STABILIZED LIQUID COMPOSITION FOR ANTI-hIL-4Rα ANTIBODIES

Abstract

The present invention relates to a stabilized liquid composition for an anti-hIL-4Rα antibody, and more specifically, to a liquid composition comprising an anti-hIL-4Rα antibody, an antigen-binding fragment thereof or a variant thereof and an amino acid or a pharmaceutically acceptable salt thereof.

Description

[0001] Specification

[0002] Title

[0003] STABILIZED LIQUID COMPOSITION FOR ANTI-hlL-4Ra ANTIBODIES

[0004] Technical Field

[0005] The present invention relates to a liquid composition for an anti-hlL-4Ra antibody, and specifically, to a liquid composition comprising an anti-hlL-4Ra antibody, an antigen-binding fragment thereof or a variant thereof and an amino acid or a pharmaceutically acceptable salt thereof.

[0006] Background

[0007] Human interleukin receptor alpha (hlL-4Ra) is a receptor capable of binding to interleukin-4 (IL-4) and interleukin-13 (IL-13) with high affinity, and inhibition of IL-4Ra may effectively block related biological functions mediated by IL-4 and IL-13. Accordingly, an anti-hlL-4Ra antibody which binds to hlL-4Ra and inhibits the same has wide applicability, and may be used to treat allergic diseases such as allergic rhinitis, asthma, allergy and atopic dermatitis, and to treat rhinosinusitis, nasal polyps, chronic obstructive pulmonary diseases, tissue fibrosis, tumors, autoimmune diseases, and the like.

[0008] As an anti-hlL-4Ra antibody, there is dupilumab, an antibody (U. S. Patent No.

[0009] 7, 605, 237, Korean Patent No. 10-1474227) developed by Regeneron Pharmaceuticals Inc. Dupilumab was approved by the Food and Drug Administration (FDA) in 2017 and is used for treatment of allergic diseases (e.g., atopic eczema). Dupilumab is an anti-hlL-4Ra antibody with very high affinity (affinity constant (KD) of pM level).

[0010] In order to subsequently use the anti-hlL-4Ra antibody, the antibody needs to be formulated, so as to maintain its stability, but if the antibody is not properly formulated, the antibody is likely to deteriorate, aggregate, or be undesirably chemically modified. In particular, when an antibody or the like is formulated into a liquid formulation, a problem such as an increase in viscosity, etc., may occur depending on additives or the like added for stability. For example, the viscosity of a formulation comprising sugar may cause a decrease in an interaction between molecules, thereby limiting a flow of the formulation, resulting in an increase in theviscosity. Thus, there is still a need to develop antibodies capable of replacing sugars.

[0011] Related Art References

[0012] Patent Documents

[0013] (Patent Document 1) Patent Document 1: US7605237B2

[0014] (Patent Document 2) Patent Document 2: KR101474227B1

[0015] Description of the Invention

[0016] Technical Problem

[0017] The present invention provides a stabilized liquid composition for an anti-hlL-4Ra antibody.

[0018] The present invention provides a liquid composition comprising an anti-hlL-4Ra antibody, an antigen-binding fragment thereof or a variant thereof and at least two amino acids or pharmaceutically acceptable salts thereof.

[0019] Technical Solution

[0020] A liquid composition according to the present invention comprises an anti-hlL-4Ra antibody, an antigen-binding fragment thereof or a variant thereof and at least two amino acids or pharmaceutically acceptable salts thereof.

[0021] In the present invention, the anti-hlL-4Ra antibody may be an antibody binding to human interleukin receptor alpha (hlL-4Ra), in which the anti-hlL-4Ra antibody herein may comprehensively refer to an anti-hlL-4Ra antibody, an antigen-binding fragment thereof or a variant thereof.

[0022] In embodiments of the present invention, the anti-hlL-4Ra antibody may be dupilumab. Dupilumab is an antibody having the following heavy and light chain amino acid sequences.

[0023] Heavy EVQLVESGGG LEQPGGSLRL SCAGSGFTFR DYAMTWVRQA PGKGLEWVSS ISGSGGNTYY chain ADSVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCAKDR LSITIRPRYY GLDVWGQGTT (SEQ

[0024] VTVSSASTKG PSVFPLAPCS RSTSESTAAL GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA ID NO:

[0025] VLQSSGLYSL SSWTVPSSS LGTKTYTCNV DHKPSNTKVD KRVESKYGPP CPPCPAPEFL

[0026] 1)

[0027] GGPSVFLFPP KPKDTLMISR TPEVTCVVVD VSQEDPEVQF NWYVDGVEVH NAKTKPREEQ FNSTYRVVSV LTVLHQDWLN GKEYKCKVSN KGLPSSIEKT ISKAKGQPRE PQVYTLPPSQ EEMTKNQVSL TCLVKGFYPS DIAVEWESNG QPENNYKTTP PVLDSDGSFF LYSRLTVDKS

[0028]

[0029] RWQEGNVFSC SVMHEALHNH YTQKSLSLSL GK

[0030] Light DIVMTQSPLS LPVTPGEPAS ISCRSSQSLL YSIGYNYLDW YLQKSGQSPQ LLIYLGSNRA chain SGVPDRFSGS GSGTDFTLKI SRVEAEDVGF YYCMQALQTP YTFGQGTKLE IKRTVAAPSV (SEQ

[0031] FIFPPSDEQL KSGTASVVCL LNNFYPREAK VQWKVDNALQ SGNSQESVTE QDSKDSTYSL ID NO:

[0032] SSTLTLSKAD YEKHKVYACE VTHQGLSSPV TKSFNRGEC

[0033] 2)

[0034]

[0035] In other words, in embodiments of the present invention, the liquid composition of the present invention may comprise dupilumab, an antigen-binding fragment thereof, or a variant thereof.

[0036] In the present invention, the term "antigen-binding fragment" may refer to any fragment which retains an antigen-binding function of an antibody, and exemplary antigen-binding fragments may comprise Fab, Fab', F(ab')2, Fv, and the like, but are not limited thereto.

[0037] In the present invention, the term "variant" may comprehensively refer to an antibody which comprises the same CDR as that of a parent antibody, or in which a part of a parent antibody CDR amino acid sequence is mutated (substituted, added, or deleted) under conditions of targeting the same epitope. Such a variant may be appropriately controlled by those skilled in the art to improve the affinity, immunity and the like of the antibody within a range in which a binding ability to the same epitope is maintained.

[0038] In the present invention, an amino acid or a pharmaceutically acceptable salt thereof may be histidine, arginine, lysine, proline, or pharmaceutically acceptable salts thereof.

[0039] In the present invention, the at least two amino acids or the pharmaceutically acceptable salts thereof may be at least two selected from the group consisting of histidine, arginine, lysine, proline, and pharmaceutically acceptable salts thereof. Specifically, in the present invention, the at least two amino acids or the pharmaceutically acceptable salts thereof may be at least two selected from the group consisting of histidine, pharmaceutically acceptable salt of histidine, arginine, pharmaceutically acceptable salt of arginine, lysine, pharmaceutically acceptable salt of lysine, proline and pharmaceutically acceptable salt of proline.In embodiments of the present invention, the liquid composition comprises at least two selected from the group consisting of histidine, arginine, lysine, proline, and pharmaceutically acceptable salts thereof.

[0040] In the present invention, the liquid composition may comprise three amino acids or pharmaceutically acceptable salts thereof.

[0041] In embodiments of the present invention, the three amino acids or the pharmaceutically acceptable salts thereof may be three selected from the group consisting of histidine, arginine, lysine, proline, and pharmaceutically acceptable salts thereof. Specifically, in the present invention, the three amino acids or the pharmaceutically acceptable salts thereof may be three selected from the group consisting of histidine, pharmaceutically acceptable salt of histidine, arginine, pharmaceutically acceptable salt of arginine, lysine, pharmaceutically acceptable salt of lysine, proline and pharmaceutically acceptable salt of proline.

[0042] In the present invention, the term "pharmaceutically acceptable salt" refers to a salt commonly used in the pharmaceutical field. For example, the pharmaceutically acceptable salts may comprise inorganic ion salts prepared from calcium, potassium, sodium, magnesium, etc.; inorganic acid salts prepared from hydrochloric acid, nitric acid, phosphoric acid, bromic acid, iodic acid, perchloric acid, sulfuric acid, hydroiodic acid, etc.; organic acid salts prepared from acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonicacid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbricacid, carbonic acid, vanillic acid, etc.; sulfonic acid salts prepared from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, etc.; amino acid salts prepared from glycine, arginine, lysine, etc.; amine salts prepared from trimethylamine, triethylamine, ammonia, pyridine, picoline, etc.; and the like, but are not limited thereto.

