 mM to about 40 mM, from about 1 mM to about 35 mM, from about 1 mM to about 30 mM, from about 1 mM to about 25 mM, from about 1 mM to about 20 mM, from about 1 mM to about 15 mM, from about 1 mM to about 10 mM, from about 1 mM to about 5 mM, from about 5 mM to about 100 mM, from about 5 mM to about 90 mM, from about 5 mM to about 80 mM, from about 5 mM to about 75 mM, from about 5 mM to about 70 mM, from about 5 mM to about 65 mM, from about 5 mM to about 60 mM, from about 5 mM to about 55 mM, from about 5 mM to about 50 mM, from about 5 mM to about 45 mM, from about 5 mM to about 40 mM, from about 5 mM to about 35 mM, from about 5 mM to about 30 mM, from about 5 mM to about 25 mM, from about 5 mM to about 20 mM, from about 5 mM to about 15 mM, from about 5 mM to about 10 mM, from about 10 mM to about 100 mM, from about 10 mM to about 90 mM, from about 10 mM to about 80 mM, from about 10 mM to about 75 mM, from about 10 mM to about 70 mM, from about 10 mM to about 65 mM, from about 10 mM to about 60 mM, from about 10 mM to about 55 mM, from about 10 mM to about 50 mM, from about 10 mM to about 45 mM, from about 10 mM to about 40 mM, from about 10 mM to about 35 mM, from about 10 mM to about 30 mM, from about 10 mM to about 25 mM, from about 10 mM to about 20 mM, from about 10 mM to about 15 mM, from about 15 mM to about 100 mM, from about 15 mM to about 90 mM, from about 15 mM to about 80 mM, from about 15 mM to about 75 mM, from about 15 mM to about 70 mM, from about 15 mM to about 65 mM, from about 15 mM to about 60 mM, from about 15 mM to about 55 mM, from about 15 mM to about 50 mM, from about 15 mM to about 45 mM, from about 15 mM to about 40 mM, from about 15 mM to about 35 mM, from about 15 mM to about 30 mM, from about 15 mM to about 25 mM, from about 15 mM to about 20 mM, from about 16 mM to about 24 mM, from about 17 mM to about 23 mM, from about 18 mM to about 22 mM, from about 19 mM to about 21 mM, from about 20 mM to about 100 mM, from about 20 mM to about 90 mM, from about 20 mM to about 80 mM, from about 20 mM to about 75 mM, from about 20 mM to about 70 mM, 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,It contains histidine at 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.

[0265] In some embodiments, the pharmaceutical composition contains histidine at 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.

[0266] In some embodiments, the pharmaceutical composition has a pH of about 5.2 to about 6.8. In some embodiments, the pH of the pharmaceutical composition is about 5.2. In some embodiments, the pH of the pharmaceutical composition is about 5.3. In some embodiments, the pH of the pharmaceutical composition is about 5.4. In some embodiments, the pH of the pharmaceutical composition is about 5.5. In some embodiments, the pH of the pharmaceutical composition is about 5.6. In some embodiments, the pH of the pharmaceutical composition is about 5.7. In some embodiments, the pH of the pharmaceutical composition is about 5.8. In some embodiments, the pH of the pharmaceutical composition is about 5.9. In some embodiments, the pH of the pharmaceutical composition is about 6.0. In some embodiments, the pH of the pharmaceutical composition is about 6.1. In some embodiments, the pH of the pharmaceutical composition is about 6.2. In some embodiments, the pH of the pharmaceutical composition is about 6.3. In some embodiments, the pH of the pharmaceutical composition is about 6.4. In some embodiments, the pH of the pharmaceutical composition is about 6.5. In some embodiments, the pH of the pharmaceutical composition is about 6.6. In some embodiments, the pH of the pharmaceutical composition is about 6.7. In some embodiments, the pH of the pharmaceutical composition is about 6.8.

[0267] II.G. Surfactant In some embodiments, the pharmaceutical compositions disclosed herein further comprise a surfactant. Any surfactant can be used in the pharmaceutical compositions disclosed herein. In some embodiments, the surfactant is polysorbate 20, polysorbate 80, or poloxamer 188. In certain embodiments, the pharmaceutical composition comprises polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.001% to at least about 1% w / v of polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% to at least about 0.1%, at least about 0.02% to at least about 0.1%, at least about 0.03% to at least about 0.1%, at least about 0.04% to at least about 0.1%, at least about 0.05% to at least about 0.1%, at least about 0.01% to at least about 0.09%, at least about 0.01% to at least about 0.8%, at least about 0.01% to at least about 0.7%, at least about 0.01% to at least about 0.6%, at least about 0.01% to at least about 0.5%, at least about 0.02% to at least about 0.09%, at least about 0.03% to at least about 0.08%, at least about 0.04% to at least about 0.07%, or at least about 0.04% to at least about 0.06% w / v of polysorbate 80. In some embodiments, the pharmaceutical composition comprises at least about 0.01% to at least about 0.1% w / v of polysorbate 80.

[0268] In some embodiments, the pharmaceutical composition comprises at least about 0.01% w / v, at least about 0.02% w / v, at least about 0.03% w / v, at least about 0.04% w / v, at least about 0.05% w / v, at least about 0.06% w / v, at least about 0.07% w / v, at least about 0.08% w / v, at least about 0.09% w / v or at least about 0.1% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.03% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.04% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.05% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.06% w / v of polysorbate 80. In certain embodiments, the pharmaceutical composition comprises at least about 0.07% w / v of polysorbate 80.

[0269] In some embodiments, the pharmaceutical composition is from about 0.001% to about 1% w / v, from about 0.001% w / v to about 0.9% w / v, from about 0.001% w / v to about 0.8% w / v, from about 0.001% w / v to about 0.7% w / v, from about 0.001% w / v to about 0.6% w / v, from about 0.001% w / v to about 0.5% w / v, from about 0.001% w / v to about 0.4% w / v, from about 0.001% w / v to about 0.3% w / v, from about 0.001% w / v to about 0.2% w / v, from about 0.001% w / v to about 0.1% w / v, from about 0.001% w / v to about 0.09% w / v, from about 0.001% w / v to about 0.08% w / v, from about 0.001% w / v to about 0.07% w / v, from about 0.001% w / v to about 0.06% w / v, from about 0.001% w / v to about 0.05% w / v, from about 0.01% w / v to about 0.9% w / v, from about 0.01% w / v to about 0.8% w / v, from about 0.01% w / v to about 0.7% w / v, from about 0.01% w / v to about 0.6% w / v, from about 0.01% w / v to about 0.5% w / v, from about 0.01% w / v to about 0.4% w / v, from about 0.01% w / v to about 0.3% w / v, from about 0.01% w / v to about 0.2% w / v, from about 0.01% w / v to about 0.1% w / v, from about 0.01% w / v to about 0.09% w / v, from about 0.01% w / v to about 0.08% w / v, from about 0.01% w / v to about 0.07% w / v, from about 0.01% w / v to about 0.06% w / v, from about 0.01% w / v to about 0.05% w / v, from about 0.02% w / v to about 0.1% w / v, from about 0.02% w / v to about 0.09% w / v, from about 0.02% w / v to about 0.08% w / v, from about 0.02% w / v to about 0.07% w / v, from about 0.02% w / v to about 0.06% w / v, from about 0.02% w / v to about 0.05% w / v, from about 0.03% w / v to about 0.1% w / v, from about 0.03% w / v to about 0.09% w / v, from about 0.03% w / v to about 0.08% w / v, from about 0.03% w / v to about 0.07% w / v, from about 0.03% w / v to about 0.06% w / v, from about 0.03% w / v to about 0.05% w / v, from about 0.04% w / v to about 0.1% w / v, from about 0.04% w / v to about 0.09% w / v, from about 0.04% w / v to about 0.08% w / v, from about 0.04% w / v to about 0.07% w / v, from about 0.04% w / v to about 0.06% w / v, from about 0.04% w / v to about 0.05%, from about 0.05% w / v to about 0.1% w / v, from about 0.05% w / v to about 0.09% w / v, from about 0.05% w / v to about 0.It contains 0.8% 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 of polysorbate 80.

[0270] In some embodiments, the pharmaceutical composition contains 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 of polysorbate 80.

[0271] II.H. Endoglycosidase hydrolase Any endoglycosidase hydrolase can be used in the pharmaceutical compositions and methods disclosed herein. In some embodiments, the endoglycosidase hydrolase cleaves hyaluronic acid at the hexosaminide β(1-4) or (1-3) bond. In some embodiments, the endoglycosidase hydrolase comprises the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4 or HYALPS1.

