Antibody Formulations

Abstract

Provided herein is a liquid composition comprising a monoclonal antibody at a high concentration, for example, greater than about 100 mg / mL, that exhibits storage stability and low viscosity. In an exemplary embodiment, the liquid composition comprises less than about 400 mM arginine glutamate, and in an alternative exemplary embodiment, the liquid composition comprises proline and a buffer.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS The benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 63 / 232,299, filed August 12, 2021, and U.S. Provisional Patent Application No. 63 / 316,604, filed March 4, 2022, is hereby claimed, the disclosures of which are incorporated herein by reference in their entireties.

[0002] Incorporation by Reference of Electronically Submitted Materials The computer readable nucleotide / amino acid sequence listing submitted contemporaneously herewith is incorporated by reference in its entirety and is identified as follows: 99.1 KB file entitled "A-2756-WO01-SEC_SeqListing.xml", created on July 19, 2022. [Background technology]

[0003] Higher concentrations of therapeutic proteins in drug formulations can cause problems. For example, formulations with high concentrations of protein can lead to aggregation resulting in the formation of high molecular weight (HMW) species. HMW species can be a concern in some protein formulations. Aggregation can also potentially affect the subcutaneous bioavailability and pharmacokinetics of therapeutic proteins, and can lead to loss of biological activity and increased immunogenicity of the protein. High concentration protein formulations can result in high viscosity, which can adversely affect the loading and administration of drug products.

[0004] Thus, there is a need in the art for highly concentrated formulations of antibodies that have low viscosity, high stability and low levels of aggregation. Summary of the Invention [Means for solving the problem]

[0005] Data is provided herein showing the initial stability, storage stability and low viscosity of high concentration antibody liquid compositions comprising arginine glutamate or proline. Advantageously, the liquid compositions are isotonic and therefore suitable for administration to a subject by injection or infusion. Surprisingly, the formulations provided herein contain lower amounts of arginine glutamate or proline compared to prior art formulations, while still retaining the desired properties with respect to initial aggregation, stability and viscosity. Thus, the present disclosure provides liquid compositions, e.g., isotonic liquid compositions, comprising a monoclonal antibody at a concentration of greater than about 100 mg / mL, arginine glutamate and a surfactant, and having a pH of about 4.5 to about 5.5. Also provided are liquid compositions, e.g., isotonic liquid compositions, comprising a monoclonal antibody at a concentration of greater than about 100 mg / mL, proline, a buffer and a surfactant, and having a pH of about 4.5 to about 5.5. In various embodiments, the concentration of the monoclonal antibody is less than about 300 mg / mL or less than about 250 mg / mL. In an exemplary embodiment, the liquid composition of the present disclosure comprises about 110 mg / mL to about 250 mg / mL of the monoclonal antibody. In various aspects, the concentration of the monoclonal antibody is about 120 mg / mL to about 180 mg / mL. Optionally, the liquid composition comprises about 120 mg / mL of the monoclonal antibody. In alternative aspects, the liquid composition comprises about 135 mg / mL to about 165 mg / mL of the monoclonal antibody or about 140 mg / mL to about 160 mg / mL of the monoclonal antibody. In a representative example, the liquid composition comprises about 140 mg / mL or about 150 mg / mL of the monoclonal antibody. In various aspects, the monoclonal antibody of the liquid composition of the present disclosure is an IgG1 antibody. Alternatively, in various examples, the monoclonal antibody of the liquid composition of the present disclosure is an IgG2 antibody. In an exemplary embodiment, the monoclonal antibody is an anti-IL-15 antibody, an anti-PD-1 antibody, an anti-RANKL antibody, or an anti-GITR antibody. Representative antibodies are described herein. In various embodiments, the liquid composition comprises about 200 mM to about 400 mM arginine glutamate. Optionally, the liquid composition comprises about 225 mM to about 350 mM arginine glutamate.In various examples, the liquid composition comprises about 250 mM to about 325 mM arginine glutamate, or about 200 mM to about 300 mM, or about 200 mM arginine glutamate. In various aspects, the monoclonal antibody is formulated with about 50 mM to about 300 mM arginine base, optionally about 85 mM to about 190 mM L-arginine. In various aspects, the monoclonal antibody is formulated with about 135 mM to about 165 mM arginine base. In various examples, the monoclonal antibody is formulated with about 155 mM to about 185 mM glutamic acid. In a representative example, the monoclonal antibody is formulated with about 150 mM arginine base and about 170 mM glutamic acid. In various examples, the monoclonal antibody is formulated with about 136 mM arginine base and about 159 mM glutamic acid. In various examples, the liquid composition comprises a molar ratio of arginine to glutamate of about 0.7:1.0 to about 1.1:1.0. For example, the molar ratio of arginine to glutamate is about 0.8:1.0 to about 1.1:1.0. In various embodiments, arginine and glutamate are the only amino acids present in the liquid composition. In a representative example, the liquid composition comprises (a) about 150 mg to about 165 mg of a monoclonal antibody, (b) about 22 mg to about 26 mg of L-arginine (e.g., about 24 mg to about 25 mg), (c) about 22 mg to about 26 mg of glutamate (e.g., about 23 mg to about 24 mg), and (d) about 0.01 mg of PS80, and the pH of the liquid composition is about 4.7 to about 5.3. In various examples, the liquid composition consists essentially of (a) to (d) or consists only of (a) to (d). For example, the liquid composition does not include an additional buffer or sugar. In an alternative exemplary embodiment, the liquid composition of the present disclosure comprises proline and a buffer instead of arginine glutamate. In various embodiments, the liquid composition comprises from about 200 mM to about 300 mM proline, optionally from about 225 mM to about 275 mM proline or from about 235 mM to about 265 mM. In various examples, the liquid composition comprises from about 240 mM to about 260 mM proline. In various embodiments, the proline is L-proline and / or proline is the only amino acid present in the liquid composition.In various embodiments, the buffer is selected from the group consisting of succinate, glutamate, histidine and acetate buffers. Preferably, the buffer is an acetate buffer, for example, an acetate buffer prepared with glacial acetic acid. In an exemplary embodiment, the buffer is prepared with about 1 mM to about 50 mM of buffering agent, optionally glacial acetic acid. In a representative example, the buffer is prepared with about 18 mM to about 22 mM of buffering agent, optionally 20 mM of glacial acetic acid. Optionally, the liquid composition comprises about 30 mM to about 38 mM of buffering agent, for example about 34 mM of acetate. The pH of the buffer in various embodiments is titrated with sodium hydroxide. In an exemplary embodiment, the surfactant is amphipathic and / or non-ionic, optionally a polysorbate. In a representative example, the surfactant is polysorbate 20 (PS20) or polysorbate 80 (PS80) or a mixture thereof. The liquid composition, in an exemplary embodiment, comprises a surfactant at a concentration of about 0.001% (w / v) to about 0.050% (w / v). Optionally, the surfactant is present at a concentration of about 0.005% (w / v) to about 0.025% (w / v) or about 0.01% (w / v) ± 0.001% (w / v) surfactant. In a preferred embodiment, the liquid composition comprises about 0.01% (w / v) polysorbate 80 (PS80). The pH of the liquid composition of the present disclosure is about 4.70 to about 5.30, optionally about 5.0. In an exemplary embodiment, the liquid composition contains (a) about 150 mg to about 165 mg of monoclonal antibody, (b) about 22 mg to about 26 mg of L-arginine, (c) about 22 mg to about 26 mg of glutamate, and (d) about 0.01 mg of PS80 per mL of liquid composition, and the pH of the liquid composition is about 4.7 to about 5.3. In various embodiments, the liquid composition contains about 150 mg to about 165 mg of monoclonal antibody per mL of liquid composition in about 180 mM to about 220 mM proline, about 30 mM to about 38 mM acetate, and about 0.01% (w / v) PS80, and the pH of the liquid composition is about 4.7 to about 5.3.In an exemplary embodiment, the liquid composition is an isotonic liquid composition in which less than about 5% of the antibody is degraded after storage at 2° C. to 8° C. for about 20 months to about 26 months as determined by size exclusion chromatography (SEC), and the liquid composition has a viscosity of 1000 s at 25° C. -1 and is less than 30 cP.

[0006] Further provided herein is a method of preparing a liquid composition comprising a target concentration of a monoclonal antibody that is greater than about 100 mg / mL. In an exemplary embodiment, the liquid composition is an isotonic liquid composition in which less than about 5% of the antibody is degraded after storage at 2° C. to 8° C. for about 20 months to about 26 months as determined by size exclusion chromatography (SEC), and the viscosity of the liquid composition is greater than about 1000 s at 25° C. -1 In an exemplary embodiment, the method includes (a) combining the monoclonal antibody with a diafiltration (DF) buffer comprising (i) about 50 mM to about 300 mM arginine base and (ii) an amount of glutamate to achieve a molar ratio of arginine to glutamate of about 0.7:1.0 to about 1.1:1.0 (e.g., about 0.8:1.0 to about 1.1:1.0), and (b) adding a surfactant. Optionally, the DF buffer comprises 85 mM to about 190 mM arginine. Optionally, the DF buffer comprises about 135 mM to about 165 mM arginine base. In a preferred embodiment, the DF buffer comprises about 155 mM to about 185 mM glutamate, e.g., about 150 mM arginine base and about 170 mM glutamate. In various examples, the pH of the DF buffer is about the same as the final pH of the prepared liquid composition. Optionally, the final pH of the prepared liquid composition is about 4.5 to about 5.5, optionally about 4.7 to about 5.3. In various examples, the surfactant is PS80 and / or is present at a final concentration of about 0.01% (w / v). Provided herein are liquid compositions prepared by the methods of the present disclosure.

[0007] The present disclosure further provides an article comprising any one of the isotonic liquid compositions of the present disclosure. Optionally, the article comprises about 1 mL to about 5 mL of the isotonic liquid composition.

[0008] Also provided is a pre-filled syringe containing any one of the isotonic liquid compositions of the present disclosure, optionally containing about 1 mL to about 5 mL of the present isotonic liquid composition.

[0009] Further provided by the present disclosure is a vial containing any one of the isotonic liquid compositions of the present disclosure. Optionally, the vial contains about 1 mL to about 5 mL of the isotonic liquid composition.

[0010] The present disclosure also provides an autoinjector comprising any one of the isotonic liquid compositions of the present disclosure.

[0011] The present disclosure provides a method for treating a disease in a subject. In an exemplary embodiment, the method comprises administering to the subject an isotonic liquid composition according to any one of the preceding claims in an amount effective to treat the disease. Further, the use of the isotonic liquid composition of the present disclosure for treating the disease is provided. [Brief description of the drawings]

[0012] [Figure 1] FIG. 1 is a graph of the % HMW species formed in a given antibody formulation with a given target antibody concentration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] The present disclosure provides liquid compositions containing high concentrations of antibodies, e.g., monoclonal antibodies. Collectively, antibodies form a family of plasma proteins known as immunoglobulins and contain immunoglobulin domains. (Janeway et al., Immunobiology: The Immune System in Health and Disease, 4 thed., Elsevier Science Ltd. / Garland Publishing, 1999). As used herein, the term "antibody" refers to a protein having the conventional immunoglobulin type, including heavy and light chains, and including variable and constant regions. For example, an antibody may be an IgG, which is a "Y-shaped" structure with two pairs of identical polypeptide chains, each pair having one "light" chain (usually having a molecular weight of about 25 kDa) and one "heavy" chain (usually having a molecular weight of about 50-70 kDa). An antibody has a variable region and a constant region. In the IgG type, the variable region is generally about 100-110 or more amino acids, includes three complementarity determining regions (CDRs), and is primarily responsible for antigen recognition and is substantially different from other antibodies that bind to different antigens. The constant region allows the antibody to recruit cells and molecules of the immune system. The variable region is made up of the N-terminal region of each light chain and heavy chain, while the constant region is made up of the C-terminal portion of each heavy chain and light chain (Janeway et al., "Structure of the Antibody Molecule and the Immunoglobulin Genes", Immunobiology: The Immune System in Health and Disease, 4 th ed.Elsevier Science Ltd. / Garland Publishing, (1999)).

[0014] The general structure and properties of antibody CDRs have been described in the art. Briefly, in the antibody scaffold, CDRs are embedded within frameworks in the variable regions of the heavy and light chains, where they constitute the regions largely involved in antigen binding and recognition. A variable region usually comprises at least three heavy or light chain CDRs (Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Public Health Service NIH, Bethesda, Md.; see also Chothia and Lesk, 1987, J. Mol. Biol. 196:901-917; Chothia et al., 1989, Nature 342:877-883), which are located within framework regions (referred to as framework regions 1-4, FR1, FR2, FR3 and FR4 by Kabat et al., 1991; see also Chothia and Lesk, 1987, supra).

[0015] The antibody may include any constant region known in the art. Human light chains are classified as kappa and lambda light chains. Heavy chains are classified as mu, delta, gamma, alpha, or epsilon, and the antibody isotypes are defined as IgM, IgD, IgG, IgA, and IgE, respectively. IgG has several subclasses, including but not limited to IgG1, IgG2, IgG3, and IgG4. IgM has subclasses, including but not limited to IgM1 and IgM2. The embodiments of the present disclosure include all such classes or isotypes of antibodies. The light chain constant region may be, for example, a kappa- or lambda-type light chain constant region, such as a human kappa- or lambda-type light chain constant region. The heavy chain constant region may be, for example, an alpha-, delta-, epsilon-, gamma-, or mu-type heavy chain constant region, such as a human alpha-, human delta-, human epsilon-, human gamma-, or human mu-type heavy chain constant region. Thus, in exemplary embodiments, the antibody is of the isotype IgA, IgD, IgE, IgG or IgM, including any one of IgG1, IgG2, IgG3 or IgG4.

[0016] The antibody may be a monoclonal antibody in a representative example. Thus, the present disclosure provides a liquid composition comprising a monoclonal antibody. Alternatively, the liquid composition may be a polyclonal antibody composition. In some embodiments, the antibody comprises a sequence substantially similar to a naturally occurring antibody produced by a mammal, such as a mouse, rabbit, goat, horse, chicken, hamster, human, etc. In this respect, the antibody may be considered a mammalian antibody, such as a mouse antibody, rabbit antibody, goat antibody, horse antibody, chicken antibody, hamster antibody, human antibody, etc. In certain aspects, the antibody is a human antibody. In certain aspects, the antibody is a chimeric antibody or a humanized antibody. The term "chimeric antibody" refers to an antibody that contains domains from two or more different antibodies. A chimeric antibody may, for example, contain a constant domain from one species and a variable domain from a second species, or more commonly, may contain stretches of amino acid sequences from at least two species. A chimeric antibody may also contain domains from two or more different antibodies within the same species. The term "humanized" when used in reference to an antibody refers to an antibody having at least the CDR regions from a non-human source that have been modified to have a structure and immune function more similar to a true human antibody than the original source antibody. For example, humanization can include grafting CDRs from a non-human antibody, such as a mouse antibody, onto a human antibody. Humanization can also include selecting amino acid substitutions to make the non-human sequence more similar to the human sequence.

[0017] In an exemplary embodiment, the antibody comprises: (a) a heavy chain (HC) complementarity determining region (CDR) 1 amino acid sequence set forth in Table A, or a variant sequence thereof that differs in only 1-4 amino acids (e.g., 1, 2, 3, 4 amino acids) or has at least 90% or about 90% sequence identity; (b) a HC CDR2 amino acid sequence set forth in Table A, or a variant sequence thereof that differs in only 1-4 amino acids or has at least 90% or about 90% sequence identity; (c) a HC CDR3 amino acid sequence set forth in Table A, or a variant sequence thereof that differs in only 1-4 amino acids or has at least 90% or about 90% sequence identity; (d) a light chain (LC) CDR1 amino acid sequence set forth in Table A, or a variant sequence thereof that differs in only 1-4 amino acids or has at least 90% or about 90% sequence identity; (e) a LC CDR2 amino acid sequence set forth in Table A, or a variant sequence thereof that differs in only 1-4 amino acids or has at least 90% or about 90% sequence identity; (f) a LC CDR3 amino acid sequence set forth in Table A, or a variant sequence thereof that differs in only 1-4 amino acids or has at least or about 90% sequence identity; or (g) a combination of two, three, four, five, or six of any of (a)-(f). In exemplary aspects, the antibody comprises at least one or two of the LC CDR1, LC CDR2, and LC CDR3 amino acid sequences set forth in Table A and the HC CDR amino acid sequences set forth in Table A. In exemplary aspects, the antibody comprises at least one or two of the HC CDR1, HC CDR2, and HC CDR3 amino acid sequences set forth in Table A and the LC CDR amino acid sequences set forth in Table A. In some embodiments, the antibody comprises all three such CDRs. In exemplary embodiments, the antibody comprises three, four, five or all six of the CDR amino acid sequences set forth in a single row of SEQ ID NO: in Table A. In representative examples, the antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2 and LC CDR3 of SEQ ID NO: 1-6, respectively.In various examples, the antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NOs: 11-16, respectively. In various embodiments, the antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NOs: 21-26, respectively. In a representative example, the antibody comprises HC CDR1, HC CDR2, HC CDR3, LC CDR1, LC CDR2, and LC CDR3 of SEQ ID NOs: 31-36, respectively. In an exemplary embodiment, the antibody comprises HC variable (var) region sequences and / or LC var region sequences as shown in Table A. In exemplary embodiments, the antibody comprises the HC var region sequence of SEQ ID NO:7 and / or the LC var region sequence of SEQ ID NO:8, the antibody comprises the HC var region sequence of SEQ ID NO:17 and / or the LC var region sequence of SEQ ID NO:18, the antibody comprises the HC var region sequence of SEQ ID NO:27 and / or the LC var region sequence of SEQ ID NO:28. In representative examples, the antibody comprises a full length (FL) HC and / or FL LC sequence as shown in Table A. In exemplary embodiments, the antibody comprises a FL HC of SEQ ID NO:9 and / or a FL LC of SEQ ID NO:10, a FL HC of SEQ ID NO:19 and / or a FL LC of SEQ ID NO:20, a FL HC of SEQ ID NO:29 and / or a FL LC of SEQ ID NO:30, or a FL HC of SEQ ID NO:31 and / or a FL LC of SEQ ID NO:32.