[0043] In embodiments of the present invention, the pharmaceutically acceptable salt of the amino acid may be a hydrochloride, but is not limited thereto. Specifically, the pharmaceutically acceptable salt of the amino acid may be arginine hydrochloride, lysine hydrochloride, etc.

[0044] In one embodiment of the present invention, the liquid composition may comprise two selected from the group consisting of histidine, arginine, lysine, proline,and pharmaceutically acceptable salts thereof. For example, the liquid composition may comprise histidine and lysine hydrochloride, or may comprise histidine and arginine hydrochloride, or may comprise histidine and proline, but is not necessarily limited thereto.

[0045] In another embodiment of the present invention, the liquid composition may comprise three selected from the group consisting of histidine, arginine, lysine, proline, and pharmaceutically acceptable salts thereof. For example, the liquid composition may comprise histidine, lysine hydrochloride and proline, or may comprise histidine, lysine hydrochloride and arginine hydrochloride, or may comprise histidine, lysine hydrochloride and arginine, or may comprise histidine, proline and arginine hydrochloride, but is not necessarily limited thereto.

[0046] In embodiments of the present invention, the liquid composition may comprise (a) histidine or a pharmaceutically acceptable salt thereof; and (b) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of arginine, lysine, proline, and pharmaceutically acceptable salts thereof. Specifically, the liquid composition may comprise (a) histidine or a pharmaceutically acceptable salt thereof; and (b) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of arginine, pharmaceutically acceptable salt of arginine, lysine, pharmaceutically acceptable salt of lysine, proline and pharmaceutically acceptable salt of proline.

[0047] For example, (a) may be histidine or histidine hydrochloride, and (b) may be arginine, arginine hydrochloride, lysine, lysine hydrochloride, proline, or proline hydrochloride. Specifically, (a) may be histidine, and (b) may be lysine hydrochloride, arginine, arginine hydrochloride, or proline. More specifically, (a) may be histidine and (b) may be lysine hydrochloride, or (a) may be histidine and (b) may be arginine, or (a) may be histidine and (b) may be arginine hydrochloride, or (a) may be histidine and (b) may be proline.

[0048] In embodiments of the present invention, the liquid composition may comprise (a) and (b) at a molar concentration ratio of (a) 1: (b) 5-10 (an (a): (b) molar concentration ratio of 1:5-10). Specifically, the liquid composition may comprise (a) and (b) at a molar concentration ratio of 1: 5, 1: 5.5, 1: 6, 1: 6.5, 1: 7, 1: 7.5, 1: 8, 1: 8.5, 1: 9, 1: 9.5, or 1: 10.

[0049] In embodiments of the present invention, the liquid composition may comprise(c) histidine or a pharmaceutically acceptable salt thereof; (d) lysine or a pharmaceutically acceptable salt thereof; and (e) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of arginine, proline, and pharmaceutically acceptable salts thereof. Specifically, the liquid composition may comprise (c) histidine or a pharmaceutically acceptable salt thereof; (d) lysine or a pharmaceutically acceptable salt thereof; and (e) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of arginine, a pharmaceutically acceptable salt of arginine, proline and a pharmaceutically acceptable salt of proline.

[0050] For example, (c) may be histidine or histidine hydrochloride, (d) may be lysine or lysine hydrochloride, and (e) may be arginine, arginine hydrochloride, proline, or proline hydrochloride. Specifically, (c) may be histidine, (d) may be lysine hydrochloride, and (e) may be arginine, arginine hydrochloride, or proline. More specifically, (c) may be histidine, (d) may be lysine hydrochloride, and (e) may be arginine, or (c) may be histidine, (d) may be lysine hydrochloride, and (e) may be arginine hydrochloride, or (c) may be histidine, (d) may be lysine hydrochloride, and (e) may be proline.

[0051] In embodiments of the present invention, the liquid composition may comprise (c), (d), and (e) at a molar concentration ratio of (c) 1: (d) 1-5: (e) 1-5 (a (c): (d): (e) molar concentration ratio of 1: 1-5: 1-5). Specifically, the liquid composition may comprise (c), (d), and (e) at a molar concentration ratio of (c) 1: (d) 1.5-5: (e) 1.5-5 (a (c): (d): (e) molar concentration ratio of 1: 1.5-5: 1.5-5).

[0052] For example, the liquid composition may comprise (c), (d), and (e) at a molar concentration ratio of 1: 1.5: 4.5, 1: 2.5: 2.5, 1: 2.5: 5, 1: 3: 3, 1: 4.5: 1.5, 1: 5: 2.5, or 1: 5: 5.

[0053] In embodiments of the present invention, the liquid composition may comprise (f) histidine or a pharmaceutically acceptable salt thereof; (g) proline or a pharmaceutically acceptable salt thereof; and (h) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of lysine, arginine, and pharmaceutically acceptable salts thereof. Specifically, the liquid composition may comprise (f) histidine or a pharmaceutically acceptable salt thereof; (g) proline or a pharmaceutically acceptable salt thereof; and (h) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of lysine,pharmaceutically acceptable salt of lysine, arginine and pharmaceutically acceptable salt of arginine.

[0054] For example, (f) may be histidine or histidine hydrochloride, (g) may be proline or proline hydrochloride, and (h) may be lysine, lysine hydrochloride, arginine, or arginine hydrochloride. Specifically, (f) may be histidine, (g) may be proline, and (h) may be lysine hydrochloride, arginine, or arginine hydrochloride. More specifically, (f) may be histidine, (g) may be proline, and (h) may be lysine hydrochloride, or (f) may be histidine, (g) may be proline, and (h) may be arginine, or (f) may be histidine, (g) may be proline, and (h) may be arginine hydrochloride.

[0055] In embodiments of the present invention, the liquid composition may comprise (f), (g), and (h) at a molar concentration ratio of (f) 1: (g) 1-5: (h) 1-5 (an (f): (g): (h) molar concentration ratio of 1: 1-5: 1-5). Specifically, the liquid composition may comprise (f), (g), and (h) at a molar concentration ratio of (f) 1: (g) 1.5-5: (h) 1.5-5 (an (f): (g): (h) molar concentration ratio of 1: 1.5-5: 1.5-5).

[0056] For example, the liquid composition may comprise (f), (g), and (h) at a molar concentration ratio of 1: 1.5: 4.5, 1: 2.5: 2.5, 1: 2.5: 5, 1: 3: 3, 1: 4.5: 1.5, 1: 5: 2.5, or 1: 5: 5.

[0057] In embodiments of the present invention, the liquid composition may comprise the anti-hlL-4Ra antibody, the antigen-binding fragment thereof, or the variant thereof at a concentration of 150 to 175 mg / mL. Specifically, the liquid composition may comprise the anti-hlL-4Ra antibody, the antigen-binding fragment thereof, or the variant thereof at a concentration of 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, or 175 mg / mL.

[0058] In embodiments of the present invention, the liquid composition may comprise an amino acid or a pharmaceutically acceptable salt thereof of the present invention individually or at least two thereof in an amount of 20 mM or more to 250 mM or less. Specifically, the liquid composition may comprise the amino acid or pharmaceutically acceptable salt thereof of the present invention individually or in a combination of at least two amino acids or pharmaceutically acceptable salts thereof in an amount of 20 mM or more, 25 mM or more, 30 mM or more, 35 mM or more, 40 mM or more, 45 mM or more, 50 mM or more, 60 mM or more, 70 mM or more, 80 mM or more, 90 mM or more, 100 mM or more, 110 mM or more, 120 mM or more, 130 mM or more, 140 mM or more, 150 mM or more, 160 mM or more, 170 mM or more, 180 mM ormore, 190 mM or more, 200 mM or more, 220 mM or more, and 250 mM or less. In one embodiment of the present invention, the liquid composition may comprise a combination of at least two amino acids or pharmaceutically acceptable salts thereof in an amount of 40 mM to 250 mM, specifically 45 mM to 220 mM, but the present invention is not limited thereto.

[0059] In embodiments of the present invention, the liquid composition may have a viscosity of 21 cP or less. Specifically, the liquid composition may preferably have a viscosity of 16 cP or less, 15 cP or less, 14.5 cP or less, 13.5 cP or less, 12.5 cP or less, 11.5 cP or less, 11 cP or less, 10 cP or less, more preferably 9 cP or less, 8 cP or less, 7.5 cP or less, or 7 cP or less.

[0060] According to the present invention, it may be possible to provide a liquid composition which comprises an anti-hlL-4Ra antibody, an antigen-binding fragment thereof or a variant thereof, and at least two amino acids or pharmaceutically acceptable salts thereof, thereby achieving a viscosity of 21 cP or less, preferably 16 cP or less, 15 cP or less, 14.5 cP or less, 13.5 cP or less, 12.5 cP or less, 11.5 cP or less, 11 cP or less, 10 cP or less, more preferably 9 cP or less, 8 cP or less, 7.5 cP or less, or 7 cP or less.