[0272] In some embodiments, the endoglycosidase hydrolase includes hyaluronidase. In some embodiments, the endoglycosidase hydrolase includes a hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variants thereof, and any isoforms. In some embodiments, the endoglycosidase hydrolase includes rHuPH20 or a fragment thereof. In some embodiments, as shown in Table 1, the endoglycosidase hydrolase includes an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% sequence identity with amino acids 36-490 of SEQ ID NO: 87. In some embodiments, the endoglycosidase hydrolase includes the catalytic domain of rHuPH20 (UniProt ID number P38567-1). In some embodiments, the endoglycosidase hydrolase includes the rHuPH20 mature peptide (amino acids 36-490 of SEQ ID NO: 87).

[0273]

Table 1

[0274] In some embodiments, the pharmaceutical composition includes the ENHANZE drug delivery technology of Halozyme Therapeutics (see U.S. Patent No. 7,767,429, which is hereby incorporated by reference in its entirety). ENHANZE uses a co-formulation of an antibody and the recombinant human hyaluronidase enzyme (rHuPH20), which according to rHuPH20, removes the conventional limitations due to the extracellular matrix regarding the volume of biologic agents and drugs that can be delivered subcutaneously (see U.S. Patent No. 7,767,429). In some embodiments, the pharmaceutical composition of the present disclosure may further include a recombinant human hyaluronidase enzyme, such as rHuPH20.

[0275] Recombinant human hyaluronidase PH20 (rHuPH20, Halozyme Therapeutics Inc.) is a glycosylated 447 - amino - acid single - chain recombinant human polypeptide that locally depolymerizes hyaluronan in the subcutaneous (SC) space at the injection site. Hyaluronan is a repeating polymer of N - acetyl - glucosamine and glucuronic acid that contributes to the soluble gel - like component of the extracellular matrix of the skin. Depolymerization of hyaluronan by rHuPH20 results in a transient decrease in the viscosity of the gel - like phase of the extracellular matrix and an increase in hydraulic conductance that promotes the dispersion and absorption of the injected drug (see rHuPH20IB). The use of rHuPH20 can shorten the dosing time, reduce the dosing frequency, and enable potential improvements in the PK profile of co - administered drugs, including improved absorption, increased bioavailability, acceleration of the time to maximum concentration (Tmax), increase in maximum concentration (Cmax), and reduction of PK variability, allowing for large - volume delivery for rapid SC injection (e.g., about 2 mL to 20 mL).

[0276] The half - life of rHuPH20 in the skin is less than 30 minutes, and the local permeability barriers in these tissues recover to pre - injection levels within 24 to 48 hours after hyaluronidase injection. One study showed that rHuPH20 was not systemically detectable in healthy volunteers and patients after SC administration at doses of 10,000 U and 30,000 U. Another study of the PK of rHuPH20 (Halozyme study HALO - 104 - 104) showed that the plasma concentration of rHuPH20 decreased rapidly, with a very short t1 / 2 (≤10.4 minutes), and the plasma concentration became 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.

[0277] Subcutaneous injection of rHuPH20 is 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 injection of rHuPH20 can be administered alone or concomitantly with lactated Ringer's, normal saline, co-injected drugs (morphine, ceftriaxone, insulin, and insulin analogs), or biologic agents (immunoglobulin G [IgG] and adalimumab) and is well tolerated.

[0278] In some embodiments, 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 fragments thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase comprising one or more amino acid substitutions in the α-helix region relative to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof. In some embodiments, the endoglycosidase hydrolase 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 fragments thereof. In some embodiments, the endoglycosidase hydrolase comprises a modified hyaluronidase in which 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 fragments thereof.

[0279] In some embodiments, the endoglycosidase hydrolase comprises a modified rHuPH20, which comprises one or more amino acid substitutions in the α-helix region, the linker region, or both the α-helix region and the linker region as compared to wild-type rHuPH20. In some embodiments, the endoglycosidase hydrolase comprises a modified rHuPH20, which comprises a deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids as compared to wild-type rHuPH20. In some embodiments, the endoglycosidase hydrolase comprises a modified rHuPH20, which comprises one or more amino acid substitutions in the α-helix region, the linker region, or both the α-helix region and the linker region as compared to wild-type rHuPH20, and which comprises a deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids as compared to wild-type rHuPH20.

[0280] Further non-limiting examples of endoglycosidase hydrolases are found in European Patent No. 3636752, which is hereby incorporated by reference in its entirety.

[0281] In some embodiments, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in U.S. Patent No. 9,447,401; U.S. Patent No. 10,865,400; U.S. Patent No. 11,041,149; U.S. Patent No. 11,066,656; U.S. Patent No. 8,927,249; U.S. Patent No. 9,284,543; U.S. Patent No. 10,588,983; U.S. Patent Application No. 10 / 328,130; and / or U.S. Patent No. 9,993,529, each of which is incorporated herein by reference in its entirety. In some embodiments, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in International Publication No. WO 2013 / 102144; International Publication No. WO 2010 / 077297; International Publication No. WO 2015 / 003167; International Publication No. WO 2004 / 078140; International Publication No. WO 2009 / 128917; International Publication No. WO 2012 / 174478; and / or International Publication No. WO 2012 / 174480, each of which is incorporated herein by reference in its entirety. In some embodiments, the endoglycosidase hydrolase comprises an amino acid sequence that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% identical to an amino acid sequence selected from the amino acid sequences shown in SEQ ID NOs: 88-136. In some embodiments, the endoglycosidase hydrolase comprises an amino acid sequence selected from the amino acid sequences shown in SEQ ID NOs: 88-136.

[0282] In some embodiments, the endoglycosidase hydrolase is any polypeptide having endoglycosidase hydrolase activity disclosed in U.S. Patent Application Publication No. 2021 / 0155913A1 and / or U.S. Patent Application Publication No. 2021 / 0363270A1 and / or International Publication No. WO 20 / 022791, International Publication No. WO 20 / 197230 and / or International Publication No. WO 21 / 150079, each of which is incorporated herein by reference in its entirety. In some embodiments, the endoglycosidase hydrolase comprises an amino acid sequence that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% identical to an amino acid sequence selected from the amino acid sequences shown in SEQ ID NOs: 137 - 347. In some embodiments, the endoglycosidase hydrolase comprises an amino acid sequence that is at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99% or about 100% identical to the amino acid sequence shown in SEQ ID NO: 176. In some embodiments, the endoglycosidase hydrolase comprises an amino acid sequence selected from the amino acid sequences shown in SEQ ID NOs: 137 - 347. In some embodiments, the endoglycosidase hydrolase comprises the amino acid sequence shown in SEQ ID NO: 176. In some embodiments, the endoglycosidase hydrolase is HP46 (corresponding to SEQ ID NO: 348, SEQ ID NO: 44 in International Publication No. WO 2020 / 197230).

[0283] In certain embodiments, the pharmaceutical compositions disclosed herein include hyaluronidase. In some embodiments, the pharmaceutical composition includes hyaluronidase at a concentration sufficient to administer at least about 20,000 units of hyaluronidase. In some embodiments, the pharmaceutical composition includes hyaluronidase at a concentration sufficient to administer at least about 24,000 units of hyaluronidase. In some embodiments, the pharmaceutical composition includes hyaluronidase at a concentration sufficient to administer at least about 50,000 units of hyaluronidase. In some embodiments, the pharmaceutical composition includes hyaluronidase at a concentration sufficient to administer at least about 75,000 units of hyaluronidase. In some embodiments, the pharmaceutical composition includes hyaluronidase at a concentration sufficient to administer at least about 100,000 units of hyaluronidase. In some embodiments, the hyaluronidase is rHuPH20. In other embodiments, the pharmaceutical composition does not include hyaluronidase.