[0018] [Table 1]

[0019] In an exemplary embodiment, the antibody is an anti-IL-15 antibody described in the art. For example, the antibody is an anti-IL-15 antibody described in U.S. Patent No. 10,301,384, which in various embodiments is incorporated herein by reference. In various embodiments, the antibody comprises (i) a heavy chain variable region selected from SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:44, SEQ ID NO:53, SEQ ID NO:39, SEQ ID NO:40, SEQ ID NO:41, SEQ ID NO:42; SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:48, SEQ ID NO:49, SEQ ID NO:50, SEQ ID NO:51, SEQ ID NO:52, SEQ ID NO:54, and SEQ ID NO:55, and (ii) a light chain variable region selected from SEQ ID NO:56, SEQ ID NO:57, SEQ ID NO:58, SEQ ID NO:59, SEQ ID NO:60, and SEQ ID NO:61. Optionally, the antibody comprises the amino acid sequence of any one of SEQ ID NOs:62-64, 68, 71, and 72.

[0020] antibody concentration In exemplary embodiments, compositions of the present disclosure include an antibody at a concentration greater than about 100 mg / mL, and optionally less than about 450 mg / mL, less than about 400 mg / mL, about 350 mg / mL, less than about 300 mg / mL, or less than about 250 mg / mL. In various examples, the antibody may be present at a concentration of from about 110 mg / mL to about 300 mg / mL, e.g., from about 110 mg / mL to about 290 mg / mL, from about 110 mg / mL to about 280 mg / mL, from about 110 mg / mL to about 270 mg / mL, from about 110 mg / mL to about 260 mg / mL, from about 110 mg / mL to about 250 mg / mL, from about 110 mg / mL to about 240 mg / mL, from about 110 mg / mL to about 230 mg / mL, from about 110 mg / mL to about 220 mg / mL, or from about 110 mg / mL to about 260 mg / mL. / mL, about 110mg / mL to about 210mg / mL, about 110mg / mL to about 200mg / mL, about 110mg / mL to about 190mg / mL, about 110mg / mL to about 180mg / mL, about 110mg / mL to about 1 70mg / mL, about 110mg / mL to about 160mg / mL, about 110mg / mL to about 150mg / mL, about 110mg / mL to about 140mg / mL, about 110mg / mL to about 130mg / mL, about 110mg / mL ~120mg / mL, 120mg / mL~300mg / mL, 130mg / mL~300mg / mL, 140mg / mL~300mg / mL, 150mg / mL~300mg / mL, 160m g / mL~about 300mg / mL, about 170mg / mL~about 300mg / mL, about 180mg / mL~about 300mg / mL, about 190mg / mL~about 300mg / mL, about 200mg / mL~about 300mg / mL, about It is present in the composition at a concentration of 210 mg / mL to about 300 mg / mL, about 220 mg / mL to about 300 mg / mL, about 230 mg / mL to about 300 mg / mL, about 240 mg / mL to about 300 mg / mL, about 250 mg / mL to about 300 mg / mL, about 260 mg / mL to about 300 mg / mL, about 270 mg / mL to about 300 mg / mL, about 280 mg / mL to about 300 mg / mL, or about 290 mg / mL to about 300 mg / mL.In various examples, the concentration of the antibody is from about 120 mg / mL to about 250 mg / mL, optionally from about 120 mg / mL to about 240 mg / mL, from about 120 mg / mL to about 230 mg / mL, from about 120 mg / mL to about 220 mg / mL, from about 120 mg / mL to about 210 mg / mL, from about 120 mg / mL to about 200 mg / mL, from about 120 mg / mL to about 190 mg / mL, from about 120 mg / mL to about 180 mg / mL, from about 120 mg / mL to about 170 mg / mL, from about 120 mg / mL to about 160 mg / mL, from about 120 mg / mL to about 150 mg / mL, from about 120 mg / mL to about 140 mg / mL, from about 120mg / mL to about 130mg / mL, about 130mg / mL to about 250mg / mL, about 140mg / mL to about 250mg / mL, about 150mg / mL to about 250mg / mL, about 160mg / mL to about 250mg / mL, about 170mg / mL to about 250mg / mL, about 180mg / mL to about 250mg / mL, about 190mg / mL to about 250mg / mL, about 200mg / mL to about 250mg / mL, about 210mg / mL to about 250mg / mL, about 220mg / mL to about 250mg / mL, about 230mg / mL to about 250mg / mL, or about 240mg / mL to about 250mg / mL. In various examples, the concentration of the antibody in the liquid composition is about 160 mg / mL to about 250 mg / mL, for example, about 180 mg / mL to about 225 mg / mL or about 180 mg / mL to about 200 mg / mL. In some embodiments, the antibody is present in the composition at a concentration of about 130 mg / mL to about 225 mg / mL, about 130 mg / mL to about 220 mg / mL or about 130 mg / mL to about 200 mg / mL. In various examples, the antibody is present in the composition at a concentration of about 135 mg / mL to about 165 mg / mL, optionally about 140 mg / mL to about 160 mg / mL. In exemplary embodiments, the liquid composition comprises about 120 mg / mL of antibody, about 140 mg / mL, about 150 mg / mL or about 165 mg / mL. In exemplary embodiments, the liquid composition comprises about 150 mg / mL.

[0021] Arginine Glutamate In various examples, the liquid composition comprises greater than 10 mM or between about 10 mM and less than about 450 mM arginine glutamate, such as less than about 440 mM, less than about 430 mM, less than 420 mM, less than 410 mM arginine glutamate. In various embodiments, the liquid composition may be from about 10 mM to about 400 mM, from about 25 mM to about 400 mM, from about 50 mM to about 400 mM, from about 75 mM to about 400 mM, from about 100 mM to about 400 mM, from about 125 mM to about 400 mM, from about 150 mM to about 400 mM, from about 200 mM to about 300 mM, from about 200 mM to about 400 mM, from about 225 mM to about 350 mM or about 400 mM, from about 250 mM to about 325 mM or about 400 mM, from about 275 mM to about 400 mM, from about 300 mM to about 400 mM, from about 325 mM to about 400 mM, from about 350 mM about 10 mM to about 400 mM, about 375 mM to about 400 mM, about 10 mM to about 375 mM, about 10 mM to about 350 mM, about 10 mM to about 325 mM, about 10 mM to about 300 mM, about 10 mM to about 275 mM, about 10 mM to about 250 mM, about 10 mM to about 225 mM, about 10 mM to about 200 mM, about 10 mM to about 175 mM, about 10 mM to about 150 mM, about 10 mM to about 125 mM, about 10 mM to about 100 mM, about 10 mM to about 75 mM, about 10 mM to about 50 mM, or about 10 mM to about 25 mM arginine glutamate. In an exemplary embodiment, the liquid composition comprises at least or about 50 mM, at least or about 75 mM, at least or about 100 mM, and / or less than about 450 mM, less than about 400 mM, less than about 350 mM, less than about 300 mM, less than about 250 mM, or less than about 200 mM, of arginine glutamate. In a representative example, the liquid composition comprises about 75 mM to about 250 mM, about 100 mM to about 200 mM, or about 125 mM to about 175 mM, of arginine glutamate. In various examples, the liquid composition comprises about 200 mM of arginine glutamate.In an exemplary embodiment, the liquid composition has a concentration of about 250 mM to about 350 mM, for example, about 260 mM to about 350 mM, about 270 mM to about 350 mM, about 280 mM to about 350 mM, about 290 mM to about 350 mM, about 300 mM to about 350 mM, about 310 mM to about 350 mM, about 320 mM to about 350 mM, about 330 mM to about 350 mM, about 340 mM to about 350 mM, or about 360 mM to about 350 mM. The liquid composition may comprise from about 260 mM to about 340 mM or from about 270 mM to about 330 mM, from about 250 mM to about 350 mM, from about 250 mM to about 340 mM, from about 250 mM to about 330 mM, from about 250 mM to about 320 mM, from about 250 mM to about 310 mM, from about 250 mM to about 300 mM, from about 250 mM to about 290 mM, from about 250 mM to about 280 mM, from about 250 mM to about 270 mM, or from about 250 mM to about 260 mM of arginine glutamate. In an exemplary embodiment, the liquid composition comprises from about 260 mM to about 340 mM or from about 270 mM to about 330 mM of arginine glutamate. In various embodiments, the arginine glutamate is a salt comprising an arginine base and glutamic acid. In various embodiments, arginine glutamate is a salt comprising L-arginine base and L-glutamic acid. In various examples, arginine glutamate is a salt of arginine comprising a glutamate counterion. For purposes herein, the term "glutamate" refers to glutamate, its conjugate acid (glutamic acid), or a combination thereof. In various embodiments, the liquid composition comprises about 70 mM to about 210 mM arginine (also referred to herein as "arginine base") and about 80 mM to about 240 mM glutamate. In various embodiments, the composition comprises about 70 mM to about 210 mM arginine base and about 80 mM to about 240 mM glutamic acid. In various embodiments, the liquid composition comprises about 100 mM to about 170 mM arginine base, optionally about 120 mM to about 150 mM arginine base. In various embodiments, the arginine base is L-arginine base. In an exemplary embodiment, the liquid composition comprises about 136 mM arginine base. In an exemplary embodiment, the liquid composition comprises about 136 mM L-arginine base. In various embodiments, the liquid composition comprises about 120 mM to about 200 mM glutamate, optionally about 140 mM to about 175 mM glutamate. In an exemplary embodiment, the liquid composition comprises about 159 mM glutamate.In various embodiments, the composition of the present disclosure comprises about 120 mM to about 200 mM glutamic acid, e.g., L-glutamic acid, optionally about 140 mM to about 175 mM glutamic acid, e.g., L-glutamic acid. In an exemplary embodiment, the composition comprises about 159 mM glutamic acid, e.g., L-glutamic acid. In various examples, the liquid composition comprises about 100 mM to about 200 mM arginine and about 100 mM to about 200 mM glutamate. Optionally, the liquid composition comprises about 125 mM to about 175 mM arginine or about 125 to about 150 mM arginine and about 125 mM to about 200 mM glutamate or about 140 mM to about 185 mM glutamate. In various examples, the liquid composition comprises about 136 mM arginine base and about 159 mM glutamate. In various examples, the composition comprises about 100 mM to about 200 mM arginine and about 100 mM to about 200 mM glutamic acid. Optionally, the composition comprises about 125 mM to about 175 mM arginine, e.g., L-arginine base, or about 125 mM to about 150 mM arginine, e.g., L-arginine base, and about 125 mM to about 200 mM glutamic acid, e.g., L-glutamic acid, or about 140 mM to about 185 mM glutamic acid, e.g., L-glutamic acid. In various examples, the composition comprises about 136 mM L-arginine base and about 159 mM glutamic acid, e.g., L-glutamic acid. In various embodiments, the composition comprises about 120 mM to about 200 mM glutamic acid, optionally about 140 mM to about 175 mM glutamic acid. In an exemplary embodiment, the composition comprises about 159 mM glutamic acid. In various examples, the composition comprises about 100 mM to about 200 mM L-arginine base and about 100 mM to about 200 mM L-glutamic acid. Optionally, the composition comprises about 125 mM to about 175 mM L-arginine base or about 125 to about 150 mM L-arginine base and about 125 mM to about 200 mM L-glutamic acid or about 140 mM to about 185 mM L-glutamic acid. In various examples, the composition comprises about 136 mM L-arginine base and about 159 mM L-glutamic acid.

[0022] In various embodiments, the antibody is formulated with about 25 mM to about 190 mM arginine (e.g., L-arginine base) and about 25 mM to about 200 mM glutamic acid (e.g., L-glutamic acid). For purposes herein, the specified amount of excipient following "formulated with" refers to the amount of the specified excipient in the DF buffer used in preparing the liquid composition comprising the monoclonal antibody. Thus, an antibody formulated with about 25 mM to about 190 mM arginine and about 25 mM to about 200 mM glutamic acid, in various embodiments, means that the DF buffer into which the antibody was replaced or combined contained about 25 mM to about 190 mM arginine and about 25 mM to about 200 mM glutamic acid. In various examples, the antibodies are formulated with about 50 mM to about 300 mM arginine, or 85 mM to about 190 mM arginine. In various aspects, the antibodies are formulated with 100 mM to about 180 mM arginine (e.g., about 100 mM to about 170 mM, about 100 mM to about 160 mM, about 100 mM to about 150 mM, about 100 mM to about 140 mM, about 100 mM to about 130 mM, about 100 mM to about 120 mM, about 100 mM to about 110 mM, about 110 mM to about 180 mM, about 120 mM to about 180 mM, about 130 mM to about 180 mM, about 140 mM to about 180 mM, about 150 mM to about 180 mM, about 160 mM to about 180 mM, about 170 mM to about 180 mM, about 120 mM to about 170 mM, about 130 mM to about 160 mM, about 135 mM to about 155 mM, or about 135 mM to about 165 mM) and about 110 mM 110 mM to about 240 mM glutamic acid (e.g., about 110 mM to about 180 mM, about 110 mM to about 170 mM, about 110 mM to about 160 mM, about 110 mM to about 150 mM, about 110 mM to about 140 mM, about 110 mM to about 130 mM, about 110 mM to about 120 mM, about 120 mM to about 180 mM, about 130 mM to about 180 mM, about 40 mM to about 180 mM, about 150 mM to about 180 mM, about 160 mM to about 180 mM, about 170 mM to about 180 mM, about 120 mM to about 170 mM, about 130 mM to about 160 mM, about 140 mM to about 160 mM, about 145 mM to about 155 mM glutamic acid, or about 155 mM to about 185 mM glutamic acid).In various examples, the antibody is formulated with about 135 mM to about 165 mM arginine and about 145 mM to about 185 mM glutamic acid.

[0023] In various examples, the antibody is formulated in about 10 mM to about 125 mM arginine and about 25 mM to about 225 mM glutamate. For purposes herein, the specified amount of excipient following "formulated in" refers to the amount of the specified excipient in the liquid composition comprising the monoclonal antibody. Thus, an antibody formulated in about 10 mM to about 125 mM arginine and about 25 mM to about 225 mM glutamate, in various examples, means that the liquid composition comprises the antibody and about 10 mM to about 125 mM arginine and about 25 mM to about 225 mM glutamate. In various embodiments, the antibody is administered in the presence of about 55 mM to about 135 mM arginine (e.g., about 55 mM to about 125 mM, about 55 mM to about 115 mM, about 55 mM to about 105 mM, about 55 mM to about 95 mM, about 55 mM to about 85 mM, about 55 mM to about 75 mM, about 55 mM to about 65 mM, about 65 mM to about 135 mM). arginine) and about 130 mM to about 210 mM Glutamate (e.g., about 130 mM to about 200 mM, about 130 mM to about 240 mM, about 130 mM to about 180 mM, about 130 mM to about 170 mM, about 130 mM to about 160 mM, about 130 mM to about 150 mM, about 130 mM to about 140 mM, about 140 mM to about 210 mM, about 150 mM to about 2 In various examples, the composition comprises the antibody and about 10 mM to about 125 mM arginine base, e.g., L-arginine base, and about 25 mM to about 225 mM glutamic acid, e.g., L-glutamic acid.In various embodiments, the antibodies may be administered with about 55 mM to about 135 mM L-arginine base (e.g., about 55 mM to about 125 mM, about 55 mM to about 115 mM, about 55 mM to about 105 mM, about 55 mM to about 95 mM, about 55 mM to about 85 mM, about 55 mM to about 75 mM, about 55 mM to about 65 mM, about 65 mM to about about 130 mM to about 210 mM, about 135 mM, about 75 mM to about 135 mM, about 85 mM to about 135 mM, about 95 mM to about 135 mM, about 105 mM to about 135 mM, about 115 mM to about 145 mM, about 125 mM to about 135 mM, about 75 mM to about 115 mM, about 85 mM to about 105 mM L-arginine base) and about 130 mM to about 210 mM 0 mM glutamic acid (e.g., about 130 mM to about 200 mM, about 130 mM to about 240 mM, about 130 mM to about 180 mM, about 130 mM to about 170 mM, about 130 mM to about 160 mM, about 130 mM to about 150 mM, about 130 mM to about 140 mM, about 140 mM to about 210 mM, about 150 mM to about 210 mM, about 160 mM to about 210 mM, about 170 mM to about 210 mM, about 180 mM to about 210 mM, about 190 mM to about 210 mM, about 200 mM to about 210 mM, about 150 mM to about 190 mM, about 160 mM to about 180 mM, or about 165 mM to about 175 mM L-glutamic acid.