[0061] In the present invention, the liquid composition may not comprise sugar. For example, the sugar may be sugar such as sucrose or trehalose. In embodiments of the present invention, the liquid composition may not comprise sucrose and / or trehalose. In the present invention, the sugar may not comprise sugar alcohol.

[0062] In embodiments of the present invention, the liquid composition may comprise sugar alcohol, but the present invention is not necessarily limited thereto. In other embodiments of the present invention, the liquid composition may not comprise sugar alcohol. In one embodiment, the sugar alcohol may be sorbitol.

[0063] According to the present invention, the liquid composition may comprise at least two amino acids or pharmaceutically acceptable salts thereof of the present invention, even though it comprises a high concentration of antibodies and does not comprise sugar, and thus may lower the viscosity compared to a formulation which does not comprise the same, thereby providing a stabilized liquid composition comprising an antibody having a low viscosity.

[0064] In the case of protein drugs with high viscosity, there may be problems with stability such as aggregation, precipitation or the like. In addition, in the case of aninjection with high viscosity, the break loose force and gliding force may increase, making it difficult to administer the drug in an accurate and consistent dose and potentially causing problems such as pain induction at the injection site. Conventionally, in order to solve a problem with an increase in the viscosity of the liquid composition of the antibody, an additional additive such as sugar was comprised, but the viscosity may not decrease to a sufficient level or may have a different effect (typically, glycation) on the quality of a drug substance. In addition, even when a viscosity modifier other than sugar is used, there may be cases where an effect of viscosity reduction is not shown and / or stability is not secured.

[0065] However, the liquid composition according to the present invention may provide a stable liquid composition having a low viscosity by comprising at least two amino acids of the present invention or pharmaceutically acceptable salts thereof, even without comprising other viscosity modifiers or sugars. Accordingly, the physical stability of the liquid composition may be increased, and the degeneration or inactivation of the antibody may be prevented. In addition, the liquid composition including an antibody of the present invention may exhibit excellent convenience in administration. Also, the liquid composition comprising the antibody of the present invention having a low viscosity may be advantageous for comprising a high volume of antibodies. Although it is often difficult to comprise a high concentration of protein in an liquid formulation having a high viscosity, the liquid composition according to the present invention may contain a relatively high concentration of protein in a formulation, and thus may help increase the efficacy of a drug.

[0066] In embodiments of the present invention, the liquid composition according to the present invention may comprise a pharmaceutically acceptable additive.

[0067] In embodiments of the present invention, the pharmaceutically acceptable additive may comprise a buffer, a pH adjusting agent, a surfactant, etc., but the additive that may be used in the present invention is not limited thereto.

[0068] In embodiments of the present invention, the buffer may comprise a buffer such as acetic acid, citric acid, phosphoric acid, boric acid, or a salt thereof, but is not limited thereto. In one embodiment, the buffer may be acetate, but is not limited thereto. The buffer may comprise histidine, but is not limited thereto.

[0069] In embodiments of the present invention, the pH adjusting agent may comprise sodium hydroxide, hydrochloric acid, etc., but is not limited thereto.In embodiments of the present invention, the surfactant may be selected from any pharmaceutically acceptable surfactants capable of uniformly dispersing a protein (e.g., an antibody) in a liquid formulation medium.

[0070] In embodiments of the present invention, the surfactant may be a nonionic surfactant. Specifically, the surfactant may comprise poloxamer, polysorbate, a sorbitan ester of other fatty acids, polyethylene-polypropylene glycol, a polyoxyethylene compound, sodium dodecyl sulphate (SDS), etc., but is not limited thereto.

[0071] In one embodiment, the poloxamer may comprise a PEO-PPO-PEO copolymer (PEO being poly(ethylene oxide) and PPO being poly(propylene oxide)), etc. Specifically, the poloxamer may comprise poloxamer 188, etc.

[0072] In one embodiment, the polysorbate may comprise polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, etc.

[0073] In one embodiment, the sorbitan ester of another fatty acid may refer to a sorbitan ester of a fatty acid other than polysorbate. For example, sorbitan polyethoxylate, etc. may be comprised.

[0074] In one embodiment, the polyoxyethylene compound may comprise polyoxyethylene-stearate, polyoxyethylene alkyl ether (alkyl: C1-C30), polyoxyethylene monolauryl ether, alkylphenyl polyoxyethylene copolymer (alky: C1-C30), etc.

[0075] In embodiments of the present invention, the surfactant may be poloxamer or polysorbate. Specifically, the surfactant may be poloxamer 188, polysorbate 20, or polysorbate 80.

[0076] In embodiments of the present invention, the liquid composition may comprise the surfactant at a concentration of 0.05 to 15 mg / mL. Specifically, the liquid composition may comprise the surfactant at a concentration of 0.05 mg / mL or higher, 0.1 mg / mL or higher, 0.5 mg / mL or higher, 1 mg / mL or higher, 1.5 mg / mL or higher, 2 mg / mL or higher, 3 mg / mL or higher, 4 mg / mL or higher, 5 mg / mL or higher, 6 mg / mL or higher, 7 mg / mL or higher, 8 mg / mL or higher, 9 mg / mL or higher, or 10 mg / mL or higher, and at a concentration of 15 mg / mL or lower.

[0077] In embodiments of the present invention, the liquid composition may comprise the surfactant at a concentration of 0.05 to 15 mg / mL. Specifically, the liquid composition may comprise the surfactant at a concentration of 0.1 to 15 mg / mL, andmore specifically, at a concentration of 0.1 to 10 mg / mL.

[0078] The liquid composition according to the present invention, by comprising the surfactant (e.g., poloxamer or polysorbate), may provide a stable liquid composition capable of suppressing an increase in viscosity or reducing viscosity by mitigating nonspecific interactions between an interfacial stabilizer and proteins in a protein formulation. In addition, it may provide a stable liquid composition capable of reducing the formation of visible and subvisible particles under various stress conditions by preferentially adsorbing to the air-liquid interface or the container-liquid interface and suppressing interfacial denaturation and aggregation of proteins.

[0079] Accordingly, the physical stability of the liquid composition may be increased, and the degeneration or inactivation of the antibody may be prevented. In addition, the liquid composition may exhibit excellent convenience in administration.

[0080] The liquid composition according to the present invention comprises an anti-hlL-4Ra antibody, an antigen-binding fragment thereof, or a variant thereof; at least two amino acids or pharmaceutically acceptable salts thereof; and a surfactant.

[0081] In the present invention, the liquid composition may not comprise sugar.

[0082] The liquid composition according to the present invention comprises an anti-hlL-4Ra antibody, an antigen-binding fragment thereof, or a variant thereof; three amino acids or pharmaceutically acceptable salts thereof; and a surfactant, and the liquid composition does not comprise sugar.

[0083] In embodiments of the present invention, the three amino acids or the pharmaceutically acceptable salts thereof may be histidine, arginine, lysine, proline or pharmaceutically acceptable salts thereof.

[0084] In embodiments of the present invention, the three amino acids or the pharmaceutically acceptable salts thereof may be the three selected from the group consisting of histidine, arginine, lysine, proline and pharmaceutically acceptable salts thereof. Specifically, in the present invention, the three amino acids or the pharmaceutically acceptable salts thereof may be the three selected from the group consisting of histidine, pharmaceutically acceptable salt of histidine, arginine, pharmaceutically acceptable salt of arginine, lysine, pharmaceutically acceptable salt of lysine, proline and pharmaceutically acceptable salt of proline.

[0085] More specifically, the three amino acids or the pharmaceutically acceptable salts thereof may be selected from the group consisting of histidine, histidinehydrochloride, arginine, arginine hydrochloride, lysine, lysine hydrochloride, proline and proline hydrochloride. For example, the three may be histidine, lysine hydrochloride, and proline; histidine, proline, and arginine hydrochloride; histidine, lysine hydrochloride, and arginine; or histidine, lysine hydrochloride, and arginine hydrochloride, but are not limited thereto.

[0086] In embodiments of the present invention, the liquid composition may comprise (i) histidine or a pharmaceutically acceptable salt thereof; (j) lysine or a pharmaceutically acceptable salt thereof; and (k) arginine or a pharmaceutically acceptable salt thereof at a molar concentration ratio of (i) 1: (j) 1-5: (k) 1-5 (an (i): (j): (k) molar concentration ratio of 1: 1-5: 1-5). Specifically, the liquid composition may comprise (i), (j), and (k) at a molar concentration ratio of (i) 1: (j) 1.5-5: (k) 1.5-5 (an (i): (j): (k) molar concentration ratio of 1: 1.5-5: 1.5-5).