[0284] In some embodiments, the pharmaceutical composition comprises at least about 50 units to at least about 48,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50 units / mL (U / mL) to at least about 5000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50 U / mL, at least about 100 U / mL, at least about 150 U / mL, at least about 200 U / mL, at least about 250 U / mL, at least about 300 U / mL, at least about 350 U / mL, at least about 400 U / mL, at least about 450 U / mL, at least about 500 U / mL, at least about 750 U / mL, at least about 1000 U / mL, at least about 1500 U / mL, at least about 2000 U / mL, at least about 2500 U / mL, at least about 3000 U / mL, at least about 3500 U / mL, at least about 4000 U / mL, at least about 4500 U / mL, at least about 5000 U / mL, at least about 5500 U / mL, at least about 6000 U / mL, at least about 6500 U / mL, at least about 7000 U / mL, at least about 7500 U / mL, at least about 8000 U / mL, at least about 8500 U / mL, at least about 9000 U / mL, at least about 9500 U / mL or at least about 10,000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 500 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 1000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 2000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 2500 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 3000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20).In some embodiments, the pharmaceutical composition comprises at least about 3500 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 4000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 4500 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 5000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 6000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 7000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 8000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 9000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 10,000 U / mL of an endoglycosidase hydrolase (e.g., rHuPH20).

[0285] In some embodiments, the pharmaceutical composition comprises at least about 50 units to at least about 100,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 500 units to at least about 100,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50 units, at least about 100 units, at least about 150 units, at least about 200 units, at least about 250 units, at least about 300 units, at least about 400 units, at least about 500 units, at least about 600 units, at least about 700 units, at least about 800 units, at least about 900 units, at least about 1000 units, at least about 1500 units, at least about 2000 units, at least about 2500 units, at least about 3000 units, at least about 4000 units, at least about 5000 units, at least about 10,000 units, at least about 15,000 units, at least about 20,000 units, at least about 25,000 units, at least about 30,000 units, at least about 35,000 units, at least about 40,000 units, at least about 45,000 units, at least about 48,000 units, at least about 50,000 units, at least about 55,000 units, at least about 60,000 units, at least about 65,000 units, at least about 70,000 units, at least about 75,000 units, at least about 80,000 units, at least about 85,000 units, at least about 90,000 units, at least about 95,000 units or at least about 100,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 20,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 30,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 40,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 50,000 units of an endoglycosidase hydrolase (e.g., rHuPH20).In some embodiments, the pharmaceutical composition comprises at least about 60,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 70,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 80,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 90,000 units of an endoglycosidase hydrolase (e.g., rHuPH20). In some embodiments, the pharmaceutical composition comprises at least about 100,000 units of an endoglycosidase hydrolase (e.g., rHuPH20).

[0286] It will be readily apparent to those skilled in the art that the amount of endoglycosidase hydrolase (e.g., rHuPH20) can be expressed in units or U / mL, or the amount of endoglycosidase hydrolase (e.g., rHuPH20) can be expressed in mg / mL (or other weight-based units). For example, in some embodiments, the pharmaceutical composition comprises an amount of endoglycosidase hydrolase (e.g., rHuPH20) expressed as at least about 500 U / mL or at least about 0.00455 mg / mL. In another example, in some embodiments, the pharmaceutical composition comprises an amount of endoglycosidase hydrolase (e.g., rHuPH20) expressed as at least about 2000 U / mL or at least about 0.0182 mg / mL.

[0287] In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase (e.g., rHuPH20) in an amount of from about 50 units (U) to about 100,000 U, from about 500 U to about 100,000 U, from about 1000 U to about 100,000 U, from about 5000 U to about 100,000 U, from about 10,000 U to about 100,000 U, from about 15,000 U to about 100,000 U, from about 20,000 U to about 100,000 U, from about 500 U to about 50,000 U, from about 1000 U to about 50,000 U, from about 5000 U to about 50,000 U, from about 10,000 U to about 50,000 U, from about 15,000 U to about 50,000 U, from about 20,000 U to about 50,000 U, from about 15,000 U to about 45,000 U, from about 16,000 U to about 40,000 U, from about 17,000 U to about 35,000 U, from about 18,000 U to about 30,000 U, from about 19,000 U to about 29,000 U, from about 19,000 U to about 28,000 U, from about 19,000 U to about 27,000 U, from about 19,000 U to about 26,000 U, from about 19,000 U to about 25,000 U, from about 19,000 U to about 24,000 U, from about 19,000 U to about 23,000 U, from about 19,000 U to about 22,000 U, from about 19,000 U to about 21,000 U, from about 20,000 U to about 28,000 U, from about 21,000 U to about 27,000 U, from about 22,000 U to about 26,000 U, or from about 23,000 U to about 25,000 U.

[0288] In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase (e.g., rHuPH20) in an amount of 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.

[0289] In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase (e.g., rHuPH20) at 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, 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 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, 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.

[0290] In some embodiments, the pharmaceutical composition comprises an endoglycosidase hydrolase (e.g., rHuPH20) at 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.

[0291] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL.

[0292] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL.

[0293] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0294] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL.

[0295] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL.

[0296] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0297] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL.

[0298] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL.

[0299] In certain embodiments, the pharmaceutical composition comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL. In certain embodiments, the pharmaceutical composition comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0300] In some embodiments, the pharmaceutical composition comprises (a) about 1200 mg of nivolumab; (b) about 400 mg of relatlimab; (c) about 8.68 mg of histidine; (d) about 11.8 mg of histidine HCl H2O; (e) about 479 mg of sucrose; (f) about 2.80 mg of polysorbate 80; (g) about 0.110 mg of pentetic acid; and (h) about 4.18 mg of methionine; and (i) about 0.102 mg of rHuPH20, wherein (a)-(h) are reconstituted in water to a final volume of at least about 15 mL. In some embodiments, the pharmaceutical composition comprises (a) about 1200 mg of nivolumab; (b) about 200 mg of relatlimab; (c) about 8.68 mg of histidine; (d) about 11.8 mg of histidine HCl H2O; (e) about 479 mg of sucrose; (f) about 2.80 mg of polysorbate 80; (g) about 0.110 mg of pentetic acid; and (h) about 4.18 mg of methionine; and (i) about 0.102 mg of rHuPH20, wherein (a)-(h) are reconstituted in water to a final volume of at least about 15 mL. In certain embodiments, the pharmaceutical composition comprises (a) about 960 mg of an anti-PD-1 antibody; (b) about 320 of an anti-LAG-3 antibody; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) about 960 mg of nivolumab; (b) about 320 mg of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20.

[0301] In certain embodiments, the pharmaceutical composition comprises: (a) about 960 mg of an anti-PD-1 antibody; (b) about 360 of an anti-LAG-3 antibody; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises: (a) about 960 mg of nivolumab; (b) about 320 mg of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 24,000 U of rHuPH20.

[0302] In certain embodiments, 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 of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20. In certain embodiments, the unit dose described herein comprises: (a) about 80 mg / mL of nivolumab; (b) about 26.7 mg / mL of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20.

[0303] In certain embodiments, the unit dose described herein comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL. In certain embodiments, the unit dose described herein comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL.

[0304] In certain embodiments, the unit dose described herein comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL. In certain embodiments, the unit dose described herein comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 26.7 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0305] In certain embodiments, the unit doses described herein comprise: (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 of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20. In certain embodiments, the unit doses described herein comprise: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20.

[0306] In certain embodiments, the unit doses described herein comprise: (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 of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2400 U / mL of rHuPH20. In certain embodiments, the unit doses described herein comprise: (a) about 80 mg / mL of nivolumab; (b) about 13.35 mg / mL of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2400 U / mL of rHuPH20.

[0307] In certain embodiments, the unit dose described herein comprises (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL. In certain embodiments, the unit dose described herein comprises (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0308] In certain embodiments, the unit dose described herein comprises (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL. In certain embodiments, the unit dose described herein comprises (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2000 U / mL.

[0309] In certain embodiments, the unit dosage described herein comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL. In certain embodiments, the unit dosage described herein comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 2400 U / mL.

[0310] In certain embodiments, the unit dosage described herein comprises: (a) an anti-PD-1 antibody at about 80 mg / mL; (b) an anti-LAG-3 antibody at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL. In certain embodiments, the unit dosage described herein comprises: (a) nivolumab at about 80 mg / mL; (b) relatlimab at about 13.35 mg / mL; (c) histidine at about 20 mM; (d) sucrose at about 250 mM; (e) polysorbate 80 at about 0.05% w / v; (f) pentetic acid at about 50 μM; (g) methionine at about 5 mM; and (h) rHuPH20 at about 0.0182 mg / mL.

