Anti il-6 antibody preparation

Abstract

To provide a stable aqueous pharmaceutical preparation containing anti IL-6 antibody which is suitable for therapeutic use.SOLUTION: An antibody preparation contains approximately 5 mg / mL to approximately 120 mg / mL of anti IL-6 antibody and approximately 5 mM to approximately 15 mM of methionine.SELECTED DRAWING: None

Description

[Technical Field]

[0001] 1. CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 841,662, filed May 1, 2019, and European Patent Application No. 19181345.0, filed June 19, 2019, both of which are incorporated herein by reference in their entireties.

[0002] 2. Sequence Listing The instant application contains a Sequence Listing which has been submitted via EFS-Web and is hereby incorporated by reference in its entirety. [Background technology]

[0003] 3.Background technology Elevated IL-6 levels are involved in various diseases and conditions, such as autoimmune diseases, inflammatory diseases, and cancer. See US5856135, WO2004 / 020633, US2006 / 0257407A1, US7291721, and US8198414. Antibodies that bind to and neutralize IL-6 or that reduce IL-6 signaling by binding to the IL-6 receptor have been approved for the treatment of rheumatoid arthritis and Castleman's disease. Recently, anti-IL6 antibodies have been demonstrated to be useful in the treatment of hepcidin-mediated disorders in genotypically selected patients; see US2017 / 0029499A1. For the treatment of diuretic resistance, see WO2018 / 144773. For the treatment of inflammatory cardiovascular diseases, see US2019 / 0241650.

[0004] Therapeutic use of anti-IL-6 antibodies is facilitated by formulations that maintain the stability of the antibody under various conditions. It is important that the therapeutic formulation allow for storage without unacceptable loss of activity of the active antibody, minimize the accumulation of undesirable products such as aggregates or degradation species (e.g., fragmented, oxidized, deamidated, or isomerized species), contain an appropriate concentration of antibody, and contain no components that are incompatible with therapeutic use.

[0005] There is a need in the art for stable aqueous pharmaceutical formulations comprising anti-IL-6 antibodies that are suitable for therapeutic use. Summary of the Invention

[0006] 4. Overview We have designed, produced, and tested anti-IL-6 antibody formulations that reduce the formation of aggregates, acidic species, and oxidized species, which can be used to treat IL-6-mediated diseases.

[0007] Thus, in a first aspect, an antibody formulation is provided herein, which comprises about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody and about 5 mM to about 15 mM of methionine.

[0008] In some embodiments, the anti-IL-6 antibody comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, wherein the VH domain comprises the VH CDR1 sequence of SEQ ID NO: 1, the VH CDR2 sequence of SEQ ID NO: 2, and the VH CDR3 sequence of SEQ ID NO: 3, and the VL domain comprises the VL CDR1 sequence of SEQ ID NO: 4, the VL CDR2 sequence of SEQ ID NO: 5, and the VL CDR3 sequence of SEQ ID NO: 6. In some embodiments, the anti-IL-6 antibody comprises the VH domain amino acid sequence of SEQ ID NO: 7 and the VL domain amino acid sequence of SEQ ID NO: 8. In some embodiments, the anti-IL-6 antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10.

[0009] In some embodiments, the formulation comprises about 7.5 mg / mL to about 30 mg / mL of anti-IL-6 antibody. In some embodiments, the formulation comprises about 7.5 mg / mL of anti-IL-6 antibody. In some embodiments, the formulation comprises about 15 mg / mL of anti-IL-6 antibody. In some embodiments, the formulation comprises about 30 mg / mL of anti-IL-6 antibody.

[0010] In some embodiments, the formulation comprises about 10 mM methionine.

[0011] In some embodiments, the formulation comprises about 0.03% to about 0.1% (w / v) polysorbate 80. In some embodiments, the formulation comprises about 0.05% to about 0.1% (w / v) polysorbate 80. In some embodiments, the formulation comprises about 0.07% (w / v) polysorbate 80.

[0012] In some embodiments, the formulation further comprises about 1% to about 40% (w / v) trehalose, hi some embodiments, the formulation comprises about 5% (w / v) trehalose.

[0013] In some embodiments, the formulation further comprises about 10 mM to about 200 mM arginine, hi some embodiments, the formulation comprises about 70 mM arginine.

[0014] In some embodiments, the formulation further comprises about 10 mM to about 100 mM histidine, hi some embodiments, the formulation comprises about 20 mM histidine.

[0015] In some embodiments, the antibody formulation has a pH of about 5.0 to about 7.0, hi some embodiments, the antibody formulation has a pH of about 6.0.

[0016] In another aspect, provided herein is an antibody formulation comprising about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody, about 5 mM to about 15 mM methionine, and about 0.03% to about 0.1% (w / v) polysorbate 80. In some embodiments, the anti-IL-6 antibody has a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10.

[0017] In another aspect, provided herein is an antibody formulation comprising: a) about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody; b) about 1% to about 40% (w / v) trehalose; c) about 0.03% to about 0.1% (w / v) polysorbate 80; d) about 10 mM to about 200 mM arginine; e) about 5 mM to about 15 mM methionine; and f) about 10 mM to about 100 mM histidine, wherein the antibody formulation has a pH of about 5.0 to about 7.0. In some embodiments, the anti-IL-6 antibody has a heavy chain amino acid sequence of SEQ ID NO:9 and a light chain amino acid sequence of SEQ ID NO:10.