[0087] For example, the liquid composition may comprise (i), (j), and (k) at a molar concentration ratio of 1: 1.5: 4.5, 1: 2.5: 2.5, 1: 2.5: 5, 1: 3: 3, 1: 4.5: 1.5, 1: 5: 2.5, or 1: 5: 5.

[0088] In embodiments of the present invention, the surfactant may be poloxamer or polysorbate. Specifically, the surfactant may be poloxamer 188, polysorbate 20, or polysorbate 80.

[0089] In embodiments of the present invention, the liquid composition may comprise the surfactant at a concentration of 0.05 to 15 mg / mL. Specifically, the liquid composition may comprise the surfactant at a concentration of 0.05 mg / mL or higher, 0.1 mg / mL or higher, 0.5 mg / mL or higher, 1 mg / mL or higher, 1.5 mg / mL or higher, 2 mg / mL or higher, 3 mg / mL or higher, 4 mg / mL or higher, 5 mg / mL or higher, 6 mg / mL or higher, 7 mg / mL or higher, 8 mg / mL or higher, 9 mg / mL or higher, or 10 mg / mL or higher, and at a concentration of 15 mg / mL or lower.

[0090] In embodiments of the present invention, the liquid composition may further comprise a buffer. Specifically, the buffer may be acetic acid or acetate.

[0091] In embodiments of the present invention, the anti-hlL-4Ra antibody, an antigen-binding fragment thereof, or a variant thereof may be dupilumab, an antigenbinding fragment thereof, or a variant thereof. Specifically, dupilumab, an antigenbinding fragment thereof, or a variant thereof may be comprised at a concentration of 150 to 175 mg / mL. Specifically, the liquid composition may comprise the anti-hlL-4Ra antibody, the antigen-binding fragment thereof, or the variant thereof at aconcentration of 150 mg / mL, 155 mg / mL, 160 mg / mL, 165 mg / mL, 170 mg / mL, or 175 mg / mL.

[0092] In embodiments of the present invention, the liquid composition may have a viscosity of 21 cP or less. Specifically, the liquid composition may preferably have a viscosity of 16 cP or less, 15 cP or less, 14.5 cP or less, 13.5 cP or less, 12.5 cP or less, 11.5 cP or less, 11 cP or less, or 10 cP or less, more preferably 9 cP or less, 8 cP or less, 7.5 cP or less, or 7 cP or less.

[0093] In embodiments of the present invention, the liquid composition may have a pH of 5 to 6.5. Specifically, the liquid composition may have a pH of 5.3 to 6.1, more specifically, a pH of 5.5 to 5.9.

[0094] In embodiments of the present invention, the liquid composition according to the present invention may comprise an additional stabilizer. In embodiments of the present invention, the liquid composition may further comprise sorbitol, ethylenediaminetetraacetic acid, diethylenetriaminepentaacetic acid, etc., as a stabilizer in addition to the amino acid.

[0095] The liquid composition according to the present invention may be used for treating or preventing allergic diseases by using antibody proteins binding to an interleukin receptor or variants thereof.

[0096] In the present invention, the allergic diseases may comprise atopic dermatitis, asthma, rhinosinusitis accompanied by nasal polyps, eosinophil esophagitis, prurigo nodularis, chronic obstructive pulmonary disease, etc.

[0097] The present invention provides a use of the liquid composition for preventing or treating allergic diseases.

[0098] The present invention provides a use of the liquid composition for preparing a medicament for preventing or treating allergic diseases.

[0099] The present invention provides a method for preventing or treating allergic diseases, comprising administering the liquid composition to a subject in need thereof.

[0100] In embodiments of the present invention, the administering may comprise administering a therapeutically effective amount of the liquid composition to a subject in need thereof.

[0101] In the present invention, the term "prevention" refers to any act of suppressing allergic diseases or delaying the onset of allergic diseases in a subject through administration of the liquid composition according to the present invention.In the present invention, the term "treatment" refers to any act in which administration of the liquid composition according to the present invention ameliorates or favorably changes symptoms associated with allergic diseases in a subject.

[0102] In the present invention, the term "administration(administering)" means introducing a predetermined substance into a subject by an appropriate method.

[0103] In the present invention, the term "subject" refers to all animals, including mice, rats, livestock, humans and the like, that have developed a disease or may develop a disease, and specifically may be a mammal including a human, but is not limited thereto.

[0104] In the present invention, the term "therapeutically effective amount" refers to an amount sufficient to treat a disease with a reasonable benefit-to-risk ratio applicable to medical treatment, and enough to avoid unacceptable side effects. Such an amount may be determined by a person skilled in the art based on factors including the patient’s sex, age, weight, health condition, type and severity of a disease, activity of a drug, sensitivity to a drug, method, timing, and route of administration, excretion rate, duration of treatment, and the presence of any combination or concurrently used drugs, as well as other factors well known in the medical field. A specific therapeutically effective amount for a particular patient is preferably applied depending on the type and degree of the desired response; a specific composition, including whether different agents are used; the age, weight, general health condition, sex, and diet of a patient; the timing and route of administration; excretion rate of the composition; duration of treatment; the presence of drugs used together with or concurrently with the specific composition; and other analogous factors well known in the medical field.

[0105] The present invention also comprises the following aspects (1) to (40) relating to a liquid composition, a use thereof and a method of treatment comprising the administration thereof.

[0106] (1 ) The present invention provides a liquid composition comprising an anti-hlL-4Ra antibody, an antigen-binding fragment thereof or a variant thereof and at least two amino acids or pharmaceutically acceptable salts thereof.

[0107] (2) According to (1), wherein the at least two amino acids or the pharmaceutically acceptable salts thereof may be at least two selected from the group consisting of histidine, arginine, lysine, proline and pharmaceutically acceptable salts thereof.(3) According to (1) or (2), wherein the liquid composition may comprise at least two selected from the group consisting of histidine, arginine, lysine, proline, histidine hydrochloride, arginine hydrochloride, lysine hydrochloride, and proline hydrochloride.

[0108] (4) According to (1), wherein the liquid composition may comprise three amino acids or the pharmaceutically acceptable salts thereof.

[0109] (5) According to any one of (1) to (4), wherein the three amino acids or pharmaceutically acceptable salts thereof may be the three selected from the group consisting of histidine, arginine, lysine, proline and pharmaceutically acceptable salts thereof.

[0110] (6) According to any one of (1 ) to (5), wherein the liquid composition may have a viscosity of 21 cP or less.

[0111] (7) According to any one of (1 ) to (5), wherein the liquid composition may have a viscosity of 14.5 cP or less.

[0112] (8) According to any one of (1 ) to (5), wherein the liquid composition may have a viscosity of 8 cP or less.

[0113] (9) According to any one of (1) to (8), wherein the liquid composition may comprise the anti-hlL-4Ra antibody, the antigen-binding fragment thereof, or the variant thereof in an amount of 150 to 175 mg / mL.

[0114] (10) According to any one of (1) to (9), wherein the liquid composition may comprise at least one pharmaceutically acceptable additive selected from the group consisting of a stabilizer, a buffer, and a surfactant.

[0115] (11) According to (10), wherein the surfactant may be Poloxamer or Polysorbate.

[0116] (12) According to (10) or (11), wherein the surfactant may be Poloxamer 188, Polysorbate 20 or Polysorbate 80.

[0117] (13) According to any one of (1) to (12), wherein the liquid composition may not comprise sugar.

[0118] (14) According to any one of (1 ) to (13), wherein the anti-hlL-4Ra antibody, the antigen-binding fragment thereof, or the variant thereof may be dupilumab, an antigenbinding fragment thereof, or a variant thereof.

[0119] (15) According to (14), wherein the liquid composition may comprise dupilumab, the antigen-binding fragment thereof, or the variant thereof in an amountof 150 to 175 mg / mL.

[0120] (16) According to any one of (1) to (15), wherein the liquid composition may comprise:

[0121] (a) histidine or a pharmaceutically acceptable salt thereof; and

[0122] (b) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of arginine, lysine, proline, and pharmaceutically acceptable salts thereof.

[0123] (17) According to (16), wherein the liquid composition may comprise (a) and (b) at a molar concentration ratio of (a) 1: (b) 5-10.

[0124] (18) According to any one of (1) to (15), wherein the liquid composition may comprise:

[0125] (c) histidine or a pharmaceutically acceptable salt thereof;

[0126] (d) lysine or a pharmaceutically acceptable salt thereof; and

[0127] (e) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of arginine, proline, and pharmaceutically acceptable salts thereof.

[0128] (19) According to (18), wherein the liquid composition may comprise (c), (d), and (e) at a molar concentration ratio of (c) 1: (d) 1-5: (e) 1-5.