[0311] In some embodiments, the unit dose described herein comprises (a) about 1200 mg of nivolumab; (b) about 400 mg of relatlimab; (c) about 8.68 mg of histidine; (d) about 11.8 mg of histidine HCl H2O; (e) about 479 mg of sucrose; (f) about 2.80 mg of polysorbate 80; (g) about 0.110 mg of pentetic acid; and (h) about 4.18 mg of methionine; and (i) about 0.102 mg of rHuPH20, wherein (a)-(h) are reconstituted in at least about 15 mL of final volume in water. In some embodiments, the unit dose described herein comprises (a) about 1200 mg of nivolumab; (b) about 200 mg of relatlimab; (c) about 8.68 mg of histidine; (d) about 11.8 mg of histidine HCl H2O; (e) about 479 mg of sucrose; (f) about 2.80 mg of polysorbate 80; (g) about 0.110 mg of pentetic acid; and (h) about 4.18 mg of methionine; and (i) about 0.102 mg of rHuPH20, wherein (a)-(h) are reconstituted in at least about 15 mL of final volume in water.

[0312] In certain embodiments, the unit dose described herein comprises (a) about 960 mg of an anti-PD-1 antibody; (b) about 320 of an anti-LAG-3 antibody; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) about 960 mg of nivolumab; (b) about 320 mg of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20.

[0313] In certain embodiments, the unit dose described herein comprises (a) about 960 mg of an anti-PD-1 antibody; (b) about 360 of an anti-LAG-3 antibody; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 2000 U / mL of rHuPH20. In certain embodiments, the pharmaceutical composition comprises (a) about 960 mg of nivolumab; (b) about 320 mg of relatlimab; (c) about 20 mM of histidine; (d) about 250 mM of sucrose; (e) about 0.05% w / v of polysorbate 80; (f) about 50 μM of pentetic acid; (g) about 5 mM of methionine; and (h) about 24,000 U of rHuPH20.

[0314] II.I. Additional Therapeutic Agents In some embodiments, the pharmaceutical compositions disclosed herein further comprise an additional therapeutic agent.

[0315] The additional therapeutic agent can include any therapy and / or any standard of care therapy known in the art for the treatment of the subject's tumor. In some embodiments, the additional therapeutic agent comprises an anti-cancer agent. In some embodiments, the anti-cancer agent comprises a tyrosine kinase inhibitor, an anti-angiogenic agent, a checkpoint inhibitor, a checkpoint stimulator, a chemotherapeutic agent, an immunotherapeutic agent, a platinum agent, an alkylating agent, a taxane, a nucleoside analog, an antimetabolite, a topoisomerase inhibitor, an anthracycline, a vinca alkaloid or any combination thereof.

[0316] In some embodiments, the tyrosine kinase inhibitor comprises 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, pemigatinib (also known as PEMAZYRE), everolimus (also known as AFINITOR or ZORTRESS), gefitinib (IRESSA, a small molecule TKI of EGFR), imatinib (e.g., imatinib mesylate), lapatinib (e.g., lapatinib ditosylate, also known as TYKERB), 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 of EGFR), afatinib (GILOTRIF, a small molecule TKI of EGFR), dacomitinib (VIZIMPRO, a small molecule TKI of EGFR), osimertinib (TAGRISSO, a small molecule TKI of EGFR), alectinib (ALECENSA, a small molecule TKI of ALK), ceritinib (ZYKADIA, a small molecule TKI of ALK and ROS-1), brigatinib (ALUNBRIG (registered trademark), 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.

[0317] In some embodiments, the anti-angiogenic agent comprises an inhibitor of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), platelet-derived growth factor (PDGF), PDGF receptor (PDGFR), angiopoietin (Ang), tyrosine kinase (Tie) receptor containing Ig-like and EGF-like domains, hepatocyte growth factor (HGF), tyrosine protein kinase Met (c-MET), C-type lectin family 14 member A (CLEC14A), multimerein 2 (MMRN2), shock protein 70-1A (HSP70-1A), epidermal growth factor (EGF), EGFR, or any combination thereof. In some embodiments, the anti-angiogenic agent comprises bevacizumab (also known as AVASTIN), ranibizumab (also known as LUCENTIS), ramucirumab (also known as CYRAMZA), aflibercept (also known as EYLEA or ZALTRAP), tanibirumab, orlaratumab (also known as LARTRUVO), nesvacumab, AMG780, MEDI3617, vanucizumab, lirilumab, ficlatuzumab, TAK-701, ofatumumab, emibetuzumab, or any combination thereof.

[0318] In some embodiments, the checkpoint stimulator comprises an agonist of 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), CD28H, or any combination thereof.

[0319] In some embodiments, the chemotherapeutic agent comprises an alkylating agent, an antimetabolite, an antitumor antibiotic, a mitotic inhibitor, a hormone or hormone regulator, a protein tyrosine kinase inhibitor, an epidermal growth factor inhibitor, a proteasome inhibitor, other neoplastic agents, or any combination thereof.

[0320] In some embodiments, the immunotherapeutic agent comprises an antibody that specifically binds to 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.

[0321] In some embodiments, the platinum agent comprises cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin (e.g., triplatin tetranitrate), lipoplatin, phenanthriplatin, or any combination thereof.

[0322] In some embodiments, 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.

[0323] In some embodiments, the taxane comprises paclitaxel, albumin-bound paclitaxel, docetaxel, cabazitaxel, or any combination thereof.

[0324] In some embodiments, the nucleoside analog comprises cytarabine, gemcitabine, lamivudine, entecavir, telbivudine, or any combination thereof.

[0325] In some embodiments, the antimetabolite comprises capecitabine, cladribine, clofarabine, cytarabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, pemetrexed, pentostatin, pralatrexate, thioguanine, or any combination thereof.

[0326] In some embodiments, the topoisomerase inhibitor comprises etoposide, mitoxantrone, doxorubicin, irinotecan, topotecan, camptothecin, or any combination thereof.

[0327] In some embodiments, the anthracycline is doxorubicin, daunorubicin, epirubicin, idarubicin, or any combination thereof.

[0328] In some embodiments, the vinca alkaloid is vinblastine, vincristine, vinorelbine, vindesine, vincaminol, vinepidine, vinburnine, or any combination thereof.

[0329] In some embodiments, the checkpoint inhibitor is a cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitor, a T cell immunoglobulin and ITIM domain (TIGIT) inhibitor, a T cell immunoglobulin and mucin domain-containing 3 (TIM-3) inhibitor, a TIM-1 inhibitor, a TIM-4 inhibitor, a B7-H3 inhibitor, a B7-H4 inhibitor, a B cell and T cell lymphocyte attenuator (BTLA) inhibitor, a V-domain Ig suppressor of T cell activation (VISTA) inhibitor, an indoleamine 2,3-dioxygenase (IDO) inhibitor, a nicotinamide adenine dinucleotide phosphate oxidase isoform 2 (NOX2) inhibitor, a killer cell immunoglobulin-like receptor (KIR) inhibitor, an adenosine A2a receptor (A2aR) inhibitor, a transforming growth factor beta (TGF-β) inhibitor, a phosphoinositide 3-kinase (PI3K) inhibitor, a CD47 inhibitor, a CD48 inhibitor, a CD73 inhibitor, a CD113 inhibitor, a sialic acid-binding immunoglobulin-like lectin 7 (SIGLEC-7) inhibitor, a SIGLEC-9 inhibitor, a SIGLEC-15 inhibitor, a glucocorticoid-induced TNFR-related protein (GITR) inhibitor, a galectin-1 inhibitor, a galectin-9 inhibitor, a carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1) inhibitor, a G protein-coupled receptor 56 (GPR56) inhibitor, a glycoprotein A repeat predominant (GARP) inhibitor, a 2B4 inhibitor, a programmed death 1 homolog (PD1H) inhibitor, a leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) inhibitor, or any combination thereof.

[0330] In some embodiments, the additional therapeutic agent comprises a second antibody. In some embodiments, the additional therapeutic agent comprises an antibody that specifically binds 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 embodiments, the additional therapeutic agent comprises IL-2 (e.g., bempegaldesleukin). In some embodiments, the additional therapeutic agent comprises IL12-Fc (e.g., BMS-986415).

[0331] In some embodiments, 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 embodiments, the anti-CTLA-4 antibody is any anti-CTLA-4 antibody disclosed herein. In some embodiments, the additional therapeutic agent comprises tremelimumab. In some embodiments, the additional therapeutic agent comprises ipilimumab.

[0332] In some embodiments, the additional therapeutic agent comprises an anti-CD137 antibody. The anti-CD137 antibody can be any antibody that binds to CD137 and inhibits its activity. In some embodiments, the anti-CD137 antibody comprises any anti-CD137 antibody disclosed herein. In some embodiments, the additional therapeutic agent comprises urelumab.

