Preparations of human anti-TSLP antibodies and methods for treating inflammatory diseases

Abstract

To provide a human anti-TSLP antibody preparation and a method for treating inflammatory diseases. [Solution] This specification provides an aqueous composition comprising (a) an anti-TSLP antibody at a concentration greater than about 140 mg / mL, (b) a surfactant, and (c) at least one basic amino acid or a salt thereof. Also provided is an aqueous composition comprising (a) an anti-TSLP antibody at a concentration greater than about 140 mg / mL, (b) a surfactant, and (c) at least one calcium or magnesium salt. Related manufacturing articles, pre-filled syringes, and vials containing the compositions of this disclosure are also provided. This specification provides the use of the compositions for treating inflammatory diseases, such as atopic dermatitis. This specification also provides a method for producing a stable liquid antibody having a viscosity of less than about 100 cP.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Applications No. 62 / 976,007 (filed February 13, 2020) and No. 63 / 148,105 (filed February 10, 2021), which are incorporated herein by reference in their entirety.

[0002] This disclosure relates to human anti-TSLP monoclonal antibodies, including high-concentration aqueous formulations of tezeperumab and its biosimilars.

[0003] Incorporation by referencing electronically submitted materials The computer-readable nucleotide / amino acid sequence listing submitted concurrently with this specification is incorporated in its entirety by reference and identified as follows: a 9911-byte ASCII (text) file created on 11 February 2021, filename "54250_Seqlisting.txt". [Background technology]

[0004] A brief explanation of related technologies In a recent phase 2 randomized, double-blind, placebo-controlled clinical trial, tezeperumab (also known as AMG157 and MED9929) was administered to humans at doses ranging from 70 mg to 280 mg. Patients treated with tezeperumab showed a clinically significant reduction in asthma exacerbations compared to those treated with placebo.

[0005] Increased protein concentrations in a formulation can cause problems. For example, formulations containing high concentrations of protein may lead to aggregation, resulting in the formation of high molecular weight species (HMWS). HMWS can be a particular concern in some protein formulations. Aggregation can also potentially affect the subcutaneous bioavailability and pharmacokinetics of therapeutic proteins, and may lead to loss of bioactivity and increased immunogenicity of the protein. High-concentration protein formulations can also increase viscosity, which can negatively impact the filling and administration of the drug product.

[0006] Therefore, there is a need in this field for a high-concentration tezepermab formulation that has low viscosity, high stability, and a low level of aggregation. [Overview of the project] [Means for solving the problem]

[0007] Data demonstrating the viscosity-reducing effect of specific excipients on high-concentration antibody preparations are provided herein for the first time. This data supports the viscosity-reducing effect of basic amino acids or their salts, as well as calcium or magnesium salts. This data also supports the stability of such high-concentration antibody preparations.

[0008] Accordingly, this disclosure provides compositions, such as aqueous compositions, comprising (a) an anti-TSLP antibody in a concentration greater than about 140 mg / mL, (b) a surfactant, and (c) at least one basic amino acid or a salt thereof. Also intended are aqueous compositions comprising (a) an anti-TSLP antibody in a concentration greater than about 140 mg / mL, (b) a surfactant, and (c) at least one basic amino acid or a salt thereof, wherein the basic amino acid is present in a concentration of about 10 mM to about 200 mM. In exemplary cases, the basic amino acid is arginine. Optionally, the salt is an organic salt of arginine. In various embodiments, the arginine salt is arginine acetate, arginine aspartate, arginine glutamate, arginine glycolate, arginine lactate, arginine methanesulfonate, arginine propionate, or a combination thereof. In exemplary cases, the basic amino acid is histidine. Optionally, the salt is an organic salt of histidine. In exemplary embodiments, the histidine salt is histidine acetate, histidine aspartate, histidine glutamate, histidine glycolate, histidine lactate, histidine methanesulfonate, histidine propionate, or a combination thereof. In various cases, the basic amino acid is lysine. Optionally, the salt is an organic salt of lysine. In various embodiments, the lysine salt is lysine acetate, lysine aspartate, lysine glutamate, lysine glycolate, lysine lactate, lysine methanesulfonate, lysine propionate, or a combination thereof.

[0009] This disclosure also provides compositions, such as aqueous compositions, comprising (a) an anti-TSLP antibody in a concentration greater than about 140 mg / mL, (b) a surfactant, and (c) at least one calcium or magnesium salt. Furthermore, aqueous compositions comprising (a) an anti-TSLP antibody in a concentration greater than about 140 mg / mL, (b) a surfactant, and (c) at least one calcium or magnesium salt, comprising about 15 mM to about 150 mM of the calcium or magnesium salt, are also intended. In exemplary embodiments, the calcium or magnesium salt comprises a chloride-less counterion. Optionally, the counterion is an acetate, aspartate, glutamate, glycolate, lactate, methanesulfonate, propionate, or a combination thereof. In various embodiments, the calcium salt is calcium acetate, calcium aspartate, calcium glutamate, calcium glycolate, calcium lactate, calcium methanesulfonate, calcium propionate, or a combination thereof. In exemplary cases, magnesium salts include magnesium acetate, magnesium aspartate, magnesium glutamate, magnesium glycolate, magnesium lactate, magnesium methanesulfonate, magnesium propionate, or combinations thereof. In various cases, the compositions of the present disclosure contain about 50 mM to about 150 mM of a basic amino acid or a salt thereof, or about 50 mM to about 150 mM of a calcium salt or magnesium salt.

[0010] In various embodiments, the compositions of the Disclosure further optionally comprise N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline, sodium acetate, trisacetate, histidine salt, or calcium salt in amounts of about 50 mM to about 150 mM, or about 50 mM to about 250 mM. In various embodiments, the compositions of the Disclosure comprise (i) an arginine salt and (ii) NAR and / or methionine. In various embodiments, the arginine salt is arginine glutamate. In various cases, the compositions of the Disclosure comprise (i) calcium and (ii) NAR and / or methionine. In exemplary embodiments, the calcium salt is calcium glutamate. In exemplary embodiments, the compositions of the Disclosure contain an anti-TSLP antibody at a concentration of about 160 mg / mL to about 250 mg / mL, optionally about 160 mg / mL to about 225 mg / mL, for example, about 170 mg / mL to about 200 mg / mL, optionally about 175 mg / mL to about 185 mg / mL, for example, 180 mg / mL. In exemplary embodiments, the compositions of the Disclosure have a pH of about 4.5 to about 6.75, optionally about 4.8 to about 6.0. In exemplary embodiments, the viscosity of the compositions of the Disclosure is 23°C, 1000 s. -1 Therefore, less than 100 cP, optionally 23°C, 1000s -1 Therefore, it is less than 75 cP, for example, less than 60 cP or less than 50 cP.

[0011] In exemplary cases, the compositions of the present disclosure include a surfactant that is amphiphilic and / or nonionic. In various embodiments, the surfactant is a polysorbate, e.g., polysorbate 20 or polysorbate 80, or a mixture thereof. Optionally, the surfactant is present in concentrations of less than 0.005% (w / v), or about 0.005% (w / v) to about 0.015% (w / v), and optionally, about 0.010% (w / v) ± 0.0025% (w / v), e.g., at surfactant concentrations of about 0.005% (w / v), 0.010% (w / v), or 0.015% (w / v).

[0012] In various embodiments, the aqueous composition contains 25-190 mM arginine base and 25-200 mM glutamic acid. In various embodiments, the aqueous composition contains 140 mM arginine base and 150 mM glutamic acid. In various embodiments, the aqueous composition containing arginine and glutamate contains 0-250 mM proline. In various embodiments, the aqueous composition contains 80 mM arginine base, 85 mM glutamic acid and 100 mM L-proline. In various embodiments, the aqueous composition containing arginine, glutamate and optionally proline contains 0.01% (w / v) polysorbate 80. In various embodiments, the aqueous composition contains 140 mM arginine base, 150 mM glutamic acid and 0.01% (w / v) polysorbate 80. In various embodiments, the aqueous composition contains 80 mM arginine base, 85 mM glutamic acid, 100 mM L-proline, and 0.01% (w / v) polysorbate 80.

[0013] In various embodiments, the aqueous composition contains 10 to 125 mM arginine base and 25 to 225 mM glutamic acid. In various embodiments, the aqueous composition contains 95 mM arginine base and 170 mM glutamic acid. In various embodiments, the aqueous composition containing arginine and glutamate contains 0 to 220 mM proline. In various embodiments, the aqueous composition contains 50 mM arginine base, 95 mM glutamic acid and 85 mM L-proline. In various embodiments, the aqueous composition containing arginine and glutamate contains 0.01% (w / v) polysorbate 80. In various embodiments, the aqueous composition contains 95 mM arginine base, 170 mM glutamic acid and 0.01% (w / v) polysorbate 80. In various embodiments, the aqueous composition contains 50 mM arginine base, 95 mM glutamic acid, 85 mM L-proline, and 0.01% (w / v) polysorbate 80.

[0014] In various embodiments, the aqueous composition contains 15-130 mM calcium and 30-300 mM glutamate. In various embodiments, the aqueous composition contains 100 mM calcium and 230 mM glutamate. In various embodiments, the aqueous composition containing calcium and glutamate contains 0-250 mM proline. In various embodiments, the aqueous composition contains 60 mM calcium, 140 mM glutamate, and 70 mM L-proline. In various embodiments, the aqueous composition contains 15-195 mM calcium and 25-320 mM glutamate. In various embodiments, the aqueous composition contains 110 mM calcium and 240 mM glutamate. In various embodiments, the aqueous composition contains 0-220 mM proline. In various embodiments, the aqueous composition contains 70 mM calcium, 145 mM glutamate, and 60 mM L-proline. In various embodiments, the aqueous composition containing calcium and glutamate contains 0.01% (w / v) polysorbate 80. In various embodiments, the aqueous composition contains 100 mM calcium, 230 mM glutamate, and 0.01% (w / v) polysorbate 80. In various embodiments, the aqueous composition contains 60 mM calcium, 140 mM glutamate, 70 mM L-proline, and 0.01% (w / v) polysorbate 80. In various embodiments, the aqueous composition contains 110 mM calcium, 240 mM glutamate, and 0.01% (w / v) polysorbate 80. In various embodiments, the aqueous composition contains 70 mM calcium, 145 mM glutamate, 60 mM L-proline, and 0.01% (w / v) polysorbate 80.

[0015] In various embodiments, the aqueous compositions described herein have a pH of about 4.5 to about 6.75. In various embodiments, the aqueous compositions have a pH of about 4.7 to about 6.0. In various embodiments, the aqueous compositions have a pH of about 5.1 to about 5.7. In various embodiments, the aqueous compositions have a pH of about 4.7 to about 5.3. In various embodiments, the aqueous compositions described herein have a pH of about 4.7, 4.8, 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, or 5.7.

[0016] In various cases, the composition is isotonic or has an osmotic pressure in the range of approximately 200 mOsm / kg to approximately 500 mOsm / kg, approximately 225 mOsm / kg to approximately 400 mOsm / kg, or approximately 250 mOsm / kg to approximately 350 mOsm / kg. Optionally, the composition is isotonic or has an osmotic pressure greater than approximately 350 mOsm / kg.

[0017] In exemplary cases, the composition is suitable for short-term storage at 25°C, 30°C, or 40°C, or for long-term storage at approximately -30°C or approximately 2°C to approximately 8°C. For example, as determined by size exclusion chromatography (SEC), less than 0.5% of the therapeutic protein is degraded after 6 months of storage at 2°C to 8°C, and optionally, the therapeutic protein may be contained in a glass vial or syringe. In various cases, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after at least or approximately 12 months of storage at approximately 2°C to approximately 8°C. In various embodiments, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after approximately 20 to approximately 26 months of storage at approximately 2°C to approximately 8°C. In exemplary cases, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after approximately 30 to approximately 40 months of storage at approximately 2°C to approximately 8°C. In exemplary cases, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after storage for approximately 2 to 3 years at approximately 2°C to approximately 8°C. Also, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after storage for approximately 24 to 36 months at 2°C to 8°C, and optionally, less than 2% of the antibody is degraded after 24 or 36 months at 2°C to 8°C. In various embodiments, as determined by SEC, less than 5% of the antibody is degraded after storage for at least 2 weeks at near room temperature (e.g., 25°C) (optionally, after storage for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, or at least 6 months). In various cases, as determined by SEC, less than 5% of the antibodies are degraded after storage at 2°C to 8°C for approximately 24 to 36 months, followed by storage at near room temperature (e.g., 25°C) for at least 2 weeks, or at least about 1 month, or at least about 2 months.Optionally, when determined by size exclusion chromatography (SEC), less than about 5% of the antibody is degraded after storage at a temperature greater than about 20°C for at least or about 2 weeks, optionally at least or about 4 weeks or about 8 weeks. In various embodiments, the temperature is greater than 25°C or about 25°C, or greater than 30°C or about 30°C, or greater than 40°C or about 40°C.

[0018] Also provided herein are manufactured articles. In an exemplary embodiment, the article comprises a composition of the present disclosure, optionally an aqueous composition of about 1 mL to about 5 mL (e.g., about 1 mL to about 3 mL).

[0019] Also provided herein is a prefilled syringe comprising a composition of the present disclosure, optionally a composition of about 1 mL to about 5 mL (e.g., about 1 mL to about 3 mL).

[0020] Also provided is a vial comprising a composition of the present disclosure, optionally an aqueous composition of about 1 mL to about 5 mL (e.g., about 1 mL to about 3 mL).

[0021] Also disclosed herein is an autoinjector containing the aqueous composition described herein. In various embodiments, the autoinjector is Ypsomed YpsoMate®. In various embodiments, the autoinjector is disclosed in WO 2018 / 226565, WO 2019 / 094138, WO 2019 / 178151, WO 2012 / 072577, WO 2020 / 081479, WO 2020 / 081480, International Application No. PCT / US20 / 70590, PCT / US20 / 70591, PCT / US20 / 53180, PCT / US20 / 53179, PCT / US20 / 53178, or PCT / US20 / 53176.

[0022] This specification provides for the use of the compositions of the present disclosure for treating inflammatory diseases. In an exemplary embodiment, the inflammatory disease is selected from the group consisting of asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE), nasal polyps, chronic urticaria, Ig-induced diseases (such as IgA nephropathy and lupus nephritis), eosinophilic gastritis, chronic rhinosinusitis without nasal polyps, and idiopathic pulmonary fibrosis (IPF). Optionally, the inflammatory disease is atopic dermatitis. Optionally, the inflammatory disease is COPD.

[0023] The present disclosure provides a method for treating an inflammatory disease in a subject. In an exemplary embodiment, the method comprises administering to the subject a therapeutically effective amount of the composition of the present disclosure. In various embodiments, the inflammatory disease is selected from the group consisting of asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE), nasal polyps, chronic urticaria, Ig-induced diseases (such as IgA nephropathy and lupus nephritis), eosinophilic gastritis, chronic rhinosinusitis without nasal polyps, and idiopathic pulmonary fibrosis (IPF). Optionally, the inflammatory disease is atopic dermatitis. Optionally, the inflammatory disease is COPD. In various cases, the composition of the present disclosure is administered to the subject by subcutaneous administration. In an exemplary case, an aqueous composition of about 1 mL to about 5 mL (e.g., about 1 mL to about 3 mL) is administered to the subject.

[0024] Furthermore, a method for manufacturing a stable, liquid antibody composition is provided, which has a viscosity of less than about 100 cP and comprises (A) an anti-TSLP antibody at a concentration of more than about 140 mg / mL, (B) a surfactant, and (C) a basic amino acid or its salt, a calcium salt, a magnesium salt, or a combination thereof. In an exemplary embodiment, the method comprises (i) combining the antibody with an aqueous solution comprising about 50 mM to about 150 mM of a basic amino acid or its salt, a calcium salt, a magnesium salt, or a combination thereof, and (ii) adding a surfactant to achieve a final concentration of the surfactant of about 0.01% (w / v) ± 0.005% (w / v).

[0025] Further aspects and advantages will be apparent to those skilled in the art from a review of the following detailed description in conjunction with the drawings. While compositions, articles, and methods are susceptible to various forms of embodiment, the following description includes specific embodiments, under the understanding that this disclosure is illustrative and not intended to limit the invention to the specific embodiments described herein. With respect to the compositions, articles, and methods described herein, optional features including, but not limited to, components, their compositional ranges, substitutions, conditions, and processes are intended to be selected from the various aspects, embodiments, and examples provided herein. [Brief explanation of the drawing]

[0026] [Figure 1] Figure 1 is a graph of viscosity (cP) of two different formulations containing therapeutic proteins, plotted as a function of protein concentration (mg / mL). [Figure 2] Figure 2 is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipients (100 mM or 150 mM of the indicated amounts). The viscosity of a control without excipients is also provided. Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. [Figure 3] Figure 3 is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipient (indicated amount, 60 mM). The viscosity of a control without the excipient is also provided. Each formulation contained tezeperumab at a concentration of approximately 190 mg / mL. [Figure 4] Figure 4 is a graph of the viscosity (cP) of several different tezepermab formulations containing the indicated excipients (in indicated amounts). The viscosity of a control without excipients is also provided. Each formulation contained tezepermab at a concentration of approximately 210 mg / mL. The bar immediately next to 0.05% PVP is for formulations containing 100 mM sodium acetate and 75 mM arginine acetate. The percentages indicated are %(w / v). [Figure 5]Figure 5 is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipients (indicated amounts (mM)). The viscosity of a control without excipients is also provided. Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. [Figure 6] Figure 6 is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipient (indicated amount (60 mM)). The viscosity of a control without the excipient is also provided. Each formulation contained tezeperumab at a concentration of approximately 190 mg / mL. [Figure 7] Figure 7 is a graph of the viscosity (cP) of two different tezeperumab formulations containing the indicated excipient (indicated amount (60 mM)). The viscosity of a control without the excipient is also provided. Each formulation contained tezeperumab at a concentration of approximately 190 mg / mL. [Figure 8] Figure 8 is a table of protein concentrations, viscosity, and pH for several different tezeperumab formulations containing the indicated excipients (in indicated amounts (mM)). [Figure 9] Figure 9A is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipient (indicated amount (150 mM)). The viscosity of a control without the excipient is also provided. Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. Figure 9B is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipient (indicated amount (90 mM)). The viscosity of a control without the excipient is also provided. Each formulation contained tezeperumab at a concentration of approximately 195 mg / mL. [Figure 10] Figure 10 is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipients (indicated amounts (mM)). The viscosity of a control without excipients is also provided. Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. [Figure 11] Figure 11 is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipient (indicated amount (150 mM)). The viscosity of a control without the excipient is also provided. Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. [Figure 12] Figure 12 is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipients (in indicated amounts (50 mM to 150 mM)). The viscosity of a control without excipients is also provided. Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. [Figure 13] Figure 13A is a graph of the viscosity (cP) of several different tezeperumab formulations containing 150 mM arginine acetate (indicated pH (4.75–5.7)). The viscosity of a control formulation without excipients and a formulation containing 150 mM proline is also provided. Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. Figure 13B is a graph of the viscosity (cP) of several different tezeperumab formulations containing 60 mM histidine acetate (indicated pH (5.5–6.5)). Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. [Figure 14] Figure 14 is a graph of the viscosity (cP) of several different tezeperumab formulations containing the indicated excipients (indicated amounts (33 mM to 150 mM)). The viscosity of a control without excipients is also provided. Each formulation contained tezeperumab at a concentration of approximately 210 mg / mL. [Figure 15A-B] Figures 15A–15D show size exclusion chromatography (SEC) analysis of different anti-TSLP formulations under stress conditions: Figure 15A, -30°C; Figure 15B, 5°C; Figure 15C, 25°C; Figure 15D, 40°C. [Figure 15C] Figures 15A–15D show size exclusion chromatography (SEC) analysis of different anti-TSLP formulations under stress conditions: Figure 15A, -30°C; Figure 15B, 5°C; Figure 15C, 25°C; Figure 15D, 40°C. [Figure 15D] Figures 15A–15D show size exclusion chromatography (SEC) analysis of different anti-TSLP formulations under stress conditions: Figure 15A, -30°C; Figure 15B, 5°C; Figure 15C, 25°C; Figure 15D, 40°C. [Figure 16] Figure 16 shows the cation exchange chromatography (CEX) analysis (main peak %) of different anti-TSLP formulations under stress conditions. [Figure 17]Figure 17 shows RCE-SDS analysis of heavy and light chain release and stability under various storage conditions over a 6-month period. [Figure 18] Figure 18 shows the viscosity of different anti-TSLP formulations under stress conditions. [Modes for carrying out the invention]

[0027] definition The foregoing explanation is provided solely for the purpose of clarifying understanding, and modifications within the scope of the present invention may be obvious to those skilled in the art; therefore, no unnecessary limitations should be inferred from them.

