Anti-PD1 antibody preparations

Abstract

The present invention relates to pharmaceutical compositions of anti-PD-1 antibodies comprising a monocarboxylic or dicarboxylic acid buffer, arginine and / or lysine, and a surfactant.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical composition of an anti-PD1 antibody comprising a monocarboxylic or dicarboxylic acid buffer, arginine and / or lysine, and a surfactant. [Background technology]

[0002] Programmed cell death protein 1 (PD-1) is a cell surface protein that acts as an immune checkpoint and prevents autoimmune diseases by suppressing T cell inflammatory activity. PD-1 binds to two ligands, PD-L1 and PD-L2. PD-L1 overexpression has been found in several cancer types, and inhibition of the interaction between PD-1 and PD-L1 has been found to enhance T cell responses and thereby mediate antitumor activity.

[0003] Several antibodies targeting either PD-1 or PD-L1 have been developed. Pembrolizumab, marketed under the trade name Keytruda®, is a humanized IgG4 antibody that binds to PD-1 and blocks its interaction with PD-L1. It is currently approved for the treatment of several cancer types, including melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, bladder cancer, and Hodgkin's lymphoma. Nivolumab, marketed under the trade name Opdivo®, is a fully human IgG4 antibody that binds to PD-1 and blocks its interaction with PD-L1. It is currently approved for the treatment of melanoma, non-small cell lung cancer, and renal cell carcinoma.

[0004] Patent Documents 1 and 2 disclose liquid and lyophilized formulations of pembrolizumab containing a histidine buffer, polysorbate 80, and sucrose. Patent Document 3 discloses a formulation of an anti-PD1 antibody containing sodium acetate, α,α-trehalose dihydrate, and polysorbate 20 at pH 5.2.

[0005] Patent Document 4 describes a pharmaceutical formulation containing an anti-PD1 antibody, citrate, histidine, mannitol, sodium chloride, edetate, and polysorbate 20 or polysorbate 80, with a pH of 5.5 to 6.5.

[0006] Patent Document 5 discloses a pharmaceutical composition containing an anti-PD1 antibody, histidine, sucrose, proline, and polysorbate 80, having a pH of 6.0. Patent document 6 describes a formulation of an anti-PD1 antibody containing a buffer, a stabilizer, a non-ionic surfactant, and an antioxidant.

[0007] Patent Document 7 discloses a pharmaceutical composition containing an anti-PD1 antibody, histidine, sucrose, polysorbate 20, and EDTA, and having a pH of 6.5. Patent Document 8 describes a pharmaceutical composition containing an anti-PD1 antibody, a disaccharide, a buffer, a chelating agent, and a polysorbate, and having a pH of 4.5 to 5.5.

[0008] Patent document 9 describes a pharmaceutical composition comprising an anti-PD1 antibody, a buffer, a stabilizer, a surfactant, and an antioxidant. Patent document 10 discloses a pharmaceutical preparation of an anti-PD1 antibody that does not contain a buffer.

[0009] Patent Document 11 discloses a formulation of a biopharmaceutical containing at least one monocarboxylic or dicarboxylic acid or a salt thereof. Patent Document 12 describes a liquid pharmaceutical composition comprising an anti-PD1 antibody, a histidine or citrate buffer, a sugar or sugar alcohol, and a non-ionic surfactant.

[0010] Patent Document 13 describes a liquid pharmaceutical composition comprising an anti-PD1 antibody, a citrate buffer, an amino acid such as arginine or lysine, and a non-ionic surfactant. Nevertheless, there remains a need for stable formulations of anti-PD1 antibodies that are safe for administration to human patients, particularly for subcutaneous administration. [Prior art documents] [Patent documents]

[0011] [Patent Document 1] International Publication No. 2012 / 135408 [Patent Document 2] International Publication No. 2019 / 160751 [Patent Document 3] International Publication No. 2017 / 054646 [Patent Document 4] International Publication No. 2018 / 028383 [Patent Document 5] International Publication No. 2018 / 187057 [Patent Document 6] International Publication No. 2018 / 204368 [Patent Document 7] International Publication No. 2019 / 142149 [Patent Document 8] International Publication No. 2019 / 171253 [Patent Document 9] International Publication No. 2020 / 097141 [Patent Document 10] International Publication No. 2021 / 118321 [Patent Document 11] European Patent Application Publication No. 2471554 [Patent Document 12] International Publication No. 2021 / 123202 [Patent Document 13] International Publication No. 2022 / 268887 Summary of the Invention

[0012] The present invention provides (a) an anti-human PD1 antibody; (b) arginine and / or lysine, (c) a nonionic surfactant; (d) a monocarboxylic or dicarboxylic acid having a backbone of 2 to 6 carbon atoms or at least one salt thereof, preferably an unbranched monocarboxylic or dicarboxylic acid having a backbone of 4, 5, or 6 carbon atoms; The liquid pharmaceutical composition has a pH of 5.0 to 5.8.

[0013] In one embodiment, the monocarboxylic or dicarboxylic acid having a backbone of 2 to 6 carbon atoms or at least one salt thereof is selected from the group consisting of acetate, adipate, succinate, malate, glutamate, and tartrate.

[0014] In one embodiment, the buffer is present at a concentration of 1 mM to 50 mM, preferably 10 mM. In one embodiment, the non-ionic surfactant is polysorbate 20 or polysorbate 80, preferably polysorbate 80.

[0015] In one embodiment, the non-ionic surfactant is present in a concentration of 0.1 mg / ml to 0.4 mg / ml, preferably 0.2 mg / ml. In one embodiment, the liquid pharmaceutical composition comprises arginine at a concentration of 50 mM to 350 mM, preferably 150 mM.

[0016] In one embodiment, the liquid pharmaceutical composition comprises lysine at a concentration of 50 mM to 150 mM, preferably 70 mM to 140 mM or 70 mM to 130 mM. In one embodiment, the pharmaceutical composition does not contain trehalose, and preferably does not contain any sugars or sugar alcohols.

[0017] In one embodiment, the pharmaceutical composition does not contain methionine or histidine, and preferably does not contain any antioxidants. In one embodiment, the anti-human PD1 antibody is pembrolizumab.

[0018] In one embodiment, the anti-human PD1 antibody is present at a concentration of 100 to 200 mg / ml, preferably 165 mg / ml, or at a concentration of 20 to 80 mg / ml, preferably 25 mg / ml.

[0019] The present invention also relates to a liquid pharmaceutical composition comprising acetate buffer, arginine, polysorbate 20 or polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.0 to 5.8.

[0020] The present invention also relates to a liquid pharmaceutical composition comprising adipic acid buffer, arginine or lysine, polysorbate 20 or polysorbate 80, optionally trehalose, pembrolizumab, and water for injection, and having a pH of 5.0 to 5.8.

[0021] The present invention also relates to a liquid pharmaceutical composition comprising succinate buffer, arginine, polysorbate 20 or polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.0 to 5.8.

[0022] The present invention also relates to a liquid pharmaceutical composition comprising acetate buffer, lysine, polysorbate 20 or polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.0 to 5.8.

[0023] The present invention also relates to a liquid pharmaceutical composition comprising adipic acid buffer, arginine or lysine, polysorbate 20 or polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.0 to 5.8.

[0024] The present invention also relates to a liquid pharmaceutical composition comprising succinate buffer, lysine, polysorbate 20 or polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.0 to 5.8.

[0025] The present invention also relates to the liquid pharmaceutical composition for use in treating cancer, preferably wherein the cancer is melanoma, non-small cell lung cancer, classical Hodgkin's lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer, small cell lung cancer, microsatellite instability-high or mismatch repair deficient cancer, primary mediastinal large B-cell lymphoma, gastric or gastroesophageal junction adenocarcinoma, esophageal cancer, hepatocellular carcinoma, Merkel cell carcinoma, endometrial cancer, tumor mutational burden-high cancer, cutaneous squamous cell carcinoma, triple-negative breast cancer, or cervical cancer. DETAILED DESCRIPTION OF THE INVENTION

[0026] The present invention, as illustratively described below, may suitably be practiced in the absence of any element(s), limitation(ies), not specifically disclosed herein.

[0027] The present invention will be described in terms of particular embodiments but the invention is not limited thereto but only by the claims. When the term "comprising" is used in the present specification and claims, it does not exclude other elements. For the purposes of the present invention, the term "consisting of" is considered to be a preferred embodiment of the term "comprising" and excludes the presence of other elements. Hereinafter, when a group is defined as comprising at least a certain number of embodiments, this is to be understood as also disclosing a group that preferably consists only of these embodiments.

[0028] For the purposes of the present invention, the term "obtained" is considered to be a preferred embodiment of the term "obtainable". Hereinafter, if, for example, a cell or organism is defined as being obtainable by a particular method, this is to be understood as also disclosing the cell or organism obtained by this method.

[0029] Where an indefinite or definite article such as "a", "an" or "the" is used when referring to a singular noun, this includes a plural of that noun unless something else is specifically stated.

[0030] As used herein, the term "pharmaceutical composition" refers to any composition containing a chemical or biological substance or active ingredient, which is intended for use in the medical cure, treatment, or prevention of disease, and which is in a form that allows the active ingredient to be effective. In particular, a pharmaceutical composition does not contain excipients that are unacceptably toxic to the subject to which the composition is administered. A pharmaceutical composition is sterile, i.e., aseptic, and free of all living microorganisms and their spores. The pharmaceutical composition used in the present invention is liquid and stable.

[0031] In the "liquid composition," the pharmaceutically active agent, e.g., an anti-PD1 antibody, may be combined with various excipients to ensure stable active drug after storage. In one embodiment, the liquid pharmaceutical composition used in the present invention is not lyophilized at any time, i.e., the manufacturing method does not include a lyophilization step, and the composition is not lyophilized for storage. The liquid composition may be stored in vials, IV bags, ampoules, cartridges, and prefilled or ready-to-use syringes.

[0032] In another embodiment, the liquid composition is freeze-dried after its preparation. The terms "lyophilization", "lyophilized" and "freeze-dried" refer to a process in which the material to be dried is first frozen, and then the ice or frozen solvent is removed by sublimation in a vacuum environment. Preferably, the freeze-dried formulation is prepared by freeze-drying the liquid pharmaceutical composition of the present invention. Those skilled in the art are familiar with the freeze-drying protocol.

[0033] A "stable" liquid composition is one in which the anti-PD1 antibody contained therein essentially maintains its physical stability and / or chemical stability and / or biological activity during storage for a certain period of time.Preferably, the composition essentially maintains its physical and chemical stability and its biological activity during storage.Various analytical techniques for measuring protein stability are available in the art, and are reviewed in, for example, Peptide and Protein Drug Delivery, 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, New York, Pub. (1991) and Jones, Adv. Drug Delivery Rev., 1993, 10:29-90.For example, stability can be measured over a selected period of time at a selected temperature. Stability can be assessed qualitatively and / or quantitatively in a variety of different ways, including assessing aggregate formation (e.g., using size exclusion chromatography, by measuring turbidity, and / or by visual inspection), assessing charge heterogeneity using cation exchange chromatography or capillary zone electrophoresis, amino- or carboxy-terminal sequence analysis, mass spectrometry, SDS-PAGE analysis to detect aggregated or fragmented molecules, peptide map (e.g., trypsin or LYS-C) analysis, assessing antagonist biological activity or binding, etc. Suitable methods for determining stability are described in the Examples herein.

[0034] Preferably, the pharmaceutical composition is stable for at least 1-2 weeks at a temperature of about 40° C., and / or for at least 3 months, preferably 6 or 9 months, more preferably 1 year at a temperature of about 5° C., and / or for at least 2 weeks or 1 month at a temperature of about 25° C. Furthermore, the formulation is preferably stable after freezing (e.g., to −80° C.) and thawing the formulation at 25° C., e.g., after 1, 2, 3, or 4 cycles of freezing and thawing, as described in the Examples herein.

[0035] For example, in the pharmaceutical composition of the present invention, the percentage of high molecular weight species of anti-PD1 antibody relative to the total amount of anti-PD-1 antibody as measured by size exclusion chromatography is 10% or less, preferably 5% or less, more preferably 3% or less, and most preferably 2% or less after 2 weeks of storage at a temperature of about 40°C.

[0036] Alternatively, in the pharmaceutical composition of the present invention, the percentage of high molecular weight species of anti-PD1 antibody relative to the total amount of anti-PD1 antibody as measured by size exclusion chromatography is 10% or less, preferably 5% or less, more preferably 3% or less, and most preferably 2% or less after storage at a temperature of about 5°C for 1 month, 3 months, 6 months, or 9 months.

[0037] A "buffer" is an aqueous solution consisting of a mixture of a weak acid and its conjugate base, or vice versa, that resists changes in its pH, thus maintaining the pH at a nearly constant value. Buffers of the present invention preferably have a pH in the range of about 5.0 to about 5.8, preferably about 5.2 to about 5.7, more preferably about 5.2 to 5.5, and most preferably about 5.2 or 5.5.

[0038] The buffers used in the present invention are based on monocarboxylic or dicarboxylic acids and / or at least one salt thereof having a backbone of 2 to 6 carbon atoms, preferably unbranched monocarboxylic or dicarboxylic acids having a backbone of 4, 5, or 6 carbon atoms. Monocarboxylic acids contain one carboxy group, and dicarboxylic acids contain two carboxy groups. As used herein, the term "monocarboxylic or dicarboxylic acid having a backbone of n carbon atoms" refers to monocarboxylic or dicarboxylic acids having a linear alkyl or alkylene backbone of n carbon atoms. The backbone may have side chains, such as methyl groups, but the carbon atoms contained in these side chains are not counted as carbon atoms in the backbone. According to this definition, cyclic sugar acids such as ascorbic acid do not have a linear alkyl or alkylene backbone and are therefore not considered "monocarboxylic or dicarboxylic acids having a backbone of n carbon atoms." As used herein, the term "2 to 6 carbon atoms" is intended to include compounds having a backbone of 2, 3, 4, 5, or 6 carbon atoms.