[0129] (20) According to any one of (1) to (15), wherein the liquid composition may comprise:

[0130] (f) histidine or a pharmaceutically acceptable salt thereof;

[0131] (g) proline or a pharmaceutically acceptable salt thereof; and

[0132] (h) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of lysine, arginine, and pharmaceutically acceptable salts thereof.

[0133] (21) According to (20), wherein the liquid composition may comprise (f), (g), and (h) at a molar concentration ratio of (f) 1: (g) 1-5: (h) 1-5.

[0134] (22) The present invention provides a liquid composition comprising an anti-hlL-4Ra antibody, an antigen-binding fragment thereof or a variant thereof;

[0135] at least two amino acids or pharmaceutically acceptable salts thereof; and a surfactant.

[0136] (23) The present invention provides a liquid composition comprising an anti-hlL-4Ra antibody, an antigen-binding fragment thereof or a variant thereof;

[0137] three amino acids or pharmaceutically acceptable salts thereof; and

[0138] a surfactant,wherein the liquid composition does not comprise sugar.

[0139] (24) According to (22), wherein the liquid composition may not comprise sugar. (25) According to (22) or (24), wherein the at least two amino acids or the pharmaceutically acceptable salts thereof may be at least two selected from the group consisting of histidine, arginine, lysine, proline and pharmaceutically acceptable salts thereof.

[0140] (26) According to (23), wherein the three amino acids or the pharmaceutically acceptable salts thereof may be the three selected from the group consisting of histidine, arginine, lysine, proline and pharmaceutically acceptable salts thereof.

[0141] (27) According to any one of (22) to (26), wherein the liquid composition may have a viscosity of 21 cP or less.

[0142] (28) According to any one of (22) to (26), wherein the liquid composition may have a viscosity of 14.5 cP or less.

[0143] (29) According to any one of (22) to (26), wherein the liquid composition may have a viscosity of 8 cP or less.

[0144] (30) According to any one of (22) to (29), wherein the liquid composition may comprise the anti-hlL-4Ra antibody, the antigen-binding fragment thereof, or the variant thereof in an amount of 150 to 175 mg / mL.

[0145] (31) According to any one of (22) to (30), wherein the liquid composition may further comprise at least one pharmaceutically acceptable additive selected from the group consisting of a stabilizer and a buffer.

[0146] (32) According to any one of (22) to (31), wherein the surfactant may be Poloxamer or Polysorbate.

[0147] (33) According to any one of (22) to (32), wherein the surfactant may be Poloxamer 188, Polysorbate 20 or Polysorbate 80.

[0148] (34) According to any one of (22) to (33), wherein the anti-hlL-4Ra antibody, the antigen-binding fragment thereof, or the variant thereof may be dupilumab, an antigen-binding fragment thereof, or a variant thereof.

[0149] (35) According to (34), wherein the liquid composition may comprise dupilumab, the antigen-binding fragment thereof, or the variant thereof in an amount of 150 to 175 mg / mL.

[0150] (36) According to any one of (22) to (35), wherein the liquid composition may comprise:(i) histidine or a pharmaceutically acceptable salt thereof;

[0151] (j) lysine or a pharmaceutically acceptable salt thereof; and

[0152] (k) arginine or a pharmaceutically acceptable salt thereof at a molar concentration ratio of (i) 1:(j) 1-5:(k) 1-5.

[0153] (37) The liquid composition according to any one of (1) to (36), may be for preventing or treating allergic diseases.

[0154] (38) The present invention provides a use of the liquid composition according to any one of (1) to (36) for preventing or treating allergic diseases.

[0155] (39) The present invention provides a use of the liquid composition according to any one of (1 ) to (36) for preparing a medicament for preventing or treating allergic diseases.

[0156] (40) The present invention provides a method for preventing or treating allergic diseases, comprising administering the liquid composition according to any one of (1) to (36) to a subject in need thereof.

[0157] Advantageous Effects

[0158] The liquid composition according to the present invention may comprise at least two amino acids or pharmaceutically acceptable salts thereof of the present invention, even though it comprises a high concentration of antibodies and does not comprise sugar, thereby providing a stabilized composition having a low viscosity.

[0159] Brief Description of Drawings

[0160] FIG. 1 is a drawing showing a viscosity of liquid compositions according to Examples and Comparative Examples of the present invention.

[0161] FIG. 2 is a drawing showing a viscosity of liquid compositions according to Examples and Comparative Examples of the present invention.

[0162] Mode for Invention

[0163] Hereinafter, the present invention will be described in more detail through exemplary embodiments. These exemplary embodiments are provided only for the purpose of illustrating the present invention, and thus the scope of the present invention is not limited thereto.Preparation of liquid composition and evaluation of viscosity (1) -Evaluation of viscosity according to amino acid combination

[0164] Liquid compositions of Examples 1 to 6 and Comparative Examples 1 and 2 having components and contents according to Table 1 below were prepared.

[0165] Specifically, in order to obtain a liquid composition comprising dupilumab in an amount of at least 150 mg / mL or more, a solution having a composition of Table 1 below and comprising dupilumab in a desired pH range was subjected to buffer exchange at a concentration of a target buffer (acetate) shown in Table 1, and then 80-fold concentrated polysorbate solution was added to prepare each formulation (liquid composition) at a concentration of the final target buffer and stabilizer as shown in Table 1 below. The prepared liquid formulation (liquid composition) was sterile-filtered, and the liquid formulation was filled into a container having a specific dosage unit, such as a vial or pre-filled mixed syringe.

[0166]

Table 1

[0167] Compar Compar

[0168] ative ative Example Example Example Example Example Example Component

[0169] Example Example 1 2 3 4 5 6 1 2

[0170] Dupilumab

[0171] 150 150 150 150 150 150 150 150 mg / mL

[0172] Acetate

[0173] 32.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 mM

[0174] Sucrose

[0175] 148 - - - - - - - mM

[0176] Histidine

[0177] - 20.0 20.0 20.0 20.0 20.0 20.0 20.0 mM

[0178] Lysine- hydrochlorid

[0179] - - 100 - - 50 50 - e

[0180] mM

[0181] Arginine- hydrochlorid

[0182] 25 - - - 100 - 50 50 e

[0183] mM

[0184] Proline

[0185] - - - 200 - 100 - 100 mM

[0186] Polysorbate 2 2 2 2 2 2 2 2

[0187]

[0188] 80

[0189] mg / mL

[0190]

[0191] The viscosity of liquid compositions of Examples 1 to 6 and Comparative Examples 1 and 2 was measured.

[0192] Specifically, each liquid composition was left alone at room temperature for 30 minutes or more, after which viscosity analysis was performed, and the results thereof are shown in Table 2 and FIG. 1 below.

[0193] Here, the viscosity may mean an absolute viscosity and may be expressed in units of centipoise (cP).

[0194]

Table 2

[0195] Compara Compara

[0196] tive tive Example Example Example Example Example Example Example Example 1 2 3 4 5 6 1 2

[0197] Viscosity 9.9 11.7 10.8 10.0 8.2 8.2 7.0 7.8

[0198]

[0199] Referring to Table 2 and FIG. 1, it can be confirmed that the liquid compositions of Examples 1 to 6 comprising at least two amino acids or pharmaceutically acceptable salts thereof exhibit a lower viscosity than Comparative Example 2 comprising one amino acid and not comprising sugar. In addition, it can be confirmed that the liquid compositions of Examples 1 to 6 exhibit a viscosity similar to or lower than that of the liquid composition of Comparative Example 1.

[0200] Thus, it can be confirmed that the viscosity of the liquid composition may be reduced by comprising the antibody and at least two amino acids or pharmaceutically acceptable salts thereof according to the present invention.

[0201] A drop in viscosity of the formulation provides important advantages in many aspects, comprising physical stability, manufacturing efficiency, ease of administration of the drug, etc. Thus, the reduction in viscosity may be considered an important strategy not only to control the properties of the drug, but also to increase the overall periodic quality and efficiency of the drug. In other words, the liquid composition according to the present invention may lower the viscosity, and thus, may provide physical stability of the drug (antibody), and may increase the quality and efficiency thereof.Preparation of liquid composition and evaluation of viscosity (2) Liquid compositions of 22 formulations having the components and contents according to Table 3 below were prepared. A two- to ten-fold concentrated solution for each stabilizer concentration of Table 3 below prepared in advance was used in the buffer solution (acetate) comprising dupilumab, and diluted in accordance with a composition of each formulation as shown in Table 3 below, so as to prepare each formulation at a final dupilumab protein concentration. Each prepared formulation was sterile-filtered, filled into a container having a specific dosage unit, such as a vial or pre-filled mixed syringe, stored, and then measured for viscosity. The results thereof are shown in Table 3 and FIG. 2 below.