[0024] In various embodiments, the antibody is formulated with about 70 mM to about 210 mM arginine and about 80 mM to about 240 mM glutamic acid. In various embodiments, the antibody is formulated with about 100 mM to about 170 mM arginine base, optionally about 120 mM to about 150 mM arginine base. In an exemplary embodiment, the antibody is formulated with about 136 mM arginine base. In various embodiments, the antibody is formulated with about 120 mM to about 200 mM glutamic acid, optionally about 140 mM to about 175 mM glutamic acid. In an exemplary embodiment, the antibody is formulated with about 159 mM glutamic acid. In various embodiments, the glutamic acid is L-glutamic acid. In various examples, the antibody is formulated with about 100 mM to about 200 mM arginine and about 100 mM to about 200 mM glutamic acid. Optionally, the antibody is formulated with about 125 mM to about 175 mM arginine or about 125 mM to about 150 mM arginine and about 125 mM to about 200 mM glutamic acid or about 140 mM to about 185 mM glutamic acid. In various examples, the antibody is formulated with 150 mM arginine base and about 170 mM glutamic acid. In various aspects, the arginine glutamate present in the liquid composition is made with about 25 mM to about 190 mM arginine and about 25 mM to about 200 mM glutamic acid.In various embodiments, the antibody may be administered in the presence of 100 mM to about 180 mM arginine (e.g., about 100 mM to about 170 mM, about 100 mM to about 160 mM, about 100 mM to about 150 mM, about 100 mM to about 140 mM, about 100 mM to about 130 mM, about 100 mM to about 120 mM, about 100 mM to about 110 mM, about 110 mM to about 120 mM, about 120 mM to about 130 mM, about 130 mM to about 140 mM, about 140 mM to about 150 mM, about 150 mM to about 160 mM, about 160 mM to about 170 mM, about 170 mM to about 180 mM, about 180 mM to about 190 mM, about 190 mM to about 200 mM, about 200 mM to about 210 mM, about 210 mM to about 220 mM, about 220 mM to about 230 mM, about 230 mM to about 240 mM, about 240 mM to about 250 mM, about 250 mM to about 260 mM, about 260 mM to about 270 mM, about 270 mM to about 280 mM, about 280 mM to about 290 mM, about 290 mM to about 300 mM, about 290 mM to about 310 mM, about 290 mM to about 320 mM, about 290 mM to about 330 mM, about 290 mM to about 340 mM, about 290 mM to about 350 mM, about 290 mM to about 360 mM, about 290 mM to about 370 mM, about 290 mM to about 380 mM, M ~ about 180mM, about 120mM - about 180mM, about 130mM - about 180mM, about 140mM - about 180mM, about 150mM - about 180mM, about 160 180mM to about 180mM, about 170mM to about 180mM, about 120mM to about 170mM, about 130mM to about 160mM, about 135mM to about 155mM) and about 1 10 mM to about 240 mM glutamic acid (e.g., about 110 mM to about 180 mM, about 110 mM to about 170 mM, about 110 mM to about 160 mM, about 110 mM to about 150 mM, about 110 mM to about 140 mM, about 110 mM to about 130 mM, about 110 mM to about 120 mM, about 120 mM to about 180 mM, about 130 mM to about 140 mM, about 110 mM to about 150 mM, about 110 mM to about 160 mM, about 110 mM to about 170 mM, about 110 mM to about 180 mM, about 130 mM to about 180 mM, about 130 mM to about 190 mM, about 190 mM to about 200 mM, about 200 mM to about 210 mM, about 200 mM to about 220 mM, about 200 mM to about 230 mM, about 200 mM to about 240 mM, about 200 mM to about 250 mM, about 200 mM to about 260 mM, about 200 mM to about 270 mM, about 200 mM to about 280 mM, about 200 mM to about 290 mM, about 200 mM to about 300 mM, about 200 mM to about 310 mM, about 200 mM to about 320 mM, about 200 mM to about 330 mM, about 200 mM to about 340 mM, about 200 mM to about 350 mM, about 200 mM to about 360 mM, about 200 mM to about 370 mM, about 200 mM to about 380 mM, about 200 mM to about 390 mM, The liquid composition is formulated with about 135 mM to about 145 mM arginine and about 145 mM to about 155 mM glutamic acid). In various examples, the arginine glutamate present in the liquid composition is made with about 70 mM to about 210 mM arginine base and about 80 mM to about 240 mM glutamic acid. In various embodiments, the arginine glutamate present in the liquid composition is made with about 100 mM to about 170 mM arginine base, or about 120 mM to about 150 mM arginine base and about 120 mM to about 200 mM glutamic acid, or about 140 mM to about 175 mM glutamic acid. In various embodiments, the arginine glutamate present in the liquid composition is made with about 136 mM arginine base and about 159 mM glutamic acid.

[0025] In various examples, the antibody is formulated in about 10 mM to about 125 mM arginine and about 25 mM to about 225 mM glutamate. In various aspects, the liquid composition is formulated in about 55 mM to about 135 mM arginine (e.g., about 55 mM to about 125 mM, about 55 mM to about 115 mM, about 55 mM to about 105 mM, about 55 mM to about 95 mM, about 55 mM to about 85 mM, about 55 mM to about 75 mM, about 55 mM to about 65 mM, about 65 mM to about about 135 mM, about 75 mM to about 135 mM, about 85 mM to about 135 mM, about 95 mM to about 135 mM, about 105 mM to about 135 mM, about 115 mM to about 145 mM, about 125 mM to about 135 mM, about 75 mM to about 115 mM, about 85 mM to about 105 mM arginine) and about 130 mM to about 210 mM 130 mM to about 200 mM, about 130 mM to about 240 mM, about 130 mM to about 180 mM, about 130 mM to about 170 mM, about 130 mM to about 160 mM, about 130 mM to about 150 mM, about 130 mM to about 140 mM, about 140 mM to about 210 mM, about 150 mM In various embodiments, the antibody comprises from about 70 mM to about 210 mM arginine base and from about 80 mM to about 240 mM glutamate. In various embodiments, the antibody is formulated in about 100 mM to about 170 mM arginine base, or about 120 mM to about 150 mM arginine base and about 120 mM to about 200 mM glutamate, or about 140 mM to about 175 mM glutamate. In various embodiments, the antibody is formulated in about 136 mM arginine base and about 159 mM glutamate. In various examples, the antibody is formulated in about 10 mM to about 125 mM arginine and about 25 mM to about 225 mM glutamate.In various embodiments, the liquid composition comprises about 55 mM to about 135 mM arginine (e.g., about 55 mM to about 125 mM, about 55 mM to about 115 mM, about 55 mM to about 105 mM, about 55 mM to about 95 mM, about 55 mM to about 85 mM, about 55 mM to about 75 mM, about 55 mM to about 65 mM, about 65 mM to about 1 about 35 mM, about 75 mM to about 135 mM, about 85 mM to about 135 mM, about 95 mM to about 135 mM, about 105 mM to about 135 mM, about 115 mM to about 145 mM, about 125 mM to about 135 mM, about 75 mM to about 115 mM, about 85 mM to about 105 mM L-arginine base) and about 130 mM to about 21 0 mM L-glutamic acid (e.g., about 130 mM to about 200 mM, about 130 mM to about 240 mM, about 130 mM to about 180 mM, about 130 mM to about 170 mM, about 130 mM to about 160 mM, about 130 mM to about 150 mM, about 130 mM to about 140 mM, about 140 mM to about 210 mM, about 150 mM In various embodiments, the antibody comprises from about 70 mM to about 210 mM arginine base and from about 80 mM to about 240 mM glutamic acid. In various embodiments, the antibody is formulated in about 100 mM to about 170 mM arginine base, or about 120 mM to about 150 mM arginine base and about 120 mM to about 200 mM glutamic acid, or about 140 mM to about 175 mM glutamic acid. In various embodiments, the antibody is formulated in about 136 mM arginine base and about 159 mM glutamic acid.

[0026] In an exemplary embodiment, the liquid composition of the present disclosure comprises, per mL of liquid composition, (a) about 150 mg to about 165 mg of monoclonal antibody, (b) about 22 mg to about 26 mg of L-arginine, (c) about 22 mg to about 26 mg of glutamate, and (d) about 0.01 mg of PS80, the liquid composition having a pH of about 4.7 to about 5.3 and 0.01% (w / v) polysorbate 80. In various embodiments, the arginine is L-arginine. In an exemplary embodiment, the glutamate is L-glutamate. In an exemplary embodiment, a composition of the disclosure comprises, per mL of liquid composition, (a) about 150 mg to about 165 mg of monoclonal antibody, (b) about 22 mg to about 26 mg of L-arginine base, (c) about 22 mg to about 26 mg of L-glutamic acid, and (d) about 0.01 mg of PS80, the liquid composition having a pH of about 4.7 to about 5.3 and 0.01% (w / v) polysorbate 80. Optionally, the pH is about 4.7 to about 5.3. In an exemplary embodiment, the liquid composition of the present disclosure contains, per mL of the liquid composition, (i) about 135 mg to about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, a HC CDR2 of SEQ ID NO: 2, a HC CDR3 of SEQ ID NO: 3, a light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, a LC CDR2 of SEQ ID NO: 5, and a LC CDR3 of SEQ ID NO: 6, (ii) about 21 mg to about 26 mg of arginine base, (iii) about 21 mg to about 26 mg of glutamate, and (iv) about 0.01 mg of PS80, and the pH of the liquid composition is about 4.5 to about 5.5. Optionally, the pH is about 4.7 to about 5.3. In various embodiments, the arginine is L-arginine. In an exemplary embodiment, the glutamate is L-glutamate.In an exemplary embodiment, the composition of the present disclosure comprises (i) about 135 mg to about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, a HC CDR2 of SEQ ID NO: 2, a HC CDR3 of SEQ ID NO: 3, a light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, a LC CDR2 of SEQ ID NO: 5, and a LC CDR3 of SEQ ID NO: 6, (ii) about 21 mg to about 26 mg of L-arginine base, (iii) about 21 mg to about 26 mg of L-glutamic acid, and (iv) about 0.01 mg of PS80, and the pH of the liquid composition is about 4.5 to about 5.5. Optionally, the pH is about 4.7 to about 5.3. In an exemplary embodiment, the liquid composition of the present disclosure comprises, per mL of liquid composition, (i) about 150 mg of oldesekimab, (ii) about 23.6 mg of arginine base, (iii) about 23.4 mg of glutamic acid, and (iv) about 0.01% (w / v) polysorbate 80 (PS80), and the pH of the liquid composition is about 5.0. In an exemplary embodiment, the composition of the present disclosure comprises (i) about 150 mg of oldesekimab, (ii) about 23.6 mg of L-arginine base, (iii) about 23.4 mg of L-glutamic acid, and (iv) about 0.01% (w / v) polysorbate 80 (PS80), and the pH of the liquid composition is about 5.0. Oldesekimab comprises HC CDR1-CDR3 of SEQ ID NOs: 1-3, respectively, and LC CDR1-CDR3 of SEQ ID NOs: 4-6, respectively. Oldecekimab comprises a heavy chain variable region comprising the sequence of SEQ ID NO: 7 and a light chain variable region of SEQ ID NO: 8. Oldecekimab also comprises a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10. In an exemplary embodiment, the liquid composition of the present disclosure comprises about 150 mg or about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, a HC CDR2 of SEQ ID NO: 2, a HC CDR3 of SEQ ID NO: 3, a light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, a LC CDR2 of SEQ ID NO: 5, and a LC CDR3 of SEQ ID NO: 6, formulated in a solution comprising about 21 mg to about 26 mg of arginine base, about 21 mg to about 26 mg of glutamate, and about 0.01 mg of PS80 per mL of liquid composition, and the pH of the liquid composition is about 4.5 to about 5.5.In an exemplary embodiment, the liquid composition of the present disclosure comprises about 150 mg or about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, a HC CDR2 of SEQ ID NO: 2, a HC CDR3 of SEQ ID NO: 3, a light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, a LC CDR2 of SEQ ID NO: 5, and a LC CDR3 of SEQ ID NO: 6, formulated with a solution comprising about 21 mg to about 26 mg of arginine base, about 21 mg to about 26 mg of glutamic acid, and about 0.01 mg of PS80 per mL of liquid composition, and the pH of the liquid composition is about 4.5 to about 5.5.

[0027] Proline In an exemplary embodiment, the liquid composition of the present disclosure includes proline, e.g., L-proline, D-proline. In an exemplary aspect, the liquid composition of the present disclosure includes L-proline. In some aspects, proline is the only amino acid present in the composition. In various embodiments, the liquid composition includes about 50 mM to about 400 mM proline or about 100 mM to about 350 mM proline. In an exemplary aspect, the liquid composition of the present disclosure includes about 115 mM to about 345 mM proline. In a representative example, the liquid composition of the present disclosure includes about 170 mM to about 290 mM proline, optionally about 200 mM to about 255 mM proline, e.g., about 230 mM proline. In an exemplary aspect, the liquid composition of the present disclosure includes about 100 mM to about 300 mM L-proline. Optionally, the liquid composition comprises from about 75 mM to about 400 mM, from about 100 mM to about 400 mM, from about 125 mM to about 400 mM, from about 150 mM to about 400 mM, from about 175 mM to about 400 mM, from about 200 mM to about 400 mM, from about 225 mM to about 400 mM, from about 250 mM to about 400 mM, from about 275 mM to about 400 mM, from about 300 mM to about 400 mM, from about 325 mM to about 400 mM, from about 350 mM to about 400 mM, from about 3 including 75 mM to about 400 mM, about 50 mM to about 375 mM, about 50 mM to about 350 mM, about 50 mM to about 325 mM, about 50 mM to about 300 mM, about 50 mM to about 275 mM, about 50 mM to about 250 mM, about 50 mM to about 225 mM, about 50 mM to about 200 mM, about 50 mM to about 175 mM, about 50 mM to about 150 mM, about 50 mM to about 125 mM, about 50 mM to about 100 mM, or about 50 mM to about 75 mM. In various examples, the concentration of proline in the liquid composition is about 200 mM to about 300 mM, about 225 mM to about 275 mM, about 235 mM to about 265 mM, or about 240 mM to about 260 mM. In various embodiments, the liquid composition comprises at least about 50 mM or at least or about 100 mM and less than about 260 mM proline.

[0028] In exemplary embodiments in which the liquid composition includes proline, the isotonic liquid composition also includes a buffer. The buffer can be, for example, an organic buffer. The buffer, in some aspects, is centered around, for example, pH 4.0-6.0, or 4.5-5.5, or 4.2, or 5.7 at 25° C. In various embodiments, the buffer can have a pKa within 1 pH unit of pH 5.0-5.2 at 25° C. One such buffer is acetic acid / acetate, which has a pKa of about 4.75 at 25° C. Other alternative buffers contemplated include ion-based buffers including succinate (pKa of 4.21 at 25° C.), propionate (pKa of 4.87 at 25° C.), malate (pKa of 5.13 at 25° C.), pyridine (pKa of 5.23 at 25° C.), and piperazine (pKa of 5.33 at 25° C.). It is contemplated that the buffer may be provided as a sodium salt (or disodium salt as appropriate), or in the alternative, as a potassium, magnesium, or ammonium salt. In various embodiments, the buffer is a succinate, glutamate, histidine, or acetate buffer, or a combination thereof. Acetate-based buffers are particularly contemplated. In some embodiments, the buffer is made with glacial acetic acid, and optionally the pH of the buffer is achieved by adding sodium hydroxide until the target pH or final pH of the buffer is achieved. In various embodiments, the target pH or final pH of the buffer is about 4.5 to about 5.5, optionally about 4.7 to about 5.3 or about 5.0. In a representative example, the composition comprises about 1 mM to about 100 mM of the buffer. In a representative example, the composition comprises about 1 mM to about 50 mM of the buffer, such as about 1 mM to about 40 mM of the buffer, or about 1 mM to about 30 mM. In various embodiments, the composition comprises about 5 mM to about 40 mM, optionally about 10 mM to about 30 mM, about 15 mM to about 25 mM, about 10 mM to about 40 mM, about 15 mM to about 40 mM, or about 20 mM to about 40 mM. In a representative example, the DF buffer used to prepare the liquid composition of the present disclosure comprises about 1 mM to about 50 mM buffer, e.g., about 1 mM to about 40 mM buffer, or about 1 mM to about 30 mM.In various aspects, the DF buffer comprises about 5 mM to about 40 mM, optionally about 10 mM to about 30 mM buffer, about 10 mM to about 40 mM buffer, about 15 mM to about 40 mM buffer, or about 20 mM to about 40 mM buffer. In certain embodiments, the buffer is an acetate buffer. Optionally, the DF buffer comprises about 18 mM to about 22 mM buffer, e.g., about 20 mM buffer. In representative alternative aspects, the DF buffer comprises less acetate at lower pH. For example, such a DF buffer may comprise about 8 mM to about 17 mM buffer, e.g., about 10 mM buffer to about 15 mM, about 10 mM, and has a pH of about 3.5. Optionally, the buffer is made from glacial acetic acid, and sodium hydroxide is added until the target pH is reached. In various examples, the composition comprises about 30 mM to about 38 mM of buffer, optionally about 33 mM to about 38 mM or about 34 mM to about 38 mM of buffer (e.g., acetate). In various embodiments, the composition comprises about 32 mM to about 36 mM of buffer (e.g., acetate). In various embodiments, the composition comprises about 34 mM to about 36 mM of buffer (e.g., acetate). As described herein, in various embodiments, the concentration of the buffer depends on the concentration of the antibody. In various embodiments, the liquid composition comprises about 20 mM to about 40 mM, optionally about 30 mM to about 38 mM, when the concentration of the antibody is about 150 mg / mL. Optionally, when the antibody has a concentration of about 150 mg / mL and the liquid composition has a pH of 4.7 to 5.3, the composition contains about 32 mM to about 36 mM or about 33 mM to about 35 mM of a buffer (e.g., acetate).

[0029] In various embodiments, the liquid composition contains, per mL of the liquid composition, (i) about 135 mg to about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, a HC CDR2 of SEQ ID NO: 2, a HC CDR3 of SEQ ID NO: 3, a light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, a LC CDR2 of SEQ ID NO: 5, and a LC CDR3 of SEQ ID NO: 6, (ii) about 23 mg to about 30 mg of proline, (iii) about 0.5 mg to about 2 mg of acetate, and (iv) about 0.01% (w / v) polysorbate 80 (PS80), and the pH of the liquid composition is about 4.5 to about 5.5. In various embodiments, the liquid composition comprises, per mL of the liquid composition, (i) about 150 mg of oldesekimab, (ii) about 23 mg to about 30 mg of proline, (iii) about 0.5 mg to about 2 mg of acetate, and (iv) about 0.01% (w / v) of polysorbate 80 (PS80), and the pH of the liquid composition is about 4.5 to about 5.5. In various examples, the liquid composition comprises, per mL of the liquid composition, (i) about 150 mg of oldesekimab, (ii) about 26.5 mg of proline, (iii) about 1.2 mg of acetate, and (iv) about 0.01 mg of PS80, and the pH of the liquid composition is about 5.0.