[0039] In one embodiment, the buffer is an acetate buffer. The acetate buffer can be prepared by mixing acetic acid with an acetate salt, such as sodium acetate, or by mixing acetic acid with a base, such as sodium hydroxide, arginine, and / or lysine. The acetate buffer has a concentration of 1 mM to 50 mM, preferably 2 mM to 40 mM, more preferably 3 mM to 30 mM, even more preferably 4 mM to 20 mM, and most preferably 10 mM.

[0040] According to the present invention, the acetate buffer has a pH in the range of about 5.0 to 5.8, preferably about 5.1 to 5.7, more preferably about 5.2 to 5.5, and most preferably about 5.2 or 5.5.

[0041] In one embodiment, the acetate buffer has a concentration of 10 mM and a pH of 5.5. In one embodiment, the acetate buffer has a concentration of 10 mM and a pH of 5.2. In one embodiment, the buffer is an adipic acid buffer. The adipic acid buffer can be prepared by mixing adipic acid with an adipic acid salt, such as sodium adipate, or by mixing adipic acid with a base, such as sodium hydroxide, arginine, and / or lysine. The adipic acid buffer has a concentration of 1 mM to 50 mM, preferably 2 mM to 40 mM, more preferably 3 mM to 30 mM, even more preferably 4 mM to 20 mM, and most preferably 10 mM.

[0042] According to the present invention, the adipic acid buffer has a pH in the range of about 5.0 to 5.8, preferably about 5.1 to 5.7, more preferably about 5.2 to 5.5, and most preferably about 5.2 or 5.5.

[0043] In one embodiment, the adipic acid buffer has a concentration of 10 mM and a pH of 5.5. In one embodiment, the adipic acid buffer has a concentration of 10 mM and a pH of 5.2.

[0044] In one embodiment, the buffer is a succinate buffer. The succinate buffer can be prepared by mixing succinic acid with a succinate salt such as sodium succinate, or by mixing succinic acid with a base such as sodium hydroxide, arginine, and / or lysine. The succinate buffer has a concentration of 1 mM to 50 mM, preferably 2 mM to 40 mM, more preferably 3 mM to 30 mM, even more preferably 4 mM to 20 mM, and most preferably 10 mM.

[0045] According to the present invention, the succinate buffer has a pH in the range of about 5.0 to 5.8, preferably about 5.1 to 5.7, more preferably about 5.2 to 5.5, and most preferably about 5.2 or 5.5.

[0046] In one embodiment, the succinate buffer has a concentration of 10 mM and a pH of 5.5. In one embodiment, the succinate buffer has a concentration of 10 mM and a pH of 5.2. In one embodiment, the buffer is a malic acid buffer. The malic acid buffer can be prepared by mixing malic acid with a malic acid salt, such as sodium malate, or by mixing malic acid with a base, such as sodium hydroxide, arginine, and / or lysine. The malic acid buffer has a concentration of 1 mM to 50 mM, preferably 2 mM to 40 mM, more preferably 3 mM to 30 mM, even more preferably 4 mM to 20 mM, and most preferably 10 mM.

[0047] According to the present invention, the malic acid buffer has a pH in the range of about 5.0 to 5.8, preferably about 5.1 to 5.7, more preferably about 5.2 to 5.5, and most preferably about 5.2 or 5.5.

[0048] In one embodiment, the malic acid buffer has a concentration of 10 mM and a pH of 5.5. In one embodiment, the malic acid buffer has a concentration of 10 mM and a pH of 5.2. As used herein, "surfactant" refers to an amphipathic compound, i.e., a compound containing both hydrophobic and hydrophilic groups that reduces the surface tension (or interfacial tension) between two liquids or between a liquid and a solid. "Nonionic surfactants" do not have a charged group in their head. The formation of insoluble particles during freeze / thaw cycles of antibody-containing compositions can be significantly inhibited by the addition of surfactants. Examples of "nonionic surfactants" include, for example, polyoxyethylene glycol alkyl ethers, such as octaethylene glycol monododecyl ether and pentaethylene glycol monododecyl ether; polyoxypropylene glycol alkyl ethers; glucoside alkyl ethers, such as decyl glucoside, lauryl glucoside, and octyl glucoside; polyoxyethylene glycol octylphenol ethers, such as Triton X-100; polyoxyethylene glycol alkylphenol ethers, such as nonoxynol-9; glycerol alkyl esters, such as glyceryl laurate; polyoxyethylene glycol sorbitan alkyl esters, such as polysorbate; sorbitan alkyl esters, such as Span; cocamide MEA, cocamide DEA, and dodecyldimethylamine oxide; polyethylene glycol and polypropylene glycol block copolymers, such as poloxamer (e.g., poloxamer 188); and polyethoxylated tallow amine (POEA). The liquid pharmaceutical composition of the present invention may contain one or more of these surfactants in combination. In a preferred embodiment, the pharmaceutical composition of the present invention contains only one non-ionic surfactant.

[0049] Preferred nonionic surfactants for use in the liquid pharmaceutical compositions of the present invention are polysorbates such as polysorbate 20, 40, 60, or 80, more preferably polysorbate 20 (i.e., Tween 20) or polysorbate 80 (i.e., Tween 80). In another embodiment, the nonionic surfactant used in the liquid pharmaceutical compositions of the present invention is poloxamer 188.

[0050] The concentration of the nonionic surfactant is in the range of 0.005 to 0.06% (w / v), preferably 0.008 to 0.05% (w / v), and most preferably 0.01 to 0.04% (w / v), relative to the total volume of the composition.

[0051] In a preferred embodiment, the nonionic surfactant is polysorbate 20. In a preferred embodiment, the nonionic surfactant is polysorbate 20 having a concentration in the range of 0.05 to 0.6 mg / ml, preferably in the range of 0.08 to 0.5 mg / ml, and most preferably in the range of 0.1 to 0.4 mg / ml. In a preferred embodiment, the nonionic surfactant is polysorbate 20 having a concentration of 0.2 mg / ml.

[0052] In another preferred embodiment, the nonionic surfactant is polysorbate 80 having a concentration in the range of 0.05 to 0.6 mg / ml, preferably in the range of 0.08 to 0.5 mg / ml, more preferably in the range of 0.1 to 0.4 mg / ml, and most preferably 0.2 mg / ml.

[0053] In a particularly preferred embodiment, the non-ionic surfactant is polysorbate 80 having a concentration of 0.2 mg / ml. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain sugars or sugar alcohols. Sugar alcohols are organic compounds derived from sugars containing a hydroxyl group attached to each carbon atom. Suitable sugar alcohols include glycerol, mannitol, sorbitol, and xylitol. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain non-reducing sugars. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain sucrose. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain trehalose.

[0054] The liquid pharmaceutical composition of the present invention may contain one or more amino acids other than histidine. Amino acids are organic compounds containing an amino group, a carboxyl group, and a side chain specific to each amino acid. The amino acids that can be present in the liquid pharmaceutical composition of the present invention can be selected from the group consisting of arginine, lysine, aspartic acid, glutamic acid, serine, threonine, asparagine, glutamine, cysteine, glycine, proline, alanine, valine, isoleucine, methionine, phenylalanine, tyrosine, and tryptophan.

[0055] In one embodiment, the liquid pharmaceutical composition of the present invention comprises arginine. In one embodiment, the liquid pharmaceutical composition of the present invention comprises lysine. In one embodiment, the liquid pharmaceutical composition of the present invention comprises arginine and lysine. In one embodiment, arginine is the only amino acid present in the liquid pharmaceutical composition of the present invention. In one embodiment, lysine is the only amino acid present in the liquid pharmaceutical composition of the present invention. In one embodiment, arginine and lysine are the only amino acids present in the liquid pharmaceutical composition of the present invention.

[0056] Arginine and / or lysine may be added to the liquid pharmaceutical composition as a free base or its hydrochloride. In one embodiment, arginine is added as a mixture of free base arginine and arginine hydrochloride, i.e., arginine hydrochloride (arginine-HCl). In one embodiment, lysine is added as a mixture of free base lysine and lysine hydrochloride, i.e., lysine hydrochloride (lysine-HCl). In one embodiment, arginine is added as a mixture of free base arginine and arginine hydrochloride, i.e., arginine hydrochloride, and lysine is added as a mixture of free base lysine and lysine hydrochloride, i.e., lysine hydrochloride.

[0057] In one embodiment, the liquid pharmaceutical composition of the present invention comprises arginine at a concentration of 50 mM to 350 mM, preferably 60 mM to 330 mM, or 60 mM to 300 mM, or 60 mM to 280 mM, more preferably 70 mM to 250 mM, or 70 mM to 220 mM, or 70 mM to 200 mM, and most preferably 70 mM or 150 mM. In one embodiment, the liquid pharmaceutical composition of the present invention comprises arginine at a concentration of 150 mM. In one embodiment, the liquid pharmaceutical composition of the present invention comprises arginine at a concentration of 70 mM.

[0058] In one embodiment, the liquid pharmaceutical composition of the present invention comprises lysine at a concentration of 50 mM to 200 mM, preferably 55 mM to 180 mM, or 55 mM to 170 mM, more preferably 60 mM to 160 mM, or 60 mM to 150 mM, even more preferably 70 mM to 140 mM, and most preferably 70 mM, 120 mM, 130 mM, or 140 mM. In one embodiment, the liquid pharmaceutical composition of the present invention comprises lysine at a concentration of 70 mM. In one embodiment, the liquid pharmaceutical composition of the present invention comprises lysine at a concentration of 120 mM. In one embodiment, the liquid pharmaceutical composition of the present invention comprises lysine at a concentration of 130 mM. In one embodiment, the liquid pharmaceutical composition of the present invention comprises lysine at a concentration of 140 mM.

[0059] In one embodiment, the liquid pharmaceutical composition of the present invention does not contain sodium chloride. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain any sodium salts. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain any inorganic salts. As used herein, "inorganic salt" refers to an ionic compound that has osmolality-regulating properties. Inorganic salts such as sodium chloride (NaCl) can dissociate into their constituent ions in solution; i.e., NaCl dissociates into Na+ and Cl- ions, both of which affect the osmotic pressure, or osmolality, of the solution. Exemplary inorganic salts that are not present in the liquid pharmaceutical composition of the present invention are potassium chloride, calcium chloride, sodium chloride, sodium phosphate, potassium phosphate, and sodium bicarbonate.

[0060] In one embodiment, the liquid pharmaceutical composition of the present invention does not contain EDTA. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain pentetic acid. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain any chelating agent. A chelating agent is capable of forming at least one bond with a metal atom. Chelating agents are typically multidentate ligands used in compositions as stabilizers, capable of forming complexes with species that might otherwise promote instability. Examples of chelating agents include aminopolycarboxylic acids, hydroxyaminocarboxylic acids, N-substituted glycines, 2-(2-amino-2-oxoethyl)aminoethanesulfonic acid (BES), deferoxamine (DEF), niacinamide, desoxycholate, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), nitrilotriacetic acid (NTA), N-2-acetamido-2-iminodiacetic acid (ADA), bis(aminoethyl)glycol ether, N,N,N',N'-tetraacetic acid (EGTA), trans-diaminobenzyl methyl ester (TMA), and bis(aminoethyl)glycol ether (BMA). Aminocyclohexanetetraacetic acid (DCTA), N-hydroxyethyliminodiacetic acid (HIMDA), N,N-bis-hydroxyethylglycine (bicine), N-(trishydroxymethylmethyl)glycine (tricine), glycylglycine, sodium desoxycholate, ethylenediamine, propylenediamine, diethylenetriamine, triethylenetetraamine (triene), ethylenediaminetetraacetate EDTA, disodium EDTA, EDTA, calcium EDTA, oxalic acid, and malate.

[0061] In one embodiment, the liquid pharmaceutical composition of the present invention does not contain methionine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain L-methionine or L-methionine-HCl. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain any antioxidants. Antioxidants are compounds that inhibit oxidation by reacting with oxidizing agents. In the present invention, arginine is not considered an antioxidant. In the present invention, lysine is not considered an antioxidant. In the present invention, arginine and lysine are not considered antioxidants.

[0062] In one embodiment, the liquid pharmaceutical composition of the present invention does not contain proline. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain glycine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain glutamic acid. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain serine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain tyrosine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain tryptophan. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain leucine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain phenylalanine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain threonine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain aspartate. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain asparagine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain glutamine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain alanine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain cysteine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain isoleucine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain valine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain any amino acids other than arginine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain any amino acids other than lysine. In one embodiment, the liquid pharmaceutical composition of the present invention does not contain any amino acids other than arginine and lysine.

[0063] In one embodiment, the liquid pharmaceutical composition of the present invention is free of EDTA and proline.In one embodiment, the liquid pharmaceutical composition of the present invention is free of DTPA and methionine. In one embodiment, the liquid pharmaceutical composition comprises arginine and / or lysine in combination with a sugar. In one embodiment, the liquid pharmaceutical composition comprises arginine and / or lysine in combination with a non-reducing sugar. In one embodiment, the liquid pharmaceutical composition comprises arginine and / or lysine in combination with trehalose. In one embodiment, the liquid pharmaceutical composition comprises arginine and / or lysine in combination with sucrose.

[0064] The term "sugar" refers to an organic compound containing only carbon, hydrogen, and oxygen, typically with a 2:1 hydrogen:oxygen atomic ratio and the empirical formula Cm(HO)n. The term "sugar" includes monosaccharides, disaccharides, oligosaccharides, and polysaccharides. Examples of sugars include glucose, fructose, galactose, xylose, ribose, sucrose, mannose, lactose, maltose, trehalose, starch, and glycogen. Preferably, the sugar is a non-reducing sugar. A non-reducing sugar is a sugar that does not contain a free aldehyde or ketone group and therefore cannot act as a reducing agent. Preferably, the non-reducing sugar is selected from sucrose and trehalose.

[0065] In one embodiment, the sugar is trehalose. Trehalose is a non-reducing sugar. It is a disaccharide formed by a 1,1-glycosidic bond between a glucose unit and a fructose unit. Preferably, the dihydrate form of trehalose is used. The concentration of trehalose dihydrate in the liquid pharmaceutical composition of the present invention is 80 mM to 200 mM, preferably 90 mM to 180 mM, more preferably 100 mM to 170 mM or 100 mM to 160 mM, even more preferably 110 mM to 150 mM or 110 mM to 140 mM, and most preferably 120 mM.