[0018] In another aspect, provided herein is an antibody formulation comprising: a) about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody (the anti-IL-6 antibody has a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10); b) about 5% (w / v) trehalose; c) about 0.07% (w / v) polysorbate 80; d) about 70 mM arginine; e) about 10 mM methionine; and f) about 20 mM histidine; and the antibody formulation has a pH of about 6.0.

[0019] In some embodiments, the formulation comprises about 7.5 mg / mL of anti-IL-6 antibody. In some embodiments, the formulation comprises about 15 mg / mL of anti-IL-6 antibody. In some embodiments, the formulation comprises about 30 mg / mL of anti-IL-6 antibody.

[0020] In some embodiments, the formulation has a viscosity of less than 10 cP at 25°C.

[0021] In some embodiments, the formulation has less than 5% soluble aggregates after 20 hours of stirring at 300 rpm as measured by size exclusion high performance liquid chromatography (SEC-HPLC).

[0022] In some embodiments, the formulation has less than 50% acidic species as measured by imaging-detected capillary isoelectric focusing (icIEF) after 2 weeks of incubation at 45° C. In some embodiments, the acidic species measured are generated by deamidation, isomerization, oxidation, or degradation.

[0023] In some embodiments, the formulation has less than 5% oxidized species after 2 weeks of incubation at 45° C. as measured by reverse phase high performance liquid chromatography (RP-HPLC).

[0024] In some embodiments, the formulation has less than 50% charge variants as measured by imaging capillary isoelectric focusing (icIEF) after 12 months of storage at 5±3° C. In some embodiments, the formulation has less than 50% acidic species as measured by imaging capillary isoelectric focusing (icIEF) after 12 months of storage at 5±3° C.

[0025] In some embodiments, the formulation has less than 10% oxidized species as measured by reverse phase high performance liquid chromatography (RP-HPLC) after 12 months of storage at 5±3° C. In some embodiments, the formulation has less than 6% oxidized species as measured by reverse phase high performance liquid chromatography (RP-HPLC) after 12 months of storage at 5±3° C.

[0026] In some embodiments, the formulation has less than a 50% reduction in potency after 12 months of storage at 5±3° C. as measured by IL-6 binding ELISA. In some embodiments, the formulation has less than a 30% reduction in potency after 12 months of storage at 5±3° C. as measured by IL-6 binding ELISA. In some embodiments, the formulation has less than a 50% reduction in potency after 12 months of storage at 5±3° C. as measured by HEK Blue cell-based bioassay. In some embodiments, the formulation has less than a 30% reduction in potency after 12 months of storage at 5±3° C. as measured by HEK Blue cell-based bioassay.

[0027] In some embodiments, the formulation is suitable for parenteral administration. In some embodiments, the formulation is suitable for intravenous administration. In some embodiments, the formulation is suitable for subcutaneous administration.

[0028] In another aspect, provided herein is a unit dosage form comprising an antibody formulation. In some embodiments, the unit dosage form comprises about 7.5 mg of an anti-IL-6 antibody. In some embodiments, the unit dosage form comprises about 15 mg of an anti-IL-6 antibody. In some embodiments, the unit dosage form comprises about 30 mg of an anti-IL-6 antibody.

[0029] 5. Brief description of the drawings These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description and accompanying drawings. [Brief explanation of the drawings]