[0028] Throughout this specification and the subsequent claims, unless contextually required to provide another meaning, the words “comprise” and variations such as “comprises” and “comprising” will be understood to mean the inclusion of the integer or process or group of integers or processes being described, but not the exclusion of any other integer or process or group of integers or processes.

[0029] Throughout this specification, where a composition is described as containing components or raw materials, it is also understood that, unless otherwise specified, the composition may essentially consist of or consist of any combination of the listed components or raw materials. Similarly, where a method is described as containing specific steps, it is also understood that, unless otherwise specified, the method may essentially consist of or consist of any combination of the listed steps. The inventions disclosed exemplary herein may preferably be carried out in the absence of any elements or steps not specifically disclosed herein.

[0030] The methods disclosed herein, and the execution of their individual steps, can be carried out manually and / or with the help of automation provided by electronic equipment. Although the methods have been described in relation to specific embodiments, those skilled in the art will readily understand that other ways of performing the actions related to the methods may be used. For example, the order of the various steps can be changed without departing from the scope or spirit of the methods unless otherwise specified. In addition, some of the individual steps can be combined, omitted, or further subdivided into additional steps.

[0031] Unless otherwise stated, the compositions and methods are intended to include embodiments that include any combination of one or more additional optional elements, properties, and steps described below (including those shown in the figures).

[0032] In jurisdictions where patents for methods performed on the human body are prohibited, “administering” a composition to a human subject shall be limited to prescribing a controlled substance for self-administration by a human subject using any technique (e.g., oral, inhalation, topical application, injection, insertion, etc.). The broadest and most reasonable interpretation is intended to be consistent with the laws or regulations defining patentable subject matter. In jurisdictions where patents for methods performed on the human body are not prohibited, “administering” a composition includes both methods performed on the human body and the aforementioned activities.

[0033] All maximum numerical limits given throughout this specification should be understood to include, as an alternative, the range formed by all corresponding smaller numerical limits, as if such ranges were explicitly stated. All minimum numerical limits given throughout this specification should include, as an alternative, the range formed by all higher numerical limits, as if such ranges were explicitly stated. All numerical ranges given throughout this specification should include, as if all narrower numerical ranges contained within such wider numerical ranges were explicitly stated herein. Dimensions and values ​​disclosed herein should be understood to include disclosures of both the stated value and the corresponding exact numerical value; for example, a value stated as "approximately 10mM" should be understood to include "10mM" as an alternative disclosure.

[0034] All patents, publications, and references cited herein are fully incorporated herein by reference. In the event of any conflict between this disclosure and the cited patents, publications, and references, this disclosure shall prevail.

[0035] Unless otherwise specified, the following terms used in this Application, including in the Specification and Claims, have the following definitions:

[0036] When used in the specification and the attached claims, the indefinite articles "a" and "an" and the definite article "the" include plural and singular referents unless the context explicitly indicates otherwise.

[0037] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by an ordinary person skilled in the art to which this disclosure belongs. The following references provide, but are not limited to, general definitions of many of the terms used herein: Singletonet al., DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2nd Ed. 1994); THE CAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker Ed., 1988); THE GLOSSARY OF GENETICS, 5th Ed., R. Rieger et al. (Eds.), Springer Verlag (1991); and Hale & Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY (1991).

[0038] The terms “approximately” or “about” mean an acceptable error to a particular value as determined by those skilled in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms “approximately” or “about” mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the terms “approximately” or “about” mean within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given number or range. Whenever the terms “approximately” or “about” precede a first number in a set of two or more numbers, it is understood that the terms “approximately” or “about” apply to each of those numbers in the set.

[0039] The term "specifically binds" refers to an antibody or polypeptide that is "antigen-specific," "specific," "selective binder," "specific binder," "antigen target," or "immunoreactive" to the antigen and binds to the target antigen with higher affinity than other antigens on the associated protein. In this specification, the drug is considered to bind specifically to target proteins, for example, to surface antigens (e.g., T cell receptor, CD3), cytokines (e.g., TSLP, IL-4, IL-5, IL-13, IL-17, IFN-γ, TNF-α), etc.

[0040] The terms "antibody" or "immunoglobulin" refer to canonical tetrameric glycoproteins consisting of two substantially full-length heavy chains and two substantially full-length light chains, each containing a variable region and a substantially full-length constant region. The antigen-binding moiety can be generated by recombinant DNA techniques or by enzymatic or chemical cleavage of intact antibodies. The term "antibody" includes monoclonal antibodies, polyclonal antibodies, chimeric antibodies, human antibodies, and humanized antibodies.

[0041] Antibody variants include antibody fragments and antibody-like proteins that have structural changes in canonical tetrameric antibodies. Typically, antibody variants include a V region with a change in the constant region, or, alternatively, the addition of a V region to the constant region in a non-canonical manner. Examples include multispecific antibodies (e.g., bispecific antibodies with an extra V region), antibody fragments capable of binding to antigens (e.g., Fab', F'(ab)2, Fv, single-chain antibodies, bispecific antibodies), and biparatopic peptides and recombinant peptides that exhibit the above insofar as they exhibit the desired biological activity.

[0042] Antibody fragments include, in particular, Fab, Fab', F(ab')2, Fv, domain antibodies (dAb), complementarity-determining region (CDR) fragments, CDR-grafted antibodies, single-chain antibodies (scFv), single-chain antibody fragments, chimeric antibodies, bispecific antibodies, trispecific antibodies, quadruplespecific antibodies, minibodies, linear antibodies; chelated recombinant antibodies, tribodies or vibodies, intrabodies, nanobodies, small modular immunopharmaceuticals (SMIPs), antigen-binding domain immunoglobulin fusion proteins, single-domain antibodies (including camelized antibodies), VHH-containing antibodies, or variants or derivatives thereof, as well as polypeptides containing at least a portion of immunoglobulins sufficient to confer specific antigen binding to the polypeptide, such as antigen-binding moieties of antibodies containing 1, 2, 3, 4, 5, or 6 CDR sequences, insofar as the antibody retains the desired biological activity.

[0043] "Valency" refers to the number of antigen-binding sites on each antibody or antibody fragment that targets an epitope. A typical full-length IgG molecule or F(ab)2 is "bivalent" in that it has two identical target-binding sites. "Monovalent" antibody fragments, such as F(ab)' or scFc, have a single antigen-binding site. Trivalent or tetravalent antigen-binding proteins can also be manipulated to become polyvalent.

[0044] A "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies; that is, the individual antibodies that make up that population are identical except for naturally occurring mutations that may exist in small amounts.

[0045] The term "inhibit TSLP activity" includes inhibiting any one or more of the following: - Binding of TSLP to its receptor; -Proliferation, activation, or differentiation of TSLPR-expressing cells in the presence of TSLP; - Inhibition of Th2 cytokine production in polarized assays in the presence of TSLP; - Activation or maturation of dendritic cells in the presence of TSLP; - Mast cell cytokine release in the presence of TSLP. For example, see U.S. Patent No. 7982016B2, column 6 and Example 8, and U.S. Patent Application Publication No. 2012 / 0020988A1, Examples 7-10.

[0046] The terms "sample" or "biological sample" refer to specimens obtained from subjects for use in this method, and include urine, whole blood, plasma, serum, saliva, sputum, tissue biopsy, cerebrospinal fluid, peripheral blood mononuclear cells with in vitro stimulation, peripheral blood mononuclear cells without in vitro stimulation, intestinal lymphoid tissue with in vitro stimulation, intestinal lymphoid tissue without in vitro stimulation, bowel lavage, bronchioloalveolar lavage, nasal lavage, and induced sputum.

[0047] The terms “treat,” “treating,” and “treatment” refer to the temporary or permanent elimination, reduction, suppression, or improvement of the clinical symptoms, onset, or progression of an event, disease, or condition associated with an inflammatory disorder as described herein, either partially or completely. As recognized in the relevant art, a drug used as a therapeutic agent may reduce the severity of a given condition, but it does not need to eliminate all symptoms of the disease to be considered a useful therapeutic agent. Similarly, a prophylactically administered treatment does not need to be completely effective in preventing the onset of a condition in order to constitute a viable prophylactic agent. It is sufficient to simply reduce the impact of the disease (e.g., by reducing the number or severity of its symptoms, or by increasing the effectiveness of another treatment, or by producing another beneficial effect), or by reducing the likelihood that the disease will develop or worsen in a subject. One embodiment of this disclosure relates to a method for determining the effectiveness of a treatment, comprising administering a therapeutic agent to a patient in an amount and time sufficient to induce a sustained improvement above baseline in an index reflecting the severity of a particular disorder.

[0048] The term "therapeutic dose" refers to the amount of a drug that is effective in improving or alleviating the symptoms or signs of a disease or disorder.

[0049] In this specification, the term “cytokine” refers to one or more small (5–20 kD) proteins released by cells that have specific effects on cellular behavior, such as intercellular interactions and communication, or the proliferation and differentiation of immune cells. Functions of cytokines in the immune system include promoting the influx of circulating leukocytes and lymphocytes into immunological encounter sites; stimulating the development and proliferation of B cells, T cells, peripheral blood mononuclear cells (PBMCs), and other immune cells; and providing antimicrobial activity. Exemplary immune cytokines include, but are not limited to, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17A, IL-17F, IL-18, IL-21, IL-22, interferons (including IFN-alpha, beta, and gamma), tumor necrosis factor (including TNF-alpha and beta), transforming growth factors (including TGF-alpha and beta), granulocyte colony-stimulating factor (GCSF), granulocyte-macrophage colony-stimulating factor (GMCSF), and thymic-stromal lymphocyte necrosis factor (TSLP).

[0050] "T helper (Th)1 cytokine" or "Th1-specific cytokine" refers to Th1 "Th2 cytokines" or "Th2-specific cytokines" refer to cytokines expressed (intracellularly and / or secreted) by T cells, including IFN-γ, TNF-α, and IL-12. "Th2 cytokines" or "Th2-specific cytokines" refer to cytokines expressed (intracellularly and / or secreted) by Th2 T cells, including IL-4, IL-5, IL-13, and IL-10. "Th17 cytokines" or "Th17-specific cytokines" refer to cytokines expressed (intracellularly and / or secreted) by Th17 T cells, including IL-17A, IL-17F, IL-22, and IL-21. Certain populations of Th17 cells express IFN-γ and / or IL-2 in addition to the Th17 cytokines listed herein. Multifunctional CTL cytokines include IFN-γ, TNF-α, IL-2, and IL-17.

[0051] Low viscosity anti-TSLP antibody composition Tezeperumab is effective at concentrations ranging from 70 mg to 280 mg, and anti-TSLP antibodies are sometimes formulated at doses of 110 mg / mL or 140 mg / mL. Formulations with high protein concentrations may exhibit increased viscosity to the point where they can adversely affect the function of devices used to administer the antibody to patients. Similarly, the ability of healthcare professionals to manually inject the drug into patients may be impaired. Furthermore, high viscosity may be prohibited during manufacturing. Formulations with high protein concentrations also present challenges from the standpoint of protein stability. For example, aggregation resulting in the formation of high molecular weight species (HMWS) can occur in formulations containing high protein concentrations. Therefore, it is desirable to provide low-viscosity, isotonic liquid formulations of anti-TSLP antibodies such as tezeperumab that are suitable for parenteral administration and can be stored for long periods at cold temperatures (e.g., 2-8°C and -30°C, etc.) or for short periods at room temperature (e.g., 20-25°C, etc., for patient convenience).

[0052] To overcome the problem of high viscosity in formulations with high protein concentrations, the Disclosure provides compositions, for example, aqueous compositions, comprising (a) an anti-TSLP antibody in a concentration greater than about 140 mg / mL, (b) a surfactant, and (c) at least one basic amino acid or a salt thereof. The Disclosure also provides compositions, for example, aqueous compositions, comprising (a) an anti-TSLP antibody in a concentration greater than about 140 mg / mL, (b) a surfactant, and (c) at least one calcium or magnesium salt. Based at least in part on the data provided herein and not bound by any particular theory, the compositions of the Disclosure represent low-viscosity compositions containing high concentrations of therapeutic protein that can be administered to patients in need without complications due to high viscosity. Based at least in part on the data provided herein and not bound by any particular theory, the compositions of this disclosure are very stable, provided they exhibit minimal degradation after being stored at cold temperatures (e.g., 2–8°C and -30°C, etc.) (short-term and / or long-term storage) or short-term storage at room temperature (e.g., approximately 20–25°C).

[0053] Basic amino acids In exemplary embodiments, the compositions of the present disclosure comprise basic amino acids or salts thereof. As used herein, the term “basic amino acid” refers to an amino acid having a basic side chain at neutral pH. Basic amino acids have sufficiently high pKas to be prone to binding to protons and acquiring a positive charge in the process. Basic amino acids in exemplary embodiments include a side chain containing nitrogen that binds to a proton (and is protonated) or releases its binding to a proton (and is deprotonated). In exemplary embodiments, basic amino acids may equilibrate between NH2 (deprotonated) and NH3+ (protonated) forms, or between NH (deprotonated) and NH2+ (protonated) forms, or between N (deprotonated) and NH+ (protonated) forms. At physiological pH, for example, about pH 7.0, the protonated form is dominant for basic amino acids. In exemplary embodiments, the basic amino acid is arginine (Arg;R), or lysine (Lys,K), or histidine (His,H). The basic amino acid may be either an L-isomer or a D-isomer, but in exemplary cases, the basic amino acid is the L-isomer of the amino acid, e.g., L-Arg, L-Lys, L-His. In exemplary cases, the basic amino acid is arginine. In exemplary cases, the basic amino acid is histidine. In various cases, the basic amino acid is lysine.

[0054] In exemplary embodiments, the basic amino acid is a derivative of arginine, such as L-2-amino-3-guanidinopropionic acid or 4-guanidinobutyric acid. In exemplary embodiments, the basic amino acid is a compound of formula I: [ka] The formula includes the structure [wherein n is 1-16, or 1-10, or 1-7, or 1-6, or 2-6, or 2, or 3, or 4, or 5].

[0055] In exemplary embodiments, the basic amino acid is a derivative of lysine, such as 5-hydroxylysine, ornithine, N-acetyl-L-lysine, or 2,4-diaminobutyric acid. [ka] [n is 1-16, or 1-10, or 1-7, or 1-6, or 2-6, or 2, or 3, or 4, or 5, and each of R1 and R2 is H, C1-C 18 Alkyl, (C1~C 18 Alkyl)OH, (C1~C 18 Alkyl)NH2, (C1~C 18 Alkyl)SH, (C0-C4 alkyl)(C3-C6) cycloalkyl, (C0-C4 alkyl)(C2-C5 heterocycle), (C0-C4 alkyl)(C6-C 10 [R7 is independently selected from the group consisting of (aryl) and (C1-C4 alkyl)(C3-C9 heteroaryl), where R7 is H or OH].

[0056] In exemplary embodiments, the basic amino acid is a derivative of histidine, such as desaminohistidine, hydroxyl-histidine, acetyl-histidine, homo-histidine, N-methylhistidine, α-methylhistidine, imidazole acetate, or α,α-dimethylimidazole acetate (DMIA).

[0057] In various embodiments, the compositions of this disclosure include salts of basic amino acids. In exemplary cases, the salts are pharmaceutically acceptable salts. As used herein, the term “pharmaceutically acceptable salt” means a salt of a compound that retains the biological activity of the parent compound and is not biologically or otherwise undesirable. Such salts can be prepared in situ during the final isolation and purification of the analogues, or they can be prepared individually by reacting the free basic functional group with a suitable acid. Many of the compounds disclosed herein can form acid and / or base salts in the presence of an amino and / or carboxyl group or similar group.

[0058] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Typical acid addition salts include, but are not limited to, acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, and undecanoate. Examples of salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid.

[0059] Base addition salts can also be prepared in situ by reacting the carboxylic acid-containing portion with a suitable base such as a pharmaceutically acceptable metal cation hydroxide, carbonate, or bicarbonate, or with ammonia or a primary, secondary, or tertiary organic amine during the final isolation and purification of the salicylic acid source. Examples of pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal-based cations such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts, as well as non-toxic quaternary ammonia and amine cations, particularly ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, and ethylammonium. Other representative organic amines useful for forming base addition salts include, for example, ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines.

[0060] Furthermore, the basic nitrogen-containing group can be quaternized with analogs of the disclosure, such as chlorides, bromides, and lower alkyl halides such as methyl, ethyl, propyl, and butyl iodide; chlorides, bromides, and long-chain halides such as medecyl, lauryl, myristyl, and stearyl iodides; and arylalkyl halides such as benzyl bromide and phenethyl. This yields water-soluble, oil-soluble, or dispersible products.

[0061] In exemplary embodiments, the basic amino acid is arginine, and the compositions of the present disclosure include arginine salts. In various embodiments, the arginine salt is an organic salt of arginine. In various embodiments, the arginine salt is arginine acetate, arginine aspartate, arginine glutamate, arginine glycolate, arginine lactate, arginine methanesulfonate, arginine propionate, or a combination thereof.

[0062] In exemplary embodiments, the basic amino acid is histidine, and the compositions of the present disclosure include histidine salts. In various embodiments, the histidine salt is an organic salt of histidine. In exemplary embodiments, the histidine salt is histidine acetate, histidine aspartate, histidine glutamate, histidine glycolate, histidine lactate, histidine methanesulfonate, histidine propionate, or a combination thereof.

[0063] In exemplary embodiments, the basic amino acid is lysine, and the compositions of the present disclosure include lysine salts. In various embodiments, the lysine salt is an organic salt of lysine. In various embodiments, the lysine salt is lysine acetate, lysine aspartate, lysine glutamate, lysine glycolate, lysine lactate, lysine methanesulfonate, lysine propionate, or a combination thereof.

[0064] In various cases, the compositions of the Disclosure contain about 10 mM to about 300 mM, or about 50 mM to about 300 mM, a basic amino acid or a salt thereof. In exemplary embodiments, the compositions of the Disclosure contain about 10 mM to about 200 mM, about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 50 mM to about 150 mM, about 50 mM to about 100 mM, about 50 mM to about 90 mM, about 50 mM to about 80 mM, about 50 mM to about 70 mM, about 50 mM to about 60 mM, about 50 mM to about 55 mM, about 55 mM to about 200 mM, It contains basic amino acids or their salts in concentrations of approximately 60 mM to 200 mM, 70 mM to 200 mM, 80 mM to 200 mM, 90 mM to 200 mM, 100 mM to 200 mM, 150 mM to 200 mM, 160 mM to 200 mM, 170 mM to 200 mM, 180 mM to 200 mM, or 190 mM to 200 mM. In various cases, the compositions of the Disclosure contain about 50 mM to about 100 mM (e.g., about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM) or about 100 mM to about 200 mM (e.g., about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM) of basic amino acids or salts thereof. In various cases, the compositions of the Disclosure contain about 50 mM to about 100 mM, or about 50 mM to about 75 mM, or about 75 mM to about 100 mM of basic amino acids or salts thereof. In various cases, the compositions of the Disclosure contain about 100 mM to about 200 mM, or about 100 mM to about 150 mM, or about 150 mM to about 200 mM of a basic amino acid or a salt thereof. In exemplary embodiments, the compositions of the Disclosure contain about 10 mM to about 200 mM of a basic amino acid or a salt thereof.