[0066] In one embodiment, the sugar is sucrose. Sucrose is a non-reducing sugar. It is a disaccharide formed by a 1,2-glycosidic bond between two α-glucose units. The concentration of sucrose in the liquid pharmaceutical composition of the present invention is 80 mM to 200 mM, preferably 90 mM to 180 mM, more preferably 100 mM to 170 mM or 100 mM to 160 mM, even more preferably 110 mM to 150 mM or 110 mM to 140 mM, and most preferably 120 mM.

[0067] In one embodiment, the liquid pharmaceutical composition of the present invention comprises 50 mM to 150 mM arginine and 80 mM to 200 mM trehalose dihydrate, preferably 55 mM to 140 mM, 55 mM to 130 mM, or 55 mM to 120 mM arginine and 90 mM to 180 mM trehalose dihydrate, more preferably 60 mM to 110 mM, 60 mM to 100 mM, or 60 mM to 90 mM arginine and and 100 mM to 170 mM or 100 mM to 160 mM trehalose dihydrate, even more preferably 65 mM to 85 mM, 65 mM to 80 mM, or 65 mM to 75 mM arginine and 110 mM to 150 mM, or 110 mM to 140 mM trehalose dihydrate, and most preferably the liquid pharmaceutical composition of the present invention comprises 70 mM arginine and 120 mM trehalose dihydrate.

[0068] In one embodiment, the liquid pharmaceutical composition of the present invention comprises 50 mM to 150 mM of lysine and 80 mM to 200 mM of trehalose dihydrate, preferably 55 mM to 140 mM, 55 mM to 130 mM, or 55 mM to 120 mM of lysine and 90 mM to 180 mM of trehalose dihydrate, more preferably 60 mM to 110 mM, 60 mM to 100 mM, or 60 mM to 90 mM of lysine and Preferably, the liquid pharmaceutical composition of the present invention comprises 100 mM to 170 mM or 100 mM to 160 mM trehalose dihydrate, even more preferably 65 mM to 85 mM, 65 mM to 80 mM, or 65 mM to 75 mM lysine and 110 mM to 150 mM, or 110 mM to 140 mM trehalose dihydrate, and most preferably, the liquid pharmaceutical composition of the present invention comprises 70 mM lysine and 120 mM trehalose dihydrate.

[0069] In one embodiment, the liquid pharmaceutical composition of the present invention comprises 50 mM to 150 mM arginine and 80 mM to 200 mM sucrose, preferably 55 mM to 140 mM, 55 mM to 130 mM, or 55 mM to 120 mM arginine and 90 mM to 180 mM sucrose, more preferably 60 mM to 110 mM, 60 mM to 100 mM, or 60 mM to 90 mM arginine. Preferably, the liquid pharmaceutical composition of the present invention comprises 70 mM arginine and 120 mM sucrose, more preferably 65 mM to 85 mM, or 65 mM to 80 mM, or 65 mM to 75 mM arginine and 110 mM to 150 mM, or 110 mM to 140 mM sucrose, and most preferably, the liquid pharmaceutical composition of the present invention comprises 70 mM arginine and 120 mM sucrose.

[0070] In one embodiment, a liquid pharmaceutical composition of the present invention comprises lysine and sucrose. In one embodiment, the liquid pharmaceutical composition of the present invention comprises 50 mM to 150 mM lysine and 80 mM to 200 mM sucrose, preferably 55 mM to 140 mM, or 55 mM to 130 mM, or 55 mM to 120 mM lysine and 90 mM to 180 mM sucrose, more preferably 60 mM to 110 mM, or 60 mM to 100 mM, or 60 mM to 90 mM lysine and 100 mM to 170 mM, or 100 mM to 160 mM sucrose, even more preferably 65 mM to 85 mM, or 65 mM to 80 mM, or 65 mM to 75 mM lysine and 110 mM to 150 mM, or 110 mM to 140 mM sucrose, and most preferably the liquid pharmaceutical composition of the present invention comprises 70 mM lysine and 120 mM sucrose.

[0071] The terms "antibody" or "immunoglobulin" are used herein in the broadest sense and include full-length antibodies, genetically engineered antibodies, recombinant antibodies, multivalent antibodies, monoclonal antibodies, polyclonal antibodies, bispecific antibodies, multispecific antibodies, chimeric antibodies, humanized antibodies, fully human antibodies, as well as fragments of such antibodies so long as they remain functional and exhibit the desired biological activity. The "biological activity" of an antibody refers to the ability of the antibody to bind to an antigen and generate a biological response that can be measured in vitro or in vivo.

[0072] A full-length antibody comprises antigen-binding variable regions of the light chain (VL) and heavy chain (VH), a light chain constant region (CL), and heavy chain constant domains CH1, CH2, and CH3. The terms "antibody fragment" or "antigen-binding fragment" are used herein in the broadest sense and include a portion of a full-length antibody, preferably including the antigen-binding or variable region thereof. Antibody fragments retain the original specificity of the parent immunoglobulin. Examples of antibody fragments include, for example, Fab, Fab', F(ab')2, and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragment(s).

[0073] A "monoclonal antibody" is an antibody that is specific for a single epitope on an antigen, i.e., directed against a single determinant on the antigen. Methods for producing monoclonal antibodies are known to those skilled in the art.

[0074] The term "recombinant antibody" refers to any antibody prepared, expressed, produced, or isolated by recombinant means, e.g., an antibody isolated from a transgenic host cell (such as, for example, an NS0 or CHO cell) or from an animal transgenic for immunoglobulin genes, or an antibody expressed using a recombinant expression vector transfected into a host cell (such as, for example, an SP2 / 0 mouse myeloma cell).

[0075] "Humanized antibodies" are human antibodies whose antigen-binding portions (CDRs) are derived from a non-human species, such as a mouse, and therefore have different specificity compared to the parent immunoglobulin. The CDR protein sequences can be modified to increase their similarity to antibody variants naturally produced in humans.

[0076] A "fully human antibody" is an antibody in which all parts of the antibody, including the antigen-binding portions (CDRs), are derived from humans. The term "anti-PD1 antibody" refers to an antibody that specifically binds to cell death protein 1 (PD-1) and inhibits the binding of PD-1 to its ligand PD-L1, and optionally inhibits the binding of PD-1 to its ligands PD-L1 and PD-L2. The anti-PD1 antibody thereby abolishes the inhibitory effect of PD-1 / PD-L1 interaction on T cells. Known anti-PD1 antibodies include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, and cetrelimab.

[0077] Pembrolizumab (also known as MK-3475, SCH900475, and lambrolizumab) is a humanized IgG4 mAb having the structure described in WHO Drug Information, Vol. 27, No. 2, pp. 161-162 (2013). It comprises light chain CDRs according to SEQ ID NOs: 1, 2, and 3, and heavy chain CDRs according to SEQ ID NOs: 6, 7, and 8. The amino acid sequence of the light chain variable region is set forth in SEQ ID NO: 4, and the amino acid sequence of the heavy chain variable region is set forth in SEQ ID NO: 9. The amino acid sequence of the complete light chain is set forth in SEQ ID NO: 5, and the amino acid sequence of the complete heavy chain is set forth in SEQ ID NO: 10. Pembrolizumab is approved for the treatment of patients with, among other things, unresectable or metastatic melanoma, as well as certain patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC), classical Hodgkin lymphoma (cHL), urothelial carcinoma, gastric cancer, microsatellite instability-high (MSI-H) cancer, and non-small cell lung cancer. The currently marketed formulation of pembrolizumab contains 10 mM histidine, 70 mg / ml sucrose, 0.2 mg / ml polysorbate 80, and water for injection, pH 5.5, and is supplied at a concentration of 25 mg / ml.

[0078] Nivolumab (also known as ONO-4538, BMS-936558, and MDX1106) is a fully human monoclonal IgG4 antibody containing the heavy and light chain amino acid sequences and CDRs set forth in Table 2 of WO2018 / 204368. Pembrolizumab is approved for the treatment of patients with melanoma, renal carcinoma, non-small cell lung cancer, and urothelial carcinoma. The currently marketed nivolumab formulation contains 30 mg / ml mannitol, 0.008 mg / ml pentetic acid, 0.2 mg / ml polysorbate 80, 2.92 mg / ml sodium chloride, 5.88 mg / ml sodium citrate dihydrate, and water for injection, pH 6.0, and is supplied at a concentration of 10 mg / ml.

[0079] In one embodiment, the liquid pharmaceutical composition does not comprise an anti-LAG3 antibody or an anti-CTLA-4 antibody. In one embodiment, the anti-human PD-1 antibody is not a bispecific antibody that binds to human PD-1 and another target.

[0080] In one embodiment, the anti-human PD-1 antibody is the only antibody present in the liquid pharmaceutical composition of the invention. In one embodiment, pembrolizumab is the only antibody present in the liquid pharmaceutical composition of the invention.

[0081] In one embodiment, the anti-human PD-1 antibody is the only pharmaceutically active agent present in the liquid pharmaceutical composition. In one embodiment, pembrolizumab is the only pharmaceutically active agent present in the liquid pharmaceutical composition.

[0082] In one embodiment, the concentration of the anti-PD1 antibody in the liquid pharmaceutical composition of the present invention is 100 mg / ml to 200 mg / ml, preferably 110 mg / ml to 195 mg / ml, 120 mg / ml to 190 mg / ml, or 130 mg / ml to 185 mg / ml, more preferably 140 mg / ml to 180 mg / ml, 145 mg / ml to 175 mg / ml, or 150 mg / ml to 170 mg / ml, or 155 mg / ml to 170 mg / ml, or 160 mg / ml to 170 mg / ml, and most preferably 165 mg / ml.

[0083] In one embodiment, the concentration of the anti-PD1 antibody in the liquid pharmaceutical composition of the present invention is 10 to 80 mg / ml, preferably 15 to 70 mg / ml or 15 to 60 mg / ml, more preferably 20 to 50 mg / ml or 20 to 40 mg / ml, and most preferably 25 mg / ml. Liquid pharmaceutical compositions having such antibody concentrations are suitable for intravenous administration.

[0084] In one embodiment, the liquid pharmaceutical compositions of the present invention are isotonic, i.e., have an osmotic pressure essentially the same as that of human blood, which typically ranges from 270 to 328 mOsm. Osmotic pressure can be determined, for example, using a vapor pressure or ice osmometer.

[0085] In one embodiment, the liquid pharmaceutical composition of the present invention has a low viscosity necessary for subcutaneous administration. * Less than 1 second, preferably 19 mPa * seconds, preferably less than 18 mPa * seconds, most preferably 17 mPa * In one embodiment, the liquid pharmaceutical composition of the present invention has a shear viscosity of 10 to 20 mPa. * seconds, preferably 11 to 19 mPa * seconds, preferably 12 to 18 mPa * seconds, most preferably 13-17 mPa * It has a shear viscosity of less than 1 / 2 second.

[0086] In one embodiment, the liquid pharmaceutical composition of the present invention has a low viscosity necessary for subcutaneous administration. In one embodiment, the concentration of the anti-PD1 antibody in the liquid pharmaceutical composition of the present invention is 165 mg / ml, and the liquid pharmaceutical composition of the present invention has a viscosity of 20 mPa. * Less than 1 second, preferably 19 mPa * seconds, preferably less than 18 mPa * seconds, most preferably 17 mPa * In one embodiment, the concentration of the anti-PD1 antibody in the liquid pharmaceutical composition of the present invention is 165 mg / ml, and the liquid pharmaceutical composition of the present invention has a shear viscosity of 10 to 20 mPa. * seconds, preferably 11 to 19 mPa * seconds, preferably 12 to 18 mPa * seconds, most preferably 13-17 mPa * It has a shear viscosity of less than 1 / 2 second.

[0087] In one embodiment, the liquid pharmaceutical composition of the present invention has a low viscosity necessary for subcutaneous administration. In one embodiment, the concentration of pembrolizumab in the liquid pharmaceutical composition of the present invention is 165 mg / ml, and the liquid pharmaceutical composition of the present invention has a viscosity of 20 mPa. * Less than 1 second, preferably 19 mPa * seconds, preferably less than 18 mPa * seconds, most preferably 17 mPa *In one embodiment, the liquid pharmaceutical composition of the present invention has a pembrolizumab concentration of 165 mg / ml and a shear viscosity of 10 to 20 mPa. * seconds, preferably 11 to 19 mPa * seconds, preferably 12 to 18 mPa * seconds, most preferably 13-17 mPa * It has a shear viscosity of less than 1 / 2 second.

[0088] The pharmaceutical composition of the present invention may be used in the treatment of cancer, in particular in the treatment of melanoma, non-small cell lung cancer, classical Hodgkin's lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer, esophageal cancer, small cell lung cancer, microsatellite instability-high or mismatch repair deficient cancer, primary mediastinal large B-cell lymphoma, gastric or gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, Merkel cell carcinoma, endometrial cancer, tumor mutational burden-high cancer, cutaneous squamous cell carcinoma, triple-negative breast cancer, or cervical cancer.

[0089] The pharmaceutical compositions of the present invention may also contain additional active agents, particularly additional antitumor agents such as chemotherapeutic agents. Examples of such chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolomelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryocystatin; kallistatin; CC-1065 (including its synthetic analogs azozelesin, carzelesin, and bizelesin); cryptophycins (particularly cryptophycins). cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs, KW-2189, and CBI-TMI); eleutherobin; pancratistatin; sarcodictin; spongistatins; nitrogen mustards, e.g., chlorambucil, chlornaphazine, colofosfamide, estramstatin, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembicin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, e.g., carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine; antibiotics, e.g., enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma II and calicheamicin phi II); dynemicins, including dynemicin A; bisphosphonates, e.g., clodronate; esperamicin;and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, ausramycin, azaserine, bleomycin, cactinomycin, carabicin, kaminokaicin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyanomonofolino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin) , epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfiromycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as , denopterin, methotrexate, pteropterin, trimetrexate; purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostatin, testolactone; anti-adrenals such as aminoguanine Lutethimide, mitotane, trilostane; folic acid supplements, e.g., folinic acid; aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elformithine; elliptinium acetate; epothilones; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids, e.g., maytansine and ansamitocin; mitoguazone;Mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllic acid; 2-ethylhydrazide; procarbazine; razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pivobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, e.g., pak Included are ritaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; the topoisomerase inhibitor RFS2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Also, antihormonal agents that act to regulate or inhibit hormone action on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen, raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); aromatase inhibitors that inhibit the enzyme aromatase, which regulates estrogen production in the adrenal glands, such as, for example, 4(5)-imidazole, aminoglutethimide, megestrol acetate, exemestane, formestane, fadrozole, vorozole, letrozole, and anastrozole;and antiandrogens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0090] In an alternative embodiment, the pharmaceutical compositions of the present invention may be administered in combination with any of the chemotherapeutic agents listed above, but the chemotherapeutic agent is present in a separate pharmaceutical composition.