[0030] [Figure 1] FIG. 1 shows the effect of L-arginine-HCl on the viscosity of COR-001 formulations at 25° C. with increasing protein concentration. [Figure 2] Figure 2 shows the effect of polysorbate 80 on aggregation of COR-001 formulations upon agitation. The concentrations of COR-001 were 5 mg / mL, 50 mg / mL, and 120 mg / mL, respectively. [Figure 3A] Figures 3A, 3B, and 3C show the effect of methionine on the stability of COR-001 formulations against thermal stress. Figure 3A shows the percentage of aggregates in COR-001 formulations at 45°C in the absence or presence of 5 mM, 10 mM, or 15 mM methionine as measured by SEC-HPLC. Figure 3B shows the percentage of acidic species in COR-001 formulations at 45°C in the absence or presence of 5 mM, 10 mM, or 15 mM methionine as measured by icIEF. Figure 3C shows the percentage of oxidized species in COR-001 formulations at 45°C in the absence or presence of 5 mM, 10 mM, or 15 mM methionine as measured by oxidation testing. The concentrations of COR-001 were 10 mg / mL and 50 mg / mL, respectively. [Figure 3B] See Figure 3A. [Figure 3C] See Figure 3A. [Figure 4A] 4A and 4B show the change in pH over time under accelerated and stressed conditions, respectively, with FIG. 4A showing the change in pH over time under accelerated conditions and FIG. 4B showing the change in pH over time under stressed conditions. [Figure 4B] See Figure 4A. [Figure 5A] Figures 5A and 5B show the change in polysorbate 80 over time under accelerated and stress conditions, with Figure 5A showing the change in polysorbate 80 over time under accelerated conditions and Figure 5B showing the change in polysorbate 80 over time under stress conditions. [Figure 5B] See Figure 5A. [Figure 6A] Figures 6A and 6B show the change in protein concentration over time under accelerated and stressed conditions, with Figure 6A showing the change in protein concentration over time under accelerated conditions and Figure 6B showing the change in protein concentration over time under stressed conditions. [Figure 6B] See Figure 6A. [Figure 7A]Figure 7 shows the change in monomer (non-aggregated bivalent full-length IgG antibody) over time under accelerated and stress conditions as measured by SEC-UHPLC, where Figure 7A shows the change in % monomer over time under accelerated conditions and Figure 7B shows the change in % monomer over time under stress conditions. [Figure 7B] See Figure 7A. [Figure 8A] Figures 8A and 8B show the change in HMW over time under accelerated and stress conditions as measured by SEC-UHPLC, with Figure 8A showing the change in HMW% over time under accelerated conditions and Figure 8B showing the change in HMW% over time under stress conditions. [Figure 8B] See Figure 8A. [Figure 9A] Figures 9A and 9B show the change in LMW over time under accelerated and stress conditions as measured by SEC-UHPLC, with Figure 9A showing the change in LMW% over time under accelerated conditions and Figure 9B showing the change in LMW% over time under stress conditions. [Figure 9B] See Figure 9A. [Figure 10A] Figures 10A and 10B show the change in IgG over time under accelerated and stress conditions as measured by non-reducing CE-SDS, with Figure 10A showing the change in IgG% over time under accelerated conditions and Figure 10B showing the change in IgG% over time under stress conditions. [Figure 10B] See Figure 10A. [Figure 11A] Figures 11A and 11B show the change in HHL over time under accelerated and stress conditions as measured by non-reducing CE-SDS, with Figure 11A showing the change in HHL% over time under accelerated conditions and Figure 11B showing the change in HHL% over time under stress conditions. [Figure 11B] See Figure 11A. [Figure 12A]Figures 12A and 12B show the change in HC+LC over time under accelerated and stress conditions as measured by reduced CE-SDS, with Figure 12A showing the change in HC+LC% over time under accelerated conditions and Figure 12B showing the change in HC+LC% over time under stress conditions. [Figure 12B] See Figure 12A. [Figure 13A] Figures 13A and 13B show the change in the major species over time under accelerated and stress conditions as measured by icIEF, with Figure 13A showing the change in the % major species over time under accelerated conditions and Figure 13B showing the change in the % major species over time under stress conditions. [Figure 13B] See Figure 13A. [Figure 14A] Figures 14A and 14B show the change in acidic species over time under accelerated and stress conditions as measured by icIEF, with Figure 14A showing the change in % acidic species over time under accelerated conditions and Figure 14B showing the change in % acidic species over time under stress conditions. [Figure 14B] See Figure 14A. [Figure 15A] Figures 15A and 15B show the change in basic species over time under accelerated and stress conditions as measured by icIEF, with Figure 15A showing the change in % basic species over time under accelerated conditions and Figure 15B showing the change in % basic species over time under stress conditions. [Figure 15B] See Figure 15A. [Figure 16A] Figures 16A and 16B show the change in oxidation levels over time under accelerated and stress conditions as measured by RP-HPLC, with Figure 16A showing the change in % oxidation over time under accelerated conditions and Figure 16B showing the change in % oxidation over time under stress conditions. [Figure 16B] See Figure 16A. [Figure 17A]Figures 17A, 17B, and 17C show the change in sub-visible particle levels over time under accelerated conditions as measured by MFI, with Figure 17A showing the change in particles 2 microns and larger over time, Figure 17B showing the change in particles 10 microns and larger over time, and Figure 17C showing the change in particles 25 microns and larger over time. [Figure 17B] See Figure 17A. [Figure 17C] See Figure 17A. [Figure 18A] Figures 18A and 18B show the change in antibody potency over time under accelerated and stress conditions as measured by IL-6 binding ELISA assay, where Figure 18A shows the change in % IL-6 binding compared to the reference standard over time under accelerated conditions and Figure 18B shows the change in % IL-6 binding compared to the reference standard over time under stress conditions. [Figure 18B] See Figure 18A. [Figure 19A] Figures 19A and 19B show the change in antibody potency over time under accelerated and stress conditions as measured by a HEK Blue cell-based bioassay, with Figure 19A showing the change in % IL-6 binding relative to the reference standard over time under accelerated conditions and Figure 19B showing the change in % IL-6 binding relative to the reference standard over time under stress conditions. [Figure 19B] See Figure 19A. [Figure 20] FIG. 20 shows the change in pH over time under long-term storage conditions. [Figure 21] FIG. 21 shows the change in polysorbate 80 over time under long-term storage conditions. [Figure 22] FIG. 22 shows the change in protein concentration over time under long-term storage conditions. [Figure 23A]Figures 23A, 23B, and 23C show the change in monomer (non-aggregated bivalent full-length IgG antibody), HMW, and LMW by SEC over time under long-term storage conditions; Figure 23A shows the change in % monomer over time (arrows point to the boundaries of % monomer at 24 months with 95% confidence linear kinetic prediction for all lots, the lots shown are closest to the limits); Figure 23B shows the change in % HMW over time (arrows point to the boundaries of % HMW at 24 months with 95% confidence linear kinetic prediction for all lots, the lots shown are closest to the limits); and Figure 23C shows the change in % LMW over time. [Figure 23B] See Figure 23A. [Figure 23C] See Figure 23A. [Figure 24] 1 shows an overlay of the chromatographic profile of lot CMC-M-0061 comparing the change under long-term storage conditions with the change at 3 months under accelerated (25° C.) and stressed (40° C.) conditions. [Figure 25A] Figures 25A and 25B show the change in IgG and HHL with non-reduced CE-SDS over time under long-term storage conditions, with Figure 25A showing the change in IgG% over time (arrows point to the boundaries of IgG% at 24 months with linear kinetic prediction at 95% confidence for all lots; the lots shown are closest to the limits), and Figure 25B showing the change in HHL% over time. [Figure 25B] See Figure 25A. [Figure 26] FIG. 26 shows an overlay of electrophoretic profiles for lot CMC-M-0061 comparing changes under long-term storage conditions (5° C.) with changes at 3 months under accelerated (25° C.) and stressed (40° C.) conditions. [Figure 27] Figure 27 shows the change in HC+LC with reduced CE-SDS over time under long-term storage conditions (arrows point to the boundaries of HC+LC% at 24 months with linear kinetic prediction at 95% confidence for all lots, with the lots shown exceeding the limits). [Figure 28]FIG. 28 shows an overlay of electrophoretic profiles for lot CMC-M-0061 comparing changes under long-term storage conditions (5° C.) with changes at 3 months under accelerated (25° C.) and stressed (40° C.) conditions. [Figure 29A] Figures 29A, 29B, and 29C show the change in major, acidic, and basic species by icIEF over time under long-term storage conditions, with Figure 29A showing the change in % major species over time, Figure 29B showing the change in % acidic species over time, and Figure 29C showing the change in % basic species over time. [Figure 29B] See Figure 29A. [Figure 29C] See Figure 29A. [Figure 30] Figure 30 shows an overlay of electrophoretic profiles for lot CMC-M-0061 comparing changes under long-term storage conditions (5°C) with changes at 3 months under accelerated conditions (25°C) and stressed conditions (40°C). [Figure 31] FIG. 31 shows the change in oxidation levels over time under long-term storage conditions as measured by RP-HPLC. [Figure 32A] Figures 32A and 32B show the change in the level of sub-visible particles over time under long-term storage conditions as measured by HIAC, with Figure 32A showing the change in particles 10 microns and larger over time and Figure 32B showing the change in particles 25 microns and larger over time. [Figure 32B] See Figure 32A. [Figure 33A] Figures 33A, 33B, and 33C show the change in the level of sub-visible particles over time under long-term storage conditions as measured by MFI, with Figure 33A showing the change in particles 2 microns and larger over time, Figure 33B showing the change in particles 10 microns and larger over time, and Figure 33C showing the change in particles 25 microns and larger over time. [Figure 33B] See Figure 33A. [Figure 33C] See Figure 33A. [Figure 34A]Figures 34A and 34B show the change in antibody potency over time under long-term storage conditions, with Figure 34A showing the change in antibody potency as measured by IL-6 binding ELISA and Figure 34B showing the change in antibody potency as measured by HEK Blue bioassay. [Figure 34B] See Figure 34A. DETAILED DESCRIPTION OF THE INVENTION