[0065] In various cases, anti-TSLP antibodies, such as tezeperumab, are formulated with approximately 25 mM to 190 mM arginine and approximately 25 mM to 200 mM glutamate. In various embodiments, anti-TSLP antibodies, such as tezeperumab, are formulated with 100 mM to approximately 180 mM arginine (e.g., approximately 100 mM to 170 mM, approximately 100 mM to 160 mM, approximately 100 mM to 150 mM, approximately 100 mM to 140 mM, approximately 100 mM to 130 mM, approximately 100 mM to 12 120 mM to 120 mM, 120 mM to 120 mM, 120 mM to 120 mM, 120 mM to 120 mM, Approximately 110mM, approximately 110mM to approximately 180mM, approximately 120mM to approximately 180mM, approximately 130mM to approximately 180mM, approximately 140mM to approximately 180mM, approximately 150mM to approximately 180mM, about 160mM to about 180mM, about 170mM to about 180mM, about 120mM to about 170mM, about 130mM to about 160mM, about 135mM to about 15 5 mM) and glutamate salts of approximately 110 mM to 240 mM (for example, approximately 110 mM to 180 mM, approximately 110 mM to 170 mM, approximately 110 mM to 160 mM, approximately 110 mM to 150 mM, approximately 110 mM to 140 mM, approximately 110 mM to 130 mM, approximately 110 mM to 120 mM, approximately 120 mM to 180 mM) In various cases, anti-TSLP antibodies, such as tezeperumab, are formulated with approximately 135 mM to 145 mM arginine and approximately 145 mM to 155 mM glutamate. In various cases, anti-TSLP antibodies, such as tezeperumab, are formulated in approximately 10 mM to 125 mM arginine and approximately 25 mM to 225 mM glutamate.In various embodiments, anti-TSLP antibodies, such as tezeperumab, contain approximately 55 mM to 135 mM arginine (for example, approximately 55 mM to 125 mM, approximately 55 mM to 115 mM, approximately 55 mM to 105 mM, approximately 55 mM to 95 mM, approximately 55 mM to 85 mM, approximately 55 mM to 75 mM, approximately 55 mM to 65 mM). M, arginine of approximately 65mM to 135mM, 75mM to 135mM, 85mM to 135mM, 95mM to 135mM, 105mM to 135mM, 115mM to 145mM, 125mM to 135mM, 75mM to 115mM, 85mM to 105mM) and approximately 130mM Approximately 210 mM glutamate (for example, approximately 130 mM to 200 mM, approximately 130 mM to 240 mM, approximately 130 mM to 180 mM, approximately 130 mM to 170 mM, approximately 130 mM to 160 mM, approximately 130 mM to 150 mM, approximately 130 mM to 140 mM, approximately 140 mM to 210 mM, approximately 150 mM) The drug is formulated in glutamate at concentrations of approximately 210 mM, 160 mM to 210 mM, 170 mM to 210 mM, 180 mM to 210 mM, 190 mM to 210 mM, 200 mM to 210 mM, 150 mM to 190 mM, 160 mM to 180 mM, and 165 mM to 175 mM. In an exemplary embodiment, the composition of the present disclosure comprises more than 140 mg / mL of tezeperumab, approximately 85.5 mM to 104.5 mM of arginine, 153 mM to 187 mM of glutamate, and 0.01% (w / v) of polysorbate 80. In exemplary embodiments, the composition of the present disclosure comprises more than 140 mg / mL of tezeperumab, about 95 mM arginine, 170 mM glutamate, and 0.01% (w / v) polysorbate 80. Optionally, the pH is about 5.4 ± 0.2 or about 5.4 ± 0.1.

[0066] Calcium salts and magnesium salts In exemplary embodiments, the compositions of the present disclosure comprise a calcium salt or a magnesium salt. In various embodiments, the calcium salt or magnesium salt comprises any counterion. In exemplary embodiments, the calcium salt or magnesium salt comprises a chloride-less counterion. In exemplary embodiments, the counterion is an acetate, aspartate, glutamate, glycolate, lactate, methanesulfonate, propionate, or a combination thereof. In various embodiments, the calcium salt is calcium acetate, calcium aspartate, calcium glutamate, calcium glycolate, calcium lactate, calcium methanesulfonate, calcium propionate, or a combination thereof. In exemplary embodiments, the magnesium salt is magnesium acetate, magnesium aspartate, magnesium glutamate, magnesium glycolate, magnesium lactate, magnesium methanesulfonate, magnesium propionate, or a combination thereof.

[0067] In various cases, the compositions of the present disclosure contain about 15 mM to about 300 mM, about 15 mM to about 200 mM, or about 50 mM to about 150 mM of calcium or magnesium salts. In exemplary embodiments, the compositions of this disclosure are approximately 15 mM to approximately 200 mM, approximately 15 to approximately 150 mM, approximately 50 mM to approximately 250 mM, approximately 50 mM to approximately 200 mM, approximately 50 mM to approximately 150 mM, approximately 50 mM to approximately 100 mM, approximately 50 mM to approximately 90 mM, approximately 50 mM to approximately 80 mM, approximately 50 mM to approximately 70 mM, approximately 50 mM to approximately 60 mM, approximately 50 mM to approximately 55 mM, and approximately 55 mM to approximately 2 Contains calcium or magnesium salts in concentrations of 00mM, approximately 60mM to 200mM, approximately 70mM to 200mM, approximately 80mM to 200mM, approximately 90mM to 200mM, approximately 100mM to 200mM, approximately 150mM to 200mM, approximately 160mM to 200mM, approximately 170mM to 200mM, approximately 180mM to 200mM, or approximately 190mM to 200mM. In various cases, the compositions of the Disclosure contain calcium or magnesium salts in concentrations of about 50 mM to about 100 mM (e.g., about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM) or about 100 mM to about 200 mM (e.g., about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM). In various cases, the compositions of the Disclosure contain calcium or magnesium salts in concentrations of about 15 mM to about 130 mM, about 50 mM to about 100 mM, or about 50 mM to about 75 mM, or about 75 mM to about 100 mM. In various cases, the compositions of the present disclosure contain about 100 mM to about 200 mM, or about 100 mM to about 150 mM, or about 150 mM to about 200 mM of a calcium salt or a magnesium salt.

[0068] In various cases, anti-TSLP antibodies, such as tezeperumab, are formulated with approximately 15 mM to 130 mM calcium and approximately 30 mM to 300 mM glutamate. In various embodiments, an anti-TSLP antibody, such as tezeperumab, contains approximately 70 mM to 130 mM calcium (e.g., approximately 80 mM to 130 mM, approximately 90 mM to 130 mM, approximately 100 mM to 130 mM, approximately 110 mM to 130 mM, approximately 120 mM to 130 mM, approximately 70 mM to 120 mM, approximately 70 mM to 110 mM, approximately 70 mM to 100 mM, approximately 70 mM to 90 mM, approximately 70 mM to 80 mM, approximately 80 mM to 110 mM, approximately 90 mM to 110 mM, approximately 95 mM to 105 mM calcium), and approximately 190 mM to 270 mM glutamate (e.g., approximately 190 mM to 260 mM). M, about 190mM to about 250mM, about 190mM to about 240mM, about 190mM to about 230mM, about 190mM to about 220mM, about 190mM to about 2 10mM, about 190mM to about 200mM, about 200mM to about 270mM, about 210mM ​​to about 270mM, about 220mM to about 270mM, about 230mM It is formulated with glutamate in concentrations of approximately 270 mM, 240 mM to 270 mM, 250 mM to 270 mM, 260 mM to 270 mM, 210 mM to 250 mM, 220 mM to 240 mM, 230 mM to 240 mM, 225 mM to 235 mM, or 235 to 245 mM. In an exemplary embodiment, an anti-TSLP antibody, such as tezeperumab, is formulated with approximately 95 mM to 105 mM calcium and approximately 225 mM to 235 mM glutamate or approximately 235 to 245 mM glutamate. In various cases, anti-TSLP antibodies, such as tezeperumab, are formulated in approximately 15 mM to 195 mM calcium and approximately 25 mM to 320 mM glutamate.In various embodiments, anti-TSLP antibodies, such as tezeperumab, contain approximately 70 mM to approximately 150 mM calcium (for example, approximately 80 mM to approximately 150 mM, approximately 90 mM to approximately 150 mM, approximately 100 mM to approximately 150 mM, approximately 110 mM to approximately 150 mM, approximately 120 mM to approximately 150 mM, approximately 130 mM to approximately 150 mM, approximately 140 mM to approximately (Calcium at 150mM, approximately 70mM-140mM, approximately 70mM-130mM, approximately 70mM-120mM, approximately 70mM-110mM, approximately 70mM-100mM, approximately 70mM-90mM, approximately 70mM-80mM, approximately 90mM-130mM, approximately 100mM-120mM, and approximately 105mM-115mM) , and glutamate salts of approximately 150 mM to approximately 230 mM (for example, approximately 150 mM to approximately 220 mM, approximately 150 mM to approximately 210 mM, approximately 150 mM to approximately 200 mM, approximately 150 mM to approximately 190 mM, approximately 150 mM to approximately 180 mM, approximately 150 mM to approximately 170 mM, approximately 150 mM to approximately 160 mM, approximately 160 mM to approximately 230 mM, approximately The drug is formulated in glutamate at concentrations of approximately 170 mM to 230 mM, approximately 180 mM to 230 mM, approximately 190 mM to 230 mM, approximately 200 mM to 230 mM, approximately 210 mM to 230 mM, approximately 220 mM to 230 mM, approximately 170 mM to 210 mM, approximately 180 mM to 200 mM, and approximately 185 mM to 195 mM. In exemplary embodiments, an anti-TSLP antibody, such as tezeperumab, is formulated in approximately 105 mM to 115 mM calcium and approximately 225 mM to 235 mM glutamate or approximately 235 mM glutamate. In exemplary embodiments, the composition of the Disclosure comprises more than 140 mg / mL of tezeperumab, about 99 mM to about 121 mM of calcium, 171 mM to about 209 mM of glutamate, and 0.01% (w / v) of polysorbate 80. In exemplary embodiments, the composition of the Disclosure comprises more than 140 mg / mL of tezeperumab, about 110 mM of calcium, 240 mM of glutamate, and 0.01% (w / v) of polysorbate 80. Optionally, the pH is about 5.0 ± 0.2 or about 5.0 ± 0.1.

[0069] Combined excipients In various embodiments, the compositions of the present disclosure include two or more excipients for reducing the viscosity of high-protein concentration formulations. In various embodiments, the compositions of the present disclosure further include one or more of the following: N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline, sodium acetate, trisacetate, histidine salt, or calcium salt. In various embodiments, the compositions of the present disclosure include (i) an arginine salt and (ii) NAR and / or methionine. In various embodiments, the arginine salt is arginine glutamate. In various cases, the compositions of the present disclosure include (i) calcium and (ii) NAR and / or methionine. In exemplary embodiments, the calcium salt is calcium glutamate.

[0070] In various embodiments, one or more of N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline, sodium acetate, trisacetate, histidine salt, and calcium salt are present in the composition in amounts of about 15 mM to about 300 mM or about 50 mM to about 300 mM. In exemplary embodiments, the compositions of the present disclosure comprise one or more of N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline, sodium acetate, trisacetate, histidine salt, and calcium salt, which are present in amounts of about 15 mM to about 200 mM, about 15 to about 150 mM, about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 50 mM to about 150 mM, about 50 mM to about 100 mM, about 50 mM to about 90 mM, and about 50 mM to about It is present in the composition in amounts of 80 mM, approximately 50 mM to 70 mM, approximately 50 mM to 60 mM, approximately 50 mM to 55 mM, approximately 55 mM to 200 mM, approximately 60 mM to 200 mM, approximately 70 mM to 200 mM, approximately 80 mM to 200 mM, approximately 90 mM to 200 mM, approximately 100 mM to 200 mM, approximately 150 mM to 200 mM, approximately 160 mM to 200 mM, approximately 170 mM to 200 mM, approximately 180 mM to 200 mM, or approximately 190 mM to 200 mM. In various cases, the compositions of the present disclosure comprise one or more of N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline, sodium acetate, trisacetate, histidine salt, and calcium salt, which are present in the composition in amounts of about 50 mM to about 100 mM (e.g., about 50 mM, about 60 mM, about 70 mM, about 80 mM, about 90 mM, about 100 mM) or about 100 mM to about 200 mM (e.g., about 100 mM, about 110 mM, about 120 mM, about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM). In various cases, the compositions of the present disclosure comprise one or more of N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline, sodium acetate, trisacetate, histidine salt, and calcium salt, which are present in the composition in amounts of about 15 mM to about 200 mM, about 50 mM to about 100 mM, or about 50 mM to about 75 mM, or about 75 mM to about 100 mM.In various cases, the compositions of the present disclosure comprise one or more of N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline, sodium acetate, trisacetate, histidine salt, and calcium salt, which are present in the composition in amounts of about 100 mM to about 200 mM, or about 100 mM to about 150 mM, or about 150 mM to about 200 mM.

[0071] In various embodiments, the amount of basic amino acids or their salts, or calcium salts or magnesium salts, may decrease when combined with each other or with other viscosity-reducing excipients. In various embodiments, the amount of basic amino acids or their salts, or calcium salts or magnesium salts, when combined with each other or with other viscosity-reducing excipients such as proline, may decrease by about 50% compared to formulations that do not contain other viscosity-reducing excipients, such as proline. In exemplary cases, the viscosity-reducing excipients present in the composition are approximately 0 mM to 250 mM, approximately 0 mM to 220 mM, approximately 50 mM to 250 mM, approximately 50 mM to 200 mM, approximately 50 mM to 150 mM, approximately 50 mM to 100 mM, approximately 50 mM to 90 mM, approximately 50 mM to 80 mM, approximately 50 mM to 70 mM, approximately 50 mM to 60 mM, and approximately 50 mM to 55 mM. M exists in total amounts of approximately 55mM to 200mM, 60mM to 200mM, 70mM to 200mM, 80mM to 200mM, 90mM to 200mM, 100mM to 200mM, 150mM to 200mM, 160mM to 200mM, 170mM to 200mM, 180mM to 200mM, or 190mM to 200mM.

[0072] Optionally, the compositions of the present disclosure include one or more of the following: basic amino acids or salts thereof, and / or calcium salts, and / or magnesium salts, and / or: N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline (e.g., L-proline), sodium acetate, trisacetate, histidine salt, or calcium salt, which are present in concentrations of about 50 mM to about 250 mM, about 50 mM to about 200 mM, about 50 mM to about 150 mM, and about 50 mM to about 100 mM. It exists in total amounts of approximately 50mM to 90mM, 50mM to 80mM, 50mM to 70mM, 50mM to 60mM, 50mM to 55mM, 55mM to 200mM, 60mM to 200mM, 70mM to 200mM, 80mM to 200mM, 90mM to 200mM, 100mM to 200mM, 150mM to 200mM, 160mM to 200mM, 170mM to 200mM, 180mM to 200mM, or 190mM to 200mM. In various embodiments, the compositions described herein optionally contain proline (e.g., L-proline) in a total amount of about 0 mM to about 250 mM, about 0 mM to about 220 mM, about 25 mM to about 200 mM, about 50 mM to about 150 mM, or about 50 mM to about 100 mM. In various embodiments, proline is present in amounts of approximately 40 mM, 50 mM, 60 mM, 65 mM, 70 mM, 75 mM, 80 mM, 85 mM, 90 mM, 95 mM, 100 mM, 105 mM, 110 mM, 115 mM, 120 mM, 125 mM, 130 mM, 135 mM, 140 mM, 145 mM, 150 mM, 160 mM, 170 mM, 180 mM, 190 mM, 200 mM, 210 mM, 220 mM, 230 mM, 240 mM, or 250 mM.

[0073] In various cases, the compositions of this disclosure comprise an anti-TSLP antibody greater than 140 mg / mL, e.g., tezeperumab, a surfactant, a basic amino acid or a salt thereof, and proline. In various cases, the anti-TSLP antibody greater than 140 mg / mL, e.g., tezeperumab, is formulated with a basic amino acid or a salt thereof in an amount of about 10 mM to 200 mM or about 50 mM to about 150 mM, and a proline in an amount of about 50 mM to about 250 mM, or about 50 mM to about 150 mM. Optionally, the anti-TSLP antibody greater than 140 mg / mL, e.g., tezeperumab, is formulated with a basic amino acid or a salt thereof in an amount of about 50 mM to about 100 mM, and a proline in an amount of about 90 mM to about 150 mM. In various embodiments, the salt of a basic amino acid is arginine glutamate, and a solution containing arginine glutamate is obtained by adding a certain amount of arginine and a certain amount of glutamate. In various embodiments, an anti-TSLP antibody greater than 140 mg / mL, such as tezeperumab, is formulated with approximately 40 mM to approximately 120 mM of arginine, approximately 45 mM to approximately 125 mM of glutamate, and approximately 60 mM to approximately 140 mM of proline. Optionally, an anti-TSLP antibody, such as tezeperumab, may be formulated with approximately 50 mM to 110 mM, 60 mM to 100 mM, 70 mM to 90 mM, or 75 mM to 85 mM arginine, and approximately 55 mM to 115 mM, 65 mM to 105 mM, 75 mM to 95 mM, or 80 mM to 90 mM glutamate, and approximately 70 mM to 130 mM, 80 mM to 120 mM, 90 mM to 110 mM, or 95 mM to 105 mM proline. In various embodiments, the anti-TSLP antibody is formulated in approximately 10 mM to 90 mM arginine, approximately 55 mM to 135 mM glutamate, and approximately 45 mM to 125 mM proline.Optionally, anti-TSLP antibodies, such as tezeperumab, are formulated in approximately 20 mM to 80 mM, 30 mM to 70 mM, 40 mM to 60 mM, and 45 mM to 55 mM arginine, and approximately 65 mM to 125 mM, 75 mM to 115 mM, 85 mM to 105 mM, and 90 mM to 100 mM glutamate, and approximately 55 mM to 115 mM, 65 mM to 105 mM, 75 mM to 95 mM, 80 mM to 90 mM, or 85 mM proline. In various embodiments, the composition comprises an anti-TSLP antibody greater than 140 mg / mL, about 10 mM to about 90 mM of arginine, about 55 mM to about 135 mM of glutamate, and about 45 mM to about 125 mM of proline. Optionally, the composition comprises an anti-TSLP antibody, such as tezeperumab, and approximately 20 mM to 80 mM, 30 mM to 70 mM, 40 mM to 60 mM, and 45 mM to 55 mM of arginine, approximately 65 mM to 125 mM, 75 mM to 115 mM, 85 mM to 105 mM, and 90 mM to 100 mM of glutamate, and approximately 55 mM to 115 mM, 65 mM to 105 mM, 75 mM to 95 mM, 80 mM to 90 mM, and 85 mM of proline. In various cases, the compositions of the present disclosure include more than 140 mg / mL of tezeperumab, about 45 mM to about 55 mM of arginine, about 85.5 mM to about 104.5 mM of glutamate, and about 76.5 mM to about 93.5 mM of proline.