[0091] In an alternative embodiment, a pharmaceutical composition of the present invention is administered in conjunction with pemetrexed and platinum-based chemotherapy. In an alternative embodiment, a pharmaceutical composition of the present invention is administered in conjunction with pemetrexed and platinum-based chemotherapy in the treatment of non-small cell lung cancer. In an alternative embodiment, a pharmaceutical composition of the present invention is administered in conjunction with carboplatin and either paclitaxel or nab-paclitaxel. In an alternative embodiment, a pharmaceutical composition of the present invention is administered in conjunction with carboplatin and either paclitaxel or nab-paclitaxel in the treatment of non-small cell lung cancer.

[0092] In an alternative embodiment, a pharmaceutical composition of the invention is administered in conjunction with platinum-based chemotherapy and 5-fluorouracil. In an alternative embodiment, a pharmaceutical composition of the invention is administered in conjunction with platinum-based chemotherapy and 5-fluorouracil in the treatment of head and neck squamous cell carcinoma.

[0093] In an alternative embodiment, a pharmaceutical composition of the invention is administered with axitinib.In an alternative embodiment, a pharmaceutical composition of the invention is administered with axitinib in the treatment of renal cell carcinoma.

[0094] In an alternative embodiment, the pharmaceutical composition of the present invention is administered in conjunction with platinum-based and fluoropyrimidine-based chemotherapy. In an alternative embodiment, the pharmaceutical composition of the present invention is administered in conjunction with platinum-based and fluoropyrimidine-based chemotherapy in the treatment of esophageal cancer.

[0095] In an alternative embodiment, a pharmaceutical composition of the invention is administered in combination with lenvatinib. In an alternative embodiment, a pharmaceutical composition of the invention is administered in combination with lenvatinib in the treatment of esophageal cancer or renal cell carcinoma.

[0096] In an alternative embodiment, the pharmaceutical composition of the invention is administered in conjunction with chemotherapy. In an alternative embodiment, the pharmaceutical composition of the invention is administered in conjunction with chemotherapy in the treatment of triple-negative breast cancer.

[0097] In an alternative embodiment, a pharmaceutical composition of the invention is administered in conjunction with chemotherapy with or without bevacizumab. In an alternative embodiment, a pharmaceutical composition of the invention is administered in conjunction with chemotherapy with or without bevacizumab in the treatment of cervical cancer.

[0098] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0099] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0100] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0101] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0102] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0103] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0104] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0105] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0106] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0107] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0108] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0109] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0110] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0111] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0112] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0113] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0114] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0115] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0116] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0117] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0118] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0119] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0120] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0121] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0122] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0123] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0124] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0125] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0126] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0127] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0128] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0129] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0130] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0131] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0132] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0133] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0134] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0135] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0136] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0137] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0138] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0139] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0140] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0141] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0142] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0143] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0144] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0145] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0146] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0147] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0148] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0149] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0150] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0151] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0152] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0153] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0154] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0155] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0156] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0157] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0158] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0159] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0160] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0161] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0162] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0163] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0164] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0165] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0166] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0167] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0168] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0169] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0170] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0171] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0172] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0173] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0174] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0175] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0176] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0177] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0178] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0179] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0180] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0181] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0182] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0183] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0184] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0185] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0186] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0187] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0188] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0189] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0190] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0191] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0192] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0193] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0194] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0195] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0196] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0197] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0198] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0199] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0200] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0201] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0202] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0203] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0204] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0205] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0206] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0207] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0208] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0209] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0210] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0211] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0212] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0213] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0214] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0215] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0216] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0217] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0218] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0219] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0220] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0221] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0222] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0223] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0224] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0225] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0226] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0227] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0228] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0229] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0230] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0231] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0232] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0233] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0234] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0235] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0236] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0237] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0238] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0239] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malate buffer.

[0240] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0241] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0242] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0243] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0244] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0245] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0246] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0247] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0248] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0249] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0250] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0251] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0252] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0253] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0254] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of acetate buffer.

[0255] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0256] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of acetate buffer.

[0257] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of adipic acid buffer.

[0258] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0259] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of adipic acid buffer.

[0260] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of succinate buffer.

[0261] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0262] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of succinate buffer.

[0263] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of malic acid buffer.

[0264] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0265] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of malic acid buffer.

[0266] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0267] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0268] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0269] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0270] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0271] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0272] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0273] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0274] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0275] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0276] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0277] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0278] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0279] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0280] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0281] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0282] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0283] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0284] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0285] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0286] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0287] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0288] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0289] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0290] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of acetate buffer.

[0291] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0292] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of acetate buffer.

[0293] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of adipic acid buffer.

[0294] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0295] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of adipic acid buffer.

[0296] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of succinate buffer.

[0297] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0298] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of succinate buffer.

[0299] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of malic acid buffer.

[0300] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0301] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of malic acid buffer.

[0302] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of acetate buffer.

[0303] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of acetate buffer.

[0304] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of acetate buffer.

[0305] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of adipic acid buffer.

[0306] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0307] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of adipic acid buffer.

[0308] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of succinate buffer.

[0309] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0310] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of succinate buffer.

[0311] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of malic acid buffer.

[0312] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0313] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM of malic acid buffer.

[0314] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0315] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0316] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0317] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0318] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0319] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0320] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0321] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0322] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0323] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0324] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0325] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0326] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0327] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0328] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0329] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0330] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0331] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0332] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0333] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0334] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0335] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0336] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0337] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0338] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0339] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0340] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0341] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0342] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0343] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0344] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0345] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0346] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0347] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malate buffer.

[0348] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malate buffer.

[0349] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malate buffer.

[0350] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0351] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0352] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0353] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0354] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0355] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0356] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0357] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0358] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0359] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malate buffer.

[0360] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malate buffer.

[0361] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malate buffer.

[0362] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0363] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0364] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0365] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0366] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0367] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0368] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0369] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0370] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0371] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0372] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0373] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malate buffer.

[0374] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0375] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0376] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0377] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0378] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0379] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0380] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0381] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0382] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0383] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malate buffer.

[0384] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malate buffer.

[0385] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 165 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 1 to 50 mM malate buffer.

[0386] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0387] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0388] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0389] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0390] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0391] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0392] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0393] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0394] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0395] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0396] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0397] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0398] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0399] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0400] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0401] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0402] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0403] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0404] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0405] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0406] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0407] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0408] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0409] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0410] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0411] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0412] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0413] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0414] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0415] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0416] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0417] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0418] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0419] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0420] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0421] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0422] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0423] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0424] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0425] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0426] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0427] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0428] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0429] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0430] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0431] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0432] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0433] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 150 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0434] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM acetate buffer.

[0435] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0436] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0437] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0438] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0439] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0440] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0441] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0442] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0443] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0444] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0445] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0446] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0447] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0448] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0449] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0450] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0451] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0452] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0453] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0454] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0455] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0456] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0457] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0458] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0459] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0460] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0461] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0462] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0463] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0464] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0465] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0466] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0467] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0468] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0469] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of malic acid buffer.

[0470] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0471] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0472] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0473] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0474] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0475] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0476] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0477] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0478] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0479] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0480] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0481] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0482] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0483] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0484] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0485] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0486] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0487] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0488] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0489] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0490] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0491] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0492] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0493] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0494] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM of arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM of acetate buffer.

[0495] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0496] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM acetate buffer.

[0497] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0498] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0499] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0500] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0501] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0502] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM succinate buffer.

[0503] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0504] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0505] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.2 mg / ml of polysorbate 80, and 1 to 50 mM malic acid buffer.

[0506] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of acetate buffer.

[0507] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of acetate buffer.

[0508] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0509] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0510] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0511] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM adipic acid buffer.

[0512] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of succinate buffer.

[0513] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0514] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM succinate buffer.

[0515] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of malic acid buffer.

[0516] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM malic acid buffer.

[0517] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of malic acid buffer.

[0518] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0519] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0520] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0521] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0522] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0523] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0524] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0525] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0526] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0527] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0528] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0529] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0530] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0531] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0532] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0533] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0534] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0535] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0536] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0537] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0538] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM succinate buffer.

[0539] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0540] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0541] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0542] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0543] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of acetate buffer.

[0544] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM acetate buffer.

[0545] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM adipic acid buffer.

[0546] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM of arginine, 0.2 mg / ml of a nonionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0547] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of adipic acid buffer.

[0548] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0549] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0550] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of succinate buffer.

[0551] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM malic acid buffer.

[0552] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0553] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM of arginine, 0.2 mg / ml of a non-ionic surfactant, and 1 to 50 mM of malic acid buffer.

[0554] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0555] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0556] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0557] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0558] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0559] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0560] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0561] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0562] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0563] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0564] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0565] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0566] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0567] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0568] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM acetate buffer.

[0569] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0570] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0571] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM adipic acid buffer.

[0572] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0573] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0574] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM succinate buffer.

[0575] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0576] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0577] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.2 mg / ml polysorbate 80, and 1 to 50 mM malic acid buffer.

[0578] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0579] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0580] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0581] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0582] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 10 mM adipic acid buffer.

[0583] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 10 mM adipic acid buffer.

[0584] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0585] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0586] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0587] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malic acid buffer.

[0588] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 10 mM malic acid buffer.

[0589] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malic acid buffer.

[0590] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0591] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0592] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0593] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0594] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0595] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0596] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0597] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0598] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0599] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malic acid buffer.

[0600] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malic acid buffer.

[0601] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malic acid buffer.

[0602] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0603] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0604] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0605] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0606] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0607] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0608] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0609] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0610] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0611] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malic acid buffer.

[0612] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malic acid buffer.

[0613] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malic acid buffer.

[0614] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0615] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0616] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0617] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0618] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0619] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0620] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0621] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0622] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0623] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malic acid buffer.

[0624] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malic acid buffer.

[0625] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0626] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0627] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0628] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0629] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0630] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0631] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0632] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0633] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0634] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0635] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malic acid buffer.

[0636] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malic acid buffer.

[0637] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malate buffer.

[0638] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0639] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0640] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0641] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0642] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0643] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0644] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0645] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0646] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0647] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malate buffer.

[0648] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malate buffer.

[0649] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of an anti-human PD1 antibody, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malate buffer.

[0650] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0651] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0652] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0653] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 10 mM adipic acid buffer.

[0654] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 10 mM adipic acid buffer.

[0655] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 10 mM adipic acid buffer.

[0656] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0657] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0658] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0659] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0660] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a nonionic surfactant, and 10 mM malate buffer.

[0661] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0662] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0663] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0664] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0665] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM adipic acid buffer.

[0666] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0667] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM adipic acid buffer.

[0668] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0669] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0670] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0671] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM malate buffer.

[0672] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM malate buffer.

[0673] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0 to 5.8) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM malate buffer.

[0674] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0675] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0676] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0677] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0678] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0679] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0680] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0681] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0682] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0683] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0684] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0685] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0686] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM of arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0687] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0688] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM acetate buffer.

[0689] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0690] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0691] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM adipic acid buffer.

[0692] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0693] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0694] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM succinate buffer.

[0695] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0696] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0697] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of a non-ionic surfactant, and 10 mM malate buffer.

[0698] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0699] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0700] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0701] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM adipic acid buffer.

[0702] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM adipic acid buffer.

[0703] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM adipic acid buffer.

[0704] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0705] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0706] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM succinate buffer.

[0707] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM malate buffer.

[0708] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM malate buffer.

[0709] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.5) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM malate buffer.

[0710] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0711] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0712] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0713] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM adipic acid buffer.

[0714] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM adipic acid buffer.

[0715] In one embodiment, the invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM adipic acid buffer.

[0716] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0717] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0718] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM succinate buffer.

[0719] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 50 mM to 350 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM malate buffer.

[0720] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml of pembrolizumab, 100 mM to 200 mM arginine, 0.1 mg / ml to 0.4 mg / ml of polysorbate 80, and 10 mM malate buffer.

[0721] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.2) comprising 100 to 200 mg / ml pembrolizumab, 120 mM to 180 mM arginine, 0.1 mg / ml to 0.4 mg / ml polysorbate 80, and 10 mM malate buffer.

[0722] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0-5.8) comprising 165 mg / ml of an anti-PD1 antibody, 150 mM arginine, 0.2 mg / ml of polysorbate 80, and 10 mM acetate buffer.

[0723] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml of an anti-PD1 antibody, 150 mM arginine, 0.2 mg / ml of polysorbate 80, and 10 mM adipic acid buffer (pH 5.5).

[0724] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml of an anti-PD1 antibody, 150 mM arginine, 0.2 mg / ml of polysorbate 80, and 10 mM succinate buffer (pH 5.5).

[0725] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml of an anti-PD1 antibody, 150 mM arginine, 0.2 mg / ml of polysorbate 80, and 10 mM malate buffer (pH 5.5).

[0726] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml of an anti-PD1 antibody, 150 mM arginine, 0.2 mg / ml of polysorbate 80, and 10 mM acetate buffer (pH 5.2).

[0727] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml of an anti-PD1 antibody, 150 mM arginine, 0.2 mg / ml of polysorbate 80, and 10 mM adipic acid buffer (pH 5.2).

[0728] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml of an anti-PD1 antibody, 150 mM arginine, 0.2 mg / ml of polysorbate 80, and 10 mM succinate buffer (pH 5.2).

[0729] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml of an anti-PD1 antibody, 150 mM arginine, 0.2 mg / ml of polysorbate 80, and 10 mM malate buffer (pH 5.2).

[0730] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0-5.8) comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM acetate buffer.

[0731] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0-5.8) comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM adipic acid buffer.