[0031] 6. Detailed Description 6.1.Definition Unless otherwise defined, all technical and scientific terms used herein have the meaning commonly understood by one of ordinary skill in the art to which this invention pertains.

[0032] A "stable" antibody formulation is one in which the antibody substantially retains its physical and / or chemical stability and / or its biological activity upon storage. The storage period is generally selected based on the intended shelf life of the formulation. Various analytical techniques for measuring protein stability are available in the art. Examples of analytical techniques are described below. By "substantially retained" is intended 85% or greater retention, e.g., at least 90% retention or at least 95% retention.

[0033] A protein "retains its physical stability" in a pharmaceutical formulation if it does not exhibit significant physical changes, such as aggregation, precipitation, and / or denaturation, upon visual inspection of color and / or clarity or as measured by ultraviolet scattering or size exclusion chromatography.

[0034] A protein "retains its chemical stability" in a pharmaceutical formulation if no significant chemical alteration of the protein is demonstrated. Chemical stability can be assessed by detecting and quantifying chemically altered forms of the protein. Chemical alterations may include size modifications (e.g., clipping), which can be assessed, for example, using size exclusion chromatography, SDS-PAGE, and / or matrix-assisted laser desorption / ionization / time-of-flight mass spectrometry (MALDI / TOF MS). Other types of chemical alterations include charge changes (e.g., resulting from deamidation, oxidation, and / or isomerization), which can be assessed, for example, by ion exchange chromatography.