[0030] Surfactants The compositions of the present disclosure in various aspects include a surfactant. A surfactant is an amphiphilic (having a polar head and a hydrophobic tail) surface active agent. Surfactants preferentially accumulate at the interface, resulting in a reduction in interfacial tension. The use of surfactants can also help reduce the formation of large protein particles. In some aspects, the surfactant present in the compositions of the present disclosure is an amphiphilic and / or non-ionic surfactant. Exemplary surfactants include polyoxyethylene sorbitan fatty acid esters (e.g., polysorbate 20, polysorbate 80), alkylaryl polyethers such as oxyethylated alkylphenols (e.g., Triton™ X-100) and poloxamers (e.g., Pluronics®, e.g., Pluronic® F68), as well as any combination of the foregoing, either within or between surfactant classes. Polysorbate 20 and polysorbate 80 (and optionally mixtures thereof) are specifically contemplated. The surfactant is typically present in the composition at a concentration of about 0.0005% (w / v) to about 0.5% (w / v). In various examples, the final concentration of the surfactant in the liquid composition may be from about 0.0006% (w / v) to about 0.5% (w / v), 0.0007% (w / v) to about 0.5% (w / v), 0.0008% (w / v) to about 0.5% (w / v), 0.0009% (w / v) to about 0.5% (w / v), 0.001% (w / v) to about 0.5% (w / v), 0.002% (w / v) to about 0.5% (w / v), 0.003% (w / v) to about 0.5% (w / v), 0.004% (w / v) to about 0.5% (w / v), 0.005% (w / v) to about 0.5% (w / v), 0.00 6% (w / v) ~ approx. 0.5% (w / v), 0.007% (w / v) ~ approx. 0.5% (w / v), 0.008% (w / v) ~ approx. 0.5% (w / v), 0.009% (w / v) ~ approx. 0.5% (w / v), 0.01% (w / v) ~ approx. 0.5% (w / v), 0.02% (w / v) ~ approx. 0.5% (w / v), 0.03% (w / v) ~ approx. 0.5% (w / v), 0.04% (w / v) ~ approx. 0.5% (w / v), 0.05% (w / v) ~ approx. 0.5% (w / v), 0.06% (w / v) ~ approx. 0.5% (w / v), 0.07% (w / v) ~ approx. 0.5% (w / v), 0.08% (w / v) ~ approx. 0.5% (w / v), 0.09% (w / v) ~ approx. 0.5% (w / v), 0.1% (w / v) ~ approx. 0.5% (w / v), 0.2% (w / v) ~ approx. 0.5% (w / v), 0.3% (w / v) ~ approx. 0.5% (w / v), 0.4% (w / v) ~ approximately 0.5% (w / v), approximately 0.0005% (w / v) ~ approximately 0.4% (w / v), approximately 0.0005% (w / v) ~ approximately 0.3% (w / v), approximately 0.0005% (w / v) ~ approximately 0.2% (w / v), approximately 0. 0005% (w / v) ~ approx. 0.1% (w / v), approx. 0.0005% (w / v) ~ approx. 0.09% (w / v), approx. 0.0005% (w / v) ~ approx. 0.08% (w / v), approx. 0.0005% (w / v) ~ approx. 0.07% (w / v), approx. 0 .0005% (w / v) ~ approx. 0.06% (w / v), approx. 0.0005% (w / v) ~ approx. 0.05% (w / v), approx. 0.0005% (w / v) ~ approx. 0.04% (w / v), approx. 0.0005% (w / v) ~ approx. 0.0005% (w / v) ~ approx. 0.02% (w / v), approx. 0.0005% (w / v) ~ approx. 0.01% (w / v), approx. 0.0005% (w / v) ~ approx. 0.009% (w / v), approx. 0.0005% (w / v) ~ approx. 0.008% (w / v), about 0.0005% (w / v) to about 0.007% (w / v), about 0.0005% (w / v) to about 0.006% (w / v), about 0.0005% (w / v) to about 0.005% (w / v), about 0.0005% (w / v) to about 0.00 4% (w / v), about 0.0005% (w / v) to about 0.003% (w / v), about 0.0005% (w / v) to about 0.002% (w / v), about 0.0005% (w / v) to about 0.001% (w / v), about 0.0005% (w / v) to about 0.0009% (w / v), about 0.0005% (w / v) to about 0.0008% (w / v), about 0.0005% (w / v) to about 0.0007% (w / v), or about 0.0005% (w / v) to about 0.0005% (w / v). In representative examples, the surfactant is present at a concentration of about 0.001% (w / v) to about 0.050% (w / v), about 0.005% (w / v) to about 0.025% (w / v), or about 0.01% (w / v) ± 0.001% (w / v). For example, the formulation may be present at a concentration of about 0.005% (w / v) to about 0.The composition may comprise up to 0.05% (w / v) of a surfactant. In various embodiments, the surfactant is a polysorbate, e.g., polysorbate 20 or polysorbate 80, or a mixture thereof. Optionally, the surfactant is present at a concentration of less than 0.005% (w / v) or between about 0.005% (w / v) and about 0.015% (w / v), optionally about 0.010% (w / v) ±0.0025% (w / v) surfactant or about 0.005% (w / v), 0.010% (w / v), or 0.015% (w / v) surfactant.

[0031] pH, viscosity and osmolality In various embodiments, the pH of the liquid composition is less than about 7.0, optionally less than about 6.5, or less than about 6.0. In exemplary embodiments, the pH is from about 4.50 to about 5.75, e.g., from about 4.55 to about 5.75, from about 4.60 to about 5.75, from about 4.65 to about 5.75, from about 4.70 to about 5.75, from about 4.75 to about 5.75, from about 4.80 to about 5.75, from about 4.85 to about 5.75, from about 4.90 to about 5.75, from about 4.95 to about 5.75, from about 5.00 to about 5.75, or from about 5. 05 to about 5.75, about 5.10 to about 5.75, about 5.15 to about 5.75, about 5.20 to about 5.75, about 5.25 to about 5.75, about 5.30 to about 5.75, about 5.35 to about 5.75, about 5.40 to about 5.75, about 5.45 to about 5.75, about 5.50 to about 5.75, about 5.55 to about 5.75, about 5.60 to about 5.75, about 5.65 to about 5.75 , about 5.70 to about 5.75, about 4.50 to about 5.70, about 4.50 to about 5.65, about 4.50 to about 5.60, about 4.50 to about 5.55, about 4.50 to about 5.50, about 4.50 to about 5.45, about 4.50 to about 5.40, about 4.50 to about 5.35, about 4.50 to about 5.30, about 4.50 to about 5.25, about 4.50 to about 5.20, about 4.50 to about 5.15, about 4.50 to about 5.10, about 4.50 to about 5.05, about 4.50 to about 5.00, about 4.50 to about 4.95, about 4.50 to about 4.90, about 4.50 to about 4.85, about 4.50 to about 4.80, about 4.50 to about 4.75, about 4.50 to about 4.70, about 4.50 to about 4.65, about 4.50 to about 4.60, or about 4.50 to about 4.55. In various examples, the pH is about 4.7. In various embodiments, the pH is about 4.7 to about 5.3, optionally about 5.0.

[0032] In an exemplary embodiment, the liquid composition is characterized by a low viscosity compared to a liquid composition that does not contain arginine glutamate or proline (e.g., compared to a liquid composition that contains 5% to 10% (w / v) sucrose). In a specific embodiment, the composition has a viscosity of about 5 cP to about 30 cP, for example, about 5 cP to about 25 cP, about 5 cP to about 20 cP, about 5 cP to about 15 cP, at a temperature of about 5° C. to about 30° C. when the antibody concentration is 100 mg / mL to about 180 mg / mL (e.g., about 120 mg / mL, about 130 mg / mL, about 140 mg / mL, about 150 mg / mL, about 165 mg / mL, about 180 mg / mL). The composition is characterized by a viscosity of 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, or about 25 cP. In an exemplary embodiment, when the concentration of the antibody is about 100 mg / mL to about 165 mg / mL, the composition has a viscosity of less than about 10 cP at about 25°C and less than about 20 cP at 5°C. In an exemplary embodiment, when the concentration of the antibody is greater than about 165 mg / mL, e.g., about 190 mg / mL, the composition has a viscosity of less than about 30 cP at about 5° C. and less than about 15 cP at 25° C. Unless otherwise stated, all viscosities disclosed herein are measured at 25° C. and less than about 1000 s. -1 It refers to the viscosity measured using a viscometer at a given shear rate.

[0033] In an exemplary embodiment, the liquid composition is intended for administration to a subject by injection or infusion, and therefore the composition is isotonic with the intended site of administration. Thus, in various examples of the present disclosure, the liquid composition is an isotonic liquid composition. In representative examples, the osmolality of the composition ranges from about 250 mOsm / kg to about 350 mOsm / kg, about 270 to about 350 mOsm / kg, or about 285 to about 345 mOsm / kg, or about 300 to about 315 mOsm / kg. In this specification, the osmolality unit "mOsm / kg" is synonymous with "mOsmol / kg". For example, if the solution is in a form for parenteral administration, it can be isotonic with blood (osmolality of about 300 mOsm / kg). In an exemplary embodiment, the liquid pharmaceutical formulation has an osmolality of less than about 450 mOsm / kg (e.g., less than about 400 mOsm / kg).

[0034] stability The liquid compositions of the present disclosure exhibit high stability as evidenced by low % initial HMW species as determined by size exclusion chromatography (SEC). As used herein, "initial HMW species" refers to HMW species formed upon combining the components of the liquid composition with the antibody and / or immediately after the components are combined with the antibody. Initial HMW species refers to HMW species that are first formed and / or at storage time 0. In exemplary embodiments, less than 5% (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) of initial HMW species is detected by SEC.

[0035] In various examples, the liquid compositions of the present disclosure are storage stable (or storage stable) as indicated by a low amount of aggregates and / or a low rate of aggregate formation after storage. As described herein, the stability of such liquid compositions is indicated by a low amount of HMWS and / or a low rate of HMWS formation after storage for various times and at various temperatures. In general, a more stable liquid composition is associated with a lower amount of HMWS, a lower rate of HMWS formation, and / or a higher main peak of antibody at higher storage temperatures compared to lower temperatures. As used herein, the term "high molecular weight species" or "HMWS" refers to higher order aggregates of the antibody of the present formulation as well as lower order aggregates of the antibody of the present formulation. Lower order aggregates include, for example, dimeric species. The amount and rate of formation of aggregates can be measured or monitored by techniques such as, for example, SE-UHPLC. SE-UHPLC chromatograms of the antibodies, in some instances, show a peak at around 2.2-2.8 minutes that corresponds to the amount of HMWS in the liquid composition and a peak at around 3 minutes that reflects the amount of intact, non-aggregated form of the antibody. Storage at 37°C, as compared to storage at 4°C, allows for acceleration of stability assays, allowing the stability of a particular formulation to be determined over a shorter period of time compared to storage periods at 4°C. For example, storage at 37°C for 1, 2 or 3 months may be indicative or predictive of 36 months of storage at 4°C.

[0036] In one type of embodiment, the storage-stable liquid composition as described herein exhibits a reduced magnitude or rate of HMWS formation after 3 months of storage at 37° C. when compared to an equivalent concentration control formulation consisting of acetate and sucrose as excipients.

[0037] In another type of embodiment, the storage-stable liquid composition comprising arginine glutamate or proline as described herein exhibits a reduced magnitude of HMWS formation after 1 month of storage at 37° C., when compared to a comparable control formulation without arginine glutamate or proline. For example, the extent of formation may be reduced, such that the amount of HMWS in % by SE-UPHLC is reduced by at least about 0.1%, or about 0.2%, or about 0.3%, or about 0.4%, or about 0.5%, or about 0.6%, or about 0.7%, for example, in the range of about 0.1% to about 2%, or about 0.1% to about 1%, compared to the control formulation after 1 month of storage at 37° C.

[0038] In another type of embodiment, a storage-stable liquid composition as described herein has a low amount of HMWS by SE-UHPLC after 1 month of storage at 37° C. For example, the amount of HMWS can be 2% or less, or less than 2%, or 1.9% or less, or less than 1.9%, or 1.8% or less, or less than 1.8%, or 1.7% or less, or less than 1.7%, or 1.6% or less, or less than 1.6%, or 1.5% or less, or less than 1.5%, or 1.4% or less, or less than 1.4%, or 1.3% or less, or less than 1.3%, or 1.2% or less, or less than 1.2%. In other examples, the amount of HMWS can range, for example, from about 0.01% to about 2%, or from about 0.01% to about 1.9%, or from about 0.01% to about 1.8%, or from about 0.01% to about 1.7%, or from about 0.01% to about 1.6%, or from about 0.01% to about 1.5%, or from about 0.01% to about 1.4%, or from about 0.01% to about 1.3%, or from about 0.01% to about 1.2%. In another type of embodiment, the amount of HMWS after 1 month of storage at 37° C. by SE-UHPLC can be greater than 2%, for example greater than 2% and less than or equal to 3%, while the aggregation rate reduction provided by the amino acid aggregation inhibitor allows for a suitable product shelf life, for example, up to 3 years or up to 2 years.

[0039] In another type of embodiment, the storage-stable liquid composition as described herein has a low amount of HMWS by SE-UHPLC after 3 months of storage at 37° C. For example, the amount of HMWS can be 2% or less, or less than 2%, or 1.9% or less, or less than 1.9%, or 1.8% or less, or less than 1.8%, or 1.7% or less, or less than 1.7%, or 1.6% or less, or less than 1.6%, or 1.5% or less, or less than 1.5%, or 1.4% or less, or less than 1.4%, or 1.3% or less, or less than 1.3%, or 1.2% or less, or less than 1.2%. In other examples, the amount of HMWS can be in the range of, for example, about 0.01% to about 2%, or about 0.01% to about 1.9%, or about 0.01% to about 1.8%, or about 0.01% to about 1.7%, or about 0.01% to about 1.6%, or about 0.01% to about 1.5%, or about 0.01% to about 1.4%, or about 0.01% to about 1.3%, or about 0.01% to about 1.2%.

[0040] In another type of embodiment, a storage-stable liquid composition as described herein has a low amount of HMWS by SE-UHPLC after 36 months of storage at 4° C. For example, the amount of HMWS can be 2% or less, or less than 2%, or 1.9% or less, or less than 1.9%, or 1.8% or less, or less than 1.8%, or 1.7% or less, or less than 1.7%, or 1.6% or less, or less than 1.6%, or 1.5% or less, or less than 1.5%, or 1.4% or less, or less than 1.4%, or 1.3% or less, or less than 1.3%, or 1.2% or less, or less than 1.2%. In other examples, the amount of HMWS can be in the range of, for example, about 0.01% to about 2%, or about 0.01% to about 1.9%, or about 0.01% to about 1.8%, or about 0.01% to about 1.7%, or about 0.01% to about 1.6%, or about 0.01% to about 1.5%, or about 0.01% to about 1.4%, or about 0.01% to about 1.3%, or about 0.01% to about 1.2%.

[0041] In another type of embodiment, the storage-stable liquid composition as described herein has a high amount of antibody major peak by SE-UHPLC after 1 month of storage at 37° C. For example, the amount of major peak can be at least 95% or more than 95%, or at least 96% or more than 96%, or at least 97% or more than 97%, or at least 97.5% or more than 97.5%, or at least 98% or more than 98%, or at least 98.1% or more than 98.1%, or at least 98.2% or more than 98.2%, or at least 98.3% or more than 98.3%, or at least 98.4% or more than 98.4%, or at least 98.5% or more than 98.5%, or at least 98.6% or more than 98.6%. In other examples, the amount of the main peak may be in the range of, for example, about 95% to about 99.9%, or about 96% to about 99.9%, or about 97% to about 99.9%, or about 97.5% to about 99.9%, or about 98% to about 99.9%, or about 98.1% to about 99.9%, or about 98.2% to about 99.9%, or about 98.3% to about 99.9%, or about 98.4% to about 99.9%, or about 98.5% to about 99.9%, or about 98.6% to about 99.9%.

[0042] In another type of embodiment, the storage-stable liquid composition as described herein has a high amount of antibody major peak by SE-UHPLC after 3 months storage at 37° C. For example, the amount of major peak can be at least 95% or more than 95%, or at least 96% or more than 96%, or at least 97% or more than 97%, or at least 97.5% or more than 97.5%, or at least 98% or more than 98%, or at least 98.1% or more than 98.1%, or at least 98.2% or more than 98.2%, or at least 98.3% or more than 98.3%, or at least 98.4% or more than 98.4%, or at least 98.5% or more than 98.5%, or at least 98.6% or more than 98.6%. In other examples, the amount of the main peak may be in the range of, for example, about 95% to about 99.9%, or about 96% to about 99.9%, or about 97% to about 99.9%, or about 97.5% to about 99.9%, or about 98% to about 99.9%, or about 98.1% to about 99.9%, or about 98.2% to about 99.9%, or about 98.3% to about 99.9%, or about 98.4% to about 99.9%, or about 98.5% to about 99.9%, or about 98.6% to about 99.9%.

[0043] In another type of embodiment, the storage-stable liquid composition as described herein has a high amount of antibody major peak by SE-UHPLC after 36 months of storage at 4° C. For example, the amount of major peak can be at least 95% or more than 95%, or at least 96% or more than 96%, or at least 97% or more than 97%, or at least 97.5% or more than 97.5%, or at least 98% or more than 98%, or at least 98.1% or more than 98.1%, or at least 98.2% or more than 98.2%, or at least 98.3% or more than 98.3%, or at least 98.4% or more than 98.4%, or at least 98.5% or more than 98.5%, or at least 98.6% or more than 98.6%. In other examples, the amount of the main peak may be in the range of, for example, about 95% to about 99.9%, or about 96% to about 99.9%, or about 97% to about 99.9%, or about 97.5% to about 99.9%, or about 98% to about 99.9%, or about 98.1% to about 99.9%, or about 98.2% to about 99.9%, or about 98.3% to about 99.9%, or about 98.4% to about 99.9%, or about 98.5% to about 99.9%, or about 98.6% to about 99.9%.

[0044] In a further embodiment, it is contemplated that after storage, the storage-stable liquid composition has both a low amount of HMWS and a high amount of the main peak according to the above specifications.