[0732] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0-5.8) comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM succinate buffer.

[0733] In one embodiment, the present invention relates to a liquid pharmaceutical composition (pH 5.0-5.8) comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM malate buffer.

[0734] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM acetate buffer (pH 5.5).

[0735] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM adipic acid buffer (pH 5.5).

[0736] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM succinate buffer (pH 5.5).

[0737] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM malate buffer (pH 5.5).

[0738] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM acetate buffer (pH 5.2).

[0739] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM adipic acid buffer (pH 5.2).

[0740] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM succinate buffer (pH 5.2).

[0741] In one embodiment, the invention relates to a liquid pharmaceutical composition comprising 165 mg / ml pembrolizumab, 150 mM arginine, 0.2 mg / ml polysorbate 80, and 10 mM malate buffer (pH 5.2).

[0742] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of acetate buffer, L-arginine, polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.5.

[0743] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of acetate buffer, L-arginine, polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.2.

[0744] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of adipic acid buffer, L-arginine, polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.5.

[0745] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of adipic acid buffer, L-lysine, trehalose dihydrate, polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.5.

[0746] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of succinate buffer, L-arginine, polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.5.

[0747] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM acetate buffer, 150 mM L-arginine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.5.

[0748] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM acetate buffer, 150 mM L-arginine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.2.

[0749] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM adipic acid buffer, 150 mM L-arginine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.5.

[0750] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM adipic acid buffer, 70 mM L-lysine, 120 mM trehalose dihydrate, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.5.

[0751] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM succinate buffer, 150 mM L-arginine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.5.

[0752] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM acetate buffer, 140 mM L-lysine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.5.

[0753] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of acetate buffer, L-lysine, polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.2 or 5.5.

[0754] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of adipic acid buffer, L-lysine, polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.5.

[0755] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of succinate buffer, L-lysine, polysorbate 80, pembrolizumab, and water for injection, and having a pH of 5.5.

[0756] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM acetate buffer, 140 mM L-lysine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.2.

[0757] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM adipic acid buffer, 140 mM L-lysine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.5.

[0758] In one embodiment, the invention relates to a liquid pharmaceutical composition consisting of 10 mM succinate buffer, 140 mM L-lysine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, and having a pH of 5.5.

[0759] The pharmaceutical composition may be supplied in a vial or a pre-filled syringe. The pharmaceutical composition may be administered by intravenous infusion, for example, over a period of 30 minutes or less. Alternatively, the pharmaceutical composition may be administered by subcutaneous injection. In this case, the concentration of the anti-PD1 antibody, preferably pembrolizumab, is 100 mg / ml to 200 mg / ml, preferably 110 mg / ml to 190 mg / ml or 120 mg / ml to 180 mg / ml, more preferably 130 mg / ml to 175 mg / ml or 140 mg / ml to 170 mg / ml, and most preferably 165 mg / ml. In one embodiment, the concentration of the anti-PD1 antibody, preferably pembrolizumab, is 165 mg / ml.

[0760] While the invention has been illustrated and described in detail in the drawings and foregoing description, such illustration and description is exemplary or illustrative and is not to be considered restrictive. The invention is not limited to the disclosed embodiments. Other variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed invention, from a study of the drawings, the disclosure, and the dependent claims.

[0761] The detailed description is merely illustrative in nature and is not intended to limit the application and use. The following examples further illustrate the present invention, but are not intended to limit the scope of the present invention. Based on the description of the present invention, those skilled in the art can make various changes and modifications, and such changes and modifications are also included in the present invention.

[0762] Example Formulation development of 165mg / mL pembrolizumab formulation Example 1: Method Panel The following panel of methods for analytical characterization of highly concentrated pembrolizumab formulations was used in whole or in part in Examples 2, 3, and 4.

[0763] a. Analysis of protein content by UV-VIS Protein concentrations were determined by absorption spectroscopy at 280 nm, corrected for any aggregated particles at 320 nm, using an Implen Nanophotometer N120. The formulated drug substance was diluted with and measured against the respective placebo solutions. The protein concentration was 1.418 L*g -1 *cm -1 The concentration was calculated using an absorption coefficient of 0.01. Concentrations were reported based on the average of three replicate measurements.

[0764] b. Analysis of chemical modifications by ion exchange chromatography (IEX-HPLC) For all formulated samples, 30 μg of pembrolizumab was separated on a Thermo MabPAc SCX-10 BioLC Analytical CEX-column (074625, 4 mm × 250 mm, 10 μm) using a Thermo Ultimate 3000 HPLC system. Mobile phase A consisted of 20 mmol / L MES, pH 6.2. Mobile phase B consisted of 20 mmol / L MES, 120 mmol / L KCl, pH 6.2. Elution was performed by applying the gradient shown in Table 1.

[0765] [Table 1]

[0766] Data were recorded at 280 nm using a UV detector. Chromatogram profiles were compared to quantify the main peak, acidic variants, and basic variants. All measurements were performed in duplicate.

[0767] c. Analysis of high molecular weight species (HMWS) by size exclusion chromatography (SE-HPLC) Five micrograms of formulated pembrolizumab (diluted to 1 mg / mL) was separated on a TSKgel® UP-SW3000 SEC column (4.6 × 150 mm, 2 μm, Tosoh Bioscience) using a ThermoFisher Ultimate 3000 HPLC system with an isocratic flow rate of 0.35 mL / min (100 mmol / L sodium phosphate, 100 mmol / L sodium sulfate, 0.05% sodium azide, pH 6.7) to detect the presence of high molecular weight species (HMWS) of pembrolizumab. Data were recorded at 280 nm with a UV detector. Chromatogram profiles were compared and evaluated for HMWS and main peak relative areas. All measurements were performed in duplicate.

[0768] d. Analysis of low molecular weight species (LMWS) by non-reducing cGE (LabChip) Non-reducing capillary gel electrophoresis (cGE) was performed using a Perkin Elmer Labchip GXII Touch Protein Characterization System, a HT Protein Express Chip (760499, Perkin Elmer), and a Protein Express Assay Reagent Kit (CLS960008, Perkin Elmer) to quantify LMWS in pembrolizumab formulations. Samples were prepared according to the manufacturer's general instructions in the kit handbook (PN CLS140156, Rev. D) as follows: The formulated pembrolizumab sample was diluted with water to a concentration of 2 mg / mL, and 10 μl of this was further diluted with 35 μl of denaturation buffer. The denaturation solution consisted of sample buffer (from the reagent kit), LDS (L4632, Sigma-Aldrich), and NEM (E1271, Sigma-Aldrich). Sample denaturation was performed at 75°C for 10 minutes in a Bio-Rad real-time PCR cycler. Samples were analyzed in triplicate wells at an assay concentration of 0.091 μg / μL. Electrophoretic separation was performed using LabChip GXII Touch HT software running the preset P200 Antibody Analysis (Perkin Elmer). Electropherogram profiles and purity (main peak) and impurity (LMWS, HMWS) content were monitored.

[0769] e. Turbidity measurement by absorbance at 350 nm The turbidity of the samples was analyzed by absorbance at 350 nm using a Tecan Spark plate reader. Turbidity was measured in 384-well plates (781801, Greiner) by comparing the measured absorbance with standards according to Ph.Eur10.8, chapter 2.2.1.

[0770] f. Determination of particles invisible to the naked eye Particle sizes in the subvisible range were determined by flow imaging analysis using a Yokogawa Fluid Imaging Technologies FlowCam8100. For each measurement, 120 μl of solution was introduced into the system, and 100 μl was imaged by the system. Data were categorized by particle size according to the European Pharmacopoeia / United States Pharmacopoeia into <5 μm, 5 μm-10 μm, 10.1 μm-25 μm, and >25 μm subvisible particles.

[0771] g. Visual Appearance The visual appearance of the samples was evaluated using an inspection light box (Portable Inspection Hood MIH-PORT, Bosch) equipped with a flicker-free fluorescent lamp and black and white background plates. Samples were evaluated in their storage containers without magnification to evaluate the appearance of the samples in terms of visible particles, color, and clarity.

[0772] h. pH measurement pH was determined at room temperature using a 150 μl aliquot of sample and either a calibrated Ultra Micro ISM pH electrode or a Micro Pro-ISM pH electrode (both Mettler Toledo) connected to a SevenExcellence pH meter (Mettler Toledo). Samples were equilibrated at room temperature for at least 30 minutes before measurement.

[0773] i. Dynamic viscosity measurement Measurements were performed at 20°C and 250 s using a 60 μl sample volume and CP1 / 20 geometry. -1 The measurements were carried out on a Kinexus ultra plus rheometer at a shear rate of 100 rpm, 60 μl, and 20° C. All samples were analyzed as a single measurement.

[0774] Example 2: Screening of Pembrolizumab Formulations—Stabilizers and Viscosity-Lowering Agents a. Sample preparation To screen for a suitable formulation for highly concentrated pembrolizumab, short-term stability studies were performed at 40°C for up to 2 weeks, including mechanical and freeze / thaw stresses.

[0775] Several excipients were systematically screened to evaluate their effect on both physicochemical stabilization of the solution and viscosity reduction, a well-known problem for generating highly concentrated solutions of drugs, required to enable subcutaneous route of application.

[0776] The following excipients were tested in the formulations shown in Table 2: trehalose dihydrate, L-arginine, L-lysine, L-proline, L-phenylalanine, L-glycine, and sodium chloride. These excipients were formulated into solutions containing a target pH of 5.5, 5 mmol / L citric acid as a buffer excipient, 0.2 mg / mL polysorbate 80 as a surfactant, and pembrolizumab at concentrations ranging from 145 mg / mL to 170 mg / mL. Additionally, arginine was titrated with either HCl or phosphoric acid to evaluate the effect of the counterion chloride on phosphate in combination with arginine. The stabilizer concentrations were adjusted to provide a solution osmolality of 300 mOsm / kg ± 50 mOsm / kg, allowing for subcutaneous injection with limited pain sensation.

[0777] Using pembrolizumab at a concentration of approximately 28 mg / mL formulated in 10 mmol / L citrate, 300 mmol / L arginine, pH 5.5 (surfactant-free) as the starting material, 17 new formulations listed in Table 2 were made using a Big Tuna automated buffer exchange system (Unchained Labs, Pleasanton, CA) that uses 30 kDa MWCO filters made of polypropylene with regenerated cellulose and provides at least 96% formulation exchange. The pembrolizumab concentration was then increased, and finally, polysorbate 80 was added to the solution to achieve the target concentration.

[0778] The formulations shown in Table 2 were first analyzed for protein concentration by UV-VIS spectroscopy at 280 nm and corrected for pH adjustment before initiating the accelerated aging stability program. Storage conditions are shown in Table 3. Briefly, samples were stored at 40°C / 75% relative humidity (RH) for up to two weeks. In addition, samples were subjected to two conditions of mechanical stress (overhead rotation, orbital shaking) as well as five freeze / thaw cycles (-80°C / +25°C).

[0779] [Table 2-1]

[0780] [Table 2-2]

[0781] [Table 3]

[0782] Samples from all pull points were analyzed by size-exclusion chromatography (SE-HPLC) for the presence of high molecular weight species (HMWS) and by ion-exchange chromatography (IEX-HPLC) to detect modifications that result in charge heterogeneity. At each pull point, solutions were also controlled for appearance, the presence of subvisible particles by dynamic light scattering, and pH.

[0783] All formulations prepared according to Table 2 were analyzed for their protein content as well as dynamic viscosity and osmolality before the start of the stability study (t0). b. Protein content, osmolality, pH, and visual inspection of the prepared formulation The method was carried out as described in Example 1.

[0784] All prepared samples met the formulation acceptance criteria according to Table 2 for protein content (145 mg / mL to 170 mg / mL pembrolizumab), pH (target ±0.2), and osmolality (240 to 320 mOsmol / kg). All these parameters remained constant during 2 weeks of storage at 40°C / 75% and after freeze / thaw cycles and mechanical stress.

[0785] No visible particles or color changes were detected in all samples. c. Shear viscosity analysis All formulations prepared according to Table 2 were analyzed for their dynamic viscosity after preparation as described in Example 1.

[0786] All samples were analyzed as a single measurement and the results are shown in Table 4. Formulation (3) containing 80 mmol / L trehalose dihydrate and 80 mmol L-arginine as stabilizers and formulation (4) containing 120 mmol / L L-arginine as stabilizer showed the lowest dynamic viscosities of 9.4 and 9.0 mPa*s, respectively, compared to the trehalose dihydrate-based formulation (1) without any additional stabilizer / viscosity-reducing agent.

[0787] Lysine, when added as an excipient, was also demonstrated to effectively reduce shear viscosity: Formulation 7 containing 80 mmol / L L-lysine and 80 mmol / L trehalose dihydrate dramatically reduced shear viscosity compared to formulation 1 without the viscosity-reducing agent.

[0788] Finally, both the amino acids L-arginine and L-lysine were identified as the best viscosity-lowering agents when added at concentrations of at least 34 mmol / L in the presence of trehalose. Surprisingly, a sugar-free formulation containing only the amino acid L-arginine was also shown to have the lowest viscosity.

[0789] All other amino acids showed no or only a small effect on viscosity reduction, or even an increase in viscosity (formulation containing L-phenylalanine in combination with trehalose dihydrate (12)).

[0790] [Table 4]

[0791] d. Analysis of high molecular weight species (HMWS) by SE-HPLC The method was carried out as described in Example 1. After 2 weeks of storage at 40°C / 75% RH, HMWS levels increased slightly by 0.4%-1.0% compared to t0 in all formulations tested (see Table 5).

[0792] The best stabilization effect against aggregation was achieved using trehalose dihydrate without any additional stabilizers, as shown in formulation (1). However, partial replacement of trehalose dihydrate with the amino acids L-arginine, L-lysine, and their mixtures also resulted in the same or only a slight increase in HMWS formation. Surprisingly, a formulation in which trehalose was completely replaced with L-arginine (here: 120 mmol / L arginine (formulation (4))) was also identified as a viable formulation for preventing pembrolizumab aggregation. Furthermore, the addition of L-phenylalanine to trehalose showed good results under accelerated storage conditions, while the addition of all other amino acids and sodium chloride produced worse results (formulations (13) and (16)).