[0035] An antibody "retains its biological activity" in a pharmaceutical formulation if the biological activity of the antibody at a given time, as determined, for example, in an antigen binding assay, does not change significantly from the biological activity exhibited when the pharmaceutical formulation was prepared. The "biological activity" of a monoclonal antibody refers to the ability of the antibody to bind to an antigen and produce a measurable biological response that can be measured in vitro or in vivo. Such activity may be antagonistic or agonistic.

[0036] A "histidine buffer" is a buffer containing histidine ions. Examples of histidine buffers include histidine chloride solution, histidine acetate solution, histidine phosphate solution, and histidine sulfate solution. Histidine buffers or histidine-HCl buffers have a pH of about 5.5 to about 6.5, about 5.6 to about 6.4, about 5.7 to about 6.3, about 5.8 to about 6.2, about 5.9 to about 6.1, or about 6.0.

[0037] The term "antibody" is used in the broadest sense and specifically includes monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity.

[0038] An "antibody fragment" comprises a portion of a full-length antibody, generally the antigen-binding or variable region thereof. Examples of antibody fragments include Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, scFv (sFv) fragments, scFv-Fc fragments, diabodies, linear antibodies, single-chain antibody molecules, and multispecific antibodies formed from antibody fragments.

[0039] "Interleukin 6 (IL-6)" or "IL-6 polypeptide" refers to a polypeptide or fragment thereof having at least about 85% or more amino acid identity to the amino acid sequence provided in NCBI Accession No. NP_000591 and having IL-6 biological activity. IL-6 is a pleotropic cytokine with multiple biological functions. Exemplary IL-6 biological activities include immunostimulatory and pro-inflammatory activities. "Interleukin 6 (IL-6) nucleic acid" refers to a polynucleotide encoding an interleukin 6 (IL-6) polypeptide. An exemplary interleukin 6 (IL-6) nucleic acid sequence is provided in NCBI Accession No. NM_000600.

[0040] "IL-6 antibody" or "anti-IL-6 antibody" means an antibody that specifically binds to IL-6. Anti-IL-6 antibodies include monoclonal and polyclonal antibodies specific for IL-6, as well as antigen-binding fragments or derivatives thereof. Anti-IL-6 antibodies are described in more detail below in Section 6.2.2.1.

[0041] The "identity" percentage between a polypeptide sequence and a reference sequence is defined as the percentage of amino acid residues in the polypeptide sequence that are identical to the amino acid residues in the reference sequence after aligning the sequences and, if necessary, introducing gaps to achieve the maximum sequence identity percentage.Alignment for determining the amino acid sequence identity percentage can be achieved in various ways within the scope of the art, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software.Those skilled in the art can determine the appropriate parameters for aligning sequences, including any algorithm required to achieve maximum alignment over the entire length of the sequences being compared.Unless otherwise specified, the sequence identity percentage is determined using the BLAST algorithm with default parameters.

[0042] By "IL-6-mediated inflammatory disorder" is meant any disorder in which IL-6 is known or suspected to contribute to the pathogenesis of the disease or any of its symptoms.

[0043] "Subject" means a human or non-human mammal, including, but not limited to, cattle, horses, dogs, sheep, cats, and rodents, including mice and rats. A "patient" is a human subject.

[0044] As used herein, the terms "treat," "treating," "treatment," and the like refer to reducing or alleviating a disorder and / or its associated signs or symptoms, or slowing or halting its progression. Of course, treating a disorder or condition does not require the complete elimination of, but rather the prevention of, the disorder, condition, or symptoms associated therewith.

[0045] In this disclosure, the words "comprises," "comprising," "containing," "having," "includes," "including," and linguistic variations thereof have the meanings ascribed to them in U.S. patent law and allow for the presence of additional elements beyond those expressly recited.

[0046] The term "about" refers to and encompasses the indicated value and the range above and below that value. In certain embodiments, the term "about" refers to the specified value ±10%, ±5%, or ±1%. In certain embodiments, where applicable, the term "about" refers to the specified value ±1 standard deviation of that value. Unless otherwise specified, "about" refers to ±10% of the specified value.

[0047] When ranges are specified, the endpoints are included. Furthermore, unless otherwise indicated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges are understood to be able to assume any specific value or subrange within the stated range in different embodiments of the invention, down to one-tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0048] 6.2. Formulations In a first aspect, provided herein is a sterile, stable aqueous formulation (pharmaceutical composition) comprising an antibody. In some embodiments, the formulation further comprises at least one saccharide. In some embodiments, the formulation further comprises at least one surfactant. In some embodiments, the formulation further comprises at least one free amino acid. In some embodiments, the formulation further comprises at least one antioxidant. In some embodiments, the formulation further comprises at least one buffer component. In certain embodiments, the formulation comprises an antibody, at least one saccharide, at least one surfactant, at least one free amino acid, at least one antioxidant, and at least one buffer component. In a currently preferred embodiment, the formulation comprises about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody and about 5 mM to about 15 mM of methionine.