[0045] In exemplary embodiments, a storage-stable liquid composition contains, after storage, about 4% or less high molecular weight species (HMWS) and / or greater than about 96% of the antibody major peak as measured by SE-UHPLC. In exemplary embodiments, a storage-stable liquid composition contains, after storage, about 3% or less high molecular weight species (HMWS) and / or greater than about 97% of the antibody major peak as measured by SE-UHPLC. In exemplary embodiments, a storage-stable liquid composition contains, after storage, less than about 2% HMWS and / or greater than about 98% of the antibody major peak as measured by SE-UHPLC. In exemplary embodiments, storage is for at least 12 months, 24 months, or 36 months (e.g., at least or about 12 months, at least or about 16 months, at least or about 20 months, at least or about 24 months, at least or about 28 months, at least or about 32 months, at least or about 36 months, optionally longer) at a temperature of about 2°C to about 8°C (e.g., about 2°C, about 3°C, about 4°C, about 5°C, about 6°C, about 7°C, about 8°C). In an exemplary embodiment, storage is for about one month (e.g., about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days) at about 20° C. to about 30° C. (e.g., about 21° C. to about 30° C., about 22° C. to about 30° C., about 23° C. to about 30° C., about 24° C. to about 30° C., about 25°C to about 30°C, about 26°C to about 30°C, about 27°C to about 30°C, about 28°C to about 30°C, about 28°C to about 30°C, about 20°C to about 29°C, about 20°C to about 28°C, about 20°C to about 27°C, about 20°C to about 26°C, about 20°C to about 25°C, about 20°C to about 24°C, about 20°C to about 23°C, about 20°C to about 22°C). In an exemplary embodiment, the storage includes a first storage followed by a second storage, the first storage being at about 2°C to about 8°C for at least 12 months, 24 months, or 36 months, and the second storage being at about 20°C to about 30°C for about 1 month.In representative examples, storage-stable liquid compositions contain 2% or less high molecular weight species (HMWS), or less than 2% HMWS, or less than 1.9% HMWS, or less than 1.9% HMWS, or less than 1.8% HMWS, or less than 1.8% HMWS, or less than 1.7% HMWS, or less than 1.7% HMWS, or less than 1.6% HMWS, or less than 1.6% HMWS, or less than 1.5% HMWS, or less than 1.5% HMWS, or less than 1.4% HMWS, or less than 1.4% HMWS, or less than 1.3% HMWS, or less than 1.3% HMWS, or less than 1.2% HMWS, or less than 1.2% HMWS. In other examples, the amount of HMWS can be in the range of, for example, about 0.01% to about 2% HMWS, or about 0.01% to about 1.9% HMWS, or about 0.01% to about 1.8% HMWS, or about 0.01% to about 1.7% HMWS, or about 0.01% to about 1.6% HMWS, or about 0.01% to about 1.5% HMWS, or about 0.01% to about 1.4% HMWS, or about 0.01% to about 1.3% HMWS, or about 0.01% to about 1.2% HMWS, optionally as measured by SE-UHPLC. In alternative or further aspects, the storage stable liquid composition comprises greater than 98% antibody major peak, or at least 95% antibody major peak, or greater than 95% antibody major peak, or at least 96% antibody major peak, or greater than 96% antibody major peak, or at least 97% antibody major peak, or greater than 97% antibody major peak, or at least 97.5% antibody major peak, or greater than 97.5% antibody major peak, or at least 98% antibody major peak, or greater than 98% antibody major peak, or at least comprising 98.1% of the antibody major peak, or greater than 98.1%, or at least 98.2% of the antibody major peak, or greater than 98.2%, or at least 98.3% of the antibody major peak, or greater than 98.3% of the antibody major peak, or at least 98.4% of the antibody major peak, or greater than 98.4%, or at least 98.5% of the antibody major peak, or greater than 98.5% of the antibody major peak, or at least 98.6% of the antibody major peak, or greater than 98.6% of the antibody major peak.In other examples, the amount of the major peak, optionally as measured by SE-UHPLC, can be in the range of, for example, about 95% to about 99.9% of the antibody major peak, or about 96% to about 99.9% of the antibody major peak, or about 97% to about 99.9% of the antibody major peak, or about 97.5% to about 99.9% of the antibody major peak, or about 98% to about 99.9% of the antibody major peak, or about 98.1% to about 99.9% of the antibody major peak, or about 98.2% to about 99.9% of the antibody major peak, or about 98.3% to about 99.9% of the antibody major peak, or about 98.4% to about 99.9% of the antibody major peak, or about 98.5% to about 99.9% of the antibody major peak, or about 98.6% to about 99.9% of the antibody major peak.

[0046] In exemplary aspects, less than 5% of the antibody (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) is degraded after at least or about 12 months of storage at 2°C to 8°C as determined by SEC. In various aspects, less than 5% of the antibody (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) is degraded after about 20 months to about 26 months of storage at 2°C to 8°C as determined by SEC. In various examples, less than 5% of the antibody (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) is degraded after about 30 to about 40 months of storage at 2°C to 8°C as determined by SEC. Optionally, less than 5% of the antibody is degraded after about 36-40 months of storage at 2°C to 8°C (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) as determined by SEC. In various examples, less than about 5% of the antibody is degraded after at least or about 12 months of storage at 2°C to 8°C as determined by SEC. In various aspects, less than about 5% of the antibody is degraded after about 20 months to about 26 months of storage at about 2°C to about 8°C as determined by SEC. In a representative example, less than about 5% of the antibody is degraded after about 30 to about 40 months of storage at about 2°C to about 8°C as determined by size exclusion chromatography (SEC). In a representative example, less than about 5% of the antibody is degraded after about 2 years to about 3 years of storage at about 2°C to about 8°C as determined by size exclusion chromatography (SEC). Also, for example, as determined by size exclusion chromatography (SEC), less than about 5% of the antibody is degraded after about 24 months to about 36 months of storage at 2° C.-8° C., optionally where less than 2% of the antibody is degraded after 24 months or 36 months of storage at 2° C.-8° C. In various aspects, less than 5% of the antibody is degraded after at least 2 weeks (optionally 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) of storage at about room temperature (e.g., 25° C.) as determined by SEC.In various examples, less than 5% of the antibody is degraded after about 24 months to about 36 months of storage at 2° C.-8° C. followed by at least 2 weeks or at least about 1 month or at least about 2 months of storage at about room temperature (e.g., 25° C.) as determined by SEC. Optionally, less than about 5% of the antibody is degraded after at least or about 2 weeks, and optionally at least or about 4 weeks or about 8 weeks of storage at a temperature above about 20° C. as determined by size exclusion chromatography (SEC). In various aspects, the temperature is greater than or about 25° C., or greater than or about 30° C., or greater than or about 40° C.

[0047] In exemplary embodiments, less than 5% (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) of HMW species are detected by SEC after at least or about 12 months of storage at 2°C-8°C. In various embodiments, less than 5% (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) of HMW species are detected by SEC after about 20 months to about 26 months of storage at 2°C-8°C. In various examples, less than 5% (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) of HMW species are detected by SEC after about 30 to about 40 months of storage at 2°C-8°C. Optionally, after about 36-40 months of storage at 2°C to 8°C, less than 5% (e.g., less than or about 4%, less than or about 3%, less than or about 2%, less than or about 1%) of HMW species is detectable by SEC.

[0048] In exemplary embodiments, the liquid compositions of the present disclosure exhibit stability to one or more stresses, including, for example, stresses caused by shipping, exposure to light, exposure to heat, exposure to air, and / or freeze-thaw cycles (e.g., stresses caused by thawing a liquid composition that has been stored at freezing temperatures). In various examples, the liquid compositions are stable to freeze-thaw as evidenced by a low amount of precipitation of components of the liquid composition in the liquid composition after freeze-thaw.

[0049] Articles of manufacture, syringes and vials Further provided herein is an article of manufacture. In an exemplary embodiment, the article comprises a composition of the present disclosure, optionally comprising about 1 mL to about 5 mL, e.g., about 1 mL to about 3 mL, of the present liquid composition. In an exemplary aspect of the present disclosure, the composition is provided for storage or use, e.g., in a disposable vial, disposable syringe, or glass, glass-lined, glass-coated primary container or autoinjector. In an exemplary aspect, the composition is provided in a disposable system bag or polycarbonate carboy for frozen storage. In an alternative aspect, the composition is contained in a glass vial or syringe for storage at 2°C to 8°C. Further provided herein is a pre-filled syringe comprising the composition of the present disclosure, optionally comprising about 1 mL to about 5 mL, e.g., about 1 mL to about 3 mL, of the present composition. Further provided is a vial comprising the composition of the present disclosure, optionally comprising about 1 mL to about 5 mL, e.g., about 1 mL to about 3 mL, of the present liquid composition. In various embodiments, the article, prefilled syringe, or vial contains about 2 mL to about 3 mL (e.g., 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, about 2.9 mL) of a composition of the present disclosure, and in various embodiments, the composition comprises an antibody at a concentration of about 150 mg / mL.

[0050] In a typical example, the composition is provided for use in a ready-made and / or self-administered delivery system.In an exemplary embodiment, the composition is provided in a pre-filled syringe or autoinjector, a pen-type injector, a dual-chamber pen, etc.Such products are known in the art and are commercially available.

[0051] The compositions of the present disclosure may be suitable for administration by any acceptable route, including parenteral and, in particular, injection using a syringe. For example, injection may be performed in the upper arm, upper thigh, or abdomen. Other routes include, for example, subcutaneous, intravenous, intradermal, intramuscular, intraperitoneal, intranodal, and intrasplenic.

[0052] When the composition is in a form intended for administration to a subject, it can be made isotonic with the intended administration site.For example, when the solution is in a form intended for parenteral administration, it can be isotonic with blood.The composition is typically sterile.In certain embodiments, this can be achieved by filtration through a sterile filtration membrane.In certain embodiments, parenteral compositions are generally placed in a container with a sterile access port, for example, an intravenous solution bag or vial with a stopper that can be pierced by a hypodermic needle or a pre-filled syringe.In certain embodiments, the composition can be stored in a ready-to-use form.

[0053] Method for preparing a liquid composition Further provided by the present disclosure is a method for preparing a liquid composition comprising a target concentration of a monoclonal antibody. In an exemplary embodiment, the target concentration is greater than about 100 mg / mL. In various aspects, the target concentration is any of those described herein, including but not limited to those described in the antibody concentration section herein. Thus, in various aspects, the target concentration is from about 110 mg / mL to about 300 mg / mL, e.g., from about 110 mg / mL to about 290 mg / mL, from about 110 mg / mL to about 280 mg / mL, from about 110 mg / mL to about 270 mg / mL, from about 110 mg / mL to about 260 mg / mL, from about 110 mg / mL to about 250 mg / mL, from about 110 mg / mL to about 240 mg / mL, from about 110 mg / mL to about 23 ...60 mg / mL, from about 110 mg / mL to about 270 mg / mL, from about 110 mg / mL to about 260 mg / mL, from about 110 mg / mL to about 250 mg / mL, from about 110 mg / mL to about 240 mg / mL, from about 110 mg / mL to about 230 mg / mL, from about 110 mg / mL to about 260 mg / mL, from about 110 mg / mL to about 260 mg / mL, from about 11 ~220mg / mL, approximately 110mg / mL~210mg / mL, approximately 110mg / mL~200mg / mL, approximately 110mg / mL~190mg / mL, approximately 110mg / mL~180mg / mL, approximately 110m g / mL~about 170mg / mL, about 110mg / mL~about 160mg / mL, about 110mg / mL~about 150mg / mL, about 110mg / mL~about 140mg / mL, about 110mg / mL~about 130mg / mL, about 110mg / mL~about 120mg / mL, about 120mg / mL~about 300mg / mL, about 130mg / mL~about 300mg / mL, about 140mg / mL~about 300mg / mL, about 150mg / mL~about 300mg / mL, about 160mg / mL to about 300mg / mL, about 170mg / mL to about 300mg / mL, about 180mg / mL to about 300mg / mL, about 190mg / mL to about 300mg / mL, about 200mg / mL to about 3 00mg / mL, about 210mg / mL to about 300mg / mL, about 220mg / mL to about 300mg / mL, about 230mg / mL to about 300mg / mL, about 240mg / mL to about 300mg / mL, about 250mg / mL to about 300mg / mL, about 260mg / mL to about 300mg / mL, about 270mg / mL to about 300mg / mL, about 280mg / mL to about 300mg / mL, or about 290mg / mL to about 300mg / mL.In various examples, the target concentration of the antibody is from about 120 mg / mL to about 250 mg / mL, optionally from about 120 mg / mL to about 240 mg / mL, from about 120 mg / mL to about 230 mg / mL, from about 120 mg / mL to about 220 mg / mL, from about 120 mg / mL to about 210 mg / mL, from about 120 mg / mL to about 200 mg / mL, from about 120 mg / mL to about 190 mg / mL, from about 120 mg / mL to about 180 mg / mL, from about 120 mg / mL to about 170 mg / mL, from about 120 mg / mL to about 160 mg / mL, from about 120 mg / mL to about 150 mg / mL, from about 120 mg / mL to about 140 mg / mL, about 120mg / mL to about 130mg / mL, about 130mg / mL to about 250mg / mL, about 140mg / mL to about 250mg / mL, about 150mg / mL to about 250mg / mL, about 160mg / mL to about 250mg / mL, about 170mg / mL to about 250mg / mL, about 180mg / mL to about 250mg / mL, about 190mg / mL to about 250mg / mL, about 200mg / mL to about 250mg / mL, about 210mg / mL to about 250mg / mL, about 220mg / mL to about 250mg / mL, about 230mg / mL to about 250mg / mL, or about 240mg / mL to about 250mg / mL. In various examples, the target concentration of the antibody is about 160 mg / mL to about 250 mg / mL, for example, about 180 mg / mL to about 225 mg / mL or about 180 mg / mL to about 200 mg / mL. In some embodiments, the target concentration is about 130 mg / mL to about 225 mg / mL, about 130 mg / mL to about 220 mg / mL or about 130 mg / mL to about 200 mg / mL. In various examples, the target concentration is about 135 mg / mL to about 165 mg / mL, optionally about 140 mg / mL to about 160 mg / mL. In exemplary embodiments, the target concentration is about 120 mg / mL antibody, about 140 mg / mL, about 150 mg / mL or about 165 mg / mL.

[0054] In an exemplary embodiment, the method includes formulating the antibody with a diafiltration (DF) buffer comprising (i) arginine glutamate or (ii) proline and a buffer. Arginine glutamate, in an exemplary embodiment, comprises L-arginine base and L-glutamic acid. In various examples, the antibody is present in a first liquid composition, and a buffer exchange is performed to place the antibody in a DF buffer. After the buffer exchange, a surfactant is added. Optionally, the method includes adjusting the pH to a target pH. In various embodiments, no adjustment of the pH is required after the buffer exchange. In certain embodiments, when the DF buffer comprises arginine glutamate, no adjustment of the pH is required.

[0055] In various aspects, the method includes (a) combining the monoclonal antibody with a diafiltration (DF) buffer that includes (i) an arginine base and (ii) a glutamate salt, the molar ratio of arginine to glutamate being about 0.7:1.0 to about 1.1:1.0, and (b) adding a surfactant. In various aspects, the molar ratio of arginine to glutamate is about 0.8:1.0 to about 1.1:1.0. In various aspects, the DF buffer includes about 50 mM to about 300 mM arginine base. Optionally, the DF buffer includes about 85 mM to about 190 mM arginine or about 135 mM to about 165 mM arginine. In various examples, the DF buffer includes about 155 mM to about 185 mM glutamate. Optionally, the DF buffer comprises about 150 mM arginine and about 170 mM glutamate. Optionally, the DF buffer comprises about 136 mM arginine and about 159 mM glutamate. In various examples, the DF buffer comprises about 85 mM to about 190 mM arginine and about 85 mM to about 200 mM glutamate. In various examples, the DF buffer is made with about 80 mM to about 240 mM arginine base and about 80 mM to about 240 mM glutamic acid.In various embodiments, the DF buffer contains about 100 mM to about 180 mM arginine (e.g., about 100 mM to about 170 mM, about 100 mM to about 160 mM, about 100 mM to about 150 mM, about 100 mM to about 140 mM, about 100 mM to about 130 mM, about 100 mM to about 120 mM, about 100 mM to about 110 mM, about 110mM to about 180mM, about 120mM to about 180mM, about 130mM to about 180mM, about 140mM to about 180mM, about 150mM to about 180mM, Approximately 160mM to approximately 180mM, approximately 170mM to approximately 180mM, approximately 120mM to approximately 170mM, approximately 130mM to approximately 160mM, approximately 135mM to approximately 155mM) and about 110 mM to about 240 mM glutamate (e.g., about 110 mM to about 180 mM, about 110 mM to about 170 mM, about 110 mM to about 160 mM, about 110 mM to about 150 mM, about 110 mM to about 140 mM, about 110 mM to about 130 mM, about 110 mM to about 120 mM, about 120 mM to about 180 mM , about 130 mM to about 180 mM, about 140 mM to about 180 mM, about 150 mM to about 180 mM, about 160 mM to about 180 mM, about 170 mM to about 180 mM, about 120 mM to about 170 mM, about 130 mM to about 160 mM, about 140 mM to about 160 mM, about 145 mM to about 155 mM glutamate). In various examples, the DF buffer is made using about 100 mM to about 170 mM arginine base. In various examples, the DF buffer is made using about 120 mM to about 150 mM arginine base. In various examples, the DF buffer is made using about 136 mM arginine base. In various examples, the DF buffer is made using about 120 mM to about 200 mM glutamic acid. In various examples, the DF buffer is made with about 140 mM to about 175 mM glutamic acid. In various examples, the DF buffer is made with about 159 mM glutamic acid. In various examples, the DF buffer is made with about 136 mM arginine base and about 159 mM glutamic acid. In various examples, the DF buffer includes about 85 mM to about 125 mM arginine and about 85 mM to about 225 mM glutamate.In various examples, the DF buffer comprises about 135 mM to about 165 mM arginine base and about 155 mM to about 185 mM glutamate or about 135 mM to about 165 mM arginine base and about 155 mM to about 185 mM glutamate. In various examples, the DF buffer comprises about 135 mM to about 145 mM arginine and about 145 mM to about 155 mM glutamate. In various embodiments, the DF buffer comprises about 150 mM arginine base and about 170 mM glutamate. In exemplary embodiments, the pH of the DF buffer is about the same as the final pH (e.g., target pH) of the prepared liquid composition. Optionally, the final pH of the prepared liquid composition is about 4.5 to about 6.5. In a representative example, the first liquid composition comprises a monoclonal antibody at a concentration higher than the target concentration, and the method further comprises diluting the monoclonal antibody with DF buffer to obtain the target concentration before adding a surfactant. The surfactant can be any surfactant known in the art or described herein. Preferably, the surfactant is polysorbate 80, and optionally, the method comprises adding an amount of PS80 to obtain a final concentration of about 0.01% (w / v).