[0074] In various cases, the compositions of the present disclosure comprise an anti-TSLP antibody greater than 140 mg / mL, e.g., tezeperumab, a surfactant, a calcium or magnesium salt, and proline, e.g., L-proline. In various cases, the anti-TSLP antibody greater than 140 mg / mL, e.g., tezeperumab, is formulated with about 15 mM to about 150 mM of a calcium or magnesium salt and about 50 mM to about 150 mM of proline. Optionally, the anti-TSLP antibody greater than 140 mg / mL, e.g., tezeperumab, is formulated with about 50 mM to about 100 mM of a basic amino acid or its salt and about 90 mM to about 150 mM of proline. In various embodiments, the calcium is calcium glutamate, and a certain amount of calcium and a certain amount of glutamate are added to reach a solution containing calcium glutamate. In various cases, anti-TSLP antibodies are formulated with approximately 20 mM to 100 mM calcium, approximately 100 mM to 180 mM glutamate, and approximately 30 mM to 110 mM proline. Optionally, an anti-TSLP antibody, such as tezeperumab, may be formulated with approximately 30 mM to 90 mM, 40 mM to 80 mM, 50 mM to 70 mM, 55 mM to 65 mM, or 60 mM calcium, and approximately 110 mM to 170 mM, 120 mM to 160 mM, 130 mM to 150 mM, 135 mM to 145 mM, or 140 mM glutamate, and approximately 40 mM to 100 mM, 50 mM to 90 mM, 60 mM to 80 mM, 65 mM to 75 mM, or 70 mM proline. In various cases, anti-TSLP antibodies are formulated in approximately 30 mM to 110 mM calcium, approximately 105 mM to 185 mM glutamate, and approximately 20 mM to 100 mM proline.Optionally, anti-TSLP antibodies, such as tezeperumab, are formulated in approximately 40 mM to 100 mM, 50 mM to 90 mM, 60 mM to 80 mM, 65 mM to 75 mM, or 75 mM calcium; approximately 115 mM to 175 mM, 125 mM to 165 mM, 135 mM to 155 mM, 140 mM to 150 mM, or 145 mM glutamate; and approximately 30 mM to 90 mM, 40 mM to 80 mM, 50 mM to 70 mM, 55 mM to 65 mM, or 60 mM proline. In various cases, the composition comprises more than 140 mg / mL of anti-TSLP antibody, approximately 30 mM to 110 mM of calcium, approximately 105 mM to 185 mM of glutamate, and approximately 20 mM to 100 mM of proline. Optionally, the composition comprises an anti-TSLP antibody, such as tezeperumab, and approximately 40 mM to 100 mM, 50 mM to 90 mM, 60 mM to 80 mM, 65 mM to 75 mM, or 75 mM of calcium, approximately 115 mM to 175 mM, 125 mM to 165 mM, 135 mM to 155 mM, 140 mM to 150 mM, or 145 mM of glutamate, and approximately 30 mM to 90 mM, 40 mM to 80 mM, 50 mM to 70 mM, 55 mM to 65 mM, or 60 mM of proline. In various cases, the compositions of the present disclosure include more than 140 mg / mL of tezeperumab, about 63 mM to about 77 mM of calcium, about 130.5 mM to about 159.5 mM of glutamate, and about 54 mM to about 66 mM of proline.

[0075] surfactant The compositions of the Disclosure in various embodiments include surfactants. Surfactants are amphiphilic (having polar heads and hydrophobic tails) surface active agents. Surfactants preferentially accumulate at interfaces, reducing surface tension. The use of surfactants also helps to mitigate the formation of large protein particles. In some embodiments, the surfactants present in the compositions of the Disclosure are amphiphilic and / or nonionic surfactants. Exemplary surfactants include polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80), alkylaryl polyethers, e.g., oxyethylated alkylphenols (e.g., Triton® X-100), and poloxamers (e.g., Pluronics®, e.g., Pluronic® F68), as well as any combination of the above within or between classes of surfactants. Polysorbate 20 and polysorbate 80 (and optionally mixtures thereof) are particularly considered. In exemplary cases, surfactants are present in the composition at concentrations of less than 0.005% (w / v) or about 0.005% (w / v) to about 0.015% (w / v). For example, a formulation may contain surfactants in concentrations of about 0.005% (w / v) to about 0.015% (w / v), for example, about 0.005% (w / v), about 0.006% (w / v), about 0.007% (w / v), about 0.008% (w / v), about 0.009% (w / v), about 0.010% (w / v), about 0.011% (w / v), about 0.012% (w / v), about 0.013% (w / v), about 0.014% (w / v), and about 0.015% (w / v). In exemplary embodiments, the formulation contains about 0.005% (w / v), 0.010% (w / v), or 0.015% (w / v) of a surfactant. In various embodiments, the surfactant is a polysorbate, for example, polysorbate 20 or polysorbate 80, or a mixture thereof.Optionally, surfactants are present in concentrations of less than 0.005% (w / v), or approximately 0.005% (w / v) to approximately 0.015% (w / v), or optionally, approximately 0.010% (w / v) ± 0.0025% (w / v), for example, at surfactant concentrations of approximately 0.005% (w / v), 0.010% (w / v), or 0.015% (w / v).

[0076] antibody concentration In exemplary embodiments, the compositions of the present disclosure include an anti-TSLP antibody in a concentration greater than approximately 100 mg / mL and less than approximately 300 mg / mL or less than approximately 250 mg / mL, optionally, in a concentration of approximately 160 mg / mL to approximately 250 mg / mL, for example, approximately 180 mg / mL to approximately 225 mg / mL, or approximately 180 mg / mL to approximately 200 mg / mL. In some embodiments, the anti-TSLP antibody is approximately 160 mg / mL to 250 mg / mL, approximately 160 mg / mL to 240 mg / mL, approximately 160 mg / mL to 230 mg / mL, approximately 160 mg / mL to 220 mg / mL, approximately 160 mg / mL to 210 mg / mL, approximately 160 mg / mL to 200 mg / mL, approximately 160 mg / mL to 190 mg / mL, approximately 160 mg / mL to 180 mg / mL, approximately 160 mg / mL to 170 mg / mL The anti-TSLP antibody is present in the composition at concentrations of approximately 180 mg / mL or 190 mg / mL, approximately 200 mg / mL or 210 mg / mL.

[0077] In exemplary embodiments, the composition contains anti-TSLP antibodies in concentrations of approximately 160 mg / mL to approximately 250 mg / mL, optionally, approximately 160 mg / mL to approximately 225 mg / mL, or approximately 160 mg / mL to approximately 200 mg / mL. In various embodiments, the composition contains anti-TSLP antibodies in concentrations of approximately 175 mg / mL to approximately 185 mg / mL, optionally, approximately 175 mg / mL, approximately 176 mg / mL, approximately 177 mg / mL, approximately 178 mg / mL, approximately 179 mg / mL, approximately 180 mg / mL, approximately 181 mg / mL, approximately 182 mg / mL, approximately 183 mg / mL, approximately 184 mg / mL, or approximately 185 mg / mL. In various embodiments, the composition contains anti-TSLP antibodies in concentrations of approximately 180 mg / mL. In various cases, the concentration of anti-TSLP antibody is approximately 189 mg / mL, or approximately 190 mg / mL to approximately 230 mg / mL, or approximately 231 mg / mL. Optionally, the concentration of anti-TSLP antibody is approximately 205 mg / mL to approximately 215 mg / mL, or optionally approximately 210 mg / mL, or approximately 205 mg / mL, approximately 206 mg / mL, approximately 207 mg / mL, approximately 208 mg / mL, approximately 209 mg / mL, approximately 210 mg / mL, approximately 211 mg / mL, approximately 212 mg / mL, approximately 213 mg / mL, approximately 214 mg / mL, or approximately 215 mg / mL.

[0078] In exemplary embodiments, the anti-TSLP antibody is present in the composition at concentrations ranging from approximately 140 mg / mL to approximately 210 mg / mL, for example, approximately 180 mg / mL ± 10%, approximately 200 mg / mL ± 10%, and approximately 210 mg / mL ± 10%.

[0079] Additional excipients In exemplary embodiments, the compositions of the present disclosure may include additional components, such as acidifying agents, additives, adsorbents, aerosol sprayers, and air displacement agents. Contains any pharmaceutically acceptable ingredients, including agents, alkalizing agents, anticoagulants, anticoagulants, antimicrobial preservatives, antioxidants, disinfectants, bases, binders, buffers, chelating agents, coating agents, colorants, drying agents, surfactants, diluents, disinfectants, disintegrants, dispersants, dissolution accelerators, pigments, emollients, emulsifiers, emulsion stabilizers, injectants, film-forming agents, flavoring agents, flavor enhancers, flow enhancers, gelling agents, granulators, humectants, lubricants, mucosal adhesives, ointment bases, ointments, oily vehicles, organic bases, lozenge bases, pigments, plasticizers, glossing agents, preservatives, metal ion sequestering agents, skin penetration agents, solubilizers, solvents, stabilizers, suppository bases, surfactants, suspending agents, sweeteners, therapeutic agents, thickeners, isotonic agents, toxic agents, viscosity increasing agents, water absorbents, water-miscible cosolvents, water softeners, or wetting agents. For example, see: the Handbook of Pharmaceutical Excipients, Third Edition, AH Kibbe (Pharmaceutical Press, London, UK, 2000), this document is referenced in its entirety. Remington's Pharmaceutical Sciences, Sixteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980), this document is referenced in its entirety.

[0080] pH, viscosity, and osmotic pressure In alternative embodiments, the compositions of the present disclosure are liquids. In certain embodiments, the liquids have a pH of less than about 6.0, optionally less than about 5.7, or less than about 5.5. In some embodiments, the pH is about 4.5 to about 5.7, about 4.5 to about 5.5, about 4.7 to about 5.3, about 4.8 to about 5.4, or about 5.0 to about 5.7, for example, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, or about 5.7. In some embodiments, the pH is about 4.9, 5.0, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, or 5.7. In exemplary cases, the compositions of this disclosure have a pH of about 4.5 to about 6.75, and optionally, about 4.8 to about 6.0.

[0081] In some embodiments, the composition is characterized by having a reduced viscosity compared to a liquid composition that does not contain proline. For example, the composition is characterized by having a viscosity of less than about 24 centipoise (cP) at 23°C when the concentration of anti-TSLP antibody is less than 155 mg / mL, or optionally, a viscosity of about 6 cP when the concentration of anti-TSLP antibody is 110 mg / mL, or a viscosity of about 15 cP when the concentration of anti-TSLP antibody is 140 mg / mL. In certain embodiments, the composition is characterized by having a viscosity of about 5 cP to about 20 cP, for example, about 5 cP to about 15 cP, about 5 cP to about 10 cP, about 10 cP to about 20 cP, about 15 cP to about 20 cP, or about 5 cP, about 6 cP, about 7 cP, about 8 cP, about 9 cP, about 10 cP, about 11 cP, about 12 cP, about 13 cP, about 14 cP, about 15 cP, about 16 cP, about 17 cP, about 18 cP, about 19 cP, about 20 cP, about 21 cP, or about 22 cP, when the concentration of anti-TSLP antibody is less than 155 mg / mL (e.g., about 110 mg / mL, about 140 mg / mL).

[0082] In certain embodiments, the composition has a viscosity of about 5 cP to about 25 cP, such as about 5 cP to about 20 cP, about 5 cP to about 15 cP, about 5 cP to about 10 cP, about 10 cP to about 25 cP, about 15 cP to about 20 cP, or about 5 cP, about 6 cP, about 7 cP, about 8 cP, about 9 cP, about 10 cP, about 11 cP, about 12 cP, about 13 cP, about 14 cP, about 15 cP, about 16 cP, about 17 cP, about 18 cP, about 19 cP, about 20 cP, about 21 cP, about 22 cP, about 23 cP, about 24 cP, about 25 cP when the concentration of the anti-TSLP antibody is 180 mg / mL or higher (e.g., about 180 mg / mL, about 210 mg / mL, about 240 mg / mL). In an exemplary embodiment, the composition has a viscosity of about 15 cP ± 5 cP or about 20 cP ± 5 cP when the concentration of the antibody is about 100 mg / mL to about 180 mg / mL. Unless otherwise specified, all viscosities disclosed herein refer to viscosities measured using a rotational viscometer at 23°C at a shear rate of about 1000 1 / s.

[0083] In an exemplary embodiment, the viscosity of the composition of the present disclosure is at 23°C, 1000 s -1 and less than 100 cP, optionally at 23°C, 1000 s -1 and less than 75 cP, such as less than 60 cP, or less than 50 cP.

[0084] In an exemplary embodiment, the composition is intended for subcutaneous administration to a subject, and thus the composition is isotonic with the intended site of administration. For example, the osmotic pressure of the composition is in the range of about 270 to about 350 mOsm / kG, or about 285 to about 345 mOsm / kG, or about 300 to about 315 mOsm / kG in some embodiments. For example, if the solution is in a form intended for parenteral administration, it can be isotonic with blood (an osmotic pressure of about 300 mOsm / kG). In an exemplary embodiment, the aqueous pharmaceutical formulation has an osmotic pressure in the range of about 200 mOsm / kg to about 500 mOsm / kg, or about 225 mOsm / kg to about 400 mOsm / kg, or about 250 mOsm / kg to about 350 mOsm / kg. Optionally, the composition is isotonic or has an osmotic pressure greater than about 350 mOsm / kg.

[0085] stability In various cases, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after storage at approximately 2°C to approximately 8°C for at least or approximately 12 months. In various embodiments, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after storage at approximately 20 to approximately 26 months at approximately 2°C to approximately 8°C. In exemplary cases, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after storage at approximately 30 to approximately 40 months at approximately 2°C to approximately 8°C. In exemplary cases, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after storage at approximately 2 to approximately 3 years at approximately 2°C to approximately 8°C. Also, for example, as determined by size exclusion chromatography (SEC), less than 5% of the antibody is degraded after storage at approximately 24 to approximately 36 months at 2°C to 8°C, and optionally, less than 2% of the antibody is degraded after 24 or 36 months at 2°C to 8°C. In various embodiments, as determined by SEC, less than 5% of the antibody is degraded after storage at near room temperature (e.g., 25°C) for at least two weeks (optionally, after storage for at least one month, at least two months, at least three months, at least four months, at least five months, or at least six months). In various embodiments, as determined by SEC, less than 5% of the antibody is degraded after storage at 2°C to 8°C for about 24 to about 36 months, followed by storage at near room temperature (e.g., 25°C) for at least two weeks or at least about one month or at least about two months. Optionally, as determined by size exclusion chromatography (SEC), less than about 5% of the antibody is degraded after storage at a temperature above about 20°C for at least or about two weeks, or optionally, at least or about four weeks or about eight weeks. In various embodiments, the temperature is above 25°C or about 25°C, above 30°C or about 30°C, or above 40°C or about 40°C.

[0086] Manufactured articles, syringes, and vials Further manufactured articles are provided herein. In exemplary embodiments, the article comprises the composition of the Disclosure, optionally about 1 mL to about 5 mL, for example, about 1 mL to about 3 mL of aqueous composition. In exemplary embodiments of the Disclosure, the composition is provided for storage or use in, for example, disposable vials, disposable syringes, or glass, glass-lined, glass-coated primary containers or auto-injectors. In exemplary embodiments, the composition is provided in disposable system bags or polycarbonate carboys for cryopreservation. In alternative embodiments, the composition is in glass vials or syringes for storage at 2°C to 8°C. Further provided herein are pre-filled syringes comprising the composition of the Disclosure, optionally about 1 mL to about 5 mL, for example, about 1 mL to about 3 mL of composition. Further provided are vials comprising the composition of the Disclosure, optionally about 1 mL to about 5 mL, for example, about 1 mL to about 3 mL of aqueous composition. In various embodiments, the article, pre-filled syringe, or vial contains about 2 mL to about 3 mL, for example, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5 mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, or about 2.9 mL of the composition of the Disclosure, and in various embodiments, the composition contains tezeperumab at a concentration of about 180 mg / mL to provide about 420 mg of tezeperumab.

[0087] In exemplary cases, the composition is provided for use in ready-made and / or self-administered delivery systems. In exemplary embodiments, the composition is provided in pre-filled syringes or auto-injectors, pen injectors, dual-chamber pens, etc. Such products are known and commercially available in the art. For example, Shire, Steven, Monoclonal Antibodies: Meeting See "The Challenges in Manufacturing, Formulation, Delivery and Stability of Final Drug Product," Chapter 8: Development of delivery device technology to deal with the challenges of highly viscous mAb formulations at high concentration, Woodhead Publishing, Cambridge, UK, pages 153-162 (2015). In exemplary embodiments, compositions are provided for use with YpsoMate® autoinjectors, YpsoMate® 2.25 autoinjectors, or VarioJect® (YpsoMed, Burgdorf, Switzerland). Other autoinjectors include, for example, SelfDose® patient-controlled injectors, BD Physioject® disposable autoinjectors, and Autoject® II syringe injectors (Owen Mumford, Oxfordshire, UK). In various embodiments, the autoinjector is a YpsoMate® autoinjector. Further autoinjectors considered in the method are disclosed in International Publications No. 2018 / 226565, No. 2019 / 094138, No. 2019 / 178151, No. 2012 / 072577, No. 2020 / 081479, No. 2020 / 081480, and International Patent Applications PCT / US20 / 70590, No. PCT / US20 / 70591, No. PCT / US20 / 53180, No. PCT / US20 / 53179, No. PCT / US20 / 53178, and No. PCT / US20 / 53176, which are incorporated herein by reference.

[0088] The compositions of this disclosure may be suitable for parenteral administration, particularly by any acceptable route, including subcutaneously. For example, subcutaneous administration may be performed in the upper arm, upper leg, or abdomen. Other routes include, for example, intravenous, intradermal, intramuscular, intraperitoneal, intranodal, and intrasplenic administration. Subcutaneous administration is preferred.

[0089] If the composition is intended for administration to a target, it can be prepared to be isotonic with the intended administration site. For example, if the solution is intended for parenteral administration, it may be isotonic with blood. The composition is typically sterile. In certain embodiments, this can be achieved by filtration with a sterile filtration membrane. In certain embodiments, the parenteral composition is generally placed in an intravenous solution bag or vial having a stopper that can be penetrated by a sterile access port, such as a subcutaneous needle or pre-filled syringe. In certain embodiments, the composition can be stored in a ready-to-use form.

[0090] Anti-TSLP antibody The compositions of this disclosure include an anti-TSLP antibody. In exemplary embodiments, the anti-TSLP antibody specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO: 2. Thymic stromal lymphocyte necrosis factor (TSLP) is an epithelial cell-derived cytokine produced in response to pro-inflammatory stimuli and drives the allergic inflammatory response primarily through its activity against dendritic cells (Gilliet, J Exp Med. 197:1059-1067, 2003; Soumelis, Nat Immunol. 3:673-680, 2002; Reche, J Immunol. 167:336-343, 2001), mast cells (Allakhverdi, J Exp Med. 204:253-258, 2007) and CD34+ progenitor cells. (Sedin et al., Pharmacol Ther) 169:13-34 (2017). TSLP signals through a heterodimer receptor consisting of an interleukin (IL)-7 receptor alpha (IL-7Rα) chain and a common gamma-chain-like receptor (TSLPR) (Pandey, Nat Immunol. 1:59-64, 2000; Park, J Exp Med. 192:659-669, 2000).

[0091] Human TSLP mRNA (Brightling et al., J Allergy Clin Immunol 121:5-10 quiz 1-2 (2008); Ortega et al., NEJM 371:1198-1207 (2014)) and protein levels (Ortega et al., (2014), cited above) were increased in the airways of asthma patients compared to controls, and the magnitude of this expression correlated with disease severity. Brightling et al, (2008), cited above. Recent studies have demonstrated a link between single nucleotide polymorphisms at the human TSLP locus and protection from asthma, atopic asthma, and airway hyperresponsiveness, suggesting that differential regulation of TSLP gene expression may influence disease susceptibility. (To et al., BMC Public Health 12:204 (2012); XOLAIR® (Omalizumab): Highlights of Prescribing Information 2016. (https: / / www.gene.com / download / pdf / xolair_prescribing.pdf.); Bleecker et al., The Lancet 388:2115-2127 (2016). These data suggest that targeting TSLP may inhibit multiple biological pathways involved in asthma.

[0092] Early nonclinical studies of TSLP suggested that, after being released from airway epithelial or stromal cells, TSLP activates mast cells, dendritic cells, and T cells, leading to the release of Th2 cytokines (e.g., IL-4 / 13 / 5). Recent human data have shown a good correlation between tissue TSLP genes and protein expression, Th2 gene signature score, and tissue eosinophils in severe asthma. Therefore, anti-TSLP targeted therapy may be effective in asthma patients with Th2-type inflammation (Shikotra et al, J Allergy Clin Immunol. 129(1):104-11, 2012).