[0049] 6.2.1. Antibody concentration In some embodiments, the antibody concentration in the formulation is at least about 5 mg / mL, at least about 10 mg / mL, at least about 15 mg / mL, at least about 20 mg / mL, at least about 30 mg / mL, at least about 50 mg / mL, at least about 100 mg / mL, at least about 150 mg / mL, at least about 200 mg / mL, at least about 250 mg / mL, or at least about 300 mg / mL. In some embodiments, the antibody concentration in the formulation is about 5 mg / mL to about 300 mg / mL, about 10 mg / mL to about 250 mg / mL, about 20 mg / mL to about 200 mg / mL, about 30 mg / mL to about 150 mg / mL, or about 50 mg / mL to about 100 mg / mL. In certain embodiments, the antibody concentration in the formulation is about 5 mg / mL, about 7.5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 30 mg / mL, about 50 mg / mL, about 70 mg / mL, about 100 mg / mL, about 120 mg / mL, or about 150 mg / mL.

[0050] In some embodiments, the antibody concentration in the formulation is at least 5 mg / mL, at least 10 mg / mL, at least 15 mg / mL, at least 20 mg / mL, at least 30 mg / mL, at least 50 mg / mL, at least 100 mg / mL, at least 150 mg / mL, at least 200 mg / mL, at least 250 mg / mL, or at least 300 mg / mL. In some embodiments, the antibody concentration in the formulation is 5 mg / mL to 300 mg / mL, 10 mg / mL to 250 mg / mL, 20 mg / mL to 200 mg / mL, 30 mg / mL to 150 mg / mL, or 50 mg / mL to 100 mg / mL. In certain embodiments, the antibody concentration in the formulation is 5 mg / mL, 7.5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 30 mg / mL, 50 mg / mL, 70 mg / mL, 100 mg / mL, 120 mg / mL, or 150 mg / mL.

[0051] 6.2.2. Antibodies In various embodiments, the antibodies described herein include, for example, natural antibodies, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies) formed from at least two antibodies, antibody fragments (e.g., antibody fragments that bind to and / or recognize one or more antigens), murine antibodies, chimeric antibodies, humanized antibodies, human antibodies, and antibodies and antibody fragments isolated from antibody phage libraries.

[0052] The antibodies are directed against one or more antigens. Examples of suitable anti-inflammatory and / or anti-cancer antibodies include anti-TNFα antibodies such as adalimumab, infliximab, etanercept, golimumab, and certolizumab pegol; anti-IL1β antibodies such as canakinumab; anti-IL12 / 23 antibodies such as ustekinumab and briakinumab; anti-IL2R antibodies such as daclizumab; anti-BAFF antibodies such as belimumab; anti-CD20 antibodies such as rituximab; anti-CD22 antibodies such as epratuzumab; anti-CD25 antibodies such as daclizumab; and anti-CD30 antibodies such as iratumumab. Antibodies include, but are not limited to, anti-CD33 antibodies such as gemtuzumab; anti-CD52 antibodies such as alemtuzumab; anti-CD152 antibodies such as ipilimumab; anti-EGFR antibodies such as cetuximab; anti-VEGF antibodies such as bevacizumab; anti-HER2 antibodies such as trastuzumab and pertuzumab; anti-IL-6R antibodies such as tocilizumab, sarilumab, and bovalilizumab; and anti-IL-6 antibodies such as siltuximab, gerilizumab (also known as gelilizumab), and diltibekimab.

[0053] 6.2.2.1. Anti-IL-6 antibody In a currently preferred embodiment, the antibody formulation comprises an anti-IL-6 antibody.

[0054] In various embodiments, the antibody formulation contains about 2 mg / mL to about 200 mg / mL of anti-IL-6 antibody, for example, about 2 mg / mL to about 5 mg / mL, about 2 mg / mL to about 10 mg / mL, about 2 mg / mL to about 30 mg / mL, about 2 mg / mL to about 60 mg / mL, about 2 mg / mL to about 120 mg / mL, about 2 mg / mL to about 200 mg / mL, about 5 mg / mL to about 10 mg / mL, about 5 mg / mL to about 30 mg / mL, about 5 mg / mL to about 60 mg / mL, about 5 mg / mL to about 120 mg / mL, about The anti-IL-6 antibody may be 5 mg / mL to about 200 mg / mL, about 10 mg / mL to about 30 mg / mL, about 10 mg / mL to about 60 mg / mL, about 10 mg / mL to about 120 mg / mL, about 10 mg / mL to about 200 mg / mL, about 30 mg / mL to about 60 mg / mL, about 30 mg / mL to about 120 mg / mL, about 30 mg / mL to about 200 mg / mL, about 60 mg / mL to about 120 mg / mL, about 60 mg / mL to about 200 mg / mL, or about 120 mg / mL to about 200 mg / mL. In various embodiments, the antibody formulation comprises an anti-IL-6 antibody at a concentration of 2 mg / mL to 200 mg / mL, e.g., 2 mg / mL to 5 mg / mL, 2 mg / mL to 10 mg / mL, 2 mg / mL to 30 mg / mL, 2 mg / mL to 60 mg / mL, 2 mg / mL to 120 mg / mL, 2 mg / mL to 200 mg / mL, 5 mg / mL to 10 mg / mL, 5 mg / mL to 30 mg / mL, 5 mg / mL to 60 mg / mL, 5 mg / mL to 120 mg / mL, 5 mg / mL to 60 mg / mL, 5 mg / mL to 120 mg / mL, 5 mg / mL to 5 ... In some embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody. In some embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody. In some embodiments, the antibody formulation comprises 5 mg / mL to 120 mg / mL of anti-IL-6 antibody.