[0056] In an alternative embodiment, the method includes (a) combining the monoclonal antibody with a DF buffer comprising about 150 mM to about 300 mM proline and about 10 mM to about 50 mM acetate, and (b) adding a detergent. In an exemplary embodiment, the DF buffer comprises proline in the range of about 175 mM to about 375 mM proline or about 200 mM to about 350 mM proline. Optionally, the DF buffer contains proline at a concentration of about 200 mM to about 325 mM, about 200 mM to about 300 mM, about 200 mM to about 275 mM, about 200 mM to about 250 mM, about 200 mM to about 225 mM, about 225 mM to about 350 mM, about 250 mM to about 350 mM, about 275 mM to about 350 mM, about 300 mM to about 350 mM, or about 325 mM to about 350 mM. In various examples, the proline concentration in the DF buffer is about 200 mM to about 300 mM, about 225 mM to about 275 mM, about 235 mM to about 265 mM, or about 240 mM to about 260 mM. In various examples, the DF buffer comprises about 1 mM to about 50 mM acetate, e.g., about 1 mM to about 40 mM acetate or about 1 mM to about 30 mM acetate. In various embodiments, the DF buffer comprises about 5 mM to about 40 mM, about 10 mM to about 30 mM acetate, optionally about 15 mM to about 30 mM acetate, about 20 mM to about 30 mM acetate, or about 10 mM to about 25 mM acetate. In exemplary embodiments, acetate is present in DF buffer at a concentration of about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM, or about 30 mM.

[0057] Further provided herein are liquid compositions prepared by the methods of the present disclosure.

[0058] treatment Methods of treating disease are provided herein. The methods of treating, in exemplary embodiments, include administering a liquid composition of the present disclosure to a subject with the disease in an amount effective to treat the disease. As used herein, the term "treat" and related terms do not necessarily mean 100% or complete treatment. Rather, there are various degrees of treatment that one of skill in the art will recognize as having potential benefits or therapeutic effects. In this regard, the methods of treating disease of the present disclosure may provide any amount or level of treatment. Furthermore, the treatment provided by the methods of the present disclosure may include treatment of one or more conditions or symptoms or signs of the disease being treated. The treatment provided by the methods of the present disclosure may also include slowing the progression of the disease. For example, if the disease is cancer, the methods may treat the disease by enhancing T cell activity or NK cell activity or immune response to the cancer, reducing tumor or cancer growth, inhibiting metastasis of tumor cells, increasing cell death of tumor or cancer cells, etc. In various aspects, the methods treat to slow the onset or recurrence of the disease. In various embodiments, the method is to treat to prolong the survival of a subject.Representative examples are to delay onset or recurrence or occurrence by at least 1 day, 2 days, 4 days, 6 days, 8 days, 10 days, 15 days, 30 days, 2 months, 3 months, 4 months, 6 months, 1 year, 2 years, 3 years, 4 years or more.Therefore, the present disclosure further provides a method of delaying onset or recurrence of disease or improving the survival of a subject, comprising administering to a subject the isotonic liquid composition of the present disclosure.

[0059] disease In various embodiments, the disease is celiac disease, which causes debilitating symptoms, including intestinal mucosal damage and potentially serious medical complications.

[0060] Celiac disease is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals (Green and Cellier, 2007). Currently, approximately 1% of the United States (US) and European Union (EU) populations suffer from celiac disease, although only 10-20% of patients are diagnosed. Celiac disease was the first autoimmune disease with an antigen identified: gluten, a major protein present in some of the most common cereals (e.g., wheat, barley, rye). Modern diets are becoming increasingly rich in gluten, and gluten is also used as an additive in processed foods, cosmetics, and oral medications. Gluten is the second most common food ingredient after sugar, and is present in up to 80% of foods in some countries. The ubiquitous presence of gluten makes it very difficult, if not impossible, to completely avoid. As little as 50 mg / day (a normal diet contains >10 g / day) triggers T cell activation in the small intestine, causing intestinal mucosal damage (Catassi et al., 2007). For this reason, more than 50% of celiac disease patients on a glutted-free diet (GFD) continue to have active disease and intestinal immune activation and mucosal atrophy (Lee et al., 2003; Cranney et al., 2007; Hopper et al., 2007; Midhagen et al., 2003). Patients who continue to have symptoms despite attempts to maintain a GFD are considered to have refractory celiac disease (NRCD). NRCD is defined as "persistent symptoms, signs, or laboratory abnormalities typical of celiac disease despite 6-12 months of a gluten-free diet" (Rubio-Tapia et al., 2013). Patient advocates and experts agree that alternative treatment options, either independent of or in combination with a GFD, are urgently needed to improve the quality of life for people with celiac disease.

[0061] A rare but specific complication of persistent exposure to gluten in celiac disease is the development of refractory celiac disease (RCD), which affects approximately 1% of celiac disease patients (Lebwohl et al., 2013). RCD is characterized by severe intestinal mucosal atrophy and gastrointestinal symptoms in the absence of gluten consumption and in the presence of abnormal IELs in the small intestine (Verbeek et al., 2008, vanWanrooij et al., 2014). RCD patients can be further classified according to the proportion and characteristics of abnormal IELs. Patients with a low proportion of abnormal IELs, defined as less than 20% of total IELs (less than 20 IELs per 100 epithelial cells) as determined by flow cytometry, are referred to as type I RCD (RCD-I). These abnormal IELs are generally polyclonal, and RCD-I patients are not at increased risk for developing overt extra epithelial lymphoma (i.e., enteropathy-associated T-cell lymphoma [EATL]) and have typical 5-year survival rates (vanWanrooij et al., 2014). To treat RCD-I, corticosteroids (topical or systemic), azathioprine, purinesol, anti-TNF agents or cladribine can be used with clinical and histological improvement (Brar et al., 2007; Goerres et al., 2003). Figure 3 shows the pathophysiology of celiac disease and refractory celiac disease as described by Schuppan et al. When the percentage of abnormal IELs reaches or exceeds 20%, the patient is diagnosed with RCD type II (RCD-II). In RCD-II, IELs are typically monoclonal and the risk of developing EATL increases dramatically to over 50% (Nijeboer et al., 2015). Abnormal IELs proliferate in the absence of gluten due to the accumulation of anti-apoptotic mechanisms, and therefore the term "refractory" indicates that the disease, non-Hodgkin's slow-growing intraepithelial lymphoma, does not respond to even the strictest GFD and therefore does not appear to be gluten-dependent.

[0062] Thus, in various embodiments, the disease is refractory celiac disease or refractory celiac disease. In other embodiments, the disease is enteropathy-associated T-cell lymphoma or non-celiac gluten sensitivity. Each of the foregoing is described in WO 2017 / 217985, the entire contents of which are incorporated herein by reference.

[0063] In various embodiments, the disease is a cancer or solid tumor. The cancer treatable by the methods disclosed herein can be any cancer, for example, any malignant tumor growth or tumor caused by abnormal and uncontrolled cell division that can spread to other parts of the body via the lymphatic system or bloodstream. The cancer, in some aspects, is acute lymphocytic cancer, acute myeloid leukemia, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal or anorectum, eye cancer, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder or pleura, cancer of the nose, nasal cavity or middle ear, cancer of the oral cavity, cancer of the vulva, chronic lymphocytic leukemia, chronic myeloid cancer, colon cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, Hodgkin's disease, and other cancers. In a particular embodiment, the cancer is selected from the group consisting of head and neck cancer, ovarian cancer, ovarian cancer, cervical cancer, bladder cancer, and esophageal cancer, pancreatic cancer, gastric cancer, breast cancer, endometrial cancer, colorectal cancer, hepatocellular carcinoma, glioblastoma, bladder cancer, lung cancer, such as non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma. In certain embodiments, the tumor is non-small cell lung cancer (NSCLC), head and neck cancer, renal cancer, triple-negative breast cancer, and gastric cancer. In an exemplary embodiment, the subject has a tumor (e.g., a solid tumor, a hematological malignancy, or a lymphatic malignancy), and the pharmaceutical composition is administered to the subject in an amount effective to treat the tumor of the subject. In other exemplary embodiments, the tumor is non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), head and neck cancer, renal cancer, breast cancer, melanoma, ovarian cancer, liver cancer, pancreatic cancer, colon cancer, prostate cancer, gastric cancer, lymphoma, or leukemia, and the pharmaceutical composition is administered to the subject in an amount effective to treat the tumor of the subject. In various examples, the disease is one described in WO 2019 / 140196 or WO 2015 / 031667, the entire contents of which are incorporated herein by reference.

[0064] In representative examples, the disclosed methods of treating disease include treating or preventing a skeletal-related event (SRE), treating or preventing giant cell tumor of bone, treating or preventing hypercalcemia of malignancy, treating or preventing osteoporosis, or increasing bone mass in a subject. Optionally, treatments provided by the disclosure include: (a) treatment or prevention of SREs in subjects with bone metastases from solid tumors; (b) treatment or prevention of SREs in subjects who are adults or skeletally mature young people with giant cell tumors of bone that are unresectable or where surgical resection would result in significant morbidity; (c) treatment of hypercalcemia of malignancies that are refractory to bisphosphonate therapy in subjects; (d) treatment or prevention of SREs in subjects with multiple myeloma or with bone metastases from solid tumors; (e) treatment of osteoporosis in postmenopausal women at high risk of fracture; (f) treatment to increase bone mass in women at high risk of fracture receiving adjuvant aromatase inhibitor therapy for breast cancer; (g) treatment to increase bone mass in men at high risk of fracture receiving androgen deprivation therapy for non-metastatic prostate cancer; (h) treatment to increase bone mass in men with osteoporosis at high risk of fracture; (i) treatment with calcium or vitamin D. In various examples, the disease is one described in International Publication No. WO 2018 / 200918, the entire contents of which are incorporated herein by reference.

[0065] subject In exemplary embodiments of the present disclosure, the subject is a mammal, including but not limited to, mammals of the order Rodentia, such as mice and hamsters, and mammals of the order Lagomorpha, such as rabbits, mammals of the order Carnivora, including Felidae (cats) and Canidae (dogs), mammals of the order Artiodactyla, including Bovidae (cows) and Suidae (pigs), or mammals of the order Perissodactyla, including Equidae (horses). In some aspects, the mammal is a mammal of the order Primates, Ceboids or Simoids (monkeys), or Anthropoids (humans and apes). In some aspects, the mammal is a human. In various aspects, the subject has a neoplastic disease, such as any one of those described herein. The terms "patient", "subject" or "mammal" as used herein refer to any "patient", "subject" or "mammal", including humans, cows, horses, dogs, and cats. In one embodiment of the present invention, the mammal is a human. In various embodiments, the subject is an adult. In various examples, the subject has a disease described herein.