[0202] [Table 31

[0203] Form Form Form Form Form Form Form Form Form Form Form

[0204] ulati ulati ulati ulati ulati ulati ulati ulati ulati ulati ulati

[0205] on on on 1 on 2 on 3 on 4 on 5 on 6 on 7 on 8 on 9

[0206] 10 11 Dupilumab

[0207] protein

[0208] 150 150 150 150 150 150 150 150 150 150 150 concentration

[0209] (mg / mL)

[0210] Acetate (mM) 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 Histidine (mM) 20 20 20 20 20 20 20 20 20 20 20 Argininehydrochloride - - - - - - - 25 50 - - (mM)

[0211] Proline (mM) - - - - - 200 - - - - 100 Lysinehydrochloride - - - - - - 100 - - 100 - (mM)

[0212] Sorbitol (mM) - - 192 192 192 - - 148 148 - 100 Ethylenediamin

[0213] e

[0214] - 1.25 - - 1.25 - - - - - - tetraacetic acid

[0215] (mM)

[0216] Diethylenetriam

[0217] - 1 - 1 - - - - - 1 - ine

[0218]

[0219] pentaacetic

[0220] acid (mM)

[0221] Polysorbate 80

[0222] 2 2 2 2 2 2 2 2 2 2 2 (mg / mL)

[0223] pH 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 Viscosity (cp) 11.7 14.3 12 11.3 11.3 10.0 10.8 9.7 9.7 9.6 9.5

[0224] Form Form Form Form Form Form Form Form Form Form Form ulati ulati ulati ulati ulati ulati ulati ulati ulati ulati ulati on on on on on on on on on on on 12 13 14 15 16 17 18 19 20 21 22 Dupilumab

[0225] protein

[0226] 150 150 150 150 150 150 150 150 150 150 150 concentration

[0227] (mg / mL)

[0228] Acetate (mM) 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 Histidine (mM) 20 20 20 20 20 20 20 20 20 20 20 Arginine (mM) - - - - - - - - - 50 100 Argininehydrochloride - - 100 100 100 - - 50 50 - - (mM)

[0229] Proline (mM) - 200 - - - - 100 - 100 - - Lysinehydrochloride 50 - - - - 100 50 50 - 50 50 (mM)

[0230] Sorbitol (mM) 100 - - - - - - - - - - Ethylenediamin

[0231] e

[0232] - 1.25 - - 1.25 1.25 - - - - - tetraacetic acid

[0233] (mM)

[0234] Diethylenetriam

[0235] ine

[0236] - - - 1 - - - - - - - pentaacetic

[0237] acid (mM)

[0238] Polysorbate 80

[0239] 2 2 2 2 2 2 2 2 2 2 2 (mg / mL)

[0240] pH 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 Viscosity (cp) 8.8 8.5 8.2 8.1 8.1 7.6 8.2 7.0 7.8 6.1 5.1

[0241]

[0242] As confirmed in Table 3 and FIG. 2, formulations 1 to 5 (Comparative Example) were a group comprising one amino acid such as histidine, etc., and exhibited aviscosity value of 11.3 to 14.3 cP. Formulations 6 to 17 were a group comprising two amino acids such as histidine, etc., and exhibited a viscosity value of 7.6 to 10.8 cP, and it could be confirmed that the viscosity is relatively lower than that of the formulation comprising no amino acid. Formulations 18 to 22 were a group comprising three amino acids such as histidine, etc., and exhibited a viscosity value of 5.1 to 8.2 cP.

[0243] Specifically, from the above results,

[0244] it can be confirmed that when the sorbitol of formulation 9 (viscosity 9.7) is replaced with lysine, proline of formulations 19 and 20, respectively, the viscosity decreases to 7.0, 7.8, respectively.

[0245] It can be confirmed that when the sorbitol of formulation 11 (viscosity 9.5) is replaced with lysine of formulation 18, the viscosity decreases to 8.2.

[0246] It can be confirmed that when the sorbitol of formulation 12 (viscosity 8.8) is replaced with arginine of formulation 21, the viscosity decreases to 6.1.

[0247] Preparation of liquid composition and evaluation of viscosity (3) -Evaluation of viscosity according to protein concentration, pH

[0248] For a combination of lysine hydrochloride and arginine hydrochloride which exhibited a lowest viscosity value in the preparation and viscosity evaluation (1 ) (amino acid combination screening) of the liquid composition, the liquid composition was prepared under the conditions of dupilumab concentrations at 150 mg / mL and 175 mg / mL and at pH 5.5 and 5.9 and the viscosity was measured. The results thereof are shown in Tables 4 and 5 below.

[0249] [Table 41

[0250] Formula Formula Formula Formula Formula Formula Formula tion A tion B tion C tion D tion E tion F tion G Dupilumab

[0251] protein

[0252] 150 150 150 150 150 150 150 concentration

[0253] (mg / mL)

[0254] Acetate (mM) 12.5 12.5 12.5 12.5 12.5 12.5 12.5 Histidine (mM) 20 20 20 20 20 20 20

[0255]

[0256] Argininehydrochloride 25 30 60 90 30 60 90 (mM)

[0257] Lysinehydrochloride - 90 60 30 90 60 30 (mM)

[0258] Sucrose (mM) 146 - - - - - - Polysorbate 80

[0259] 2 2 2 2 2 2 2 (mg / mL)

[0260] pH 5.5 5.5 5.5 5.5 5.9 5.9 5.9 Viscosity (cp) 11.7 7.3 8.1 7.3 7.7 7.5 7.0

[0261]

[0262] [Table 51

[0263] Formula Formula Formula Formula Formula Formula Formula tion H tion I tion J tion K tion L tion M tion N Dupilumab

[0264] protein

[0265] 175 175 175 175 175 175 175 concentration

[0266] (mg / mL)

[0267] Acetate (mM) 12.5 12.5 12.5 12.5 12.5 12.5 12.5 Histidine (mM) 20 20 20 20 20 20 20 Argininehydrochloride 25 30 60 90 30 60 90 (mM)

[0268] Lysinehydrochloride - 90 60 30 90 60 30 (mM)

[0269] Sucrose (mM) 146 - - - - - - Polysorbate 80

[0270] 2 2 2 2 2 2 2 (mg / mL)

[0271] pH 5.5 5.5 5.5 5.5 5.9 5.9 5.9 Viscosity (cp) 14.8 12.6 12.1 11.5 12.4 13.2 10.8

[0272]

[0273] Referring to Tables 4 and 5, it was confirmed that the viscosity value varies according to the concentration of histidine, arginine and lysine in each composition of protein concentration and pH. It can be confirmed that the compositions (formulationsB to G, I to N) comprising lysine hydrochloride, arginine hydrochloride have a lower viscosity value compared to formulations A and H (Comparative Example) comprising sugar at both protein concentrations of 150 mg / mL and 170 mg / mL.

[0274] Preparation of liquid composition and evaluation of viscosity (4) - Evaluation of viscosity according to protein concentration, types of surfactants For a combination of lysine hydrochloride and arginine hydrochloride which exhibited a lowest viscosity value in the preparation and viscosity evaluation (1 ) (amino acid combination screening) of the liquid composition, the liquid composition was prepared under the conditions of dupilumab concentrations at 150 mg / mL and 175 mg / mL and at polysorbate 80 and poloxamer 188 and the viscosity was measured. The results thereof are shown in Tables 6 and 7 below.

[0275] [Table 61

[0276] Formulation Formulation Formulation Formulation Formulation Component

[0277] S1 S2 S3 S4 S5

[0278] Dupilumab

[0279] protein

[0280] 150 150 150 150 150 concentration

[0281] (mg / mL)

[0282] Acetate (mM) 12.5 12.5 12.5 12.5 12.5

[0283] Histidine (mM) 20 20 20 20 20

[0284] Argininehydrochloride 90 90 90 90 25

[0285] (mM)

[0286] Lysinehydrochloride 30 30 30 30 - (mM)

[0287] Sucrose (mM) - - - - 146 Polysorbate 80

[0288] 2 - - - 2

[0289] (mg / mL)

[0290] Poloxamer 188

[0291] - 2 3 4 - (mg / mL)

[0292] pH 5.9 5.9 5.9 5.9 5.9

[0293] Viscosity (cp) 6.7 7.1 7.2 7.6 8.8

[0294]

[0295] [Table 71

[0296] Formul Formul Formul Formul Formul Formul Formul Formul Formul Formul Formul Component ation ation ation ation ation ation ation ation ation ation ation S6 S7 S8 S9 S10 S11 S12 S13 S14 S15 S16 Dupilumab

[0297] protein

[0298] 175 175 175 175 175 175 175 175 175 175 175 concentratio

[0299] n (mg / mL)

[0300] Acetate

[0301] 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 (mM)

[0302] Histidine

[0303] 20 20 20 20 20 20 20 20 20 20 20 (mM)

[0304] Arginine- hydrochlorid 90 90 90 90 90 90 90 90 90 90 50 e (mM)

[0305] Lysine- hydrochlorid 30 30 30 30 30 30 30 30 30 30 - e (mM)

[0306] Sucrose

[0307] - - - - - - - - - - 146 (mM)

[0308] Polysorbate

[0309] - 0.1 2 3 - - - - - - 2 80 (mg / mL)

[0310] Poloxamer

[0311] - - - - 0.1 1 2 3 4 10 - 188 (mg / mL)

[0312] pH 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 Viscosity

[0313] 10.7 10.5 10.8 10.9 10.9 10.7 11.2 11.4 12.1 14.2 16.0 (cp)

[0314]

[0315] Referring to Tables 6 and 7, it can be confirmed that the compositions (formulations S1 to S4, S6 to S15) comprising lysine hydrochloride and arginine hydrochloride have a lower viscosity value compared to formulations S5 and S16 comprising sugar at both protein concentrations of 150 mg / mL and 170 mg / mL.