[0793] All formulations tested remained stable after multiple freeze / thaw cycles and after being subjected to the physical stress conditions of orbital shaking and overhead rotation.

[0794] [Table 5]

[0795] e. Detection of acidic and basic species by IEX-HPLC The method was carried out as described in Example 1. Table 6 shows the ratio of the peak area of ​​acidic species to the total peak area of ​​eluted species analyzed by IEX-HPLC for the formulations shown in Table 2.

[0796] After 2 weeks of storage at 40°C / 75% RH, the acidic species levels increased by 3.1%–5.1% compared to t0. The best results were obtained for formulations containing the amino acids L-arginine or L-lysine as the sole stabilizer (4), in combination (5), or in combination with trehalose dihydrate (formulations (2), (3), (6), (7), (8), and (9)). Interestingly, titration of L-arginine with phosphoric acid (formulations (14) and (15), resulting in L-arginine phosphate instead of L-arginine HCl) produced poorer results. Also, formulations containing L-proline, L-glycine, and L-phenylalanine in combination with trehalose dihydrate produced poorer results, showing a higher increase in acidic species.

[0797] The lowest increase in acidic species was detected in formulations combining trehalose dihydrate and sodium chloride (formulations (13) and (16)), where the addition of sodium chloride to trehalose dihydrate improved stability when compared to formulation (1) containing only trehalose dihydrate as a stabilizer.

[0798] All formulations tested remained stable after multiple freeze / thaw cycles and after being subjected to the physical stress conditions of orbital shaking and overhead rotation. In summary, the addition of L-lysine, L-arginine, and sodium chloride to trehalose dihydrate improved its chemical stability against the formation of acidic species compared to a trehalose dihydrate-based formulation (1) that did not contain these additional excipients. Interestingly, here too, the L-arginine-based formulation without trehalose dihydrate provided the best stabilization effect and was the preferred option.

[0799] Table 7 shows the ratio of the peak area of ​​basic species to the total peak area of ​​eluted species analyzed by IEX-HPLC for the formulations shown in Table 2. After 2 weeks of storage at 40°C / 75% RH, the basic species levels decreased by 2.6%–5.4% compared to t0.

[0800] The best results for stabilizing basic species against depletion were obtained with formulations containing the amino acids L-arginine or L-lysine, either alone (4) (5), or when each was formulated in combination with trehalose dihydrate (formulations (2), (3), (6), (7), (8), and (9)). One formulation (7), containing 80 mmol / L L-lysine with 80 mmol / L trehalose dihydrate, showed the best stabilizing effect, slightly superior to the other formulations tested.

[0801] Interestingly, titration of L-arginine with phosphoric acid (formulations (14) and (15), which yield L-arginine phosphate instead of L-arginine HCl) produced poorer results, and formulations containing L-proline, L-glycine, and L-phenylalanine in combination with trehalose dihydrate produced poorer results, here showing a higher reduction of basic species.

[0802] All formulations tested remained stable after multiple freeze / thaw cycles and after being subjected to the physical stress conditions of orbital shaking and overhead rotation. In summary, the addition of L-lysine and / or L-arginine to trehalose dihydrate improved the chemical stability against the reduction of basic species compared to trehalose dihydrate-based formulations without these additional excipients. The use of L-lysine was shown to be slightly more beneficial than L-arginine in these experiments.

[0803] Interestingly, here too, the L-arginine-based formulation, without the presence of trehalose dihydrate, was one of the preferred options, as it provided a very promising stabilizing effect.

[0804] [Table 6]

[0805] [Table 7]

[0806] f. Summary of test results Based on the results generated using the presented method set, several excipients and combinations thereof were identified that both stabilize high concentrations of pembrolizumab in liquid formulations against physicochemical degradation and show a positive effect on viscosity, here a decrease in viscosity, enabling a subcutaneous route of application of high concentration pembrolizumab formulations.

[0807] In particular, the amino acids L-lysine and L-arginine were confirmed to have a positive effect on viscosity reduction and stabilization of pembrolizumab against the formation of HMWS (analyzed by SE-HPLC) and to stabilize acidic and basic species (analyzed by IEX-HPLC).

[0808] Both L-lysine and L-arginine, when combined with trehalose dihydrate, were very powerful in optimizing formulations, with all mixtures being superior to a formulation containing only trehalose dihydrate (1). The best results were achieved when 60 mmol / L L-arginine was added to 120 mmol / L trehalose dihydrate (2), or when 80 mmol / L L-arginine was added to 80 mmol / L trehalose dihydrate (3), or when 80 mmol / L L-lysine was added to 80 mmol / L trehalose dihydrate (7). Comparing L-arginine (3) and L-lysine (7), the use of L-lysine was superior to arginine in stabilizing against the reduction of basic species.

[0809] Also, formulation 4 containing 120 mmol / L L-arginine without the presence of trehalose provided comparable excellent physicochemical results as well as the lowest viscosity of all tested formulations, making this sugar-free formulation the preferred choice for stabilizing high concentrations of pembrolizumab.

[0810] L-proline, L-phenylalanine, and L-glycine did not show any improvement on stability or even had a negative effect (e.g., a mixture of L-phenylalanine and trehalose leads to a large increase in dynamic viscosity).

[0811] Although the addition of sodium chloride showed a positive effect on the physicochemical stabilization of pembrolizumab, the higher increase in HMWS makes this a less preferred formulation candidate. Titration of L-arginine with phosphoric acid leads to the presence of L-arginine phosphates (14) and (15), which have a negative effect on all physicochemical parameters; therefore, the preferred option is the buffer system L-arginine / L-arginine HCl, which can be obtained by mixing both components to reach a final pH, or by titrating L-arginine with HCl.

[0812] Example 3: Buffer screening and optimization of polysorbate 80 concentration a. Sample preparation To screen potential buffer systems suitable for generating stable formulations of highly concentrated pembrolizumab at pH 5.5, short-term stability studies including mechanical and freeze / thaw stresses were performed.

[0813] Several buffer systems providing buffering capacity at pH 5.5 were systematically screened to evaluate their effect on both physicochemical stabilization of the solution and viscosity reduction: citrate, acetate, succinate, adipate, malate, and L-histidine. These buffers were tested with two exemplary combinations of excipients based on the results of Example 1: one formulation consisted of 120 mmol / L trehalose dihydrate, 70 mmol / L L-arginine, 0.2 mg / mL polysorbate 80, pH 5.5; the other consisted of 150 mmol / L L-arginine and 0.2 mg / mL polysorbate 80, pH 5.5. All formulations contained pembrolizumab at a concentration of 165 mg / mL ± 10%.

[0814] Additionally, a polysorbate 80 screen was conducted to evaluate the effect of polysorbate 80 concentration on physicochemical stability. Solutions providing polysorbate 80 concentrations ranging from 0.1 mg / mL to 0.4 mg / mL in an exemplary formulation of 165 mg / mL pembrolizumab, 5 mmol / L citrate, 120 mmol / L trehalose dihydrate, 70 mmol / L L-arginine, and 0.2 mg / mL polysorbate 80, pH 5.5, were tested.

[0815] Using pembrolizumab at a concentration of approximately 28 mg / mL formulated in 10 mmol / L citrate, 300 mmol / L L-arginine, pH 5.5 (surfactant-free) as the starting material, 14 new formulations listed in Table 8 were made using a Big Tuna automated buffer exchange system (Unchained Labs, Pleasanton, CA), which uses 30 kDa MWCO filters made of polypropylene with regenerated cellulose and provides at least 96% formulation exchange. The pembrolizumab concentration was then increased, and polysorbate 80 was added to the solution to the target concentration.

[0816] The formulations shown in Table 8 were first analyzed for protein concentration by UV-VIS spectroscopy at 280 nm and corrected for pH adjustment before initiating the accelerated aging stability program. Storage conditions are shown in Table 9. Briefly, samples were stored at 40°C / 75% relative humidity (RH) for up to 4 weeks. In addition, samples were subjected to two conditions of mechanical stress (overhead rotation, orbital shaking) as well as five freeze / thaw cycles (-80°C / +25°C).

[0817] [Table 8]

[0818] [Table 9]

[0819] Samples from all pull points were analyzed by size-exclusion chromatography (SE-HPLC) for the presence of high molecular weight species (HMWS) and by ion-exchange chromatography (IEX-HPLC) to detect modifications that result in charge heterogeneity. At each pull point, solutions were also controlled for appearance, the presence of subvisible particles by flow imaging microscopy, and pH.

[0820] b. Analysis of protein content by UV-VIS and determination of pH and osmolality All formulations prepared according to Table 8 were analyzed for their protein content, dissociation constant Kd, and pH and osmolality before the start of stability testing (t0). All samples met the acceptance criteria for all formulations listed in Table 8 for protein content (165 mg / mL pembrolizumab ± 10%), pH (target ± 0.2), and osmolality (300 mOsm / kg ± 20%).

[0821] No visible particles or color changes were detected in all samples. c. Shear viscosity analysis All formulations prepared according to Table 8 were analyzed for their dynamic viscosity after preparation. This method was carried out as described in Example 1.

[0822] Shear viscosity measurements demonstrate that formulations 8–12, all based on 150 mmol / L L-arginine, have much lower viscosities than formulations 1–7, all of which contain sugar, here 120 mmol / L trehalose dihydrate, in combination with 70 mmol / L L-arginine. Because pembrolizumab concentration also has a strong effect on viscosity, overlapping with the effects of excipient screening, formulation 2, due to its higher pembrolizumab content, is outside the scope of this ranking.

[0823] Comparing the shear viscosity in formulations (8)-(12), only a slight tendency with higher values ​​for malate was detected, and a very slight improvement could be determined with the use of succinate (10), with all other buffer systems quantified in a similar range.

[0824] Comparing formulations (1)-(7), a slight improvement in lower shear viscosity could be achieved using adipate (6) as the buffer system when formulated with 120 mmol / L trehalose dihydrate and 70 mmol / L L-arginine.

[0825] Finally, formulations of 165 mg / mL pembrolizumab formulated with 150 mmol / L L-arginine, 0.2 mg / mL polysorbate 80 have low shear viscosity, regardless of the buffer system used.

[0826] [Table 10]

[0827] d. Analysis of colloidal stability (Kd) by dynamic light scattering Samples containing more negative values ​​for Kd indicate increased protein-protein attraction. Samples (9)–(12), all containing 150 mmol / L L-arginine, no trehalose dihydrate, and buffered with either acetate, succinate, adipate, or malate, performed much better than all other formulations tested, as indicated by a higher Kd (less negative absolute values). These formulations (9)–(12) minimized attraction compared to the sugar-containing samples, a favorable attribute for pembrolizumab stabilization.

[0828] [Table 11]

[0829] e. Analysis of high molecular weight species (HMWS) by SE-HPLC The method was carried out as described in Example 1. After 4 weeks of storage at 40°C / 75% RH, HMWS levels increased slightly by 1.2% to 1.4% compared to t0 in all formulations tested (see Table 12), a low value for these accelerated storage conditions.

[0830] All tested formulations were evaluated in a similar range for HMWS production, but no clear trends were detected after analyzing the pull points. Slightly worse results were detected when using the malic acid-buffered formulation (7) containing 120 mmol / L trehalose dihydrate and 70 mmol / L L-arginine.

[0831] Finally, all buffers tested appear suitable for producing promising formulations of 165 mg / mL pembrolizumab with respect to stabilization against high molecular weight species. The effect of polysorbate 80 in the range tested was not detectable by SE-HPLC, and the formulations exhibit identical behavior in the range of 0.1 mg / mL to 0.4 mg / mL polysorbate 80 in a pH 5.5 formulation containing 165 mg / mL pembrolizumab with 5 mmol / L citrate, 120 mmol / L trehalose dihydrate, and 70 mmol / L L-arginine.

[0832] All formulations tested remained stable after multiple freeze / thaw cycles and after being subjected to the physical stress conditions of orbital shaking and overhead rotation.

[0833] [Table 12]

[0834] f. Detection of acidic and basic species by IEX-HPLC The method was carried out as described in Example 1. Table 13 shows the ratio of the peak area of ​​acidic species to the total peak area of ​​eluted species analyzed by IEX-HPLC for the formulations shown in Table 8.

[0835] After 4 weeks of storage at 40°C / 75% RH, the acidic species levels increased by 13.1%–14.0% compared to t0. All tested buffers appear to be suitable for producing promising formulations of 165 mg / mL pembrolizumab with respect to stabilization against the generation of acidic species tested in the different exemplary formulations.

[0836] When 150 mmol / L L-arginine was used (formulations (8)-(12)), all buffer systems tested performed equally well. The effect of polysorbate 80 on stabilization against the increase in acidic species is not detectable by IEX-HPLC, and formulations show identical behavior in the range of 0.1 mg / mL to 0.4 mg / mL polysorbate 80 in a pH 5.5 formulation containing 165 mg / mL pembrolizumab with 5 mmol / L citrate, 120 mmol / L trehalose dihydrate, and 70 mmol / L L-arginine.

[0837] All formulations tested remained stable after multiple freeze / thaw cycles and after being subjected to the physical stress conditions of orbital shaking and overhead rotation. Table 14 shows the ratio of the peak area of ​​basic species to the total peak area of ​​eluted species analyzed by IEX-HPLC for the formulations shown in Table 8.

[0838] All tested buffers appear to be suitable for producing promising formulations of 165 mg / mL pembrolizumab in a comparable manner with respect to stabilization against loss of basic species tested in the different exemplary formulations.

[0839] When 150 mmol / L L-arginine was used (formulations (8)-(12)), all buffer systems tested performed equally well, with the use of acetic acid appearing slightly superior in this group compared to the others.

[0840] The effect of polysorbate 80 in stabilizing basic species is not detectable by IEX-HPLC, and formulations show identical behavior in the range of 0.1 mg / mL to 0.4 mg / mL polysorbate 80 in a pH 5.5 formulation containing 165 mg / mL pembrolizumab with 5 mmol / L citrate, 120 mmol / L trehalose dihydrate, and 70 mmol / L L-arginine.

[0841] All formulations tested remained stable after multiple freeze / thaw cycles and after being subjected to the physical stress conditions of orbital shaking and overhead rotation.