[0066] Exemplary embodiments Exemplary embodiments of the present invention include, but are not limited to: 1. A liquid composition comprising: (a) a monoclonal antibody at a concentration of greater than about 100 mg / mL, (b) about 200 mM to about 400 mM arginine glutamate, and (c) a surfactant, and having a pH of about 4.5 to about 5.5. 2. A liquid composition comprising (a) a monoclonal antibody at a concentration of greater than about 100 mg / mL, (b) about 100 mM to about 350 mM proline, (c) a buffer solution, and (d) a surfactant, and having a pH of about 4.5 to about 5.5. 3. The liquid composition of embodiment 1 or 2, wherein the concentration of the monoclonal antibody is less than about 300 mg / mL. 4. The liquid composition of embodiment 3, wherein the concentration of the monoclonal antibody is less than about 250 mg / mL. 5. The liquid composition according to any one of embodiments 1 to 4, comprising about 110 mg / mL to about 200 mg / mL of the monoclonal antibody. 6. The liquid composition according to embodiment 5, wherein the concentration of the monoclonal antibody is from about 120 mg / mL to about 180 mg / mL. 7. The liquid composition of embodiment 6, comprising about 120 mg / mL of the monoclonal antibody. 8. The liquid composition of embodiment 6, comprising about 135 mg / mL to about 165 mg / mL of the monoclonal antibody. 9. The liquid composition of embodiment 8, comprising about 140 mg / mL to about 160 mg / mL of the monoclonal antibody. 10. The liquid composition of embodiment 9, comprising about 140 mg / mL of the monoclonal antibody. 11. The liquid composition of embodiment 9, comprising about 150 mg / mL of the monoclonal antibody. 12. The liquid composition according to any one of embodiments 1 to 11, wherein the monoclonal antibody is an IgG1 antibody. 13. The liquid composition according to any one of embodiments 1 to 12, wherein the monoclonal antibody binds to IL-15. 14. The liquid composition of embodiment 13, comprising heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, HC CDR2 of SEQ ID NO: 2, HC CDR3 of SEQ ID NO: 3, light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, LC CDR2 of SEQ ID NO: 5 and LC CDR3 of SEQ ID NO: 6. 15. The liquid composition of embodiment 13 or 14, comprising the HC variable region of SEQ ID NO:7 and the LC variable region of SEQ ID NO:8. 16. The liquid composition according to any one of embodiments 13 to 15, comprising an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10. 17. The liquid composition according to any one of embodiments 1 to 12, wherein the monoclonal antibody binds to PD-1. 18. The liquid composition according to embodiment 17, comprising an HC CDR1 of SEQ ID NO: 11, an HC CDR2 of SEQ ID NO: 12, an HC CDR3 of SEQ ID NO: 13, an LC CDR1 of SEQ ID NO: 14, an LC CDR2 of SEQ ID NO: 15 and an LC CDR3 of SEQ ID NO: 16. 19. The liquid composition of embodiment 17 or 18, comprising the HC variable region of SEQ ID NO: 17 and the LC variable region of SEQ ID NO: 18. 20. The liquid composition according to any one of embodiments 17 to 19, comprising an HC of SEQ ID NO:19 and an LC of SEQ ID NO:20. 21. The liquid composition of embodiment 20, wherein the monoclonal antibody binds to glucocorticoid-induced TNFR-related (GITR). 22. The liquid composition according to embodiment 21, comprising HC CDR1 of SEQ ID NO: 21, HC CDR2 of SEQ ID NO: 22, HC CDR3 of SEQ ID NO: 23, LC CDR1 of SEQ ID NO: 24, LC CDR2 of SEQ ID NO: 25 and LC CDR3 of SEQ ID NO: 26. 23. The liquid composition of embodiment 21 or 22, comprising a HC variable region of SEQ ID NO:27 and a LC variable region of SEQ ID NO:28. 24. A liquid composition according to any one of embodiments 21 to 23, comprising an HC of SEQ ID NO:29 and an LC of SEQ ID NO:30. 25. The liquid composition according to any one of embodiments 1 to 11, wherein the IgG antibody is an IgG2 antibody. 26. The liquid composition of embodiment 25, wherein the monoclonal antibody binds to RANK-L. 27. The liquid composition according to embodiment 26, comprising an HC CDR1 of SEQ ID NO: 31, an HC CDR2 of SEQ ID NO: 32, an HC CDR3 of SEQ ID NO: 33, an LC CDR1 of SEQ ID NO: 34, an LC CDR2 of SEQ ID NO: 35 and an LC CDR3 of SEQ ID NO: 36. 28. The liquid composition of embodiment 26 or 27, comprising a HC variable region of SEQ ID NO: 37 and a LC variable region of SEQ ID NO: 38. 29. A liquid composition according to any one of embodiments 26 to 28, comprising a HC of SEQ ID NO: 39 and a LC of SEQ ID NO: 40. 30. The liquid composition according to any one of embodiments 1 and 3 to 29, comprising about 225 mM to about 350 mM arginine glutamate. 31. The liquid composition according to any one of embodiments 1 and 3 to 30, comprising about 250 mM to about 325 mM arginine glutamate. 32. The liquid composition according to any one of embodiments 1 and 3 to 31, comprising about 200 mM to about 300 mM arginine glutamate. 33. A liquid composition according to any one of embodiments 1 and 3-31, comprising about 200 mM arginine glutamate. 34. The liquid composition according to any one of embodiments 1 and 3-32, comprising a molar ratio of arginine to glutamate of about 0.7:1.0 to about 1.1:1.0, optionally about 0.8:1.0 to about 1.1:1.0. 35. The liquid composition according to any one of embodiments 1 and 3-33, wherein arginine and glutamate are the only amino acids present in the liquid composition. 36. The liquid composition according to any one of the preceding embodiments, wherein the surfactant is amphiphilic and / or non-ionic. 37. The liquid composition according to embodiment 35, wherein the surfactant is a polysorbate. 38. The liquid composition according to embodiment 36, wherein the surfactant is polysorbate 20 (PS20) or polysorbate 80 (PS80) or a mixture thereof. 39. The liquid composition according to any one of embodiments 1 to 38, comprising a surfactant at a concentration of about 0.001% (w / v) to about 0.050% (w / v). 40. The liquid composition of embodiment 39, comprising a surfactant at a concentration of about 0.005% (w / v) to about 0.025% (w / v). 41. The liquid composition according to embodiment 38, comprising about 0.01% (w / v) ± 0.001% (w / v) of a surfactant. 42. The liquid composition of embodiment 39, comprising about 0.01% (w / v) polysorbate 80 (PS80). 43. The liquid composition according to any one of embodiments 1 to 42, wherein the surfactant does not significantly change the viscosity of the composition. 44. The liquid composition of any one of embodiments 1 to 43, having a pH of about 4.70 to about 5.30. 45. The liquid composition of embodiment 42, having a pH of about 5.0. 46. ​​The liquid composition of any one of embodiments 2 to 45, comprising about 200 mM to about 300 mM proline. 47. The liquid composition of any one of embodiments 2 to 46, comprising about 225 mM to about 275 mM proline. 48. The liquid composition of any one of embodiments 2 to 47, comprising about 235 mM to about 265 mM proline. 49. The liquid composition of any one of embodiments 2 to 48, comprising about 240 mM to about 260 mM proline. 50. The liquid composition according to any one of embodiments 2 to 49, wherein the proline is L-proline. 51. A liquid composition according to any one of embodiments 2 to 50, wherein proline is the only amino acid present in the composition. 52. The liquid composition according to any one of embodiments 2 to 51, wherein the buffer is selected from the group consisting of succinate, glutamate, histidine and acetate buffers. 53. The liquid composition according to embodiment 52, wherein the buffer is an acetate buffer. 54. The liquid composition according to embodiment 53, wherein the acetate buffer is prepared using glacial acetic acid. 55. The liquid composition according to any one of embodiments 2 to 54, wherein the buffer is prepared using about 1 mM to about 50 mM of a buffering agent, optionally glacial acetic acid. 56. The liquid composition according to embodiment 55, wherein the buffer is prepared with about 18 mM to about 22 mM buffering agent, optionally with 20 mM glacial acetic acid. 57. A liquid composition according to any one of embodiments 2 to 51, comprising about 30 mM to about 38 mM of a buffering agent, optionally about 34 mM of acetate. 58. The liquid composition according to any one of embodiments 52-57, wherein the pH of the buffer is titrated with sodium hydroxide. 59. The liquid composition of any one of embodiments 1 to 58, comprising 0.001% or less (w / v) of sugar, sugar alcohol, or citrate. 60. The liquid composition of any one of the preceding embodiments, comprising no more than 0.001% (w / v) disaccharides. 61. A liquid composition according to any one of the preceding embodiments, comprising 0.001% or less (w / v) of trehalose or sucrose. 62. The liquid composition of any one of embodiments 1, 3-45, and 59-61, comprising less than about 0.001% (w / v) acetate. 63. The liquid composition of any one of embodiments 1, 3-45, and 59-62, comprising less than about 0.001% (w / v) of a buffering agent. 64. Viscosity is 25℃, 1000s -1 64. The liquid composition according to any one of the preceding embodiments, wherein the viscosity is less than 50 cP at 64°C. 65. Viscosity, 25℃, 1000s -1 66. The liquid composition of embodiment 65, wherein the viscosity is less than 30 cP. 66. Viscosity: 25℃, 1000s -1 67. The liquid composition of embodiment 66, wherein the viscosity is less than 20 cP. 67. Viscosity is 25℃, 1000s -1 68. The liquid composition of embodiment 67, wherein the viscosity is less than or about 10 cP. 68. A liquid composition according to any one of the preceding embodiments, which is isotonic. 69. A liquid composition according to any one of the preceding embodiments, having an osmolality in the range of about 200 mOsm / kg to about 500 mOsm / kg, optionally such as about 225 mOsm / kg to about 400 mOsm / kg. 70. The liquid composition of embodiment 69, having an osmolality in the range of about 250 mOsm / kg to about 350 mOsm / kg. 71. A liquid composition according to any one of embodiments 1 to 70, wherein less than 5% of the antibody is degraded after storage at 2°C to 8°C for at least 12 months or about 12 months or about 20 months to about 26 months, as determined by size exclusion chromatography (SEC). 72. A liquid composition according to any one of embodiments 1 to 71, 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 SEC. 73. A liquid composition according to any one of embodiments 1 to 72, wherein less than 5% of the antibody is degraded after storage at 2°C to 8°C for about 36 to 40 months as determined by SEC. 74. A method for preparing a liquid composition comprising a monoclonal antibody at a target concentration, the target concentration being greater than about 100 mg / mL, the method comprising: (a) combining the monoclonal antibody with a diafiltration (DF) buffer comprising (i) about 50 mM to about 300 mM arginine base and (ii) an amount of glutamate to achieve a molar ratio of arginine to glutamate of about 0.7:1.0 to about 1.1:1.0; and (b) adding a surfactant. 75. The method of embodiment 74, wherein the molar ratio is from about 0.8:1.0 to about 1.1:1.0. 76. The method of embodiment 74 or 75, wherein the DF buffer comprises about 85 mM to about 190 mM L-arginine. 77. The method of any one of embodiments 74 to 76, wherein the DF buffer comprises from about 135 mM to about 165 mM arginine base. 78. The method of any one of embodiments 74 to 77, wherein the DF buffer comprises from about 155 mM to about 185 mM glutamate. 79. The method of embodiment 78, wherein the DF buffer comprises about 150 mM arginine base and about 170 mM glutamate. 80. The method of any one of embodiments 74-79, wherein the pH of the DF buffer is approximately the same as the final pH of the prepared liquid composition. 81. The method of any one of embodiments 74 to 80, wherein the final pH of the prepared liquid composition is from about 4.5 to about 5.5, optionally from about 4.7 to about 5.3. 82. The method of any one of embodiments 74-81, wherein the surfactant is Polysorbate 80. 83. The method of any one of embodiments 74-82, wherein the final concentration of the surfactant is about 0.01% (w / v). 84. A liquid composition prepared by the method of any one of embodiments 74-83. 85. A liquid composition comprising, per mL of the liquid composition, (a) approximately 150 mg to approximately 165 mg of a monoclonal antibody, (b) approximately 22 mg to approximately 26 mg of L-arginine, (c) approximately 22 mg to approximately 26 mg of glutamic acid, and (d) approximately 0.01 mg of PS80, and having a pH of approximately 4.7 to approximately 5.3. 86. The liquid composition of embodiment 84, comprising about 24 mg of L-arginine. 87. The liquid composition of embodiment 84 or 85, comprising about 23 mg of glutamic acid. 88. A liquid composition comprising about 150 mg to about 165 mg of a monoclonal antibody per mL of liquid composition in about 180 mM to about 220 mM proline, about 30 mM to about 38 mM acetate, and about 0.01% (w / v) PS80, and having a pH of about 4.7 to about 5.3. 89. The liquid composition of embodiment 87, comprising about 34 mM acetate. 90. The liquid composition of embodiment 87 or 88, comprising about 200 mM proline. 91. A liquid composition according to any one of embodiments 84 to 89, having a pH of about 5.0. 92. A liquid composition comprising (a) an anti-IL-15 antibody at a concentration greater than about 100 mg / mL, (b) about 70 mM to about 210 mM arginine base, (c) about 80 mM to about 240 mM glutamate, and (d) a surfactant, and having a pH of about 4.5 to about 5.5. 93. The liquid composition of embodiment 92, comprising about 100 mM to about 170 mM arginine base. 94. The liquid composition of embodiment 93, comprising about 120 mM to about 150 mM arginine base. 95. The liquid composition of embodiment 94, comprising about 136 mM arginine base. 96. The liquid composition of any one of embodiments 92 to 95, comprising about 120 mM to about 200 mM glutamate. 97. The liquid composition of embodiment 96, comprising about 140 mM to about 175 mM glutamate. 98. The liquid composition of embodiment 97, comprising about 159 mM glutamate. 99. The liquid composition according to any one of embodiments 92-98, wherein arginine and glutamate are the only amino acids present in the liquid composition. 100. The liquid composition of any one of embodiments 92-99, comprising less than about 0.001% (w / v) acetate. 101. The liquid composition of any one of embodiments 92-100, comprising less than about 0.001% (w / v) of a buffering agent. 102. A liquid composition comprising (a) an anti-IL-15 antibody at a concentration greater than about 100 mg / mL, (b) about 115 mM to about 345 mM proline, (c) a buffer, and (d) a surfactant, the composition having a pH of about 4.5 to about 5.5. 103. The liquid composition of embodiment 102, comprising about 170 mM to about 290 mM proline. 104. The liquid composition of embodiment 103, comprising about 200 mM to about 255 mM proline. 105. The liquid composition of embodiment 104, comprising about 230 mM proline. 106. The liquid composition according to any one of embodiments 102-105, wherein proline is the only amino acid present in the composition. 107. The liquid composition according to any one of embodiments 102 to 106, comprising from about 1 mM to about 100 mM buffer, optionally from about 1 mM to about 50 mM buffer. 108. The liquid composition according to embodiment 107, comprising from about 10 mM to about 30 mM buffer, optionally from about 15 mM to about 25 mM buffer. 109. The liquid composition according to any one of embodiments 102-108, wherein the buffer is selected from the group consisting of succinate, glutamate, histidine and acetate buffers. 110. The liquid composition according to embodiment 109, wherein the buffer is an acetate buffer. 111. The liquid composition of any one of embodiments 92 to 110, comprising 0.001% or less (w / v) of sugar, sugar alcohol, or citrate. 112. The liquid composition of any one of embodiments 92 to 111, comprising 0.001% or less (w / v) disaccharides. 113. The liquid composition of any one of embodiments 92-112, comprising 0.001% or less (w / v) of trehalose or sucrose. 114. The liquid composition of any one of embodiments 92-113, wherein the concentration of anti-IL-15 antibody is less than about 300 mg / mL. 115. The liquid composition of embodiment 114, wherein the concentration of the anti-IL-15 antibody is less than about 250 mg / mL. 116. The liquid composition of any one of embodiments 92 to 115, comprising about 110 mg / mL to about 200 mg / mL of anti-IL-15 antibody. 117. The liquid composition of embodiment 116, comprising about 135 mg / mL to about 165 mg / mL of anti-IL-15 antibody. 118. The liquid composition of embodiment 117, comprising about 140 mg / mL to about 160 mg / mL of anti-IL-15 antibody. 119. The liquid composition of embodiment 118, comprising about 150 mg / mL of anti-IL-15 antibody. 120. The liquid composition of any one of embodiments 92 to 116, comprising about 145 mg / mL to about 182 mg / mL of anti-IL-15 antibody. 121. The liquid composition of embodiment 120, comprising about 155 mg / mL to about 175 mg / mL of anti-IL-15 antibody. 122. The liquid composition of embodiment 121, comprising about 165 mg / mL of anti-IL-15 antibody. 123. The liquid composition according to any one of embodiments 92 to 122, wherein the anti-IL-15 antibody is an IgG1 antibody. 124. The liquid composition of embodiment 123, comprising heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, HC CDR2 of SEQ ID NO: 2, HC CDR3 of SEQ ID NO: 3, light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, LC CDR2 of SEQ ID NO: 5 and LC CDR3 of SEQ ID NO: 6. 125. The liquid composition according to embodiment 123 or 124, comprising the HC variable region of SEQ ID NO:7 and the LC variable region of SEQ ID NO:8. 126. The liquid composition according to any one of embodiments 123 to 125, comprising an HC of SEQ ID NO:9 and an LC of SEQ ID NO:10. 127. The liquid composition according to any one of embodiments 92 to 126, wherein the surfactant is amphiphilic and / or non-ionic. 128. The liquid composition according to embodiment 127, wherein the surfactant is a polysorbate. 129. The liquid composition according to embodiment 128, wherein the surfactant is polysorbate 20 (PS20) or polysorbate 80 (PS80) or a mixture thereof. 130. The liquid composition according to any one of embodiments 92 to 129, comprising a surfactant at a concentration of about 0.001% (w / v) to about 0.050% (w / v). 131. The liquid composition according to embodiment 130, comprising a surfactant at a concentration of about 0.005% (w / v) to about 0.025% (w / v). 132. The liquid composition according to embodiment 131, comprising about 0.01% (w / v) ± 0.001% (w / v) surfactant. 133. The liquid composition according to embodiment 132, comprising about 0.01% (w / v) of polysorbate 80 (PS80). 134. The liquid composition of any one of embodiments 92-133, wherein the surfactant does not significantly change the viscosity of the composition. 135. The liquid composition according to any one of embodiments 92 to 134, having a pH of about 4.6 to about 5.4. 136. The liquid composition of embodiment 135, having a pH of about 4.70 to about 5.30. 137. The liquid composition of embodiment 136, having a pH of about 4.8 to about 5.2. 138. The liquid composition of embodiment 137, having a pH of about 4.9 to about 5.1. 139. The liquid composition of embodiment 138, having a pH of about 5.0. 140. The viscosity of a liquid composition is 25°C, 1000s -1 The liquid composition according to any one of embodiments 92 to 139, having a viscosity of less than 50 cP. 141. The viscosity of a liquid composition is 25°C, 1000s -1 The liquid composition of embodiment 140, wherein the viscosity is less than 30 cP. 142. The viscosity of a liquid composition is 25°C, 1000s -1 The liquid composition of embodiment 141, wherein the viscosity is less than 20 cP. 143. The viscosity of a liquid composition is 25°C, 1000s -1 The liquid composition of embodiment 142, wherein the viscosity is less than or about 10 cP. 144. The liquid composition of any one of embodiments 92-143, wherein the composition is isotonic. 145. A liquid composition according to any one of embodiments 92 to 143, having an osmolality in the range of about 200 mOsm / kg to about 500 mOsm / kg, optionally such as about 225 mOsm / kg to about 400 mOsm / kg. 146. The liquid composition of embodiment 145, having an osmolality in the range of about 250 mOsm / kg to about 350 mOsm / kg. 147. A liquid composition according to any one of embodiments 92 to 146, wherein less than 5% of the antibody is degraded after storage at 2°C to 8°C for at least or about 12 months or about 20 months to about 26 months, as determined by size exclusion chromatography (SEC). 148. A liquid composition according to any one of embodiments 92 to 147, 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 SEC. 149. A liquid composition according to any one of embodiments 92 to 148, wherein less than 5% of the antibody is degraded after storage at 2°C to 8°C for about 36 to 40 months as determined by SEC. A liquid composition comprising, per 150 mL of the liquid composition, (i) about 135 mg to about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, a HC CDR2 of SEQ ID NO: 2, a HC CDR3 of SEQ ID NO: 3, a light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, a LC CDR2 of SEQ ID NO: 5, and a LC CDR3 of SEQ ID NO: 6, (ii) about 21 mg to about 26 mg of an arginine base, (iii) about 21 mg to about 26 mg of a glutamate, and (iv) about 0.01% (w / v) polysorbate 80 (PS80), and having a pH of about 4.5 to about 5.5. 151. A liquid composition comprising, per mL of the liquid composition, (i) about 135 mg to about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) complementarity determining region (CDR) 1 of SEQ ID NO: 1, a HC CDR2 of SEQ ID NO: 2, a HC CDR3 of SEQ ID NO: 3, a light chain (LC) complementarity determining region (CDR) 1 of SEQ ID NO: 4, a LC CDR2 of SEQ ID NO: 5, and a LC CDR3 of SEQ ID NO: 6, (ii) about 23 mg to about 30 mg of proline, (iii) about 0.5 mg to about 2 mg of acetate, and (iv) about 0.01% (w / v) polysorbate 80 (PS80), and having a pH of about 4.5 to about 5.5. 152. A method for preparing a liquid composition comprising a target concentration of an anti-IL-15 antibody, the target concentration being greater than about 100 mg / mL, comprising: (a) combining the antibody with a diafiltration (DF) buffer comprising about 70 mM to about 210 mM arginine base and about 80 mM to about 240 mM glutamate; and (b) adding a surfactant. 153. The method of embodiment 152, wherein the DF buffer comprises from about 100 mM to about 170 mM arginine base. 154. The method of embodiment 153, wherein the DF buffer comprises from about 120 mM to about 150 mM arginine base. 155. The method of embodiment 154, wherein the DF buffer comprises about 136 mM arginine base. 156. The method of any one of embodiments 152-154, wherein the DF buffer comprises from about 120 mM to about 200 mM glutamate. 157. The method of embodiment 156, wherein the DF buffer comprises from about 140 mM to about 175 mM glutamate. 158. The method of embodiment 157, wherein the DF buffer comprises about 159 mM glutamate. 159. The method of any one of embodiments 152-158, wherein arginine and glutamate are the only amino acids present in the DF buffer. 160. The method of any one of embodiments 152-159, wherein the pH of the DF buffer is approximately the same as the final pH of the prepared liquid composition. 161. The method of any one of embodiments 152 to 160, wherein the final pH of the prepared liquid composition is from about 4.5 to about 5.5, optionally from about 4.7 to about 5.3 or from about 4.8 to about 5.2. 162. The method of any one of claims 152 to 161, wherein the surfactant is polysorbate 80. 163. The method of any one of embodiments 152-162, wherein the final concentration of the surfactant is about 0.01% (w / v). 164. A liquid composition prepared by the method according to any one of embodiments 152-163. 165. An article of manufacture comprising the liquid composition of any one of embodiments 1-164, optionally comprising about 1 mL to about 5 mL of the liquid composition. 166. A pre-filled syringe comprising the liquid composition of any one of embodiments 1-165, optionally containing about 1 mL to about 5 mL of the liquid composition. 167. A vial comprising the liquid composition of any one of embodiments 1-166, optionally comprising about 1 mL to about 5 mL of the liquid composition. 168. An autoinjector comprising a liquid composition according to any one of embodiments 1 to 167. 169. A method for treating a disease in a subject, comprising administering to the subject a liquid composition described in any one of embodiments 1 to 168 in an amount effective to treat the disease. 170. Use of a liquid composition according to any one of embodiments 1 to 169 for treating a disease. 171. The method according to embodiment 169 or the use according to embodiment 170, wherein the disease is celiac disease. EXAMPLES

[0067] The following examples are presented merely to illustrate the present invention and are not intended to limit the scope of the invention in any way.

[0068] Example 1 This example demonstrates an exemplary method for producing a highly concentrated antibody formulation.

[0069] A series of studies was conducted to develop an isotonic, low viscosity formulation containing high concentrations of Antibody 1, an anti-IL-15 monoclonal antibody. The formulation was designed to exhibit adequate stability as characterized by initial high molecular weight (HMW) species formation, as well as low HMW species formation upon storage.