[0093] Data from other studies suggest that TSLP may promote airway inflammation via Th2-independent pathways, such as crosstalk between airway smooth muscle and mast cells (Allakhverdi et al, J Allergy Clin Immunol. 123(4):958-60, 2009; Shikotra et al, cited above). TSLP may also promote T cell induction and differentiation into Th-17 cytokine-producing cells, thereby increasing neutrophilic inflammation commonly seen in more severe asthma (Tanaka et al.). (al, Clin Exp Allergy. 39(1):89-100, 2009). These data and other new evidence suggest that blocking TSLP may help suppress multiple biological pathways, including, but not limited to, those involving Th2 cytokines (IL-4 / 13 / 5).

[0094] Antibodies specific to TSLP are considered useful in the treatment of asthma, including severe asthma, eosinophilic asthma, noneosinophilic / hypeosinophilic asthma, and other forms of asthma as described herein.

[0095] Specific binders, such as antibodies that bind to a target antigen, e.g., TSLP, and antibody variants or fragments, are useful in the methods of this disclosure. In one embodiment, the specific binder is an antibody. Antibodies may be monoclonal (MAb); recombinant; chimeric; humanized (e.g., with complementarity-determining region (CDR) grafting); human; single-chain antibody variants; and / or bispecific; and fragments; variants; or derivatives thereof. Antibody fragments include such portions of an antibody that bind to an epitope on a polypeptide of interest. Examples of such fragments include Fab and F(ab') fragments produced by enzymatic cleavage of a full-length antibody. Other binding fragments include fragments produced by recombinant DNA techniques, such as the expression of a recombinant plasmid containing a nucleic acid sequence encoding an antibody variable region.

[0096] Monoclonal antibodies can be modified for use as therapeutic or diagnostic agents. One embodiment is a “chimeric” antibody in which a portion of the heavy chain (H) and / or light chain (L) originates from a particular species or is identical or homologous to a corresponding sequence in an antibody belonging to a particular antibody class or subclass, and the remainder of the chain originates from another species or is identical or homologous to a corresponding sequence in an antibody belonging to another antibody class or subclass. Fragments of such antibodies are also included, insofar as they exhibit the desired biological activity. See U.S. Patent No. 4,816,567; Morrison et al., 1985, Proc. Natl. Acad. Sci. 81:6851-55.

[0097] In another embodiment, the monoclonal antibody is a “humanized” antibody. Methods for humanizing non-human antibodies are well known in the art, disclosed in U.S. Patent Nos. 5,585,089 and 5,693,762. Generally, a humanized antibody has one or more amino acid residues introduced from a non-human source. Humanization can be carried out, for example, by substituting at least a portion of the complementarity-determining region of a rodent with the corresponding region of a human antibody, using methods described in the art (Jones et al., 1986, Nature 321:522-25; Riechmann et al., 1998, Nature 332:323-27; Verhoeyen et al., 1988, Science 239:1534-36).

[0098] Human antibodies and antibody variants (including antibody fragments) that bind to TSLP are also included in this disclosure. Using genetically modified animals (e.g., mice) capable of producing a repertoire of human antibodies without producing endogenous immunoglobulins, such antibodies are produced by immunization with polypeptide antigens (i.e., having at least six consecutive amino acids) optionally conjugated to a carrier. See, for example, Jakobovits et al., 1993, Proc. Natl. Acad. Sci. 90:2551-55; Jakobovits et al., 1993, Nature 362:255-58; Bruggermann et al., 1993, Year in Immuno. 7:33. See also PCT applications PCT / US96 / 05928 and PCT / US93 / 06926. Further methods are described in U.S. Patent No. 5,545,807, PCT Application Nos. PCT / US91 / 245 and PCT / GB89 / 01207, and European Patent No. 546073B1 and European Patent Publication No. 546073A1. Human antibodies can also be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells as described herein.

[0099] Chimeric, CDR-grafted, and humanized antibodies and / or antibody variants are typically produced by recombinant methods. The nucleic acid encoding the antibody is introduced into a host cell and expressed using the materials and procedures described herein. In preferred embodiments, the antibody is produced in mammalian host cells such as CHO cells. Monoclonal (e.g., human) antibodies may be produced by the expression of recombinant DNA in host cells or by expression in hybridoma cells as described herein.

[0100] The antibodies and antibody variants (including antibody fragments) useful in this method include an anti-TSLP antibody, which comprises (A) a light chain variable domain comprising (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and (B) a heavy chain variable domain comprising (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, Includes.

[0101] Furthermore, (A) a light chain variable domain selected from the group consisting of (i) an amino acid sequence having at least 80% (e.g., about 85%, about 90%, about 95%, and more than 95%) identity with SEQ ID NO: 12; (ii) an amino acid sequence encoded by a polynucleotide sequence having at least 80% (e.g., about 85%, about 90%, about 95%, and more than 95%) identity with SEQ ID NO: 11; and (iii) an amino acid sequence encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions, and (B) a heavy chain variable domain having at least 80% (e.g., about 85%, about 90%) identity with SEQ ID NO: 10 (i) an amino acid sequence having identity of approximately 95%, or more than 95%; (ii) an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity (e.g., approximately 85%, approximately 90%, approximately 95%, or more than 95%) to SEQ ID NO: 9; (iii) a heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 9 under moderately stringent conditions; or (C) an antibody or antibody variant comprising the light chain variable domain of (A) and the heavy chain variable domain of (A), wherein the antibody or antibody variant specifically binds to the TSLP polypeptide represented by amino acids 29-159 of SEQ ID NO: 2.

[0102] In the example, the anti-TSLP antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 13, a light chain containing the amino acid sequence of SEQ ID NO: 14, or a heavy chain containing the amino acid sequence of SEQ ID NO: 13 and a light chain containing the amino acid sequence of SEQ ID NO: 14.

[0103] Tezeperumab comprises (A) a light chain variable domain comprising: (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5; and (B) a heavy chain variable domain comprising: (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8. This is an exemplary anti-TSLP antibody having [specific characteristic].

[0104] Tezeperumab also, (A) Light chain variable domain, (i) an amino acid sequence having at least 80% identity with SEQ ID NO: 12; (ii) an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; (iii) A light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes with the complement of the polynucleotide consisting of SEQ ID NO: 11 under moderately stringent conditions; and (B) Heavy chain variable domain, (i) an amino acid sequence having at least 80% identity with SEQ ID NO: 10; (ii) an amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; (iii) A heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes with the complement of the polynucleotide represented by SEQ ID NO: 9 under moderately stringent conditions; or (C)(A) light chain variable domain and (B) heavy chain variable domain Includes.

[0105] Other exemplary anti-TSLP antibodies are known in the art. See, for example, International Publication No. 2017 / 042701, International Publication No. 2016 / 142426, International Publication No. 2010 / 017468, U.S. Patent Application Publication No. 2012 / 0020988, and U.S. Patent No. 8,637,019. In exemplary embodiments, the anti-TSLP antibody is an antibody disclosed in one of these publications.

[0106] In various embodiments, the anti-TSLP antibody or its antibody variant is bivalent and selected from the group consisting of human antibodies, humanized antibodies, chimeric antibodies, monoclonal antibodies, recombinant antibodies, antigen-binding antibody fragments, single-chain antibodies, monomeric antibodies, bispecific antibodies, trispecific antibodies, quadrispecific antibodies, Fab fragments, IgG1 antibodies, IgG2 antibodies, IgG3 antibodies, and IgG4 antibodies. In an exemplary embodiment, the anti-TSLP antibody is an IgG2 antibody.

[0107] In various embodiments, the anti-TSLP antibody variant is selected from the group consisting of bispecificity antibodies, tripspecificity antibodies, quadrispecificity antibodies, Fab fragments, single-domain antibodies, and scFv, and its dose is adjusted so that the binding site is equimolar to that of the bivalent antibody. In exemplary embodiments, both antibody binding sites have the same binding properties as TSLP.

[0108] The antibody or antibody variant is considered to be an IgG2 antibody. An exemplary sequence of the human IgG2 constant region is available from the Uniprot database as Uniprot number P01859 and is incorporated herein by reference. Information including sequence information for the heavy and light chain constant regions of other antibodies is also publicly available through the Uniprot database and other databases well known to technicians in the field of antibody engineering and production.

[0109] In certain embodiments, antibody derivatives include tetrameric glycosylated antibodies in which the number and / or type of glycosylation sites are altered compared to the amino acid sequence of the parent polypeptide. In certain embodiments, the variant contains more or fewer N-linked glycosylation sites than the native protein. Alternatively, the existing N-linked carbohydrate chain is removed by a substitution that deletes this sequence. Alternatively, a rearrangement of the N-linked carbohydrate chain occurs in which one or more N-linked glycosylation sites (typically naturally occurring) are deleted to generate one or more new N-linked sites. Further preferred antibody variants include cysteine ​​variants in which one or more cysteine ​​residues are deleted from or substituted with another amino acid (e.g., serine) compared to the parent amino acid sequence. Cysteine ​​variants may be useful when the antibody needs to be refolded into a biologically active conformation, such as after isolation of an insoluble inclusion body. Cysteine ​​variants generally have fewer cysteine ​​residues than native proteins and usually have an even number to minimize interactions arising from unpaired cysteines.

[0110] The desired amino acid substitution (whether conserved or non-conservative) can be determined by those skilled in the art at the time such substitution is desired. In certain embodiments, amino acid substitutions can be used to identify key residues of antibodies against human TSLP, or to increase or decrease the affinity of antibodies against human TSLP described herein.

[0111] According to certain embodiments, preferred amino acid substitutions are those that (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for protein complex formation, (4) alter binding affinity, and / or (4) confer or modify other physiological or functional properties to such polypeptide. According to certain embodiments, one or more amino acid substitutions (conservative amino acid substitutions in certain embodiments) may be made within naturally occurring sequences (in certain embodiments, the portion of the polypeptide outside the domains that form intermolecular contacts). In certain embodiments, conservative amino acid substitutions typically do not substantially alter the structural features of the parent sequence (for example, the substituted amino acid should not tend to disrupt helices present in the parent sequence or other types of secondary structures that characterize the parent sequence). Examples of secondary and tertiary structures of polypeptides known to those skilled in the art are described in Proteins, Structures and Molecular Principles (Creighton, Ed., WH Freeman and Company, New York (1984)); Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, NY (1991)); and Thornton et al. Nature 354:105 (1991), which are incorporated herein by reference, respectively.

[0112] Consistent with the foregoing, in some embodiments, the compositions of the present disclosure comprise about 110 mg / mL to about 140 mg / mL of anti-TSLP antibody, about 0.01% (w / v) ± 0.005% (w / v) of polysorbate 80, more than about 2.5% (w / v) and less than about 3.0% (w / v) of L-proline, and about 20 mM to about 30 mM of acetate, wherein the viscosity of the composition is less than about 20 cP (e.g., 15 cP) at 23°C, and the pH is less than about 5.5, optionally about 5.2. Optionally, the anti-TSLP antibody comprises (A) a light chain variable domain comprising (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and (B) a heavy chain variable domain comprising (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8. In an exemplary case, the composition comprises approximately 110 mg / mL of an anti-TSLP antibody, e.g., tezeperumab, 0.01% (w / v) of polysorbate 80, approximately 2.5% (w / v) to approximately 3.0% (w / v) of L-proline, and approximately 20 mM to approximately 22 mM of acetate, wherein the composition has a pH of approximately 5.2, and the anti-TSLP antibody optionally comprises (A) a light chain variable domain, (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, and (ii) (iii) A light chain variable domain comprising a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and (B) a heavy chain variable domain comprising a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8.In an alternative case, the composition comprises approximately 140 mg / mL of an anti-TSLP antibody, e.g., tezeperumab, 0.01% (w / v) of polysorbate 80, approximately 2.6% (w / v) to approximately 2.7% (w / v) of L-proline, and approximately 23 mM to approximately 25 mM of acetate, wherein the composition has a pH of approximately 5.2, and the anti-TSLP antibody optionally comprises (A) a light chain variable domain, (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, and (ii) (iii) A light chain variable domain comprising a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and (B) a heavy chain variable domain comprising a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8.

[0113] Consistent with the foregoing, in some embodiments, the compositions of the present disclosure comprise about 180 mg / mL to about 210 mg / mL of anti-TSLP antibody, about 0.01% (w / v) ± 0.005% (w / v) of polysorbate 80, 15 to 190 mM of arginine base, 25 to 200 mM of glutamic acid, and 0 to 250 mM of proline, wherein the viscosity of the composition is less than about 22 cP at 23°C (e.g., 15, 17, or 20 cP), and the pH is less than about 5.7, optionally about 5.4. Optionally, the anti-TSLP antibody comprises (A) a light chain variable domain comprising (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and (B) a heavy chain variable domain comprising (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8. In various embodiments, the aqueous composition comprises 140 mM arginine base and 150 mM glutamic acid. In various embodiments, the aqueous composition comprises 140 mM arginine base, 150 mM glutamic acid, and 0.01% (w / v) polysorbate 80 pH 5.4. In various embodiments, the aqueous composition contains 80 mM arginine base, 85 mM glutamic acid, and 100 mM L-proline. In various embodiments, the aqueous composition contains 80 mM arginine base, 85 mM glutamic acid, 100 mM L-proline, and 0.01% (w / v) polysorbate 80 pH 5.4.

[0114] Consistent with the foregoing, in some embodiments, the compositions of the present disclosure comprise about 180 mg / mL to about 210 mg / mL of anti-TSLP antibody, about 0.01% (w / v) ± 0.005% (w / v) of polysorbate 80, 10 to 125 mM of arginine base, 25 to 225 mM of glutamic acid, and 0 to 250 mM of proline, wherein the viscosity of the composition is less than about 22 cP at 23°C (e.g., 15, 17, or 20 cP), and the pH is less than about 5.7, optionally about 5.4. Optionally, the anti-TSLP antibody comprises (A) a light chain variable domain comprising (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and (B) a heavy chain variable domain comprising (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8. In various embodiments, the aqueous composition comprises 95 mM arginine base and 170 mM glutamic acid. In various embodiments, the aqueous composition comprises 50 mM arginine base, 95 mM glutamic acid, and 85 mM L-proline. In various embodiments, the aqueous composition contains 95 mM arginine base, 170 mM glutamic acid, and 0.01% (w / v) polysorbate 80 pH 5.4. In various embodiments, the aqueous composition contains 50 mM arginine base, 95 mM glutamic acid, 85 mM L-proline, and 0.01% (w / v) polysorbate 80 pH 5.4.

[0115] Consistent with the foregoing, in some embodiments, the compositions of the present disclosure comprise about 180 mg / mL to about 210 mg / mL of anti-TSLP antibody, about 0.01% (w / v) ± 0.005% (w / v) of polysorbate 80, 15 to 130 mM of calcium, 30 to 300 mM of glutamate, and 0 to 250 mM of proline, wherein the viscosity of the composition is less than about 20 cP (e.g., 15 or 17 cP) at 23°C, and the pH is less than about 5.5, optionally about 5.0. Optionally, the anti-TSLP antibody comprises (A) a light chain variable domain comprising (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and (B) a heavy chain variable domain comprising (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8. In various embodiments, the aqueous composition comprises 100 mM calcium and 230 mM glutamate. In various embodiments, the aqueous composition comprises 60 mM calcium, 140 mM glutamate, and 70 mM L-proline. In various embodiments, the aqueous composition contains 100 mM calcium, 230 mM glutamate, and 0.01% (w / v) polysorbate 80 pH 5.0. In various embodiments, the aqueous composition contains 60 mM calcium, 140 mM glutamate, 70 mM L-proline, and 0.01% (w / v) polysorbate 80 pH 5.0.

[0116] Consistent with the foregoing, in some embodiments, the compositions of the present disclosure comprise about 180 mg / mL to about 210 mg / mL of anti-TSLP antibody, about 0.01% (w / v) ± 0.005% (w / v) of polysorbate 80, 15 to 195 mM of calcium, and 25 to 320 mM and 0 to 220 mM of proline, wherein the viscosity of the composition is less than about 20 cP (e.g., 15 or 17 cP) at 23°C, and the pH is less than about 5.5, optionally about 5.0. Optionally, the anti-TSLP antibody comprises (A) a light chain variable domain comprising (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, and (B) a heavy chain variable domain comprising (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8. In various embodiments, the aqueous composition comprises 110 mM calcium and 240 mM glutamic acid. In various embodiments, the aqueous composition comprises 70 mM calcium, 145 mM glutamate, and 60 mM L-proline. In various embodiments, the aqueous composition contains 110 mM calcium, 240 mM glutamate, and 0.01% (w / v) polysorbate 80 pH 5.0. In various embodiments, the aqueous composition contains 70 mM calcium, 145 mM glutamate, 60 mM L-proline, and 0.01% (w / v) polysorbate 80 pH 5.0.

[0117] How to use Without being bound by any particular theory, and based at least in part on the data provided herein, the compositions of this disclosure are particularly suitable for the treatment of patients suffering from inflammatory diseases. As used herein, “inflammatory disease” refers to a medical condition in which the immune system attacks its own cells or tissues, causing abnormal inflammation that results in chronic pain, redness, swelling, stiffness, and damage to normal tissues, among other things. Inflammatory diseases include, for example, asthma, chronic peptic ulcer, tuberculosis, periodontitis, sinusitis, active hepatitis, ankylosing spondylitis, rheumatoid arthritis, chronic obstructive pulmonary disease (COPD), Crohn's disease, ulcerative colitis, osteoarthritis, atherosclerosis, systemic lupus erythematosus, atopic dermatitis, eosinophilic esophagitis (EoE), nasal polyps, chronic urticaria, Ig-induced diseases (such as IgA nephropathy and lupus nephritis), eosinophilic gastritis, chronic sinusitis without nasal polyps, and idiopathic pulmonary fibrosis (IPF). In exemplary embodiments, inflammatory diseases include asthma, atopic dermatitis, COPD, eosinophilic esophagitis (EoE), nasal polyps and chronic urticaria, Ig-induced diseases (such as IgA nephropathy and lupus nephritis), eosinophilic gastritis, chronic sinusitis without nasal polyps, and idiopathic pulmonary fibrosis (IPF). In exemplary embodiments, inflammatory diseases include atopic dermatitis (AD). In various embodiments, inflammatory diseases include asthma. In various embodiments, inflammatory diseases include COPD.

[0118] Accordingly, this specification provides the use of the compositions of this disclosure for the treatment of inflammatory diseases. In exemplary embodiments, the inflammatory disease is selected from the group consisting of asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE), nasal polyps, chronic urticaria, Ig-induced diseases (such as IgA nephropathy and lupus nephritis), eosinophilic gastritis, chronic sinusitis without nasal polyps, and idiopathic pulmonary fibrosis (IPF). Optionally, the inflammatory disease is atopic dermatitis. In various embodiments, the inflammatory disease is asthma. In various embodiments, the inflammatory disease is COPD. The disclosure also provides methods for treating the inflammatory disease of interest. In exemplary embodiments, the method includes administering a therapeutically effective amount of the compositions of this disclosure to the subject. In various embodiments, the inflammatory disease is selected from the group consisting of asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), eosinophilic esophagitis (EoE), nasal polyps, chronic urticaria, Ig-induced diseases (such as IgA nephropathy and lupus nephritis), eosinophilic gastritis, chronic sinusitis without nasal polyps, and idiopathic pulmonary fibrosis (IPF). Optionally, the inflammatory disease is atopic dermatitis. In various cases, the compositions of this disclosure are administered to the subject by subcutaneous injection. In exemplary cases, about 1 mL to about 5 mL, for example, about 1 mL to about 3 mL of the aqueous composition is administered to the subject.

[0119] asthma In this specification, the term "asthma" refers to allergic, non-allergic, eosinophilic, and non-eosinophilic asthma.