[0842] [Table 13]

[0843] [Table 14]

[0844] g. Summary of test results Based on the results obtained with the presented method set, several buffer systems with a buffering capacity at pH 5.5 could be identified, which on the one hand stabilizes pembrolizumab in the liquid formulation and on the other hand provides a stable pH during storage.

[0845] The effect of different buffer systems was evaluated in two different formulations: one based on a mixture of trehalose dihydrate (120 mmol / L) and L-arginine (70 mmol / L), and the other a sugar-free formulation containing L-arginine at a concentration of 150 mmol / L. All concentrations were successfully adjusted to approximately 165 mg / mL pembrolizumab at pH 5.5, meeting the requirement for subcutaneous injection of approximately 300 mOsm / kg.

[0846] In particular, formulations of 165 mg / mL pembrolizumab in 150 mmol / L L-arginine, 0.2 mg / mL polysorbate 80 (formulations (8)-(12)) outperformed all others when analyzed for shear viscosity. This was independent of the buffer system used. When formulating pembrolizumab with 120 mmol / L trehalose dihydrate and 70 mmol / L L-arginine, the use of adipate as the buffer system (formulation (6)) appears to be an option.

[0847] Samples (8)–(12), all containing 150 mmol / L L-arginine, lacking trehalose dihydrate, and buffered with either acetate, succinate, adipate, or malate, demonstrated significantly better Kd results compared to all other formulations tested. Formulations (9)–(12) minimized attractive forces compared to sugar-containing samples, a favorable attribute for pembrolizumab stabilization. The best results were obtained using acetate as the buffering agent.

[0848] Considering the formation of HMWS (analyzed by SE-HPLC) and the stability of acidic and basic species, all buffers tested appeared suitable for producing promising formulations of 165 mg / mL pembrolizumab, with no clear trends observed.

[0849] The effect of polysorbate 80 concentration on all quality parameters tested could not be confirmed, and the formulation exhibits identical behavior over the concentration range of 0.1 mg / mL to 0.4 mg / mL when 165 mg / mL pembrolizumab is formulated with 5 mmol / L citrate, 120 mmol / L trehalose dihydrate, and 70 mmol / L L-arginine at pH 5.5. This formulation is used as an exemplary formulation, and results can be extrapolated to other formulations containing similar concentrations of pembrolizumab.

[0850] All formulations tested remained stable after multiple freeze / thaw cycles and after being subjected to the physical stress conditions of orbital shaking and overhead rotation. Example 4: Formulations selected for stability testing Based on the results shown in Examples 2 and 3, nine formulations were selected to be tested for long-term stability at target storage conditions of 2°C to 8°C and accelerated conditions of 25°C / 60% RH for up to 3 months and 40°C / 75% RH for up to 1 month.

[0851] Using the same starting materials as described in Example 3, the formulations were made into new formulations by UF / DF. The nine different formulations are shown in Table 15.

[0852] [Table 15]

[0853] Samples are stored for up to 24 months according to Table 16. In addition, samples are subjected to two conditions of mechanical stress as well as five freeze / thaw cycles.

[0854] [Table 16]

[0855] Protein stability is determined by size-exclusion chromatography (SE-HPLC) for the presence of high molecular weight species (HMWS) and by non-reducing SDS-cGE for the presence of low molecular weight species (LMWS) and HMWS. Chemical modifications such as glycation, oxidation, and deamidation are quantified by LC-ESI-MS and -MS / MS in reduced peptide mapping, and oxidation is also monitored by HIC chromatography. Ion-exchange chromatography (IEX-HPLC) and imaging capillary isoelectric focusing (icIEF) are used to detect modifications that result in charge heterogeneity. DLS is also analyzed to calculate Kd values ​​to characterize protein-protein interactions. Additionally, samples are analyzed for appearance, viscosity, turbidity, subvisible particle content, and particle size. Protein concentration of the samples is determined by UV-VIS spectroscopy. pH is also monitored during stability testing.

[0856] Example 5: Stability testing of selected formulations for high-concentration pembrolizumab Based on the results shown in Examples 2 and 3, five formulations were selected to be tested in long-term stability studies at target storage conditions of 2°C-8°C for up to 9 months, and at accelerated conditions of 25°C / 60% RH for up to 3 months and 40°C / 75% RH for up to 1 month.

[0857] Pembrolizumab having a concentration of approximately 33 mg / mL, formulated in 10 mmol / L citrate, 300 mmol / L L-arginine, pH 5.5 (surfactant-free), was used as the starting material and bulk filtered using a Sartorius Sartopore2 process filter (0.45 + 0.2 μm PES membrane, catalog number 5441307H4G-00) to generate the five new formulations listed in Table 17. Buffer exchange and concentration of pembrolizumab were performed using a Sartorius Ambr Crossflow device and tangential flow filtration with a Sartocon Slice50 filter cassette (30 kDa, catalog number 3D91465950MLPU). The buffer exchange and concentration processes were performed sequentially as an initial concentration-diafiltration-final concentration process. First, the drug substance was concentrated to reduce the process volume, followed by dialysis with five diafiltration volumes for continuous buffer exchange, resulting in greater than 99% theoretical buffer exchange. Finally, the drug substance was concentrated to its target concentration in the final formulation, and the solution was sterile filtered using a 0.22 μm vacuum filter (Merck Steriflip Sterile 50 mL PES Disposable Vacuum Filter System, catalog number SCGP00525) according to the manufacturer's instructions. The solution was then spiked with sterile polysorbate 80 solution to the target concentration and filled into sterile, depyrogenated, particle-free 2R vials (Adelphi, catalog number 1404.6.1.1) under laminar airflow conditions. The filled vials were closed with sterile 13 mm injection stoppers (Adelphi, catalog number 1625.6.1.1) and crimped with aluminum caps (Adelphi, catalog number CETW13). All vials were filled with 500 μl of solution. The formulations shown in Table 17 were first analyzed for protein concentration by UV-VIS spectroscopy at 280 nm and precise pH adjustment before storage for stability studies began.

[0858] [Table 17]

[0859] Storage conditions are shown in Table 18. Sample storage continues as described in Table 18 for up to 24 months.

[0860] [Table 18]

[0861] Protein stability was determined by size-exclusion chromatography (SE-HPLC) for the presence of high molecular weight species (HMWS) and by non-reducing SDS-cGE for the presence of low molecular weight species (LMWS). HIC chromatography was used to quantify oxidation. Ion-exchange chromatography (IEX-HPLC) and imaging capillary isoelectric focusing (icIEF) were used to detect modifications resulting in charge heterogeneity. DLS was used to characterize samples for the presence of aggregates and to calculate Kd values ​​to characterize protein-protein interactions. Additionally, samples were analyzed for appearance, viscosity, turbidity, subvisible particle content, and particle size. Protein concentration of samples was determined by UV-VIS spectroscopy. pH and dynamic viscosity were also analyzed during stability testing. Unless otherwise noted below, all methods were described and performed according to Example 1.

[0862] a. Analysis of protein content by UV-VIS, determination of pH, visible particles, turbidity, sub-visible particles and osmolality All formulations prepared according to Table 17 were analyzed for their protein content, as well as pH and osmolality, before the start of stability testing (t0). All samples met the formulation acceptance criteria according to Table 17 for protein content (165 mg / mL ± 10% pembrolizumab) and pH (target ± 0.2).

[0863] The osmolality of all samples was detected in the range of 264 mOsmol / kg to 274 mOsmol / kg, which is close to isotonic conditions, thereby limiting the sensation of pain during subcutaneous injection. Osmolality was determined by freezing point depression using an osmometer (Gonotec Osmomat 030 D-RS). Calibration was performed using sodium chloride standards (500 mOsmol / kg and 850 mOsmol / kg) and purified water. Samples were measured by dilution to a pembrolizumab concentration of 50 mg / mL. Dilution was performed using purified water.

[0864] pH was analyzed using a SevenExcellence Multiparameter system and an InLab Micro Pro-ISM pH electrode (both from Mettler Toledo). Measurements were performed according to USP at 23°C to 25°C using 150 μl of solution filled in 0.5 mL vials. Protein content determination was performed using an Implen NanoPhotometer N120. 2 μl of sample solution was diluted 1:10 in their respective placebo buffer solutions and quantified at 280 nm using an extinction coefficient of 1.418 μl / g*cm. Background correction was performed using a wavelength of 320 nm.

[0865] The solution pH of all samples remained unchanged throughout the stability program, and all samples met the criteria of 5.5±0.2 (formulations (1), (3), (4), and (5)) or 5.2±0.2 (formulation (2)) under all storage conditions. pH was determined in a single measurement. Both acidic acid and adipic acid buffer well within the specified pH range.

[0866] Additionally, pembrolizumab concentrations remained stable throughout the full stability program, with all results quantified within the acceptance criteria of 165 mg / mL ± 10% pembrolizumab. Pembrolizumab concentrations were determined in duplicate.

[0867] When the different formulations were analyzed for their visual appearance, the solutions of formulations (1), (2), (3), and (4) appeared clear and slightly yellowish with a slight opalescence, and no visible particles were detected during 9 months of storage. Identical results were achieved after stressing the samples by repeated freeze / thaw cycles or by mechanical stress.

[0868] In contrast, formulation 5 containing 120 mmol / L trehalose and 70 mM L-lysine showed the presence of visible particles beginning at 3 months of storage at 5° C., resulting in an insoluble precipitate of pembrolizumab. Visible particles were also detected in formulation 5 in samples stored at accelerated conditions.

[0869] For visual inspection, all four vials prepared for each stability condition and pull point were evaluated. All formulations were analyzed for turbidity using the Nephelostar and showed consistent values ​​with no increase after the stability program and stress testing. All values ​​were analyzed in the very low range of 5-6 NTU after 9 months of storage at 5°C.

[0870] Particles invisible to the naked eye were analyzed using Anasysta's FlowCam8100 Multi-Objective. These micron-sized protein aggregates and particles are an important quality attribute of therapeutic protein formulations due to their risk of enhancing immunogenic responses. The method was tuned to the following parameters: analytical efficiency: 60-70%; automated imaging range: 30 fps; distance to nearest neighbor: 3 µm; flow rate: 0.150 mL / min; sample volume processed: 0.100 mL.

[0871] After mechanical stress, freeze / thaw stress, and incubation at 5°C for 9 months, 25°C for 3 months, and 40°C for 1 month, all formulations performed well and met USP <788> Values ​​are shown within pharmacopoeia limits. All measurements were performed in duplicate in order to analyze subvisible particles by FlowCam.

[0872] b. Analysis of high molecular weight species (HMWS) by SE-HPLC Study samples were diluted to a final concentration of 1 mg / mL in 20 mmol / L L-histidine pH 5.5, and 5 μL of the diluted samples was injected onto a TSKgel UP-SW3000 (Tosoh, 4.6 × 150 mm, 2 μm) column to detect the high molecular weight species (HMWS) of pembrolizumab.

[0873] The protein was eluted isocratically with 0.1 M sodium phosphate buffer (pH 6.7) containing 0.05% (v / v) sodium azide at a flow rate of 0.35 mL / min at 25°C. The eluted species were detected at a wavelength of 280 nm and displayed on a graph showing the concentration of the eluted species versus time. The elution profile showed a monomer peak with non-aggregated protein and a protein peak representing high molecular weight species (HMWS) of the protein. The areas of all peaks were determined.

[0874] Table 19 summarizes the ratio of the HMWS peak area to the total peak area of ​​the eluting species for the formulations shown in Table 17. Each sample was measured as a single measurement.

[0875] [Table 19-1]

[0876] [Table 19-2]

[0877] After storage for up to 9 months at 5°C (target storage conditions), HMWS increased only slightly, indicating excellent stability. The lowest increase was achieved with 150 mmol / L L-arginine in formulations (1), (2), and (3), followed by formulation (4) containing lysine. Poorer results were achieved for formulation (5) containing L-lysine and trehalose at both the target storage conditions of 2°C-8°C and the accelerated stability conditions of 25°C / 40°C.

[0878] Overall, all formulations containing 150 mmol / L L-arginine showed very promising stabilizing effects on pembrolizumab against HMWS formation across the pH range of 5.2 to 5.5 in both adipate and acetate buffer systems tested. HMWS increased by Δ0.6% after 9 months of storage, resulting in a total HMWS content of 1.0% to 1.1%.

[0879] c. Analysis of colloidal stability (Kd) by dynamic light scattering Protein-protein interactions were quantified by kD using a DLS (dynamic light scattering) system from Wyatt Technology (Santa Barbara, CA, USA). The kD value is a measure of the balance between intermolecular repulsion and attraction. Positive kD values ​​reveal repulsion between proteins in solution, thus reducing the tendency for aggregation because the net surface charge of the proteins keeps them separated. Negative kD values ​​are related to the net attraction between molecules.

[0880] Prior to analysis, all samples were filtered through a 0.02 μm filter and diluted with 0.02 μm-filtered placebo solution to seven concentrations ranging from 1 mg / mL to 10 mg / mL. For analysis (using Wyatt Dynamics software, version 8.1.2.144), default settings for the refractive index and viscosity of water were used. Measurements were performed in duplicate, with 35 acquisitions of 1 second each as the measurement parameters. The KD value for each formulation was derived by linear regression using the equation D = D0 (1 + kD × c), where D is the diffusion coefficient (cm2 / s), D0 is the diffusion coefficient at c = 0 (cm2 / s), kD is the diffusion interaction parameter (mL / mg), and c is the concentration of pembrolizumab.

[0881] Samples (1)-(3), all containing 150 mmol / L L-arginine, no trehalose dihydrate, and buffered with either acetate or adipate, demonstrated the best results, as indicated by a higher Kd (less negative absolute value) compared to the other formulations tested. The best formulation identified in this analysis was formulation (2), which used 150 mmol / L L-arginine and had a pH of 5.2, also compared to formulation (1), which was the same formulation but at pH 5.5. Therefore, a lower pH, here about 5.2 ± 0.2, appears beneficial in supporting colloidal stability.