[0055] In typical embodiments, the anti-IL-6 antibody neutralizes the biological activity of IL-6. In some embodiments, the neutralizing antibody prevents IL-6 from binding to the IL-6 receptor.

[0056] In some embodiments, the IL-6 antibody is an anti-IL-6 monoclonal antibody. In some embodiments, the IL-6 antibody is a polyclonal composition comprising multiple types of anti-IL-6 antibodies, each of which has a unique CDR.

[0057] In some embodiments, the anti-IL-6 antibody is a Fab, Fab', F(ab')2, Fv, scFv, (scFv)2, single-chain antibody molecule, dual variable domain antibody, single variable domain antibody, linear antibody, or V-domain antibody.

[0058] In some embodiments, the anti-IL-6 antibody comprises a heavy chain constant region. In certain embodiments, the heavy chain constant region is Fc, optionally human Fc. In some embodiments, the anti-IL-6 antibody comprises a heavy chain constant region of a class selected from IgG, IgA, IgD, IgE, and IgM. In certain embodiments, the anti-IL-6 antibody comprises a heavy chain constant region of the class IgG and a subclass selected from IgG1, IgG2, IgG3, and IgG4.

[0059] In some embodiments, the antibody is bispecific or multispecific, and at least one of the antigen-binding portions has specificity for IL-6.

[0060] In some embodiments, the antibody is fully human. In some embodiments, the antibody is humanized. In some embodiments, the antibody is chimeric, having non-human V region and human C region domains. In some embodiments, the antibody is murine.

[0061] In an exemplary embodiment, the anti-IL-6 antibody has a K for binding to human IL-6 of less than 100 nM. DIn some embodiments, the anti-IL-6 antibody has a K for binding to human IL-6 of less than 75 nM, 50 nM, 25 nM, 20 nM, 15 nM, or 10 nM. D In certain embodiments, the anti-IL-6 antibody has a K for binding to human IL-6 of less than 5 nM, 4 nM, 3 nM, or 2 nM. D In selected embodiments, the anti-IL-6 antibody has a K for binding to human IL-6 of less than 1 nM, 750 pM, or 500 pM. D In specific embodiments, the anti-IL-6 antibody has a K for binding to human IL-6 of 500 pM, 400 pM, 300 pM, 200 pM, or 100 pM or less. D It has.

[0062] In typical embodiments, the anti-IL-6 antibody has an elimination half-life after intravenous administration of at least 7 days. In certain embodiments, the anti-IL-6 antibody has an elimination half-life of at least 14 days, at least 21 days, or at least 30 days.

[0063] In some embodiments, the anti-IL-6 antibody has a human IgG constant region with at least one amino acid substitution that extends serum half-life compared to an unsubstituted human IgG constant domain.

[0064] In certain embodiments, the IgG constant domain comprises substitutions at residues 252, 254, and 256, wherein the amino acid substitution at amino acid residue 252 is with tyrosine, the amino acid substitution at amino acid residue 254 is with threonine, and the amino acid substitution at amino acid residue 256 is with glutamic acid ("YTE"). See US 7,083,784 (incorporated herein by reference in its entirety). In certain extended half-life embodiments, the IgG constant domain comprises substitutions selected from T250Q / M428L (Hinton et al., J. Immunology 176:346-356 (2006)), N434A (Yeung et al., J. Immunology 182:7663-7671 (2009)), or T307A / E380A / N434A (Petkova et al., International Immunology, 18:1759-1769 (2006)).

[0065] In some embodiments, the terminal half-life of an anti-IL-6 antibody is increased by utilizing the FcRN binding properties of human serum albumin. In certain embodiments, the antibody is conjugated to albumin (Smith et al., Bioconjug. Chem., 12:750-756 (2001)). In some embodiments, the anti-IL-6 antibody is fused to a bacterial albumin-binding domain (Stork et al., Prot. Eng. Design Science 20:569-576 (2007)). In some embodiments, the anti-IL-6 antibody is fused to an albumin-binding peptide (Nguygen et al., Prot Eng Design Sel 19:291-297 (2006)). In some embodiments, the anti-IL-6 antibody is bispecific, with one specificity directed against IL-6 and one specificity directed against human serum albumin (Ablynx, WO2006 / 122825 (bispecific nanobody)).

[0066] In some embodiments, the terminal half-life of an anti-IL-6 antibody is increased by PEGylation (Melmed et al., Nature Reviews Drug Discovery 7:641-642 (2008)), HPMA copolymer conjugation (Lu et al., Nature Biotechnology 17:1101-1104 (1999)), dextran conjugation (Nuclear Medicine Communications, 16:362-369 (1995)), conjugation to homoamino acid polymers (HAPs; HAPylation) (Schlapschy et al., Prot Eng Design Sel 20:273-284 (2007)), or polysialylation (Constantinou et al., Bioconjug. Chem. 20:924-931 (2009)).