[0120] In this specification, the term “allergic asthma” refers to asthma induced by one or more inhaled allergens. Such patients have positive IgE fluorescence immunoassay (FEIA) levels for one or more allergens that trigger an asthmatic response.

[0121] Most allergic asthma cases are typically associated with Th2-type inflammation.

[0122] The term "non-allergic asthma" refers to patients with low eosinophil counts, low Th2 levels, or low IgE levels at the time of diagnosis. Patients with "non-allergic asthma" are typically negative on IgE fluorescence immunoassay (FEIA), which reacts to an allergen panel containing region-specific allergens. In addition to low IgE, these patients often have low or no eosinophil counts and low Th2 levels at the time of diagnosis.

[0123] In this specification, the term “severe asthma” refers to asthma that requires high-intensity treatment (e.g., GINA steps 4 and 5) to maintain good control, or asthma that is not well controlled despite high-intensity treatment (GINA, Global Strategy for Asthma Management and Prevention. Global Initiative for Asthma (GINA), December 2012).

[0124] In this specification, the term "eosinophilic asthma" refers to asthma patients with a screening blood eosinophil count of ≥250 cells / μL. "Hypoeosinophilic" asthma refers to asthma patients with blood or serum with a blood or serum count of less than 250 cells / μL.

[0125] In this specification, the term "Th2-type inflammation" refers to subjects with a screening serum eosinophil count of ≥140 cells / μL and a screening total serum IgE level of >100 IU / mL (Corren et al, N Engl J Med. 22;365(12):1088-98, 2011). A "high Th2" asthma population or profile refers to subjects with IgE >100 IU / mL and a serum eosinophil count of ≥140 cells / μL. A "low Th2" asthma population refers to subjects with IgE <100 IU / mL and a serum eosinophil count of ≤140 cells / μL.

[0126] Atopic dermatitis In various cases, the inflammatory disease is atopic dermatitis (AD), a common allergic inflammatory skin disease also known as eczema. AD is the most common skin disease in children and is characterized by severe itching and inflamed skin, as well as chronic lichenified, scaly plaques. The cause of AD is unknown, but current theory suggests that AD is a condition in which the major skill barrier is deficient, leading to other atopic conditions. AD has been studied by Kapur et al., Atopic dermatitis. Allergy Asthma Clin Immunol 14,52 (2018) doi:10.1186 / s13223-018-0281-6. Like asthma and allergic rhinitis, AD involves T helper type 2 (Th2) cell-mediated allergic inflammation triggered by the secretion of IL-4, IL-5, IL-13, and TNFα by CD4+ T cells. These cytokines trigger increased IgE antibody production by B cells, and IgG binds to mast cells, promoting the initiation of an allergic reaction and delivering leukocytes to the dermis of the skin. Indra, Exper Rev Proteomics 10(4):309-311(2013). In exemplary embodiments, AD is characterized by higher expression of TSLP. In various embodiments, AD is characterized by TSLP secretion by epidermal keratinocytes, which triggers TH2 cytokine-related inflammation.

[0127] In exemplary manifestations, Alzheimer's disease (AD) is chronic and may relapse periodically. In various manifestations, the patient experiences one or more of the following symptoms of AD: • Dry skin, itching, especially at night. • Red to brown or gray spots (for example, on the hands, feet, ankles, wrists, neck, upper chest, eyelids, inner elbows or knees, face or scalp), • Small, raised bumps, • Thickened, cracked, scaly skin, and • Raw, sensitive, swollen skin due to scratches. (From mayoclinic.org / diseases-conditions / atopic-dermatitis-eczema / symptoms-causes / syc-20353273)

[0128] In various forms, Alzheimer's disease (AD) is accompanied by one or more of the following conditions: asthma, hay fever, chronic itching, scaly skin, skin infections, irritant hand dermatitis, allergic rhinitis, allergic contact dermatitis, or sleep disorders.

[0129] In various embodiments, the use of the compositions of this disclosure eliminates the need for corticosteroid therapy or other drugs used to treat Alzheimer's disease (AD).

[0130] In alternative embodiments, the method includes administering the composition of the Disclosure in combination with another anti-inflammatory or anti-AD treatment. For example, in various embodiments, the method further includes administering a corticosteroid (e.g., prednisone), or a calcineurin inhibitor (e.g., tacrolimus, pimecrolimus), an antibiotic, or a biological agent (e.g., dupilumab). In exemplary embodiments, the method further includes phototherapy, such as phototherapy with sunlight, UVA, or UVB.

[0131] subject The subjects are presumably human. The subjects may be adults, adolescents, or children.

[0132] In various embodiments, the subject exhibits signs or symptoms of an inflammatory disease, such as AD or COPD, such as one or more of the above. In various embodiments, the subject also suffers from one or more of the following: asthma, hay fever, chronic itching, scaly skin, skin infection, irritant hand dermatitis, allergic contact dermatitis, or sleep disorders. In various embodiments, the subject has previously been treated or is currently being treated with anti-AD or anti-inflammatory therapies, such as corticosteroids (e.g., prednisone), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus), antibiotics, or biological agents (e.g., dupilumab). In exemplary embodiments, the method further includes phototherapy, such as phototherapy with sunlight, UVA, or UVB. Optionally, the subject has never been treated with any of the following: corticosteroids (e.g., prednisone), calcineurin inhibitors (e.g., tacrolimus, pimecrolimus), antibiotics, or biological agents (e.g., dupilumab). In exemplary embodiments, the method further includes phototherapy, e.g., phototherapy with sunlight, UVA, or UVB.

[0133] Treatment regimen, dosage, and route of administration Therapeutic antibody (or antibody variant) compositions can be delivered to a patient at multiple sites. Multiple doses may be administered simultaneously or over a period of time. In certain cases, it is beneficial to provide a continuous flow of the therapeutic composition. Additional treatments may be administered on a period-based basis, for example, hourly, daily, weekly, every two weeks, every three weeks, monthly, or at longer intervals.

[0134] In various embodiments, the amount of therapeutic agent in a given dose, such as a bivalent antibody having two TSLP binding sites, may vary depending on the size of the individual being treated and the characteristics of the disorder being treated.

[0135] In exemplary treatments, the composition provides a dose of anti-TSLP antibody or antibody variant in the range of about 210 mg to about 420 mg per day. For example, the dose provided may be about 210 mg, 280 mg, or 420 mg. In various embodiments, the composition containing anti-TSLP antibody or antibody variant may be administered in doses of about 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, or 420 mg per single dose. These concentrates may be administered in single-dose form or in repeated doses. The above doses are given every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered in a single dose of 280 mg or 420 mg every two weeks or every four weeks. In various embodiments, the anti-TSLP antibody or antibody variant is administered as a single dose of 210 mg every two or four weeks. In various embodiments, a composition containing the anti-TSLP antibody as described herein in a concentration greater than approximately 100 mg / mL or greater than approximately 140 mg / mL is administered to the subject at intervals of every two or four weeks.

[0136] Regarding antibody variants, the amount of antibody variant should be such that the number of TSLP binding sites in the dose is equimolar to that of the canonical bivalent antibody.

[0137] The compositions of this disclosure, comprising an anti-TSLP antibody or antibody variant, are intended to be administered every two weeks or every four weeks for a period of at least four months, six months, nine months, one year, or longer. In various embodiments, administration is subcutaneous or intravenous.

[0138] Manufacturing method This specification further provides a method for producing the compositions of the present disclosure. Accordingly, a method for producing a stable liquid antibody composition having a viscosity of less than about 100 cP and comprising (A) an anti-TSLP antibody at a concentration greater than about 140 mg / mL, (B) a surfactant, and (C) a basic amino acid or its salt, calcium salt, magnesium salt, or a combination thereof. In an exemplary embodiment, the method comprises (i) combining the antibody with an aqueous solution containing a basic amino acid or its salt, calcium salt, magnesium salt, or a combination thereof in a concentration of about 10 mM to about 200 mM or about 50 mM to about 150 mM, and (ii) adding the surfactant to achieve a final concentration of the surfactant of about 0.01% (w / v) ± 0.005% (w / v).

[0139] In exemplary embodiments, the composition contains an anti-TSLP antibody in an amount of approximately 160 mg / mL to approximately 250 mg / mL, optionally, approximately 180 mg / mL to approximately 225 mg / mL, or approximately 180 mg / mL to approximately 200 mg / mL. Optionally, the composition contains an anti-TSLP antibody in an amount of approximately 160 mg / mL to approximately 250 mg / mL, optionally, approximately 165 mg / mL to approximately 225 mg / mL, or approximately 165 mg / mL to approximately 200 mg / mL. In various embodiments, the composition contains anti-TSLP antibody at concentrations of approximately 175 mg / mL to approximately 185 mg / mL, and optionally, approximately 175 mg / mL, approximately 176 mg / mL, approximately 177 mg / mL, approximately 178 mg / mL, approximately 179 mg / mL, approximately 180 mg / mL, approximately 181 mg / mL, approximately 182 mg / mL, approximately 183 mg / mL, approximately 184 mg / mL, and approximately 185 mg / mL. In various embodiments, the composition contains anti-TSLP antibody at concentrations of approximately 180 mg / mL. In various cases, the concentration of anti-TSLP antibody is approximately 189 mg / mL or approximately 190 mg / mL to approximately 230 mg / mL or approximately 231 mg / mL. Optionally, the concentration of anti-TSLP antibody is approximately 205 mg / mL to approximately 215 mg / mL, optionally approximately 210 mg / mL, or approximately 205 mg / mL, approximately 206 mg / mL, approximately 207 mg / mL, approximately 208 mg / mL, approximately 209 mg / mL, approximately 210 mg / mL, approximately 211 mg / mL, approximately 212 mg / mL, approximately 213 mg / mL, approximately 214 mg / mL, or approximately 215 mg / mL. In exemplary embodiments, the aqueous solution contains an organic salt of arginine, lysine, or histidine.In exemplary embodiments, the aqueous solution comprises arginine acetate, arginine aspartate, arginine glutamate, arginine glycolate, arginine lactate, arginine methanesulfonate, arginine propionate, histidine acetate, histidine aspartate, histidine glutamate, histidine glycolate, histidine lactate, histidine methanesulfonate, histidine propionate, lysine acetate, lysine aspartate, lysine glutamate, lysine glycolate, lysine lactate, lysine methanesulfonate, lysine propionate, calcium acetate, calcium aspartate, calcium glutamate, calcium glycolate, calcium lactate, calcium methanesulfonate, calcium propionate, magnesium acetate, magnesium aspartate, magnesium glutamate, magnesium glycolate, magnesium lactate, magnesium methanesulfonate, magnesium propionate, or a combination thereof. In various embodiments, the aqueous solution contains a salt (basic amino acid salt, calcium salt, magnesium salt) at a concentration of about 15 mM to about 200 mM or about 50 mM to about 150 mM. In some embodiments, the surfactant is polysorbate 80 or polysorbate 20. In the exemplary embodiment, the surfactant is polysorbate 80, and the final concentration of PS80 is about 0.01% (w / v). In the exemplary embodiment, the anti-TSLP antibody is tezepermab.

[0140] kit This disclosure also provides kits comprising the compositions described herein, together with accompanying documentation, package labels, instructions, or other labels indicating or disclosing any of the methods or embodiments disclosed herein. In certain embodiments, this disclosure provides kits for generating single-dose units. Certain embodiments of this disclosure include kits containing single-chamber and multi-chamber pre-filled syringes (e.g., liquid syringes).

[0141] The following embodiments are provided merely to illustrate the present invention and are not intended to limit its scope in any way. [Examples]

[0142] Throughout the examples presented herein, the following abbreviations are used: DF, diafiltration; PS80, polysorbate 80; SEC, size exclusion chromatography; F#, formulation number. Furthermore, throughout the examples, the composition of the DF buffer used to prepare the final formulation containing tezepermab, as well as the estimated concentrations of the components of the final formulation, are provided.

[0143] The final concentrations of specific components in the analyzed final formulation (e.g., stability, viscosity, and optionally, after storage) differ from those in the DF or dialysis buffer, depending on the presence or absence of counterions. In the absence of counterions, the ionic strength of the formulation is lower. In such cases, the acetate co-concentrates with tezeperumab, resulting in the final formulation containing a higher concentration of acetate compared to the DF or dialysis buffer. For example, using a DF buffer containing 10 mM acetate yields approximately 20 mM to 22 mM acetate in a formulation containing 110 mg / mL of tezeperumab (pH 5.2) when neither the DF buffer nor the final formulation contains salts (e.g., arginine HCl), thus resulting in lower ionic strength. Similarly, using a DF buffer containing 10 mM acetate yields approximately 23 mM to 25 mM acetate in a formulation containing 140 mg / mL of tezeperumab (pH 5.2) when neither the DF buffer nor the final formulation contains salts (e.g., arginine HCl). In the presence of a salt (e.g., arginine HCl), the acetate does not co-enrich with tezeperumab, and therefore the acetate concentration in the DF buffer and the acetate concentration in the final composition are generally equivalent. Furthermore, excipients may be excluded by volume or may be affected by nonspecific interactions. For example, in a 110 mg / mL tezeperumab formulation, the proline concentration may be up to approximately 16.67% lower than the value indicated in the DF buffer, and in a 140 mg / mL tezeperumab formulation, the proline concentration may be up to approximately 10% to approximately 13.3% lower than the value indicated in the DF buffer. Considering the foregoing, the concentrations of the components of the final formulation are provided throughout the following examples, taking into account the above-mentioned excipient exclusion and acetate co-enrichment effects.

[0144] Example 1 This example illustrates an exemplary method for producing a high-concentration tezepermab formulation.

[0145] A series of studies were conducted to develop a formulation containing a high concentration of tezeperumab (e.g., >70 mg / mL). Since the formulation was intended for subcutaneous administration, it needed to be isotonic and exhibit a viscosity suitable for this route of administration. For example, a tezeperumab formulation (110 mg / mL) required a viscosity of approximately 15 cP at 23°C. It was also desirable that the formulation be stable after storage at 2°C–8°C for more than one year (e.g., at least two or three years).

[0146] To prepare a high-concentration tezeperumab formulation, a first solution containing tezeperumab (70 mg / mL) in acetate (pH 5.2) was dialyzed against diafiltration (DF) buffer. A total of 10 buffer exchanges were performed to achieve complete buffer exchange. Using a centrifugal concentrator, the exchanged tezeperumab solution was overconcentrated to a tezeperumab concentration of approximately 110% of the target tezeperumab concentration. For example, to achieve the target tezeperumab concentration of 180 mg / mL, the exchanged tezeperumab solution was overconcentrated to approximately 200 mg / mL. The overconcentrated solution was diluted to the target tezeperumab concentration using the same DF buffer used in the buffer exchange step.

[0147] Following the procedure described above, a series of tezeperumab formulations with various tezeperumab concentrations (ranging from approximately 150 mg / mL to approximately 250 mg / mL) were prepared for viscosity studies. Two DF buffers were used to prepare these formulations: a first DF buffer containing arginine salt (arginine glutamate) and a second DF buffer containing proline. Arginine was present in the DF buffer at 150 mM, and proline was present at 3% (w / v). Samples of each formulation were tested for viscosity using a rotational viscometer at 23°C. The reported viscosity values ​​were obtained at a shear rate of 1000 s. -1 It is located in [location / region].

[0148] Figure 1 provides the results of this assay in graph form. Figure 1 is a graph plotting the viscosity of each formulation as a function of tezeperumab concentration. As shown in this figure, viscosity increases with increasing tezeperumab concentration, regardless of the DF buffer used. The viscosity of formulations prepared using the first DF buffer was generally low, supporting the use of arginine salts in low-viscosity formulations of tezeperumab.

[0149] Since lysine is structurally similar to arginine in that both are basic amino acids, lysine glutamate was tested as an excipient to reduce viscosity and compared with formulations containing arginine glutamate. Each formulation contained approximately 195 mg / mL of tezepermab, and the DF buffer used to prepare the final formulation contained either 100 mM arginine glutamate or 100 mM lysine glutamate. Samples of each formulation were tested for viscosity using a rotational viscometer at 23°C. The reported viscosity values ​​were obtained at a shear rate of 1000 s. -1 The viscosity of the formulation containing lysine glutamate was 48.9 cP, and the viscosity of the formulation containing arginine glutamate was 35.3 cP. These data suggested that both basic amino acids or their salts were effective in reducing the viscosity of formulations containing high concentrations of tezeperumab.

[0150] Example 2 This example demonstrates the viscosity-reducing effect of various excipients on tezeperumab formulations.

[0151] Arginine and lysine functioned well to reduce the viscosity of formulations containing high concentrations of tezeperumab; therefore, tezeperumab samples were spiked with various arginine salts and lysine analogs, and the viscosity of these samples was then tested. The arginine salts used in this study were arginine hydrochloride, arginine acetate, and arginine glutamate. N-acetyllysine (NAK), a lysine analog, was tested together with lysine-containing samples. The effects of calcium and sodium salts on viscosity were also tested, particularly calcium chloride, calcium acetate, and sodium chloride.

[0152] Samples containing one of the above excipients were prepared by precisely spiking a concentrated (5-fold or 10-fold) stock solution containing one of the excipients into an aliquot of a concentrated tezeperumab solution. The concentrated tezeperumab solution was prepared by dialyzing an aqueous solution containing 110 mg / mL of tezeperumab in 10 mM sodium acetate, pH 4.4, using a dialysis tube with a molecular weight cutoff of 10,000, and then concentrating the dialyzed solution using an Amicon Ultra centrifugal concentrator, providing an aqueous composition containing 230 mg / mL or more of tezeperumab. This method produced sample sets with matched concentrations.

[0153] Before testing viscosity, the concentration of each sample was confirmed by UV absorbance gradient spectroscopy using Solo-VPE (C-Technologies) following a 5-fold weight dilution. Each sample was measured to have a tezepermab concentration of approximately 210 mg / mL. The concentration of each excipient in the sample was approximately 100 mM or approximately 150 mM. Figure 2 shows the concentrations of each excipient. The final pH of the samples was measured using a Seven Easy pH meter (Mettler Toledo).

[0154] Basically, the viscosity of each sample was tested as described in Example 1 and compared to a control sample that contained no excipients or contained proline or sucrose.

[0155] The results are shown in Figure 2. As shown in Figure 2, all samples containing arginine salt, lysine, or NAK showed lower viscosity than the control. Calcium acetate-containing samples showed lower viscosity compared to the control, while calcium chloride-containing samples showed the same viscosity as one of the controls (proline control). Sodium chloride and arginine HCl showed slightly better viscosity reduction performance. Samples containing chloride-containing excipients showed lower viscosity than the control, but these samples did not perform as well as chloride-free excipients.

[0156] Example 3 This example demonstrates the viscosity-reducing effect of various excipients in high-concentration tezepermab formulations.

[0157] Additional studies were conducted to test the viscosity-reducing effect of additional arginine salts. In these studies, each sample was measured to have a tezepermab concentration of approximately 190 mg / mL, and each sample contained 60 mM of one of the following excipients: arginine hydrochloride, arginine acetate, arginine glutamate, arginine propionate, arginine aspartate, arginine methanesulfonate, arginine glycolate, or arginine phosphate. In these studies, control samples without excipients were prepared and tested. Basically, samples were prepared as described in Examples 1 and 2 and tested for viscosity.

[0158] The results are shown in Figure 3. As shown in Figure 3, all samples containing arginine salts showed lower viscosity than the control. Among the arginine salt-containing samples, the sample containing arginine hydrochloride showed the highest viscosity, which is consistent with the data in Figure 2, and indicates that samples containing chloride-containing excipients generally do not function well as viscosity-reducing excipients.

[0159] Example 4 This example demonstrates the effect of combined excipients on viscosity.