[0070] Part A In the first study (Part A), eight formulations were prepared by diafiltration of an initial solution containing antibody 1, acetate, and sucrose against diafiltration (DF) buffer. A total of 10 buffer exchanges were performed to achieve complete buffer exchange. The buffer-exchanged antibody 1 solution was concentrated to approximately 200 mg / mL of antibody 1 using an ultrafiltration / diafiltration (UF / DF) system. The antibody 1 solution was then diluted using the same DF buffer used in the buffer exchange step to achieve a target concentration of 165 mg / mL. Polysorbate 80 (PS80) was then added to a final concentration of 0.01% (w / v). Table 1 summarizes the DF buffer used to make each formulation and the final pH of each formulation. Osmolality for each formulation was measured and found to be in the range of approximately 284 mOsm / kg to approximately 332 mOsm / kg.

[0071] [Table 2]

[0072] Stability testing: Samples of each formulation were filled into containers, sealed, and then stored at 2-8°C for 0, 4, 13, or 26 weeks, or at 30°C for 1, 2, 4, 13, or 26 weeks. The initial formation of HMW species was measured and reported as t=0. Samples were tested via size-exclusion ultra-performance liquid chromatography (SE-UHPLC). The percentage of high molecular weight (HMW) species for the sample was reported, which reflected the amount of HMW species formed after the storage period. The results of the stability assays are shown in Tables 2 and 3. The percent HMW species is shown for each sample. A lower % HMW indicated greater stability for the formulation.

[0073] [Table 3]

[0074] [Table 4]

[0075] viscosity Samples of each formulation were tested for viscosity using a viscometer at 5° C., 15° C., 20° C., 25° C., and 30° C. Viscosity values ​​reported are 1000 s -1 Figure 4 provides the results of this assay.

[0076] [Table 5]

[0077] Freeze-thaw stability To test the stability of the formulations after freeze-thaw cycles, the formulations were filled into vials and frozen at -30°C. The vials were then subjected to five freeze / thaw (F / T) cycles, freezing at (-30)°C and thawing statically at room temperature. Each container was visually inspected for color and the presence of precipitate. After five F / T cycles, most formulations appeared clear and free of visible particles, except for formulation #2, which showed many small translucent crystalline particles, and formulation #4, which showed a few small fibrous particles.

[0078] Discussion of the results: Part A Formulation No. 5 containing arginine glutamate showed very high stability as it had the lowest amount of initial HMW species at both 30° C. and 2-8° C., and the lowest amount of HMW species formed after 26 weeks of storage at each temperature (Tables 2 and 3). As shown in Table 4, Formulation No. 5 containing arginine glutamate showed the lowest viscosity among all over the temperature range (5° C. to 25° C.).

[0079] Like formulation #5, formulation #2 with NAR and proline showed very high stability after 26 weeks of storage at 30° C. However, as discussed above, this formulation was observed to have a high amount of precipitate and high degree of turbidity upon freeze-thaw cycles. Therefore, this formulation was one that was not selected for further testing.

[0080] Formulation 3, which contained proline (no NAR), also had a lower % HMW after 26 weeks of storage. Formulation 3 was also one of the formulations that exhibited lower viscosity over the temperature range.

[0081] Part B In a second study (Part B), seven formulations of Antibody 1 were prepared essentially as described above. This study tested two target concentrations of Antibody 1 (150 mg / mL and 165 mg / mL) and two pHs (4.7 and 5.2). PS80 was added to a final concentration of 0.01% to all formulations except for formulation 5b, where the final PS80 concentration was 0.005% (w / v). Table 5 summarizes the DF buffer used to make each formulation. Osmolality for each formulation was measured and found to be in the range of about 280 mOsm / kg to about 331 mOsm / kg.

[0082] [Table 6]

[0083] The stability of each formulation was tested essentially as described in Part A, while the viscosity was adjusted to 50,800 s to mimic the shear rate associated with manual extrusion of PFS. -1 The viscosity was also tested at 5° C. and 25° C. for two antibody 1 concentrations (150 mg / mL and 165 mg / mL). The stability was also tested at 40° C. during storage in this study (Part B). The viscosity was further tested at 5° C. and 25° C. for two antibody 1 concentrations (150 mg / mL and 165 mg / mL). The stability assay results are reported in Tables 6, 7, and 8, and the viscosity results are shown in Table 9.

[0084] [Table 7]

[0085] [Table 8]

[0086] [Table 9]

[0087] [Table 10]

[0088] Discussion of Results: Part B As shown in Tables 6-8, compared to formulations 1b and 2b containing acetate and sucrose, formulations 2b-5b containing arginine glutamate and formulation 6b containing proline were found to have lower % HMW species after 26 weeks of storage at 2-8°C or 30°C or after 13 weeks of storage at 40°C. Formulations 3b and 4b, each containing arginine glutamate and differing only in pH, performed particularly well among all the formulations tested. As shown in Table 9, formulations 2b-5b containing arginine glutamate and formulations 6b and 7b containing proline showed lower viscosities compared to formulations 1b and 2b. Formulation 6b showed the lowest viscosity at both antibody concentrations and both temperatures. Interestingly, the performance of arginine glutamate did not appear to be dependent on acetate, suggesting that glutamate may function dually as both a counterion to arginine and as a buffering agent.

[0089] conclusion Taken together, these data suggest that antibody 1 at concentrations greater than 100 mg / mL, formulated with about 100 mM to about 200 mM L-arginine base and about 100 mM to about 200 mM L-glutamic acid at pH 4.7-5.2, PS80 (final concentration of 0.010% (w / v)), exhibits high stability and low viscosity as evidenced by low initial HMW species formation and low HMW species formation upon storage. It was surprising that the amounts of arginine and glutamate used in these studies led to such low viscosities (<10 cP at 25° C.) given that similar formulations described in previous studies (e.g., Borwankar et al., Ind. Eng. Chem Res. 55:11225-11234 (2016)) required significantly higher amounts of salt (e.g., 450 mM) to achieve similar viscosities. In previous studies, the viscosity of a formulation containing a similar amount of arginine glutamate was approximately 170 cP.

[0090] The high stability and low viscosity of Antibody 1 at concentrations greater than 100 mg / mL formulated with about 150 mM to about 250 mM proline and about 20 mM acetate was also surprising, given that previous studies had shown that Pro achieved acceptable levels of viscosity reduction only at unrealistically high concentrations (Hung et al., Pharm Res 35:133 (2018)).

[0091] In view of the above, formulations containing arginine glutamate or proline and acetate were selected for further testing and development of formulations containing Antibody 1 at 150 mg / mL.

[0092] Example 2 This example demonstrates that antibodies other than Antibody 1 exhibit increased stability and low viscosity when formulated with arginine base and glutamic acid.

[0093] In this study, five different antibodies were formulated at different concentrations (100 mg / mL, 150 mg / mL, and 200 mg / mL) using either a test DF buffer containing L-arginine base and L-glutamic acid or a control DF buffer containing acetate and sucrose. These formulations were prepared essentially as described in Example 1. PS80 was added after UF / DF to a final concentration of 0.01% (w / v). Antibody 1 is the same as described in Example 1. Antibody 2 is an anti-PD-1 IgG1 antibody, Antibody 3 is an anti-RANKL IgG2 antibody, Antibody 4 is an anti-GITR IgG1 antibody, and Antibody 5 is a reference IgG2 antibody that binds to a different antigen than any of Antibodies 1-4. The components of the test DF buffer used for each of the five antibodies and the five control DF buffers are summarized in Table 10.

[0094] [Table 11]

[0095] Stability was tested via SE-UHPLC after 0 weeks storage at 30° C., 2 weeks storage, and 1 week storage at 40° C., and viscosity was measured essentially as described in Example 1. A summary of the results of the stability assay for each antibody, expressed as % HMW, is provided below in Table 11 and in FIG. 1, and the results of the viscosity assay are provided in Table 12.

[0096] [Table 12]

[0097] [Table 13]

[0098] [Table 14]

[0099] As shown in Table 11, formulation of antibodies with arginine glutamate led to improved stability at an antibody concentration of 200 mg / mL compared to the control DF buffer, with effects observed across all molecules and storage temperatures. The impact of arginine glutamate formulations is to reduce initial % HMW across nearly all five mAbs at three concentrations compared to the control DF buffer.

[0100] For three of the antibodies (Antibodies 1-3), the trends were fairly consistent with respect to the %HMW reduction in Arg-Glu compared to the control DF buffer at antibody concentrations of 150 mg / mL and 100 mg / mL. Antibody 5 deviated slightly from Antibodies 1-3 at higher concentrations, but still showed lower %HMW in Arg-Glu at 30°C, but higher %HMW levels at 150 mg / mL and 100 mg / mL at 40°C. The benefit of Arg-Glu over Antibody 4 appears to be protein concentration and temperature dependent, with a reversal of the %HMW trend observed at 150 mg / mL and 100 mg / mL compared to 200 mg / mL.

[0101] As shown in Table 12, the viscosity results suggest that the Arg-Glu formulation reduces viscosity at the highest protein concentrations for most mAbs compared to the control DF buffer. The results for Antibody 1 indicate that viscosity can be maintained or reduced in the Arg-Glu formulation at slightly higher protein concentrations compared to the control DF buffer formulation.

[0102] Example 3 This example describes a formulation containing high concentrations of Antibody 1.

[0103] Further studies were conducted to develop an isotonic, low viscosity formulation containing high concentrations of Antibody 1. As in Example 1, this formulation was designed to demonstrate adequate stability, as characterized by low initial high molecular weight (HMW) species formation, as well as low HMW species formation upon storage.

[0104] Four formulations (A-D) were prepared by diafiltration of an initial solution containing Antibody 1 (100 mg / mL), acetate, and sucrose against the diafiltration (DF) buffers listed in Table 13. A total of 10 buffer exchanges (10 diavolumes) were performed to achieve complete buffer exchange. The buffer-exchanged Antibody 1 solution was then concentrated to a concentration of >150 mg / mL and then diluted to achieve a target concentration of 150 mg / mL using the same DF buffer used in diafiltration. Polysorbate 80 (PS80) was added to a final concentration of 0.01% (w / v). The target pH of each formulation was 5.0.

[0105] [Table 15]

[0106] The formulations were evaluated for stability, viscosity, and other physical characteristics essentially as described in Example 1. Osmolality for each formulation was measured and found to be in the range of about 275 mOsm / kg to about 330 mOsm / kg. Viscosity was tested at 150 mg / mL and 165 mg / mL at 5° C. and 25° C. The goal of a viscosity of <10 cP at 25° C. was met by all formulations except for Formulation A at 165 mg / mL. A summary of the viscosity results is provided in Table 14.

[0107] [Table 16]

[0108] As shown in Table 14, formulations B through D met the viscosity targets at both concentrations (150 mg / mL and 165 mg / mL).

[0109] The stability of the formulations was evaluated by measuring HMWS levels via SE-UHPLC before and after 13 weeks of storage at -30°C or before and after three freeze-thaw (F / T) cycles (freezing temperature: -30°C; thawing temperature: room temperature) essentially as described in Example 1. All formulations demonstrated stability as evidenced by a <0.5% increase in HMWS after 13 weeks of storage or F / T cycles. Formulations A, B, and D demonstrated the greatest stability as only a 0.2% increase in HMWS was observed after 13 weeks of storage or F / T cycles. As liquids, formulations B and C demonstrated the strongest stability profile across multiple assays, including SEC, CEX, CE, and HIAC. Subvisible particle analysis performed by HIAC revealed that formulations B and C were essentially particle-free. Formulation B had only 416 particles (>10 μm in size) at t=0 and only 64 particles at t=13 weeks. Formulation C had only 208 particles (>10 μm in size) at t=0 and only 526 particles at t=13 weeks.

[0110] In summary, all formulations showed high stability, while formulation B met all set goals for stability and viscosity. Formulation C also showed advantages over other formulations, including high stability, low viscosity, and low subvisible particle count.

[0111] Example 4 This example demonstrates the suitability of the formulations of the present disclosure for long term storage stability.

[0112] Samples of control and test formulations containing one of antibodies 1-5 described in Example 2 at 100, 150 or 200 mg / mL were stored at -30°C or 5°C for 59 weeks. The formulations were prepared as described in Example 2 essentially as described in Example 1. The components of the test DF buffer and the five control DF buffers are summarized in Table 10. PS80 was added after UF / DF to achieve a final concentration of 0.01% (w / v). The storage stability of each formulation was measured essentially as described in Example 1. A summary of the results for each antibody expressed as % HMW is provided below in Table 15.

[0113] [Table 17]

[0114] These results show that the test formulations containing L-arginine base and L-glutamic acid had a lower starting HMW by SEC at t=0 compared to the control formulation lacking L-arginine base and L-glutamic acid, and maintained a lower amount of HMW even after 59 weeks at both storage temperatures (-30° C. and 5° C.). These data support the feasibility of long shelf life for the antibody formulations, for example, 2+ years at -30° C. or 2+ years at 2° C. to 8° C.

[0115] All references cited in this specification, including publications, patent applications, and patents, are herein incorporated by reference to the same extent as if each reference was individually and specifically indicated to be incorporated by reference and was set forth in its entirety herein.

[0116] The use of the terms "a," "an," and "the" and similar referents with respect to the description of this disclosure (and particularly with respect to the claims below) should be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms "comprising," "having," "including," and "containing" should be construed as open-ended terms including the specified components but not excluding other elements (i.e., meaning "including, but not limited to"), unless otherwise specified.

[0117] The recitation of ranges of values ​​herein, unless otherwise indicated herein, is merely intended to serve as a shorthand method of referring individually to each separate value and each endpoint falling within the range, and each separate value and endpoint is incorporated herein as if each separate value and endpoint were individually recited herein.

[0118] All methods described herein may be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any and all examples or exemplary language (e.g., "etc.") provided herein is intended only to clarify the disclosure and does not impose limitations on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0119] Preferred embodiments of the present disclosure are described herein, including the best mode known to the inventors for carrying out the present disclosure. Variations of those preferred embodiments may become apparent to those skilled in the art upon reading the above description. The inventors anticipate that those skilled in the art will adopt such variations as necessary, and the inventors intend for the present disclosure to be practiced in other forms than those specifically described herein. Accordingly, the present disclosure includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements is encompassed in the present disclosure in all possible variations thereof unless otherwise indicated herein or clearly contradicted by context.

Claims

1. 1. A liquid composition comprising: (a) about 110 mg / mL to about 200 mg / mL of an anti-IL-15 antibody; (b) about 100 mM to about 170 mM of arginine base; (c) about 140 mM to about 175 mM of glutamate; and (d) 0.001% (w / v) to 0.050% (w / v) of a surfactant; and a pH of about 4.5 to about 5.5, wherein the anti-IL-15 antibody comprises a heavy chain (HC) variable region of SEQ ID NO:7 and a light chain (LC) variable region of SEQ ID NO:

8.

2. The liquid composition described in claim 1, wherein the anti-IL-15 antibody is an IgG1 antibody.

3. 10. The liquid composition of claim 1, comprising about 120 mM to about 150 mM arginine base.

4. 10. The liquid composition of claim 1, wherein arginine and glutamate are the only amino acids present in said liquid composition.

5. 10. The liquid composition of claim 1, comprising less than about 0.001% (w / v) acetate.

6. 10. The liquid composition of claim 1, comprising less than about 0.001% (w / v) of a buffering agent other than glutamate.

7. 1. A liquid composition comprising: (a) about 110 mg / mL to about 200 mg / mL of an anti-IL-15 antibody; (b) about 170 mM to about 290 mM proline; (c) about 15 mM to about 50 mM of a buffer; and (d) about 0.001% (w / v) to about 0.050% (w / v) of a surfactant; and a pH of about 4.5 to about 5.5, wherein the anti-IL-15 antibody comprises a heavy chain (HC) variable region of SEQ ID NO:7 and a light chain (LC) variable region of SEQ ID NO:

8.

8. The liquid composition of claim 7, wherein the anti-IL-15 antibody is an IgG1 antibody.

9. 8. The liquid composition of claim 7, comprising about 200 mM to about 255 mM proline.

10. 8. The liquid composition of claim 7, wherein proline is the only amino acid present in the composition.

11. The liquid composition of claim 7 , wherein the buffer is acetate.

12. 12. The liquid composition according to claim 1, comprising 0.001% or less (w / v) of a sugar, sugar alcohol or citrate, and / or 0.001% or less (w / v) of a disaccharide.

13. 13. The liquid composition of claim 12, comprising no more than 0.001% (w / v) trehalose or sucrose.

14. The liquid composition of any one of claims 1 to 11, comprising about 150 mg / mL of an anti-IL-15 antibody.

15. The liquid composition according to any one of claims 1 to 11, comprising an HC of SEQ ID NO: 9 and an LC of SEQ ID NO:

10.

16. The liquid composition according to any one of claims 1 to 11, wherein the surfactant is polysorbate 20 (PS20) or polysorbate 80 (PS80) or a mixture thereof.

17. The liquid composition according to any one of claims 1 to 11, having a pH of about 4.7 to about 5.

3.

18. The viscosity of the liquid composition is 1000 s at 25°C. －１ The liquid composition of any one of claims 1 to 11, having a viscosity of less than or about 10 cP.

19. The liquid composition according to any one of claims 1 to 11, which is isotonic.

20. Per mL of the liquid composition: (i) about 135 mg to about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) variable region of SEQ ID NO: 7 and a light chain (LC) variable region of SEQ ID NO: 8; (ii) about 21 mg to about 26 mg arginine base; (iii) about 21 mg to about 26 mg of glutamate; and (iv) about 0.01% (w / v) polysorbate 80 (PS80) and having a pH of about 4.5 to about 5.

5.

21. Per mL of the liquid composition: (i) about 135 mg to about 165 mg of an anti-IL-15 antibody comprising a heavy chain (HC) variable region of SEQ ID NO: 7 and a light chain (LC) variable region of SEQ ID NO: 8; (ii) about 23 mg to about 30 mg proline; (iii) about 0.5 mg to about 2 mg of acetate, and (iv) about 0.01% (w / v) polysorbate 80 (PS80) and having a pH of about 4.5 to about 5.

5.

22. The liquid composition according to any one of claims 1 to 11, 20, or 21, wherein the anti-IL-15 antibody is ordesekimab.

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