[0316] Preparation of liquid composition and evaluation of viscosity (5) -Evaluation of viscosity according to amino acid combination

[0317] Liquid compositions having the components and contents according to Tables 8 and 9 below were prepared and measured for viscosity. The results thereof areshown in Tables 8 and 9 below.

[0318] [Table 81

[0319] Componen Formulati Formulati Formulati Formulati Formulati Formulati Formulati Formulati Formulati t on F1 on F2 on F3 on F4 on F5 on F6 on F7 on F8 on F9 Dupilumab

[0320] protein

[0321] concentrati 150 150 150 150 150 150 150 150 150 on

[0322] (mg / mL)

[0323] Acetate

[0324] 32.5 32.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 (mM)

[0325] Histidine

[0326] - - 20 20 20 20 20 20 20 (mM)

[0327] Argininehydrochlor - 25 - - 100 - - 90 50 ide (mM)

[0328] Lysinehydrochlor - - - 100 - - 50 30 - ide (mM)

[0329] Proline

[0330] - - - - - 200 100 - 100 (mM)

[0331] Sucrose

[0332] 190 146 - - - - - - - (mM)

[0333] Poloxamer

[0334] 188 3 3 3 3 3 3 3 3 3 (mg / mL)

[0335] pH 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 Viscosity

[0336] 11.46 10.38 11.36 7.42 6.32 9.25 8.40 7.75 7.41 (cp)

[0337]

[0338] [Table 91

[0339] Formulati Formulati Formulati Formulati Formulati Formulati Formulati Formulati Formulati Component

[0340] on F10 on F11 on F12 on F13 on F14 on F15 on F16 on F17 on F18 Dupilumab

[0341] protein

[0342] 175 175 175 175 175 175 175 175 175 concentrati

[0343] on (mg / mL)

[0344] Acetate

[0345] 32.5 32.5 12.5 12.5 12.5 12.5 12.5 12.5 12.5 (mM)

[0346]

[0347] Histidine

[0348] - - 20 20 20 20 20 20 20 (mM)

[0349] Arginine-hydrochlori - 25 - - 100 - - 90 50 de (mM)

[0350] Lysine-hydrochlori - - - 100 - - 50 30 - de (mM)

[0351] Proline

[0352] - - - - - 200 100 - 100 (mM)

[0353] Sucrose

[0354] 190 146 - - - - - - - (mM)

[0355] Poloxamer

[0356] 188 3 3 3 3 3 3 3 3 3 (mg / mL)

[0357] pH 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 5.9 Viscosity

[0358] 29.58 18.48 22.56 14.14 10.91 20.21 15.56 13.10 13.48 (cp)

[0359]

[0360] Referring to Tables 8 and 9, it can be confirmed that the liquid compositions comprising at least two amino acids or pharmaceutically acceptable salts thereof have a lower viscosity compared to the composition comprising sugar without any amino acid, the composition comprising one amino acid and sugar, or the composition comprising one amino acid without any sugar, at protein concentrations of 150 mg / mL and 175 mg / mL.

[0361] Specifically, at protein concentrations of 150 mg / mL, formulations F1 to F3 (Comparative Example) were a group comprising sugar without any amino acid, a group comprising one amino acid and sugar, or a group comprising one amino acid without any sugar, and exhibited a viscosity value of 10.38 to 11.46 cP. Formulations F4 to F6 were a group comprising two amino acids, and exhibited a viscosity value of 6.32 to 9.25 cP, and formulations F7 to F9 were a group comprising three amino acids, and exhibited a viscosity value of 7.41 to 8.40 cP. It could be confirmed that the viscosity of formulations F4 to F9 is relatively lower than that of the formulation comprising no amino acid.

[0362] In addition, at protein concentrations of 175 mg / mL, formulations F10 to F12 (Comparative Example) were a group comprising sugar without any amino acid, a group comprising one amino acid and sugar, or a group comprising one amino acidwithout any sugar, and exhibited a viscosity value of 18.48 to 29.58 cP. Formulations F13 to F15 were a group comprising two amino acids, and exhibited a viscosity value of 10.91 to 20.21 cP, and formulations F16 to F18 were a group comprising three amino acids, and exhibited a viscosity value of 13.10 to 15.56 cP. It could be confirmed that the viscosity of formulations F13 to F18 is relatively lower than that of the formulation comprising no amino acid.

[0363] Thus, it can be confirmed that the viscosity of the liquid composition may be reduced by comprising the antibody and at least two amino acids or pharmaceutically acceptable salts thereof according to the present invention.

[0364] In other words, the liquid composition according to the present invention may lower the viscosity, and thus, may provide physical stability of the drug (antibody), and may increase the quality and efficiency thereof.

[0365] Evaluation of stability of liquid composition (1)

[0366] The stability of formulations of above Tables 4 and 5 was evaluated. The stability was evaluated after storing each formulation under the conditions for stress stabilization evaluation (40°C) for four weeks. The results thereof are shown in Tables 10 and 11.

[0367] % HMW and % Monomer were measured through an SE-HPLC analysis method. The % HMW represents a high molecular weight aggregate ratio and the % Monomer represents a monomer ratio.

[0368] [Table 101

[0369] Formu Formu Formu Formu Formu Formu

[0370] Stress stabilization

[0371] lation lation lation lation lation lation

[0372] condition (week)

[0373] B C D E F G

[0374] 0 2.2 2.2 2.2 2.3 2.3 2.3

[0375] SE-HPLC 1 2.6 2.6 2.6 2.6 2.6 2.5

[0376] (HMW%) 2 2.9 2.8 2.9 2.8 2.7 2.7

[0377] 4 3.0 3.0 3.0 2.9 2.9 2.9

[0378] 0 97.3 97.3 97.3 97.2 97.3 97.3

[0379] SE-HPLC

[0380] 1 97.0 96.9 96.9 97.0 97.0 97.1

[0381]

[0382] (Monomer % 2 96.6 96.7 96.6 96.6 96.8 97.0 ) 4 96.2 96.3 96.3 96.5 96.3 96.3

[0383]

[0384]

Table 1

[0385] Formu Formu Formu Formu Formu

[0386] Stress stabilization Formu

[0387] lation lation lation lation lation

[0388] condition (week) lation I

[0389] J K L M N

[0390] 0 2.3 2.2 2.3 2.2 2.3 2.3 SE-HPLC 1 2.5 2.6 2.7 2.6 2.6 2.7

[0391] (HMW%) 2 2.9 2.9 3.0 2.9 2.8 2.9

[0392] 4 3.0 3.1 2.7 2.8 2.8 2.9 0 97.3 97.3 97.3 97.3 97.1 97.2

[0393] SE-HPLC

[0394] 1 97.0 97.2 96.8 97.1 97.2 97.0

[0395] (Monomer %

[0396] 2 96.7 96.6 96.5 96.6 96.7 96.6

[0397] )

[0398] 4 96.2 96.1 96.6 96.5 96.5 96.4

[0399]

[0400] As seen in Tables 10 and 11, it can be confirmed that the liquid composition formulation of the present invention exhibits excellent stability under stress conditions.

[0401] Evaluation of stability of liquid composition (2)

[0402] The stability of formulations of above Tables 6 and 7 was evaluated. The stability was evaluated after storing each formulation under the conditions for stress stabilization evaluation (40°C) for one month. The results thereof are shown in Tables 12 and 13.

[0403] % HMW and % Monomer were measured through an SE-HPLC analysis method. The % HMW represents a high molecular weight aggregate ratio and the % Monomer represents a monomer ratio.