[0160] Arginine acetate and calcium acetate worked well to reduce the viscosity of high-concentration tezepermab samples (Figure 2), so the effects of these excipients, either individually or in combination with other excipients, were analyzed. NAK, sodium acetate, and proline were combined with arginine acetate in three different tezepermab samples, and calcium acetate was combined with proline in another sample. As controls, samples without excipients or samples containing sodium acetate or proline were used. Furthermore, polyvinylpyrrolidone (PVP) was tested in various amounts ranging from 0.5% (w / v) to 3% (w / v) in this study. Each sample contained approximately 210 mg / mL of tezepermab and was prepared according to the procedure described in Example 2. A summary of the experiment is shown in Table 1.

[0161] [Table 1]

[0162] Viscosity was assayed essentially as described in Example 1.

[0163] The results are shown in Figure 4. As shown in Figure 4, combining proline or sodium acetate with arginine acetate resulted in lower viscosity compared to samples containing proline or sodium acetate as the sole excipient. Combining proline with calcium acetate also reduced viscosity compared to samples containing proline alone. Sodium acetate showed a viscosity-reducing effect only when combined with arginine acetate. Samples containing both arginine acetate and calcium acetate showed the lowest viscosity among all samples tested in this study. None of the tested concentrations of PVP had any effect on reducing the viscosity of the tezepermab samples.

[0164] An additional study was conducted to test arginine salts in combination with a second excipient. In this study, glycine and tris acetate were tested with and without arginine acetate. As controls, samples without excipients or samples containing proline or tris hydrochloride were used in this study. Furthermore, samples containing other arginine salts, arginine propionate, and arginine methanesulfonate were tested. In addition, samples containing tris hydrochloride were prepared and tested. Each sample contained approximately 210 mg / mL of tezepermab and was prepared according to the procedure described in Example 2. A summary of the excipients and their concentrations for each sample is shown in Table 2.

[0165] [Table 2]

[0166] The formulations were tested for viscosity and compared to control formulations that contained no excipients or 150 mM proline. Viscosity was assayed essentially as described in Example 1.

[0167] The viscosity results for each formulation are shown in Figure 5. As shown in the figure, combining arginine acetate with either tris acetate or glycine resulted in lower viscosity compared to samples containing only tris acetate or only glycine. Tris hydrochloride did not function effectively as a viscosity-reducing agent. This is consistent with previous studies suggesting that chloride-containing excipients do not adequately reduce the viscosity of high-concentration tezepermab samples.

[0168] Example 5 This example demonstrates the viscosity-reducing effect of several excipients on a sample containing a high concentration of tezepermab.

[0169] The basic amino acids arginine and lysine worked well to reduce the viscosity of formulations containing high concentrations of tezeperumab. In one study, samples containing histidine were used and compared with samples containing arginine salts. In particular, samples containing approximately 190 mg / mL of tezeperumab were prepared according to the procedure described in Example 2. The samples contained 60 mM histidine or 60 mM arginine salts (arginine hydrochloride, arginine glutamate, arginine propionate, arginine aspartate, arginine methanesulfonate, arginine glycolate, arginine phosphate). Samples containing 60 mM N-acetylarginine (NAR) or 60 mM methionine were also prepared. Basically, the viscosity of the formulations was tested as described in Example 1 and compared with a control formulation without excipients.

[0170] The results are shown in Figure 6. As shown in Figure 6, all arginine salts except arginine hydrochloride worked well to reduce the viscosity of high-concentration tezepermab samples. Histidine samples worked similarly to most arginine salts. NAR and Met-containing samples worked to reduce viscosity similarly to arginine hydrochloride.

[0171] Example 6 This embodiment demonstrates the viscosity-reducing effect of several combinations of excipients containing either arginine salts or calcium salts on samples containing high concentrations of tezepermab.

[0172] In a preliminary study, samples containing approximately 190 mg / mL of tezeperumab and 60 mM NAR, and samples containing approximately 190 mg / mL of tezeperumab and 60 mM methionine were prepared. The viscosity of each sample was measured basically as described in Example 1. As shown in Figure 7, NAR and methionine reduced the viscosity to less than 60 cP.

[0173] Arginine acetate and calcium acetate functioned well in reducing the viscosity of high-concentration tezeperumab formulations (Figure 2), so the effects of these excipients in combination with NAR or methionine were analyzed. For this purpose, a series of samples containing approximately 180 mg / mL or approximately 210 mg / mL of tezeperumab and arginine glutamate or calcium glutamate, alone, in combination with NAR or methionine, or in some cases in combination with both NAR and methionine, were prepared by ultrafiltration / diafiltration (UF / DF). The pH of each sample ranged from 5.1 to 5.3. Figure 8 shows the concentrations of each excipient in each sample, as well as the pH and viscosity of each sample.

[0174] As shown in Figure 8, the viscosity of samples containing low concentrations of tezeperumab was lower than that of samples containing high concentrations of tezeperumab. The viscosity of low-concentration tezeperumab samples ranged from approximately 22 cP to 30 cP, while the viscosity of high-concentration tezeperumab samples ranged from approximately 48 cP to 64 cP. In general, the viscosity of samples containing calcium glutamate was lower than that of samples containing arginine glutamate. At low concentrations of tezeperumab, the addition of NAR, methionine, or both further reduced the viscosity of the samples.

[0175] Example 7 This embodiment demonstrates the viscosity-reducing effect of several excipients on formulations containing high concentrations of tezepermab.

[0176] Samples containing approximately 210 mg / mL of tezeperumab and an arginine salt or another excipient known to reduce viscosity, namely β-alanine, sarcosine, and L-serine, were prepared according to the procedure described in Example 2. Each sample contained 150 mM of one of the following: β-alanine, sarcosine, L-serine, proline, or an arginine salt (arginine propionate, arginine aspartate, arginine methanesulfonate, arginine glycolate, or phosphate). The samples were tested for viscosity and compared to a control formulation containing no excipient or 150 mM proline. Viscosity was assayed essentially as described in Example 1.

[0177] The results are shown in Figure 9A. Consistent with previous studies, arginine salts worked well to reduce the viscosity of samples containing high concentrations of tezeperumab (Figure 9A). Viscosity ranged from approximately 45 cP to approximately 65 cP. None of β-alanine, sarcosine, or L-serine worked well to reduce the viscosity of the tezeperumab formulations (Figure 9A).

[0178] In another study, formulations containing approximately 195 mg / mL of tezepermab and betaine, taurine, or proline were prepared according to the procedure described in Example 2. The samples were tested for viscosity and compared to a control formulation without excipients. Viscosity was assayed essentially as described in Example 1.

[0179] The results are shown in Figure 9B. Consistent with previous studies, the samples containing arginine salts showed the greatest reduction in viscosity. The samples containing taurine had a slight effect on viscosity, which was slightly lower than that of the samples containing proline (Figure 9B). The samples containing betaine had no effect on viscosity (Figure 9B).

[0180] Example 8 This example demonstrates the effect of magnesium salts on the viscosity of high-concentration tezepermab samples.

[0181] Samples containing approximately 210 mg / mL of tezeperumab and 150 mM magnesium acetate were prepared according to the procedure described in Example 2. The samples were tested for viscosity and compared to control formulations containing no excipients or 150 mM proline. A sample containing 150 mM arginine acetate was also prepared as a positive control and tested for viscosity. To determine whether a larger amount of proline would be effective in reducing the viscosity of high-concentration tezeperumab samples, formulations containing 300 mM proline were prepared and tested. Viscosity was assayed essentially as described in Example 1.

[0182] The results are shown in Figure 10. As shown in this figure, magnesium acetate functioned similarly to arginine acetate, reducing the viscosity of the tezeperumab sample to just under 60 cP. Neither concentration of proline (150 mM or 300 mM) reduced the viscosity of the sample, similar to arginine acetate and magnesium acetate, although the viscosity of the proline-containing samples was lower than that of the control without excipients. These data suggest that magnesium salts have a viscosity-reducing effect on tezeperumab formulations.

[0183] Example 9 This example demonstrates the effect of histidine salts on the viscosity of high-concentration tezepermab.

[0184] Samples containing approximately 210 mg / mL of tezeperumab and an arginine salt, histidine salt, calcium salt, or a combination thereof were prepared according to the procedure described in Example 2. The arginine salts used in this study were arginine glycolate and arginine glutamate. The histidine salts used in this study were histidine glycolate and histidine glutamate. The calcium salt used in this study was calcium acetate. A summary of the excipients for each sample is shown in Table 3.

[0185] [Table 3]

[0186] The samples were tested for viscosity and compared to control formulations that contained no excipients or 150 mM proline. Viscosity was assayed essentially as described in Example 1.

[0187] The results are shown in Figure 11. As shown in this figure, all samples containing arginine salts, histidine salts, calcium salts, or combinations thereof reduced viscosity to less than 75 cP, while the control group showed viscosity above 100 cP.

[0188] Example 10 This example demonstrates the effect of arginine glycolate and arginine aspartate on the viscosity of high-concentration tezepermab formulations.

[0189] Samples containing approximately 210 mg / mL of tezeperumab and arginine glycolate (at concentrations of 50 mM, 75 mM, 125 mM, or 150 mM) or arginine aspartate (at concentrations of 50 mM, 75 mM, 125 mM, or 150 mM) were prepared according to the procedure described in Example 2. The samples were tested for viscosity and compared to controls that contained no excipients or 150 mM proline. Viscosity was assayed essentially as described in Example 1.

[0190] The results are shown in Figure 12. As shown in this figure, all samples containing arginine salts of any concentration reduced viscosity to less than 100 cP, while the control group showed a viscosity greater than 110 cP. Increasing the amount of arginine salt reduced viscosity, but the effect was greater with arginine glycolate.

[0191] This example demonstrated the viscosity-reducing effect of arginine salts by dose.

[0192] Example 11 This example demonstrates the effect of pH on the viscosity of high-concentration tezeperumab formulations.

[0193] Samples containing approximately 210 mg / mL of tezeperumab and either 150 mM arginine aspartate or 150 mM histidine acetate were prepared according to the procedure described in Example 2. For the arginine aspartate sample, the pH varied from 4.75 to 5.7, and for the histidine acetate sample, the pH varied from 5.5 to 6.5. The samples were tested for viscosity and compared to controls containing no excipients or 150 mM proline. Viscosity was assayed essentially as described in Example 1.

[0194] The results are shown in Figures 13A and 13B. As shown in these figures, the salts reduced viscosity to less than 50 cP (for histidine salts) or less than 60 cP (for arginine salts), and various pH levels did not adversely affect the viscosity reduction effect.

[0195] These data support the finding that formulations containing high concentrations of tezeperumab and arginine or histidine salts, with a pH of approximately 4.75 to 6.5, exhibit viscosity reduction.

[0196] Example 12 This example demonstrates the stability of a tezeperumab formulation containing arginine salt after storage at 40°C for one week.

[0197] A series of samples, each containing approximately 195 mg / mL of tezeperumab and 150 mM arginine salt, were prepared according to the procedure described in Example 2. The samples were tested for stability and compared to controls containing no excipients or 150 mM proline. For stability testing, samples were filled into containers and stored at 40°C for 1 week. Samples were tested via size exclusion chromatography (SEC) to measure their stability at various storage points. The percentage of high molecular weight (HMW) species in the samples was reported to reflect the amount of HMW species formed after the storage period. The results of the stability assay are shown in Table 4. The percentage of high molecular weight (HMW) species is shown for each sample. A lower %HMW indicated higher formulation stability.

[0198] [Table 4]

[0199] These data suggest that counterion identity affects HMW formation and, therefore, the stability of tezeperumab.

[0200] Example 13 This embodiment demonstrates the viscosity and stability of exemplary tezepermab formulations of the present disclosure after storage at -30°C, 5°C, and 25°C for up to 6 months.

[0201] To study the effects of high-concentration tezeperumab formulations on viscosity and stability during storage at various temperatures and durations, and to evaluate the robustness of formulations when subjected to stress during the formulation manufacturing process and related processes, four formulations were prepared containing a basic amino acid or its salt, calcium or magnesium salt, and approximately 180 mg / mL of tezeperumab. These formulations were then subjected to storage and / or one or more stress during the formulation manufacturing process and related processes (including stress from one or more freeze / thaw cycles, formulation pooling / mixing, bioburden reduction filtration, formulation holding, sterile filtration, filling, inspection, simulated labeling / packaging, and simulated transport).

[0202] For each formulation, the initial solution containing tezepermab was subjected to UF / DF using a specific diafiltration (DF) buffer. After UF / DF, a surfactant was added. Table 5 shows the components of each DF buffer used to achieve the desired result for the four formulations, as well as the amount of surfactant added after UF / DF. As a control, the fifth formulation (A5) was prepared using a DF buffer containing 10 mM acetate and 261 mM (3.0% (w / v)) L-proline pH 5.2, with the addition of the surfactant 0.010% (w / v) polysorbate 80 (PS80) after UF / DF.

[0203] [Table 5]

[0204] Calcium glutamate was prepared by combining calcium hydroxide with glutamate, and arginine glutamate was prepared by combining arginine base with glutamate (glutamate). The final pH was achieved by titration with glutamate and measured using a Seven Easy pH meter (Mettler Toledo). The tezeperumab concentration of each formulation was confirmed by UV absorbance gradient spectroscopy using Solo-VPE (C-Technologies) after a 5-fold weight dilution.

[0205] The final concentrations of specific components in the analyzed final formulation (e.g., stability, viscosity, and optionally, after storage) differ from those in the DF buffer. In such cases, components such as acetate, glutamate, and calcium are co-enriched with tezeperumab so that the final formulation contains higher concentrations of the component (e.g., acetate, glutamate, calcium) compared to the concentration in the DF buffer. For example, the concentration of glutamate in the DF buffer increases by up to 15% in a final formulation containing 180 mg / mL of tezeperumab, and the concentration of calcium in the DF buffer increases by up to 50% in a final formulation containing 180 mg / mL of tezeperumab.

[0206] Furthermore, excipients may be excluded by volume or may be affected by nonspecific interactions. For example, in a 110 mg / mL tezeperumab formulation, the proline concentration may be up to approximately 16.67% lower than the value indicated in DF buffer, and in a 140 mg / mL tezeperumab formulation, the proline concentration may be up to approximately 10% to approximately 13.3% lower than the value indicated in DF buffer. Also, for example, in a 180 mg / mL tezeperumab formulation, the proline concentration may be approximately 15% lower than the value indicated in DF buffer, and the arginine concentration may be approximately 40-45% lower than the value indicated in DF buffer.

[0207] The formulations in Table 5 were tested for viscosity and stability at storage, using a range of assays, or combinations thereof, used to evaluate product quality. Viscosity was measured using an AR-G2 cone-plate rheometer (TA instruments) at 23°C with a shear rate of 1000 1 / second. Unless otherwise specified, viscosity was measured in the absence of surfactants. For stability, samples of each formulation were filled into containers and then stored at temperatures ranging from approximately -30°C to approximately 40°C (e.g., -30°C, 5°C, 25°C, 40°C) for up to 6 months (e.g., 1 week, 2 weeks, 4 weeks, 3 months, 6 months). Samples were tested via size exclusion chromatography (SEC) to measure the stability of the formulations at various storage points. The percentage of high molecular weight (HMW) species and the percentage of the main peak for each formulation are reported. The percentage of the main peak reflects the amount of tezepermab (monomer form) remaining after the indicated storage period.

[0208] As shown in Figures 15A–15D and Figure 16, arginine glutamate (ArgGlu) and arginine glutamate proline (ArgGluPro) formulations offer optimal stability while maintaining reduced viscosity. A 6-month study conducted at temperatures of -30°C, 5°C, and 25°C confirmed that ArgGlu and ArgGluPro formulations exhibited minimal protein aggregation. ArgGlu and ArgGluPro formulations were also more stable than calcium glutamate (CaGlu) or calcium glutamate proline (CaGluPro) formulations under high stress at 40°C for 4 weeks.

[0209] Capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) is used to separate denatured protein size variants under non-reducing (nr) or reducing conditions (RCE-SDS). Under RCE-SDS, the release and stability of the heavy and light chains were measured. Under the test conditions, the release of the heavy and light chains was over 98%, and the stability of the heavy and light chains was over 96% (Figure 17).

[0210] Viscosity analysis showed that the ArgGlu and ArgGluPro formulations maintained a viscosity of less than 25 cP, approximately 20-22 cP or less (Figure 18).

[0211] Stability analysis at 6 months at temperatures of -30°C, 5°C, and 25°C confirmed that ArgGlu and ArgGluPro formulations exhibited minimal protein aggregation. Overall, these conditions indicate that arginine glutamate and arginine glutamate proline formulations are effective in reducing both the viscosity and protein aggregation of anti-TSLP antibody formulations.

[0212] Based on the results, Table 6 shows an exemplary range of possible excipients. The amounts of surfactants are those listed in Table 5. "Formulated with ~" refers to the amount of excipient in the diafiltration (DF) buffer. "Formulated in ~" refers to the final estimated concentration of the excipient after mixing, taking into account exclusion properties or co-concentration effects arising from the mixture.

[0213] [Table 6]

[0214] All references herein, including publications, patent applications, and patents, are incorporated herein by reference to the same extent as each reference is indicated to be incorporated herein by reference individually and specifically, and as if it were described in whole herein.

[0215] The use of the terms “one(a),” “one(an),” and “it,” and similar reference subjects in relation to the description of this disclosure (particularly in relation to the claims below), should be construed as encompassing both singular and plural unless otherwise indicated herein or unless explicitly stated otherwise or explicitly contradicted by the context. The terms “contains,” “have,” “includes,” and “contains” should be construed as open-ended terms (i.e., “contains but not limited to”) unless otherwise specified.

[0216] The enumeration of value ranges in this Specified Terms is intended only as a simplified way of referring individually to each of the distinct values ​​at each of these ranges and endpoints, unless otherwise indicated herein, and each of the distinct values ​​and endpoints is incorporated herein as if it were individually enumerated herein.

[0217] All methods described herein may be carried out in any suitable order, unless otherwise specified herein or unless it is clearly inconsistent with the context. The use of any examples or exemplary language provided herein (e.g., "etc.") is intended solely to clarify the disclosure and does not impose any limitation on the scope of the disclosure unless otherwise claimed. No language herein should be construed as indicating that any unclaimed element is essential for carrying out the disclosure.