[0333] In some embodiments, the additional therapeutic agent comprises an anti-KIR antibody. The anti-KIR antibody comprises any antibody that binds to KIR and inhibits its activity. In some embodiments, the anti-KIR antibody comprises any anti-KIR antibody disclosed herein. In some embodiments, the additional therapeutic agent comprises lirilumab.

[0334] In some embodiments, 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 embodiments, the anti-GITR antibody comprises any anti-GITR antibody disclosed herein. In some embodiments, the additional therapeutic agent comprises MK4166. In some embodiments, the a...

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

1.

3. (a) 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, (b) Approximately 10 mg / mL to approximately 500 mg / mL, approximately 10 mg / mL to approximately 450 mg / mL, approximately 10 mg / mL to approximately 400 mg / mL, approximately 10 mg / mL to approximately 350 mg / mL, approximately 10 mg / mL to approximately 300 mg / mL, approximately 10 mg / mL to approximately 250 mg / mL, approximately 10 mg / mL mL ~ approximately 200 mg / mL, approximately 10 mg / mL ~ approximately 190 mg / mL, approximately 10 mg / mL ~ approximately 180 mg / mL, approximately 10 mg / mL ~ approximately 170 mg / mL, approximately 10 mg / mL ~ approximately 160 mg / mL, approximately 10 mg / mL ~ approximately 150 mg / mL, approximately 10 mg / mL ~ approximately 140 mg / mL, approximately 10mg / mL to approximately 130mg / mL, approximately 10mg / mL to approximately 120mg / mL, approximately 10mg / mL to approximately 110mg / mL, approximately 10mg / mL to approximately 100mg / mL, approximately 10mg / mL to approximately 90mg / mL, approximately 10mg / mL to approximately 85mg / mL, approximately 10mg / mL L ~ approximately 80 mg / mL, approximately 20 mg / mL ~ approximately 500 mg / mL, approximately 20 mg / mL ~ approximately 450 mg / mL, approximately 20 mg / mL ~ approximately 400 mg / mL, approximately 20 mg / mL ~ approximately 350 mg / mL, approximately 20 mg / mL ~ approximately 300 mg / mL, approximately 20 mg / mL ~ approximately 250 mg / mL L, approximately 20 mg / mL to approximately 200 mg / mL, approximately 20 mg / mL to approximately 190 mg / mL, approximately 20 mg / mL to approximately 180 mg / mL, approximately 20 mg / mL to approximately 170 mg / mL, approximately 20 mg / mL to approximately 160 mg / mL, approximately 20 mg / mL to approximately 150 mg / mL, approximately 20 mg / mL L ~ approximately 140 mg / mL, approximately 20 mg / mL ~ approximately 130 mg / mL, approximately 20 mg / mL ~ approximately 120 mg / mL, approximately 20 mg / mL ~ approximately 110 mg / mL, approximately 20 mg / mL ~ approximately 100 mg / mL, approximately 20 mg / mL ~ approximately 90 mg / mL, approximately 20 mg / mL ~ approximately 85 mg / mL Approximately 20 mg / mL to approximately 80 mg / mL, approximately 50 mg / mL to approximately 200 mg / mL, approximately 50 mg / mL to approximately 190 mg / mL, approximately 50 mg / mL to approximately 180 mg / mL, approximately 50 mg / mL to approximately 170 mg / mL, approximately 50 mg / mL to approximately 160 mg / mL, approximately 50 mg / mL... Approximately 150 mg / mL, approximately 50 mg / mL to approximately 140 mg / mL, approximately 50 mg / mL to approximately 130 mg / mL, approximately 50 mg / mL to approximately 120 mg / mL, approximately 50 mg / mL to approximately 110 mg / mL, approximately 50 mg / mL to approximately 100 mg / mL, approximately 50 mg / mL to approximately 90 mg / mL,The anti-PD-1 antibody in concentrations of approximately 50 mg / mL to approximately 85 mg / mL, approximately 50 mg / mL to approximately 80 mg / mL, approximately 100 mg / mL to approximately 200 mg / mL, approximately 100 mg / mL to approximately 150 mg / mL, approximately 150 mg / mL to approximately 200 mg / mL, approximately 135 mg / mL to approximately 180 mg / mL, approximately 100 mg / mL to approximately 130 mg / mL, or approximately 108 mg / mL to approximately 132 mg / mL. (c) The anti-PD-1 antibody in an amount of 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, or (d) 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 m g / 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 9 5 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 1 40mg / mL, about 150mg / mL, about 160mg / mL, about 170mg / mL, about 175mg / mL, about 180mg / mL, about 190mg / mL, about 200mg / 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, Approximately 290 mg / mL, approximately 300 mg / mL, approximately 310 mg / mL, approximately 320 mg / mL, approximately 330 mg / mL, approximately 340 mg / mL, approximately 350 mg / mL, approximately 360 mg / mL , the anti-PD-1 antibody in doses of approximately 370 mg / mL, approximately 380 mg / mL, approximately 390 mg / mL, approximately 400 mg / mL, approximately 410 mg / mL, approximately 420 mg / mL, approximately 430 mg / mL, approximately 440 mg / mL, approximately 450 mg / mL, approximately 460 mg / mL, approximately 470 mg / mL, approximately 480 mg / mL, approximately 490 mg / mL, or approximately 500 mg / mL, and / or (e) 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 ~about 800mg, about 0.25mg to about 400mg, about 0.25mg to about 100mg, about 0.25mg to about 50mg, about 0.25mg ~about 40mg, about 0.25mg to about 30mg, about 0.25mg to about 20mg, about 20mg to about 2000mg, about 20mg to about 16 00mg, about 20mg to about 1200mg, about 20mg to about 800mg, about 20mg to about 400mg, about 20mg to about 100mg, about 100 mg to approximately 2000 mg, approximately 100 mg to approximately 1800 mg, approximately 100 mg to approximately 1600 mg, approximately 100 mg to approximately 1400 mg, approximately 100 mg to approximately 1200 mg, approximately 100 mg to approximately 1000 mg, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 600 mg, approximately 100 mg to approximately 400 mg, approximately 400 mg to approximately 2000 mg, approximately 400 mg to approximately 1800 mg, approximately 400 mg to approximately 1600 mg, approximately 400 mg to approximately 1400 mg, approximately 400 mg to approximately 1200 mg, or approximately 400 mg to approximately 1000 mg of the aforementioned anti-PD-1 antibody, or (f) Approximately 0.25 mg, approximately 0.5 mg, approximately 0.75 mg, approximately 1 mg, approximately 1.25 mg, approximately 1.5 mg, approximately 1.75 mg, approximately 2 mg, approximately 2.25 mg, approximately 2.5 mg, approximately 2.75 mg, approximately 3 mg, approximately 3.25 mg, approximately 3.5 mg, approximately 3.75 mg, approximately 4 mg, approximately 4.25 mg, approximately 4.5 mg, approximately 4.75 mg, approximately 5 mg, approximately 5.25 mg, approximately 5.5 mg, approximately 5.75 mg, approximately 6 mg, approximately 6.25 mg, approximately 6.5 mg, approximately 6.75 mg, approximately 7 mg, approximately 7.25 mg, approximately 7.5 mg, approximately 7.75 mg, approximately 8 mg, approximately 8.25 mg, approximately 8.5 mg, approximately 8.75 mg g, approximately 9 mg, approximately 9.25 mg, approximately 9.5 mg, approximately 9.75 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 1 20 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg Approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 8 30 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, approximately 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg, approximately 1000 mgApproximately 1040 mg, approximately 1080 mg, approximately 1100 mg, approximately 1140 mg, approximately 1180 mg, approximately 1200 mg, approximately 1240 mg, approximately 1280 mg, approximately 1300 mg, approximately 1340 mg, approximately 1380 mg, approximately 1400 mg, approximately 1440 mg, approximately 1480 mg, approximately 1500 mg, approximately 1540 mg, approximately 1580 mg, approximately 1600 mg, approximately 1640 mg, approximately 1680 mg, approximately 1700 mg, approximately 1740 mg, approximately 1780 mg, approximately 1800 mg, approximately 1840 mg, approximately 1880 mg, approximately 1900 mg, approximately 1940 mg, approximately 1980 mg, or approximately 2000 mg of the anti-PD-1 kinase, A pharmaceutical composition according to claim 1, comprising:

4. (a) at least about 3 mg / mL to at least about 200 mg / mL of the anti-LAG-3 antibody, (b) 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 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 m g / 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 m g / 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 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 2 7 mg / mL, about 1 mg / mL to about 26 mg / mL, about 1 mg / mL to about 25 mg / mL, about 1 mg / mL to about 20 mg / mL, about 1 mg / mL mL to approximately 15 mg / mL, approximately 1 mg / mL to approximately 10 mg / mL or approximately 1 mg / mL to approximately 5 mg / mL, approximately 3 mg / mL to approximately 200 mg / mL, approximately 5 mg / mL to approximately 250 mg / mL, approximately 5 mg / mL to approximately 200 mg / mL, approximately 5 mg / mL to approximately 150 mg / mL, approximately 5 mg / mL to approximately 140 mg / mL, approximately 5 mg / mL to approximately 130 mg / mL, approximately 5 mg / mL to approximately 120 mg / mL, approximately 5 mg / mL to approximately 110 mg / mL, approximately 5 mg / mL to approximately 100 mg / mL, approximately 5 mg / mL to approximately 90 mg / mL, approximately 5 mg / mL to approximately 80 mg / mL, approximately 5 mg / mL L 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 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 4 0 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 ~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 The anti-LAG-3 antibody in concentrations of approximately 20 mg / mL to 20 mg / mL, approximately 20 mg / mL to 50 mg / mL, approximately 20 mg / mL to 45 mg / mL, approximately 20 mg / mL to 40 mg / mL, approximately 20 mg / mL to 35 mg / mL, approximately 20 mg / mL to 30 mg / mL, approximately 20 mg / mL to 29 mg / mL, approximately 20 mg / mL to 28 mg / mL, approximately 20 mg / mL to 27 mg / mL, approximately 20 mg / mL to 26 mg / mL, approximately 20 mg / mL to 25 mg / mL, approximately 25 mg / mL to 30 mg / mL, approximately 25 mg / mL to 29 mg / mL, approximately 25 mg / mL to 28 mg / mL, or approximately 25 mg / mL to 27 mg / mL. (c) 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, The anti-LAG-3 antibody in an amount of 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, or (d) 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 / m L, about 13.3 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, about 1 35 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 22 0 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 m The anti-LAG-3 antibody in g / mL, approximately 330 mg / mL, approximately 340 mg / mL, approximately 350 mg / mL, approximately 360 mg / mL, approximately 370 mg / mL, approximately 380 mg / mL, approximately 390 mg / mL, approximately 400 mg / mL, approximately 410 mg / mL, approximately 420 mg / mL, approximately 430 mg / mL, approximately 440 mg / mL, approximately 450 mg / mL, approximately 460 mg / mL, approximately 470 mg / mL, approximately 480 mg / mL, approximately 490 mg / mL, or approximately 500 mg / mL, and / or (e) 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 ~about 800mg, about 0.25mg to about 400mg, about 0.25mg to about 100mg, about 0.25mg to about 50mg, about 0.25mg ~about 40mg, about 0.25mg to about 30mg, about 0.25mg to about 20mg, about 20mg to about 2000mg, about 20mg to about 160 0mg, about 20mg to about 1200mg, about 20mg to about 800mg, about 20mg to about 400mg, about 20mg to about 100mg, about 1 The anti-LAG-3 antibody in amounts of 00 mg to approximately 2000 mg, approximately 100 mg to approximately 1800 mg, approximately 100 mg to approximately 1600 mg, approximately 100 mg to approximately 1400 mg, approximately 100 mg to approximately 1200 mg, approximately 100 mg to approximately 1000 mg, approximately 100 mg to approximately 800 mg, approximately 100 mg to approximately 600 mg, approximately 100 mg to approximately 400 mg, approximately 400 mg to approximately 2000 mg, approximately 400 mg to approximately 1800 mg, approximately 400 mg to approximately 1600 mg, approximately 400 mg to approximately 1400 mg, approximately 400 mg to approximately 1200 mg, or approximately 400 mg to approximately 1000 mg, or (f) Approximately 0.25 mg, approximately 0.5 mg, approximately 0.75 mg, approximately 1 mg, approximately 1.25 mg, approximately 1.5 mg, approximately 1.75 mg, approximately 2 mg, approximately 2.25 mg, approximately 2.5 mg, approximately 2.75 mg, approximately 3 mg, approximately 3.25 mg, approximately 3.5 mg, approximately 3.75 mg, approximately 4 mg, approximately 4.25 mg, approximately 4.5 mg, approximately 4.75 mg, approximately 5 mg, approximately 5.25 mg, approximately 5.5 mg, approximately 5.75 mg, approximately 6 mg, approximately 6.25 mg, approximately 6.5 mg, approximately 6.75 mg, approximately 7 mg, approximately 7.25 mg, approximately 7.5 mg, approximately 7.75 mg, approximately 8 mg, approximately 8.25 mg, approximately 8.5 mg, approximately 8.75 mg g, approximately 9 mg, approximately 9.25 mg, approximately 9.5 mg, approximately 9.75 mg, approximately 10 mg, approximately 15 mg, approximately 20 mg, approximately 25 mg, approximately 30 mg, approximately 35 mg, approximately 40 mg, approximately 45 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 110 mg, approximately 1 20 mg, approximately 130 mg, approximately 140 mg, approximately 150 mg, approximately 160 mg, approximately 170 mg, approximately 180 mg, approximately 190 mg, approximately 200 mg, approximately 210 mg, approximately 220 mg, approximately 230 mg, approximately 240 mg, approximately 250 mg, approximately 260 mg, approximately 270 mg, approximately 280 mg, approximately 290 mg, approximately 300 mg, approximately 310 mg, approximately 320 mg, approximately 330 mg, approximately 340 mg, approximately 350 mg, approximately 360 mg, approximately 370 mg, approximately 380 mg, approximately 390 mg, approximately 400 mg, approximately 410 mg, approximately 420 mg, approximately 430 mg, approximately 440 mg, approximately 450 mg, approximately 460 mg, approximately 470 mg Approximately 480 mg, approximately 490 mg, approximately 500 mg, approximately 510 mg, approximately 520 mg, approximately 530 mg, approximately 540 mg, approximately 550 mg, approximately 560 mg, approximately 570 mg, approximately 580 mg, approximately 590 mg, approximately 600 mg, approximately 610 mg, approximately 620 mg, approximately 630 mg, approximately 640 mg, approximately 650 mg mg, approximately 660 mg, approximately 670 mg, approximately 680 mg, approximately 690 mg, approximately 700 mg, approximately 710 mg, approximately 720 mg, approximately 730 mg, approximately 740 mg, approximately 750 mg, approximately 760 mg, approximately 770 mg, approximately 780 mg, approximately 790 mg, approximately 800 mg, approximately 810 mg, approximately 820 mg, approximately 8 30 mg, approximately 840 mg, approximately 850 mg, approximately 860 mg, approximately 870 mg, approximately 880 mg, approximately 890 mg, approximately 900 mg, approximately 910 mg, approximately 920 mg, approximately 930 mg, approximately 940 mg, approximately 950 mg, approximately 960 mg, approximately 970 mg, approximately 980 mg, approximately 990 mg, approximately 1000 mgApproximately 1040 mg, approximately 1080 mg, approximately 1100 mg, approximately 1140 mg, approximately 1180 mg, approximately 1200 mg, approximately 1240 mg, approximately 1280 mg, approximately 1300 mg, approximately 1340 mg, approximately 1380 mg, approximately 1400 mg, approximately 1440 mg, approximately 1480 mg, approximately 1500 mg, approximately 1540 mg, approximately 1580 mg, approximately 1600 mg, approximately 1640 mg, approximately 1680 mg, approximately 1700 mg, approximately 1740 mg, approximately 1780 mg, approximately 1800 mg, approximately 1840 mg, approximately 1880 mg, approximately 1900 mg, approximately 1940 mg, approximately 1980 mg, or approximately 2000 mg of the anti-LAG-3 kinase, A pharmaceutical composition according to claim 1, comprising:

5. (a) at least about 5 units ("U") to at least about 100,000 U of the endoglycosidase hydrolase, (b) About 50U to about 100,000U, about 500U to about 100,000U, about 1,000U to about 100,000U, about 5,000U to about 100,000U , about 10,000U to about 100,000U, about 15,000U to about 100,000U, about 20,000U to about 100,000U, about 500U to about 50,00 0U, 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 50,0 00U, 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, approximately 18,000U to approximately 30,000U, approximately 19,000U to approximately 29,000U, approximately 19,000U to approximately 28,000U, approximately 19,000U to Approximately 27,000U, approximately 19,000U to approximately 26,000U, approximately 19,000U to approximately 25,000U, approximately 19,000U to approximately 24,000U, approximately 19,000 Endoglycosidase hydrolase in amounts of U to approximately 23,000 U, approximately 19,000 U to approximately 22,000 U, approximately 19,000 U to approximately 21,000 U, approximately 20,000 U to approximately 28,000 U, approximately 21,000 U to approximately 27,000 U, approximately 22,000 U to approximately 26,000 U, or approximately 23,000 U to approximately 25,000 U. (c) at least about 5U, at least about 10U, at least about 20U, at least about 30U, at least about 40U, at least about 50U, at least about 75U, at least about 100U, at least about 200U, at least about 300U, at least about 400U, at least about 500U, at least about 750U, at least about 1000U, at least about 2000U, at least about 3000U, at least about 4000U, at least about 5000U, at least about 6 Endoglycosidase hydrolase in amounts of 000U, at least about 7000U, at least about 8000U, at least about 9000U, at least about 10,000U, at least about 20,000U, at least about 30,000U, at least about 40,000U, at least about 50,000U, at least about 60,000U, at least about 70,000U, at least about 80,000U, at least about 90,000U, or at least about 100,000U, or (d) Approximately 50U, approximately 100U, approximately 150U, approximately 200U, approximately 250U, approximately 300U, approximately 400U, approximately 500U, approximately 600U, approximately 700U, approximately 800U, approximately 900U, approximately 1000U, approximately 150 0U, about 2000U, about 2500U, about 3000U, about 4000U, about 5000U, about 10,000U, about 15,000U, about 20,000U, about 24,000U, about 25,000U, about 3 Endoglycosidase hydrolase in amounts of 0,000 U, approximately 35,000 U, approximately 40,000 U, approximately 45,000 U, approximately 48,000 U, approximately 50,000 U, approximately 55,000 U, approximately 60,000 U, approximately 65,000 U, approximately 70,000 U, approximately 75,000 U, approximately 80,000 U, approximately 85,000 U, approximately 90,000 U, approximately 95,000 U, or approximately 100,000 U, and / or (e) Endoglycosidase hydrolase in an amount of at least about 500 U / mL to at least about 5000 U / mL (f) 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, Approximately 250U / mL to approximately 8000U / mL, approximately 300U / mL to approximately 7500U / mL, approximately 350U / mL to approximately 7000U / mL, approximately 400U / mL to approximately 6500U / mL, approximately 450U / mL to about 6000U / mL, about 500U / mL to about 5500U / mL, about 550U / mL to about 5000U / mL, about 600U / mL to about 4500U / mL, about 650U / mL to about 4000U / mL, about 700U / mL to about 3500U / mL, about 750U / mL to about 3000U / mL, about 800U / mL to about 2500U / mL, about 900U / mL to about 2500U / mL, about 1000U / mL to about 2500U / mL, about 1500U / mL to about 2500U / mL, about 1600U / mL to about 2500U / mL, about 1700U / mL to about 2500U / mL 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 / m L, the endoglycosidase hydrolase in concentrations of approximately 2200 U / mL to approximately 2500 U / mL, approximately 2300 U / mL to approximately 2500 U / mL, approximately 1500 U / mL to approximately 2500 U / mL, approximately 1600 U / mL to approximately 2400 U / mL, approximately 1700 U / mL to approximately 2300 U / mL, approximately 1800 U / mL to approximately 2200 U / mL, or approximately 1900 U / mL to approximately 2100 U / mL. (g) at least about 50 U / mL of the endoglycosidase hydrolase, (h) Endoglycosidase hydrolase in an amount of 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 U / mL, at least about 2500 U / mL, at least about 3000 U / mL, at least about 3500 U / mL, at least about 4000 U / mL, at least about 4500 U / mL, or at least about 5000 U / mL, or (i) 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 / m L, 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 / m L, about 750U / mL, about 800U / mL, about 850U / mL, about 900U / mL, about 950U / mL, about 1000U / mL, about 1100U / mL, about 1200U / mL, about 1300U / mL, about 1400U / mL, about 1500U / mL, about 1600U / mL, about 1700U / mL , approximately 1800 U / mL, approximately 1900 U / mL, approximately 2000 U / mL, approximately 2100 U / mL, approximately 2200 U / mL, approximately 2300 U / mL, approximately 2400 U / mL, approximately 2500 U / mL, approximately 3000 U / mL, approximately 3500 U / mL, approximately 4000 U / mL, approximately 4500 U / mL, approximately 5000 U / mL, approximately 5500 U / mL, approximately 6000 U / mL, approximately 6500 U / mL, approximately 7000 U / mL, approximately 7500 U / mL, approximately 8000 U / mL, approximately 8500 U / mL, approximately 9000 U / mL, approximately 9500 U / mL, or approximately 10,000 U / mL of the aforementioned endoglycosidase hydrolase. A pharmaceutical composition according to claim 1, comprising:

6. The aforementioned endoglycosidase hydrolase is (a) Cleave hyaluronic acid with hexosaminide β(1-4) or (1-3) linkages. (b) comprising the catalytic domain of hyaluronidase PH-20 (HuPH20), HYAL1, HYAL2, HYAL3, HYAL4, or HYALPS1, (c) an amino acid sequence having at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or about 100% sequence identity with amino acids 36-490 of Sequence ID No. 87, (d) containing hyaluronidase, (e) A hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, any variant thereof, and any isoform, (f) comprising rHuPH20 or a fragment thereof, (g) A modified hyaluronidase comprising one or more amino acid substitutions to a wild-type hyaluronidase selected from the group consisting of HuPH20, HYAL1, HYAL2, HYAL3, HYAL4, HYALPS1, or fragments thereof, (h) A modified hyaluronidase comprising (i) one or more amino acid substitutions in the α-helix region, (ii) one or more amino acid substitutions in the linker region, (iii) one or more deletions of N-terminal and / or C-terminal amino acids, or (iv) any combination of (i) to (iii), and / or (i) Includes modified rHuPH20, wherein the modified rHuPH20 is i. One or more amino acid substitutions in the α-helix region, linker region, or both the α-helix region and the linker region compared to wild-type rHuPH20; ii. Deletion of one or more N-terminal amino acids, one or more C-terminal amino acids, or one or more N-terminal amino acids and one or more C-terminal amino acids compared to wild-type rHuPH20; or iii. Both (i) and (ii) A pharmaceutical composition according to claim 1, comprising:

7. (a) an antioxidant or at least two antioxidants, (b) Isotonic modifiers and / or stabilizers, (c) buffering agent, (d) Surfactants, and / or (e) Additional therapeutic agents The pharmaceutical composition according to claim 1, further comprising the following:

8. (a) (i) The antioxidant is (1) Sacrificial antioxidant, metal ion chelating agent, or both, (2) Methionine, tryptophan, histidine, cysteine, ascorbic acid, glycine, or any combination thereof, and / or (3) Pentetic acid ("DTPA") or ethylenediaminetetraacetic acid ("EDTA") including, or (ii) The at least two antioxidants are (i) methionine and DTPA, or (ii) methionine and EDTA. (b) The isotonic modifier and / or stabilizer is (i) Sugars, amino acids, polyols, salts or combinations thereof, and / or (ii) Sucrose, sorbitol, trehalose, mannitol, glycerol, glycine, leucine, isoleucine, sodium chloride, proline, arginine, histidine, or any combination thereof including, (c) The buffer comprises histidine, succinate, tromethamine, sodium phosphate, sodium acetate, sodium citrate, or any combination thereof. (d) The surfactant comprises polysorbate 20, polysorbate 80, or poloxamer 188, and / or (e) The additional therapeutic agent is (i) antibody, (ii) Checkpoint inhibitors, or (iii) 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 The pharmaceutical composition according to claim 7, comprising:

9. (a)(i) Approximately 80 mg / mL of the anti-PD-1 antibody; (ii) the anti-LAG-3 antibody in an amount of approximately 26.7 mg / mL; and (iii) Approximately 0.0182 mg / mL of rHuPH20, (b)(i) Approximately 80 mg / mL of the anti-PD-1 antibody; (ii) the anti-LAG-3 antibody in an amount of approximately 26.7 mg / mL; and (iii) rHuPH2O at approximately 2000 U / mL, (c)(i) Approximately 960 mg of the anti-PD-1 antibody; (ii) Approximately 320 mg of the anti-LAG-3 antibody; and (iii) Approximately 0.0182 mg / mL of rHuPH20, (d)(i) Approximately 960 mg of the anti-PD-1 antibody; (ii) Approximately 320 mg of the anti-LAG-3 antibody; and (iii) rHuPH2O at approximately 2000 U / mL, (e)(i) Approximately 960 mg of the anti-PD-1 antibody; (ii) Approximately 320 mg of the anti-LAG-3 antibody; and (iii) Approximately 24,000 U of rHuPH20, (f)(i) Approximately 80 mg / mL of the anti-PD-1 antibody; (ii) The anti-LAG-3 antibody in an amount of approximately 26.7 mg / mL; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) Approximately 0.0182 mg / mL of rHuPH20, (g)(i) Approximately 80 mg / mL of the anti-PD-1 antibody; (ii) The anti-LAG-3 antibody in an amount of approximately 26.7 mg / mL; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) rHuPH2O at approximately 2000 U / mL, (h)(i) Approximately 80 mg / mL of the anti-PD-1 antibody; (ii) The anti-LAG-3 antibody in an amount of approximately 13.35 mg / mL; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) Approximately 0.0182 mg / mL of rHuPH20, (i) (i) Approximately 80 mg / mL of the anti-PD-1 antibody; (ii) The anti-LAG-3 antibody in an amount of approximately 13.35 mg / mL; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) rHuPH2O at approximately 2000 U / mL, (j)(i) Approximately 960 mg of the anti-PD-1 antibody; (ii) Approximately 320 mg of the anti-LAG-3 antibody; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) Approximately 0.0182 mg / mL of rHuPH20, (k)(i) Approximately 960 mg of the anti-PD-1 antibody; (ii) Approximately 320 mg of the anti-LAG-3 antibody; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) rHuPH20 at approximately 2000 U / mL, or (l)(i) Approximately 960 mg of the anti-PD-1 antibody; (ii) Approximately 320 mg of the anti-LAG-3 antibody; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) Approximately 24,000 U of rHuPH2O A pharmaceutical composition according to claim 1, comprising:

10. (a) The anti-PD-1 antibody is (i) Nivolumab, pembrolizumab, PDR001, MEDI-0680, semiprimab, tripalimab, tislerizumab, INCSHHR1210, TSR-042, GLS-010, AM-0001, STI-1110, AGEN2034, MGA012, BCD-100, IBI308, sasanlimab, BI754091, SSI-361 or any combination thereof, (ii) (1) CDR1, CDR2, and CDR3 domains of the heavy chain variable region having the amino acid sequence shown in SEQ ID NO: 13, and CDR1, CDR2, and CDR3 domains of the light chain variable region having the amino acid sequence shown in SEQ ID NO: 14; (2) Heavy chain variable regions CDR1, CDR2, and CDR3 containing the amino acid sequences shown in SEQ ID NO: 15, SEQ ID NO: 16, and SEQ ID NO: 17, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences shown in SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, respectively; (3) Heavy chain variable region and light chain variable region containing the amino acid sequences shown in SEQ ID NOs: 13 and 14, respectively; or (4) Heavy chain and light chain containing the amino acid sequences shown in SEQ ID NOs: 11 and 12, respectively. including, (b) The anti-LAG-3 antibody is (i) Relatrimab, 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, (ii) (1) 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; (2) Heavy chain variable regions CDR1, CDR2, and CDR3 containing the amino acid sequences shown in SEQ ID NO: 5, SEQ ID NO: 6, and SEQ ID NO: 7, respectively, and light chain variable regions CDR1, CDR2, and CDR3 containing the sequences shown in SEQ ID NO: 8, SEQ ID NO: 9, and SEQ ID NO: 10, respectively; (3) Heavy chain variable region and light chain variable region containing the amino acid sequences shown in SEQ ID NOs: 3 and 4, respectively; (4) Heavy and light chains containing the amino acid sequences shown in SEQ ID NOs: 1 and 2, respectively; or (5) Heavy and light chains containing the amino acid sequences shown in SEQ ID NOs. 21 and 2, respectively. including and / or (c) The anti-PD-L1 antibody includes BMS-936559, atezolizumab, durvalumab, avelumab, STI-1014, CX-072, KN035, LY3300054, BGB-A333, ICO36, FAZ053, CK-301, or any combination thereof. The pharmaceutical composition according to claim 1.

11. The pharmaceutical composition according to claim 1, wherein the anti-PD-1 antibody comprises nivolumab, and the anti-LAG-3 antibody comprises relatrimab.

12. (a) (i) nivolumab in approximately 80 mg / mL; (ii) Relatrimab at approximately 26.7 mg / mL; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) Approximately 0.0182 mg / mL of rHuPH20, (b) (i) Nivolumab at approximately 80 mg / mL; (ii) Relatrimab at approximately 26.7 mg / mL; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) rHuPH2O at approximately 2000 U / mL, (c)(i) Nivolumab at approximately 80 mg / mL; (ii) Relatrimab at approximately 13.35 mg / mL; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) Approximately 0.0182 mg / mL of rHuPH20, (d)(i) Nivolumab at approximately 80 mg / mL; (ii) Relatrimab at approximately 13.35 mg / mL; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) rHuPH2O at approximately 2000 U / mL, (e)(i) Approximately 1200 mg of nivolumab; (ii) Approximately 400 mg of relatrimab; (iii) Approximately 8.68 mg of histidine; (iv) Approximately 11.8 mg of histidine HCl H ２ O; (v) Approximately 479 mg of sucrose; (vi) Approximately 2.80 mg of polysorbate 80; (vii) Approximately 0.110 mg of pentetate; (viiii) Approximately 4.18 mg of methionine; (ix) Approximately 0.102 mg of rHuPH20, Here, (i) to (ix) are reconstituted in water to a final volume of at least approximately 15 mL. (f)(i) Approximately 960 mg of nivolumab; (ii) Approximately 320 mg of relatrimab; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) Approximately 0.0182 mg / mL of rHuPH20, (g)(i) Approximately 960 mg of nivolumab; (ii) Approximately 320 mg of relatrimab; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) rHuPH20 at approximately 2000 U / mL, or (h)(i) Approximately 960 mg of nivolumab; (ii) Approximately 320 mg of relatrimab; (iii) Approximately 20 mM histidine; (iv) Sucrose at approximately 250 mM; (v) Polysorbate 80 at approximately 0.05% w / v; (vi) Approximately 50 μM pentetate; (vii) about 5 mM methionine; and (viiii) Approximately 24,000 U of rHuPH2O A pharmaceutical composition according to claim 1, comprising:

13. (a) pH of about 5.2 to about 6.8, or (b) pH of approximately 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, or 6.8 A pharmaceutical composition according to claim 1, comprising:

14. A vial containing the pharmaceutical composition according to any one of claims 1 to 13.

15. A device comprising the pharmaceutical composition according to any one of claims 1 to 13.

16. The device according to claim 15, comprising a vial, syringe, auto-injector, wearable pump or wearable device, or pen-type syringe.

17. A pharmaceutical composition according to any one of claims 1 to 13, for use in providing treatment for a disease or disorder to a person in need thereof.

18. The pharmaceutical composition according to claim 17, wherein the pharmaceutical composition is administered subcutaneously.

19. The pharmaceutical composition according to claim 17, wherein the disease or disorder includes cancer.

20. The aforementioned cancer is (a) Squamous cell carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), squamous NSCLC, non-squamous NSCLC, glioma, gastrointestinal cancer, kidney cancer, clear cell carcinoma, ovarian cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, renal cell carcinoma (RCC), prostate cancer, hormone-resistant prostate adenocarcinoma, thyroid cancer, neuroblastoma, pancreatic cancer, glioblastoma, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, liver cancer, breast cancer, colon cancer, head and neck cancer, stomach cancer, germ cell tumor, pediatric sarcoma, sinus natural killer cancer, melanoma, bone cancer, skin cancer, uterine cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, pediatric Cancers of the cervix, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, rectal cancer, pediatric solid tumors, ureteral cancer, renal pelvis cancer, neoplasms of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axial tumors, brain tumors, brainstem gliomas, pituitary adenomas, Kaposi's sarcoma, epidermal carcinoma, squamous cell carcinoma, environmentally induced cancers including those induced by asbestos, virus-related cancers or cancers of virus origin (e.g., human papillomavirus (HPV-related or virus-derived tumors)) or any combination thereof, and / or (b) Unresectable or metastatic melanoma The pharmaceutical composition according to claim 19, comprising:

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