[0404] [Table 121

[0405] Stress stabilization condition Formulation Formulation Formulation Formulation (month) S2 S3 S4 S5

[0406] 0 0.4 0.4 0.4 0.5

[0407] SE-HPLC (HMW%)

[0408] 1 1.0 1.0 1.1 1.3

[0409] SE-HPLC (Monomer %) 0 99.6 99.6 99.6 99.5

[0410]

[0411] 1 99.0 99.0 99.0 98.7

[0412]

[0413] [Table 131

[0414] Stress

[0415] Formula Formula Formula Formula Formula Formula Formula Formula Formula Formula stabilization

[0416] tion S6 tion S7 tion S8 tion S9 tion S10 tion S11 tion S12 tion S13 tion S14 tion S15 condition (month)

[0417] SE-HPLC 0 0.4 0.5 0.5 0.4 0.4 0.4 0.4 0.4 0.4 0.4 (HMW %) 1 1.3 1.1 1.3 1.3 1.1 1.2 1.2 1.2 1.2 1.2 SE-HPLC 0 99.6 99.5 99.6 99.6 99.6 99.6 99.6 99.6 99.7 99.6 (Monomer %

[0418] 1 98.7 98.9 98.7 98.8 98.9 98.8 98.8 98.8 98.8 98.8 )

[0419]

[0420] As seen in Tables 12 and 13, it can be confirmed that the liquid composition formulation of the present invention can minimize aggregation of antibodies and exhibits excellent stability under stress conditions.

[0421] Preparation of liquid composition and evaluation of break loose force and gliding force

[0422] For evaluation of the quality and efficiency of the liquid composition, liquid compositions having the components and contents according to Table 14 below were prepared, and their break loose force and gliding force were measured. The break loose force refers to the maximum force required to initiate the movement of a plunger at rest when a drug is administered using a syringe, and the gliding force refers to the consistent force required to continue the movement of the plunger along the barrel once the plunger has started moving.

[0423] The results are shown in Table 14 below. Specifically, each liquid composition was left at room temperature for at least 30 minutes, after which its break loose force and gliding force were analyzed.

[0424] [Table 141

[0425] Component BLGF1 BLGF2 BLGF3 BLGF4 BLGF5 Dupilumab protein

[0426] 175 175 150 150 150 concentration (mg / mL)

[0427] Acetate (mM) 12.5 12.5 12.5 12.5 12.5 Histidine (mM) 20 20 20 20 20

[0428]

[0429] Arginine-hydrochloride (mM) 25 90 25 90 90 Lysine-hydrochloride (mM) - 30 - 30 30 Proline (mM) - - - - - Sucrose (mM) 146 - 146 - - Polysorbate 80 (mg / mL) 2 - 2 - 2 Poloxamer 188 (mg / mL) - 3 - 3 - pH 5.9 5.9 5.9 5.9 5.9 Break loose Force (N) 5.0 2.6 5.5 3.1 3.2 Gliding Force (N) 13.0 13.0 10.7 9.0 8.7

[0430]

[0431] Referring to Table 14, it can be confirmed that the liquid compositions comprising at least two amino acids or pharmaceutically acceptable salts thereof at protein concentrations of 150 mg / mL and 175 mg / mL show a lower break loose force than the compositions comprising sugar.

[0432] In other words, the liquid composition according to the present invention exhibits excellent convenience in administration (e.g., less user discomfort during administration, reduced pain, accurate dose administration, etc.) and may increase the quality and efficiency of the drug (antibody).

Claims

Claims1. A liquid composition comprising an anti-hIL-4Rα antibody, an antigen-binding fragment thereof or a variant thereof and at least two amino acids or pharmaceutically acceptable salts thereof.

2. The liquid composition of claim 1, wherein the at least two amino acids or the pharmaceutically acceptable salts thereof is at least two selected from the group consisting of histidine, arginine, lysine, proline and pharmaceutically acceptable salts thereof.

3. The liquid composition of claim 2, wherein the liquid composition comprises at least two selected from the group consisting of histidine, arginine, lysine, proline, histidine hydrochloride, arginine hydrochloride, lysine hydrochloride, and proline hydrochloride.

4. The liquid composition of claim 1, wherein the liquid composition comprises three amino acids or the pharmaceutically acceptable salts thereof.

5. The liquid composition of claim 4, wherein the three amino acids or the pharmaceutically acceptable salts thereof is three selected from the group consisting of histidine, arginine, lysine, proline and pharmaceutically acceptable salts thereof.

6. The liquid composition of claim 1, wherein the liquid composition has a viscosity of 21 cP or less.

7. The liquid composition of claim 1, wherein the liquid composition has a viscosity of 14.5 cP or less.

8. The liquid composition of claim 1, wherein the liquid composition has a viscosity of 8 cP or less.

9. The liquid composition of claim 1, wherein the liquid compositioncomprises the anti-hIL-4Rα antibody, the antigen-binding fragment thereof, or the variant thereof in an amount of 150 to 175 mg / mL.

10. The liquid composition of claim 1, wherein the liquid composition comprises at least one pharmaceutically acceptable additive selected from the group consisting of a stabilizer, a buffer, and a surfactant.

11. The liquid composition of claim 10, wherein the surfactant is Poloxamer or Polysorbate.

12. The liquid composition of claim 10, wherein the surfactant is Poloxamer 188, Polysorbate 20 or Polysorbate 80.

13. The liquid composition of claim 1, wherein the liquid composition does not comprise sugar.

14. The liquid composition of claim 1, wherein the anti-hIL-4Rα antibody, the antigen-binding fragment thereof, or the variant thereof is dupilumab, an antigen-binding fragment thereof, or a variant thereof.

15. The liquid composition of claim 14, wherein the liquid composition comprises dupilumab, the antigen-binding fragment thereof, or the variant thereof in an amount of 150 to 175 mg / mL.

16. The liquid composition of claim 1, wherein the liquid composition comprises:(a) histidine or a pharmaceutically acceptable salt thereof; and(b) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of arginine, lysine, proline, and pharmaceutically acceptable salts thereof.

17. The liquid composition of claim 16, wherein the liquid composition comprises (a) and (b) at a molar concentration ratio of (a) 1: (b) 5-10.

18. The liquid composition of claim 1, wherein the liquid composition comprises:(c) histidine or a pharmaceutically acceptable salt thereof;(d) lysine or a pharmaceutically acceptable salt thereof; and(e) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of arginine, proline, and pharmaceutically acceptable salts thereof.

19. The liquid composition of claim 18, wherein the liquid composition comprises (c), (d), and (e) at a molar concentration ratio of (c) 1: (d) 1-5: (e) 1-5.

20. The liquid composition of claim 1, wherein the liquid composition comprises:(f) histidine or a pharmaceutically acceptable salt thereof;(g) proline or a pharmaceutically acceptable salt thereof; and(h) one amino acid or a pharmaceutically acceptable salt thereof selected from the group consisting of lysine, arginine, and pharmaceutically acceptable salts thereof.

21. The liquid composition of claim 20, wherein the liquid composition comprises (f), (g), and (h) at a molar concentration ratio of (f) 1: (g) 1-5: (h) 1-5.

22. A liquid composition comprising an anti-hlL-4Ra antibody, an antigenbinding fragment thereof or a variant thereof;at least two amino acids or pharmaceutically acceptable salts thereof; and a surfactant.

23. A liquid composition comprising an anti-hlL-4Ra antibody, an antigenbinding fragment thereof or a variant thereof;three amino acids or pharmaceutically acceptable salts thereof; anda surfactant,wherein the liquid composition does not comprise sugar.

24. The liquid composition of claim 23, wherein the three amino acids or thepharmaceutically acceptable salts thereof is three selected from the group consisting of histidine, arginine, lysine, proline and pharmaceutically acceptable salts thereof.

25. The liquid composition of claim 23, wherein the surfactant is Poloxamer or Polysorbate.

26. The liquid composition of claim 23, wherein the liquid composition comprises:(i) histidine or a pharmaceutically acceptable salt thereof;(j) lysine or a pharmaceutically acceptable salt thereof; and(k) arginine or a pharmaceutically acceptable salt thereof at a molar concentration ratio of (i) 1:(j) 1-5:(k) 1-5.

27. The liquid composition of claim 23, wherein the liquid composition has a viscosity of 14.5 cP or less.

28. The liquid composition of claim 23, wherein the liquid composition further comprises a buffer.

29. The liquid composition of any one of claims 1 to 28, wherein the liquid composition is for preventing or treating allergic diseases.

30. A use of the liquid composition according to any one of claims 1 to 28, for preventing or treating allergic diseases.

31. A use of the liquid composition according to any one of claims 1 to 28, for preparing a medicament for preventing or treating allergic diseases.

32. A method for preventing or treating allergic diseases, comprising administering the liquid composition according to any one of claims 1 to 28 to a subject in need thereof.

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