[0218] This specification describes preferred embodiments of the Disclosure, including, for example, the best modes known to the inventors for carrying out the Disclosure. Variations of these preferred embodiments will be apparent to those skilled in the art by reading the above description. The inventors expect that those skilled in the art will adopt such variations as needed, and the inventors intend that the Disclosure will be carried out in forms other than those specifically described herein. Accordingly, this Disclosure includes all variations and equivalents of the subject matter enumerated in the claims appended to this Specification, as permitted by applicable law. Furthermore, any combination of the above elements is incorporated in this Disclosure in all possible variations, unless otherwise indicated herein or unless it is clearly inconsistent with the context. In certain embodiments, for example, the following items are provided: (Item 1) (a) an anti-TSLP antibody at a concentration greater than approximately 140 mg / mL, (b) a surfactant, and (c) at least one basic amino acid or a salt thereof, wherein the aqueous composition contains approximately 10 mM to approximately 200 mM of the basic amino acid or a salt thereof. (Item 2) The aqueous composition according to item 1, wherein the basic amino acid is arginine. (Item 3) An aqueous composition as described in item 2, comprising an organic salt of arginine. (Item 4) The aqueous composition according to item 3, wherein the arginine salt is arginine acetate, arginine aspartate, arginine glutamate, arginine glycolate, arginine lactate, arginine methanesulfonate, arginine propionate, or a combination thereof. (Item 5) The aqueous composition according to item 1, wherein the basic amino acid is histidine. (Item 6) An aqueous composition according to item 5, comprising an organic salt of histidine. (Item 7) The aqueous composition according to item 6, wherein the histidine salt is histidine acetate, histidine aspartate, histidine glutamate, histidine glycolate, histidine lactate, histidine methanesulfonate, histidine propionate, or a combination thereof. (Item 8) The aqueous composition according to item 1, wherein the basic amino acid is lysine. (Item 9) An aqueous composition according to item 8, comprising an organic salt of lysine. (Item 10) The aqueous composition according to item 9, wherein the lysine salt is lysine acetate, lysine aspartate, lysine glutamate, lysine glycolate, lysine lactate, lysine methanesulfonate, lysine propionate, or a combination thereof. (Item 11) (a) an anti-TSLP antibody in a concentration greater than approximately 140 mg / mL, (b) a surfactant, and (c) at least one calcium salt or magnesium salt, wherein the aqueous composition contains approximately 15 mM to approximately 150 mM of the calcium salt or magnesium salt. (Item 12) The aqueous composition according to item 12, wherein the calcium salt or magnesium salt contains a chloride-less counterion. (Item 13) The aqueous composition according to item 12, wherein the counterion is an acetate, aspartate, glutamate, glycolate, lactate, methanesulfonate, propionate, or a combination thereof. (Item 14) The aqueous composition according to item 13, wherein the calcium salt is calcium acetate, calcium aspartate, calcium glutamate, calcium glycolate, calcium lactate, calcium methanesulfonate, calcium propionate, or a combination thereof. (Item 15) The aqueous composition according to item 13, wherein the magnesium salt is magnesium acetate, magnesium aspartate, magnesium glutamate, magnesium glycolate, magnesium lactate, magnesium methanesulfonate, magnesium propionate, or a combination thereof. (Item 16) An aqueous composition according to any one of items 1 to 15, further comprising, optionally, N-acetylarginine (NAR), N-acetyllysine, methionine, glycine, proline, sodium acetate, trisacetate, histidine salt, or calcium salt, in an amount of about 50 mM to about 250 mM. (Item 17) The aqueous composition according to item 16, comprising an arginine salt and NAR or methionine or a combination thereof. (Item 18) The aqueous composition according to item 17, wherein the arginine salt is arginine glutamate. (Item 19) The aqueous composition according to item 18, comprising 25-190 mM arginine base and 25-200 mM glutamic acid. (Item 20) An aqueous composition according to item 18 or 19, comprising 140 mM arginine base and 150 mM glutamic acid. (Item 21) An aqueous composition according to any one of items 18 to 20, comprising 0 to 250 mM proline. (Item 22) The aqueous composition according to item 21, comprising 80 mM arginine base, 85 mM glutamic acid, and 100 mM L-proline. (Item 23) An aqueous composition according to any one of items 18 to 22, comprising 0.01% (w / v) of polysorbate 80. (Item 24) The composition according to item 23, comprising 140 mM arginine base, 150 mM glutamic acid, and 0.01% (w / v) polysorbate 80. (Item 25) The composition according to item 23, comprising 80 mM arginine base, 85 mM glutamic acid, 100 mM L-proline, and 0.01% (w / v) polysorbate 80. (Item 26) The aqueous composition according to item 18, comprising 10-125 mM arginine base and 25-225 mM glutamic acid. (Item 27) An aqueous composition according to item 18 or 26, comprising 95 mM arginine base and 170 mM glutamic acid. (Item 28) An aqueous composition according to any one of items 26 to 27, comprising 0 to 220 mM proline. (Item 29) The aqueous composition according to item 28, comprising 50 mM arginine base, 95 mM glutamic acid, and 85 mM L-proline. (Item 30) An aqueous composition according to any one of items 26 to 29, comprising 0.01% (w / v) of polysorbate 80. (Item 31) The aqueous composition according to item 30, comprising 95 mM arginine base, 170 mM glutamic acid, and 0.01% (w / v) polysorbate 80. (Item 32) The aqueous composition according to item 30, comprising 50 mM arginine base, 95 mM glutamic acid, 85 mM L-proline, and 0.01% (w / v) polysorbate 80. (Item 33) The aforementioned anti-TSLP antibody: (A) A light chain variable domain comprising (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, (B) A heavy chain variable domain comprising (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, An aqueous composition, including any one of items 1 to 32. (Item 34) The aforementioned anti-TSLP antibody: (A) Light chain variable domain, i. An amino acid sequence having at least 80% identity with SEQ ID NO: 12; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; or iii. A light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes with the complement of the polynucleotide represented by SEQ ID NO: 11 under moderately stringent conditions; or (B) Heavy chain variable domain, i. An amino acid sequence having at least 80% identity with SEQ ID NO: 10; ii. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; or iii. A heavy chain variable domain selected from the group consisting of amino acid sequences encoded by polynucleotides that hybridize under moderately stringent conditions with a complement of the polynucleotide consisting of SEQ ID NO: 9; or (C) The light chain variable domain of (A) and the heavy chain variable domain of (B) The aqueous composition according to item 33, comprising the same. (Item 35) The aqueous composition according to item 17, comprising a calcium salt and NAR or methionine or a combination thereof. (Item 36) The aqueous composition according to item 35, wherein the calcium salt is calcium glutamate. (Item 37) The aqueous composition according to item 36, comprising 15 to 130 mM of calcium and 30 to 300 mM of glutamate. (Item 38) The aqueous composition according to item 36 or 37, comprising 100 mM of calcium and 230 mM of glutamate. (Item 39) The aqueous composition according to any one of items 35 to 38, comprising 0 to 250 mM of proline. (Item 40) The aqueous composition according to item 39, comprising 60 mM of calcium, 140 mM of glutamate, and 70 mM of L-proline. (Item 41) The aqueous composition according to item 35, comprising 15 to 195 mM of calcium and 25 to 320 mM of glutamate. (Item 42) The aqueous composition according to item 35 or 41, comprising 110 mM of calcium and 240 mM of glutamate. (Item 43) The aqueous composition according to item 35 or any one of items 41 to 42, comprising 0 to 220 mM of proline. (Item 44) The aqueous composition according to item 43, comprising 70 mM of calcium, 145 mM of glutamate, and 60 mM of L-proline. (Item 4 An aqueous composition according to any one of items 35 to 44, comprising 0.01% (w / v) of polysorbate 80. (Item 46) The aqueous composition according to item 45, comprising 100 mM calcium, 230 mM glutamate, and 0.01% (w / v) polysorbate 80. (Item 47) The aqueous composition according to item 45, comprising 60 mM calcium, 140 mM glutamate, 70 mM L-proline, and 0.01% (w / v) polysorbate 80. (Item 48) The aqueous composition according to item 45, comprising 110 mM calcium, 240 mM glutamate, and 0.01% (w / v) polysorbate 80. (Item 49) The aqueous composition according to item 45, comprising 70 mM calcium, 145 mM glutamate, 60 mM L-proline, and 0.01% (w / v) polysorbate 80. (Item 50) The aforementioned anti-TSLP antibody: (A) A light chain variable domain comprising (i) a light chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 3, (ii) a light chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 4, and (iii) a light chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 5, (B) A heavy chain variable domain comprising (i) a heavy chain CDR1 sequence containing the amino acid sequence shown in SEQ ID NO: 6, (ii) a heavy chain CDR2 sequence containing the amino acid sequence shown in SEQ ID NO: 7, and (iii) a heavy chain CDR3 sequence containing the amino acid sequence shown in SEQ ID NO: 8, An aqueous composition, including any one of items 35 to 49. (Item 51) The aforementioned anti-TSLP antibody: (A) Light chain variable domain, iv. An amino acid sequence having at least 80% identity with SEQ ID NO: 12; v. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 11; or vi. A light chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes with the complement of the polynucleotide represented by SEQ ID NO: 11 under moderately stringent conditions; or (B) Heavy chain variable domain, iv. An amino acid sequence having at least 80% identity with SEQ ID NO: 10; v. An amino acid sequence encoded by a polynucleotide sequence having at least 80% identity with SEQ ID NO: 9; or vi. A heavy chain variable domain selected from the group consisting of an amino acid sequence encoded by a polynucleotide that hybridizes with the complement of the polynucleotide represented by SEQ ID NO: 9 under moderately stringent conditions; or (C)(A) light chain variable domain and (B) heavy chain variable domain The aqueous composition described in item 50, including the following: (Item 52) The aqueous composition according to any one of items 1 to 51, wherein the concentration of the anti-TSLP antibody is approximately 160 mg / mL to approximately 250 mg / mL. (Item 53) The aqueous composition according to item 52, wherein the concentration of the anti-TSLP antibody is approximately 165 mg / mL to approximately 225 mg / mL. (Item 54) The aqueous composition according to item 53, wherein the concentration of the anti-TSLP antibody is approximately 165 mg / mL to approximately 200 mg / mL. (Item 55) The aqueous composition according to item 54, wherein the concentration of the anti-TSLP antibody is approximately 175 mg / mL to approximately 185 mg / mL, and optionally approximately 180 mg / mL. (Item 56) The aqueous composition according to item 52, wherein the concentration of the anti-TSLP antibody is approximately 189 mg / mL to approximately 231 mg / mL. (Item 57) The aqueous composition according to item 52, wherein the concentration of the anti-TSLP antibody is from about 205 mg / mL to about 215 mg / mL, optionally about 210 mg / mL. (Item 58) The aqueous composition according to any one of items 1 to 57, having a pH of from about 4.5 to about 6.75. (Item 59) [[ID=S]]The aqueous composition according to item 58, having a pH of from about 4.8 to about 6.0. (Item 60) The aqueous composition according to item 59, comprising 25 to 190 mM of arginine base and 25 to 200 mM of glutamic acid. (Item 61) The aqueous composition according to item 59 or 60, comprising 140 mM of arginine base and 150 mM of glutamic acid. (Item 62) The aqueous composition according to any one of items 60 to 61, comprising 0 to 250 mM of proline. (Item 63) The aqueous composition according to item 62, comprising 80 mM of arginine base, 85 mM of glutamic acid, and 100 mM of L-proline. (Item 64) The aqueous composition according to any one of items 60 to 63, comprising 0.01% (w / v) of polysorbate 80 and having a pH of 5.4. [[ID=2?]] (Item 65) The aqueous composition according to item 60, comprising 140 mM of arginine base, 150 mM of glutamic acid, 0.01% (w / v) of polysorbate 80, and having a pH of 5.4. (Item 66) The aqueous composition according to item 60, comprising 80 mM of arginine base, 85 mM of glutamic acid, 100 mM of L-proline, 0.01% (w / v) of polysorbate 80, and having a pH of 5.4. (Item C?) The aqueous composition according to item 59, comprising 10 to 125 mM of arginine base and 25 to 225 mM of glutamic acid. (Item 68) The aqueous composition according to item 67, comprising 95 mM arginine base and 170 mM glutamic acid. (Item 69) An aqueous composition according to either item 67 or 68, comprising 0 to 220 mM proline. (Item 70) The aqueous composition according to item 69, comprising 50 mM arginine base, 95 mM glutamic acid, and 85 mM L-proline. (Item 71) An aqueous composition according to any one of items 67 to 70, comprising 0.01% (w / v) of polysorbate 80, pH 5.4. (Item 72) The aqueous composition described in item 71, comprising 95 mM arginine base, 170 mM glutamic acid, and 0.01% (w / v) polysorbate 80 at pH 5.4. (Item 73) The aqueous composition described in item 71, comprising 50 mM arginine base, 95 mM glutamic acid, 85 mM L-proline, and 0.01% (w / v) polysorbate 80 at pH 5.4. (Item 74) The aqueous composition according to item 59, comprising 15-130 mM calcium and 30-300 mM glutamate. (Item 75) The aqueous composition according to item 74, comprising 100 mM calcium and 230 mM glutamate. (Item 76) An aqueous composition according to either item 74 or 75, comprising 0 to 250 mM proline. (Item 77) The aqueous composition according to item 76, comprising 60 mM calcium, 140 mM glutamate, and 70 mM L-proline. (Item 78) The aqueous composition according to item 59, comprising 15-195 mM calcium and 25-320 mM glutamate. (Item 79) The aqueous composition according to item 78, comprising 110 mM calcium and 240 mM glutamate. (Item 80) An aqueous composition according to either item 78 or 79, comprising 0 to 220 mM proline. (Item 81) The aqueous composition according to item 80, comprising 70 mM calcium, 145 mM glutamate, and 60 mM L-proline. (Item 82) An aqueous composition according to any one of items 78 to 81, comprising 0.01% (w / v) of polysorbate 80, pH 5.0. (Item 83) The aqueous composition described in item 82, comprising 100 mM calcium, 230 mM glutamate, and 0.01% (w / v) polysorbate 80 at pH 5.0. (Item 84) The aqueous composition described in item 82, comprising 60 mM calcium, 140 mM glutamate, 70 mM L-proline, and 0.01% (w / v) polysorbate 80 at pH 5.0. (Item 85) The aqueous composition described in item 82, comprising 110 mM calcium, 240 mM glutamate, and 0.01% (w / v) polysorbate 80 at pH 5.0. (Item 86) The product described in item 82 contains 70 mM calcium, 145 mM glutamate, 60 mM L-proline, and 0.01% (w / v) polysorbate 80 at pH 5.0. Aqueous composition. (Item 87) The viscosity of the aqueous composition is 23°C, 1000s. -1 And an aqueous composition according to any one of items 1 to 86, having a concentration of less than 100 cP. (Item 88) The viscosity of the aqueous composition is 23°C, 1000s. -1 And, an aqueous composition as described in item 87, having a concentration of less than 75 cP. (Item 89) The viscosity of the aqueous composition is 23°C, 1000s.-1 And, an aqueous composition as described in item 88, having a concentration of less than 60 cP. (Item 90) The viscosity of the aqueous composition is 23°C, 1000s. -1 And, an aqueous composition as described in item 89, having a concentration of less than 50 cP. (Item 91) The aqueous composition according to any one of items 1 to 90, wherein the surfactant is amphiphilic and / or nonionic. (Item 92) The composition according to item 91, wherein the surfactant is a polysorbate. (Item 93) The composition according to item 92, wherein the surfactant is polysorbate 20 or polysorbate 80 or a mixture thereof. (Item 94) A composition according to any one of items 1 to 93, comprising a surfactant in a concentration of less than 0.005% (w / v) or between approximately 0.005% (w / v) and approximately 0.015% (w / v). (Item 95) The composition described in item 94, comprising approximately 0.010% (w / v) ± 0.0025% (w / v) of surfactant. (Item 96) The composition described in item 95, comprising approximately 0.005% (w / v), 0.010% (w / v), or 0.015% (w / v) of a surfactant. (Item 97) The composition according to any one of items 1 to 96, wherein the composition is isotonic or has an osmotic pressure in the range of about 200 mOsm / kg to about 500 mOsm / kg, about 225 mOsm / kg to about 400 mOsm / kg, or about 250 mOsm / kg to about 350 mOsm / kg. (Item 98) The composition according to any one of items 1 to 97, wherein the composition is isotonic or has an osmotic pressure greater than about 350 mOsm / kg. (Item 99) An aqueous composition according to any one of items 1 to 98, wherein less than 5% of the antibody is degraded after storage at 2°C to 8°C for at least or about 12 months, as determined by size exclusion chromatography (SEC). (Item 100) The aqueous composition according to item 99, wherein less than 5% of the antibody is degraded after storage at 2°C to 8°C for about 20 to 26 months, as determined by size exclusion chromatography (SEC). (Item 101) The aqueous composition according to item 100, wherein less than 5% of the antibody is degraded after storage at 2°C to 8°C for about 30 to about 40 months, as determined by size exclusion chromatography (SEC). (Item 102) The aqueous composition according to any one of items 1 to 101, wherein less than 5% of the antibody is degraded after storage at a temperature above 20°C for at least or about 2 weeks, or optionally, at least or about 4 weeks or 8 weeks, as determined by size exclusion chromatography (SEC). (Item 103) The aqueous composition according to item 102, wherein the temperature is greater than or about 25°C, greater than or about 30°C, or greater than or about 40°C. (Item 104) The aqueous composition according to any one of items 1 to 103, wherein the anti-TSLP antibody is an IgG2 antibody. (Item 105) The aqueous composition according to any one of items 33 to 104, wherein the anti-TSLP antibody comprises a heavy chain containing the amino acid sequence of SEQ ID NO: 13, a light chain containing the amino acid sequence of SEQ ID NO: 14, or a heavy chain containing the amino acid sequence of SEQ ID NO: 13 and a light chain containing the amino acid sequence of SEQ ID NO: 14. (Item 106) The aqueous composition according to any one of items 33 to 105, wherein the anti-TSLP antibody specifically binds to the TSLP polypeptide represented by amino acids 29 to 159 of SEQ ID NO: 2. (Item 107) The aqueous composition according to any one of items 1 to 106, wherein both binding sites of the anti-TSLP antibody have the same binding as TSLP. (Item 108) Optionally, a manufactured article comprising an aqueous composition described in any one of items 1 to 107, comprising approximately 1 mL to approximately 5 mL of the aqueous composition. (Item 109) A pre-filled syringe containing an aqueous composition as described in any one of items 1 to 107, optionally containing about 1 mL to about 5 mL of the aqueous composition. (Item 110) Optionally, a vial containing an aqueous composition as described in any one of items 1 to 107, comprising approximately 1 mL to approximately 5 mL of the aqueous composition. (Item 111) An auto-injector containing the aqueous composition of item 107. (Item 112) The auto-injector described in item 111, wherein the auto-injector is Ypsomed YpsoMate®. (Item 113) The auto-injector described in item 111 is disclosed in International Publication No. 2018 / 226565, No. 2019 / 094138, No. 2019 / 178151, No. 2012 / 072577, No. 2020 / 081479, No. 2020 / 081480, International Application No. PCT / US20 / 70590, Specification No. PCT / US20 / 70591, Specification No. PCT / US20 / 53180, Specification No. PCT / US20 / 53179, Specification No. PCT / US20 / 53178, or Specification No. PCT / US20 / 53176. (Item 114) Use of any one of the items 1 to 107 for the treatment of inflammatory diseases. (Item 115) The aforementioned inflammatory diseases include asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), nasal polyps, chronic urticaria, eosinophilic esophagitis (EoE), and Ig-induced diseases (IgA nephropathy and loop esophagitis). Use as described in item 114, selected from the group consisting of (e.g., nephritis), eosinophilic gastritis, chronic sinusitis without nasal polyps, and idiopathic pulmonary fibrosis (IPF). (Item 116) The use described in item 115, wherein the inflammatory disease is atopic dermatitis. (Item 117) A method for treating an inflammatory disease in a subject, comprising administering to the subject a therapeutically effective amount of an aqueous composition described in any one of items 1 to 107. (Item 118) The method according to item 117, wherein the inflammatory disease is selected from the group consisting of asthma, atopic dermatitis, chronic obstructive pulmonary disease (COPD), nasal polyps, chronic urticaria, eosinophilic esophagitis (EoE), Ig-induced diseases (such as IgA nephropathy and lupus nephritis), eosinophilic gastritis, chronic sinusitis without nasal polyps, and idiopathic pulmonary fibrosis (IPF). (Item 119) The method according to item 118, wherein the inflammatory disease is atopic dermatitis. (Item 120) The method according to any one of items 117 to 119, wherein the aqueous composition is administered to the subject by subcutaneous administration. (Item 121) The method according to any one of items 117 to 120, wherein approximately 10 mL to approximately 20 mL of the aqueous composition is administered to the subject. (Item 122) A method for producing a stable liquid antibody composition having a viscosity of less than approximately 100 cP and comprising (A) an anti-TSLP antibody at a concentration of more than approximately 140 mg / mL, (B) a surfactant, and (C) a basic amino acid or its salt, calcium salt, magnesium salt, or a combination thereof, wherein the method comprises (i) combining the antibody with an aqueous solution containing approximately 50 mM to approximately 150 mM of a basic amino acid or its salt, calcium salt, magnesium salt, or a combination thereof, and (ii) adding the surfactant to achieve a final surfactant concentration of approximately 0.01% (w / v) ± 0.005% (w / v).

Claims

[Claim 1] An aqueous composition comprising (a) an anti-TSLP antibody at a concentration greater than approximately 140 mg / mL, (b) a surfactant, and (c) at least one basic amino acid or a salt thereof, wherein the aqueous composition comprises approximately 10 mM to approximately 200 mM of the basic amino acid or a salt thereof.

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