[0882] [Table 20]

[0883] d. Detection of acidic and basic species by IEX-HPLC The study sample was diluted to a final concentration of 1 mg / mL with eluent A (20 mM MES, pH 6.2), and 30 μL of it was injected onto a MabPac SCX-10 (Thermo Scientific, 4 × 250 mm, 10 μm) column to detect pembrolizumab modifications that result in charge heterogeneity. Proteins were eluted at a flow rate of 1 mL / min at 40°C by applying a salt gradient (KCl) using a mixture of mobile phases A (20 mM MES, pH 6.2) and B (20 mM MES, 120 mM KCl, pH 6.2).

[0884] The eluted species were detected at a wavelength of 280 nm and displayed on a graph showing the concentration of the eluted species versus time. The elution profile showed a major peak and several peaks representing acidic and basic variants. The areas of all peaks were determined.

[0885] Table 21 summarizes the ratio of the peak area of ​​acidic species to the total peak area of ​​eluted species for the formulations shown in Table 17. Each sample was measured in triplicate.

[0886] [Table 21-1]

[0887] [Table 21-2]

[0888] After storage for up to 9 months at 5°C (target storage conditions), both acidic and basic species remained near t0 levels for all formulations tested within this stability study, suggesting promising long-term stability. Acidic species decreased by Δ0.1%-0.5% after 9 months at 5°C, while basic species increased / decreased by Δ0.1%. The main peak was determined to have a Δ0.3%-0.4%, with minimal variation relative to starting conditions.

[0889] e. Detection of acidic and basic species by icIEF The goal of imaging capillary isoelectric focusing (icIEF) is to determine the heterogeneity of charge isoforms caused by protein isoelectric points (pI) and post-translational modifications (PTMs). The power of icIEF lies in the high-resolution electropherograms that allow accurate and reproducible relative quantification of charge isoforms.

[0890] The samples were rebuffered by ultrafiltration against ultrapure water, and interfering buffer components were depleted from the samples using Detergent Removal Spin Columns (Pierce) according to the manufacturer's instructions. Protein concentration was determined by UV measurement (absorbance at 280 nm). The rebuffered samples were diluted to 1 g / L with ultrapure water. 40 μg of diluted sample (corresponding to a final protein concentration of 0.2 g / L) was mixed with 2% ampholytes (0.25% pH 9-11 and 3% pH 8-10.5), 0.35% methylcellulose, 4 M urea, and pI markers (8.18 and 9.99). Focusing was performed in two stages (1500 V for 1 min and 3000 V for 10 min). Final analysis was performed using the Imaged CE system Maurice C (ProteinSimple). Data were evaluated by pI calibration of the electropherogram using two internal pI markers and Compass for iCE software (ProteinSimple). Peak integration was performed using Empower software (Waters). Calculations by relative peak area (e.g., for peak grouping) were performed using the initial value of the relative peak area to three decimal places. The initial values ​​used in the calculations and the calculation results are reported rounded to one decimal place.

[0891] The samples shown in Table 17 were analyzed as single measurements after incubation at 40°C / 75% relative humidity for 3 months, at 25°C / 60% relative humidity for 6 months, and at 5°C for 9 months.

[0892] [Table 22-1]

[0893] [Table 22-2]

[0894] f. Analysis of low molecular weight species (LMWS) by non-reducing cGE (LabChip) Non-reducing capillary gel electrophoresis (cGE) was performed using a Perkin Elmer Labchip GXII Touch Protein Characterization System, a HT Protein Express Chip (760499, Perkin Elmer), and a Protein Express Assay Reagent Kit (CLS960008, Perkin Elmer) to quantify LMWS in pembrolizumab formulations. Samples were prepared according to the manufacturer's general instructions in the kit handbook (PN CLS140156, Rev. D) as follows: The formulated pembrolizumab sample was diluted to a concentration of 1 mg / mL with water, and 10 μl of this was further diluted with 35 μl of denaturation buffer. The denaturation buffer consisted of sample buffer (from the reagent kit), LDS (lithium dodecyl sulfate, L4632, Sigma-Aldrich), and NEM (N-ethylmaleimide, E1271, Sigma-Aldrich). Non-reducing conditions were established using a 200 mmol / L stock of NEM added at a 1:20 v / v ratio. To achieve more uniform sample denaturation, the denaturation solution was supplemented with LDS at a concentration of 1% (v / v). Sample denaturation was performed at 75°C for 10 minutes in a Bio-Rad real-time PCR cycler. The denatured samples were stored overnight at room temperature, protected from light, and assay concentrations were established by adding 35 μl of water (B. Braun) immediately prior to assay.

[0895] Samples were analyzed in triplicate wells. Electrophoretic separation was performed using LabChip GXII Touch HT software running the preset P200 Antibody Analysis (Perkin Elmer). Electropherogram profiles and purity (main peak) and impurity (LMWS, HMWS) content were monitored.

[0896] [Table 23-1]

[0897] [Table 23-2]

[0898] After storage for up to 9 months at 5°C (target storage conditions), LMWS was measured in a range comparable to the t0 value, and no increase was quantified in all formulations tested within this stability study, suggesting successful long-term storage stability with respect to LMWS generation. Additionally, all formulations remained stable after multiple freeze / thaw cycles and mechanical stress. Overall, all formulations tested within this study showed similar, very good results.

[0899] g. Detection of oxidized species by HIC Hydrophobic interaction chromatography (HIC) was used to assess the oxidation of pembrolizumab. HIC is based on the interaction between hydrophobic ligands on a stationary phase (HIC column) and the hydrophobic surface of the protein, allowing impurities to be separated by differential binding to the stationary phase.

[0900] Study samples were diluted to a final concentration of 1 mg / mL in dilution buffer (10 mM L-histidine, 7% (w / v) sucrose, 0.02% polysorbate 80, 200 mM L-methionine, pH 5.5). 1 μg of carboxypeptidase B (CPB) was added to each 125 μg sample, mixed, and incubated at 25°C for 60 minutes on a thermal shaker with cooling function set at 500 rpm. 5 μl (5 μg) of the sample was injected onto a TSKgel Butyl-NPR (TOSOH, 4.6 × 35 mm, 2.5 μm) column to detect pembrolizumab oxidation. Proteins were eluted using a mixture of mobile phases A (2 M ammonium sulfate in 100 mM sodium phosphate buffer, pH 7.0) and B (100 mM sodium phosphate buffer, pH 7.0) at a flow rate of 0.8 mL / min at 30°C using an ACQUITY UPLC H-Class Bio system from Waters, applying an ammonium salt gradient according to Table 24.

[0901] [Table 24]

[0902] The eluted species were detected using a fluorescence detector with a wavelength of 278 nm for excitation and 350 nm for emission. The elution profile was displayed on a graph showing the concentration of the eluted species versus time. The areas of Peak 1 and Peak 2, representing the oxidized variants, were determined and calculated relative to the total peak area of ​​the eluted species for the formulation shown in Table 17. Each sample was analyzed in duplicate, and all results are shown in Table 25.

[0903] [Table 25-1]

[0904] [Table 25-2]

[0905] After storage at 5°C (target storage conditions) for up to 9 months, oxidation levels increased slightly to total levels ranging from approximately 8.2% to 8.3% compared to t0 for all formulations tested within this stability study (Δ increase of 0.4% to 0.7%), suggesting successful long-term storage stability of pembrolizumab oxidation. Oxidation peak 01 remained stable in all formulations after 9 months of storage at 5°C.

[0906] In addition, all formulations remained stable after multiple freeze / thaw cycles and after mechanical stress. Overall, all formulations tested within this study showed similar, very good results.

[0907] h. Shear viscosity analysis Shear viscosity was determined at 20 °C by rheometry using a Kinexus Ultra Plus rheometer (diameter: 40 mm, cone angle: 0.5°, sample volume: 160 μl, CP 0.5° / 40 mm) with a cone-and-plate geometry. A water-filled solvent trap was used to avoid evaporation. Calibration was performed with known viscosities before every procedure. Samples were equilibrated for 2 min before each measurement. The shear viscosity ranged from 0.1 to 1000 s. -1 After increasing to 1000s -1 Dynamic viscosity was measured for 1 minute (1 data point / sec) at a constant shear rate of 1. All measurements were performed as a single measurement.

[0908] All formulations prepared according to Table 17 were analyzed for their shear viscosity after preparation and the results are shown in Table 26. It was demonstrated that formulations containing L-arginine effectively reduced the shear viscosity of formulations (1), (2) and (3) to very low levels when compared to lysine-containing formulations (4) and (5).

[0909] Nevertheless, values ​​for all formulations are well within acceptable limits for subcutaneous injection.

[0910] [Table 26]

[0911] i. Summary of research findings Based on the results obtained in this stability program, novel compositions were identified that are capable of stabilizing highly concentrated pembrolizumab in liquid formulations.

[0912] In particular, the use of 150 mmol / L L-arginine improved the stability of 165 mg / mL pembrolizumab over the pH range of 5.2 to 5.5 (Formulations 1, 2, and 3), demonstrating the pH robustness of this stabilizing effect when comparing Formulations 1 and 2. Two buffer systems providing buffering capacity at the tested pH were evaluated, with very comparable results obtained for the 10 mmol / L acetate buffer system and the 10 mmol / L adipic acid buffer system (Formulations 1 and 3).

[0913] These three formulations (buffered with either adipate or acetate) performed very well in stabilizing high concentrations of pembrolizumab. Relatively good results were also achieved when 140 mmol / L L-lysine was used in combination with 10 mmol acetic acid as the buffer system (formulation (4)), demonstrating the overall stabilizing effect of basic amino acids (represented by L-arginine and L-lysine in this study) in combination with pembrolizumab. Nevertheless, the use of L-arginine showed further improvement in reducing the viscosity of the solution.

[0914] The combination of L-lysine and trehalose resulted in visible particles after 3 months, and colloidal stability (Kd) analyzed by dynamic light scattering indicated a higher level of intermolecular attraction, which may ultimately promote pembrolizumab aggregation during the shelf life of the high-concentration pembrolizumab formulation. This was confirmed by storing the formulation under accelerated conditions, which resulted in an increase in the content of HMWS analyzed by SE-HPLC.

Claims

1. (a) an anti-human PD1 antibody; (b) arginine and / or lysine; (c) a nonionic surfactant; and (d) a mono- or dicarboxylic acid having a backbone of 2 to 6 carbon atoms or at least one salt thereof, preferably an unbranched mono- or dicarboxylic acid having a backbone of 4, 5, or 6 carbon atoms; A liquid pharmaceutical composition having a pH of 5.0 to 5.

8.

2. 2. The liquid pharmaceutical composition of claim 1, wherein the monocarboxylic or dicarboxylic acid having a backbone of 2 to 6 carbon atoms is selected from the group consisting of acetate, adipate, succinate, malate, glutamate, and tartrate.

3. The liquid pharmaceutical composition according to claim 1 or 2, wherein said buffer is present in a concentration of 1 mM to 50 mM, preferably 10 mM.

4. The liquid pharmaceutical composition according to any one of claims 1 to 3, wherein the non-ionic surfactant is polysorbate 20 or polysorbate 80, preferably polysorbate 80.

5. The liquid pharmaceutical composition according to any one of claims 1 to 4, wherein said non-ionic surfactant is present in a concentration of 0.1 mg / ml to 0.4 mg / ml, preferably 0.2 mg / ml.

6. The liquid pharmaceutical composition according to any one of claims 1 to 5, comprising arginine in a concentration of 50 mM to 350 mM, preferably 150 mM.

7. The liquid pharmaceutical composition according to any one of claims 1 to 5, comprising lysine in a concentration of 50 mM to 150 mM, preferably 70 mM to 140 mM or 70 mM to 130 mM.

8. A liquid pharmaceutical composition according to any one of claims 1 to 6, wherein said pharmaceutical composition does not contain trehalose, and preferably does not contain any sugars or sugar alcohols.

9. A liquid pharmaceutical composition according to any one of claims 1 to 8, wherein said pharmaceutical composition does not contain methionine or histidine and preferably does not contain any antioxidants.

10. The liquid pharmaceutical composition according to any one of claims 1 to 9, wherein the anti-human PD1 antibody is pembrolizumab.

11. 11. The liquid pharmaceutical composition according to any one of claims 1 to 10, wherein the anti-human PD1 antibody is present in a concentration of 100 to 200 mg / ml, preferably 165 mg / ml, or in a concentration of 20 to 80 mg / ml, preferably 25 mg / ml.

12. A liquid pharmaceutical composition comprising adipic acid buffer, arginine or lysine, polysorbate 20 or polysorbate 80, pembrolizumab, and water for injection, said liquid pharmaceutical composition having a pH of 5.0 to 5.

8.

13. 1. A liquid pharmaceutical composition consisting of adipic acid buffer, arginine or lysine, polysorbate 20 or polysorbate 80, optionally trehalose, pembrolizumab, and water for injection, wherein the liquid pharmaceutical composition has a pH of 5.0 to 5.

8.

14. A liquid pharmaceutical composition comprising succinate buffer, arginine or lysine, polysorbate 20 or polysorbate 80, pembrolizumab, and water for injection, said liquid pharmaceutical composition having a pH of 5.0 to 5.

8.

15. A liquid pharmaceutical composition consisting of 10 mM acetate buffer, 150 mM L-arginine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, having a pH of 5.2 or 5.

5.

16. A liquid pharmaceutical composition consisting of 10 mM adipic acid buffer, 150 mM L-arginine, 0.2 mg / ml polysorbate 80, 165 mg / ml water for injection, and having a pH of 5.

5.

17. A liquid pharmaceutical composition consisting of 10 mM acetate buffer, 140 mM L-arginine, 0.2 mg / ml polysorbate 80, 165 mg / ml pembrolizumab, and water for injection, having a pH of 5.

5.

18. 1. A liquid pharmaceutical composition for use in the treatment of cancer, comprising: Preferably, the cancer is melanoma, non-small cell lung cancer, classical Hodgkin's lymphoma, urothelial carcinoma, head and neck squamous cell carcinoma, renal cell carcinoma, colorectal cancer, small cell lung cancer, microsatellite instability-high or mismatch repair deficient cancer, primary mediastinal large B-cell lymphoma, gastric or gastroesophageal junction adenocarcinoma, esophageal cancer, hepatocellular carcinoma, Merkel cell carcinoma, endometrial cancer, tumor mutation burden-high cancer, cutaneous squamous cell carcinoma, triple-negative breast cancer, or cervical cancer.

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