[0067] In some embodiments, the anti-IL-6 antibody comprises all six CDRs of COR-001 (also known as diltibeximab and MEDI5117), siltuximab, gerilimuzumab, sirukumab, clazakizumab, olokizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), or FM101 (Femta Pharmaceuticals, Lonza). In some embodiments, the anti-IL-6 antibody comprises the VH and VL domains of COR-001, siltuximab, gerilimuzumab, sirukumab, clazakizumab, olokizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), or FM101 (Femta Pharmaceuticals, Lonza). In some embodiments, the anti-IL-6 antibody is COR-001 (diltibeximab), siltuximab, gerilimuzumab, sirukumab, clazakizumab, olokizumab, VX30 (VOP-R003; Vaccinex), EB-007 (EBI-029; Eleven Bio), or FM101 (Femta Pharmaceuticals, Lonza) (i.e., including its heavy and light chains).

[0068] COR-001 and derivatives In certain preferred embodiments, the anti-IL-6 antibody, or antigen-binding portion thereof, comprises all six CDRs of COR-001. The COR-001 antibody (also known as diltibekimab and MEDI5117) is described in WO2010 / 088444 and US2012 / 0034212, the disclosures of which are incorporated herein by reference in their entireties. In certain embodiments, the antibody, or antigen-binding portion thereof, comprises the COR-001 heavy chain V region and light chain V region. In a specific embodiment, the antibody is a full-length COR-001 antibody. The COR-001 antibody has the following CDR, VH, VL, heavy chain, and light chain sequences: COR-001 VH CDR1 SNYMI ((SEQ ID NO: 1) COR-001 VH CDR2 DLYYYAGDTYYADSVKG (SEQ ID NO: 2) COR-001 VH CDR3 WADDHPPWIDL (SEQ ID NO: 3) COR-001 VL CDR1 RASQGISSWLA (SEQ ID NO: 4) COR-001 VL CDR2 KASTLES (SEQ ID NO: 5) COR-001 VL CDR3 QQSWLGGS (SEQ ID NO: 6) COR-001 VH EVQLVESGGGLVQPGGSLRLSCAASGFTISSNYMIWVRQAPGKGLEWVSDLYYYAGDTYY ADSVKGRFTMSRDISKNTVYLQMNSLRAEDTAVYYCARWADDHPPWIDLWGRGTLVTVSS (SEQ ID NO: 7) COR-001 VL DIQMTQSPSTLSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKVLIYKASTLESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQSWLGGSFGQGTKLEIK (SEQ ID NO: 8) COR-001 heavy chain EVQLVESGGGLVQPGGSLRLSCAASGFTISSNYMIWVRQAPGKGLEWVSDLYYYAGDTYY ADSVKGRFTMSRDISKNTVYLQMNSLRAEDTAVYYCARWADDHPPWIDLWGRGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALAPIEKTISKAKGQPREPQVYTLPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 9) COR-001 light chain DIQMTQSPSTLSASVGDRVTITCRASQGISSWLAWYQQKPGKAPKVLIYKASTLESGVPS RFSGSGSGTEFTLTISSLQPDDFATYYCQQSWLGGSFGQGTKLEIKRTVAAPSVFIFPPS DEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTL SKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 10)

[0069] In various embodiments, the anti-IL-6 antibody is a derivative of COR-001. In some embodiments, the derivative of COR-001 comprises a VH CDR1 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 1. In some embodiments, the derivative of COR-001 comprises a VH CDR2 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 2. In some embodiments, the derivative of COR-001 comprises a VH CDR3 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 3. In some embodiments, a derivative of COR-001 comprises a VL CDR1 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 4. In some embodiments, a derivative of COR-001 comprises a VL CDR2 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 5. In some embodiments, a derivative of COR-001 comprises a VL CDR3 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 6.

[0070] In certain embodiments, a derivative of COR-001 comprises a VH domain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 7. In certain embodiments, a derivative of COR-001 comprises a VL domain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 8. In specific embodiments, a derivative of COR-001 comprises a VH domain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 7 and a VL domain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 8.

[0071] In certain embodiments, a derivative of COR-001 comprises a heavy chain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 9. In certain embodiments, a derivative of COR-001 comprises a light chain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 10. In specific embodiments, a derivative of COR-001 comprises a heavy chain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 9 and a light chain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity to SEQ ID NO: 10.

[0072] 6.2.3. Antioxidants In some embodiments, the formulation comprises an antioxidant.

[0073] In various embodiments, the antioxidant is present at a concentration of about 1 mM to about 100 mM, e.g., about 2 mM to about 80 mM, about 3 mM to about 50 mM, about 5 mM to about 30 mM, or about 10 mM to about 20 mM. In various embodiments, the antioxidant is present at a concentration of 1 mM to 100 mM, e.g., 2 mM to 80 mM, 3 mM to 50 mM, 5 mM to 30 mM, or 10 mM to 20 mM.

[0074] In certain embodiments, the antioxidant is a naturally occurring compound. In certain other embodiments, the antioxidant is a synthetic compound. In some embodiments, the antioxidant is selected from a chelating agent, a reducing agent, an oxygen scavenger, and a chain terminator, such as superoxide dismutase (SOD), vitamin C or E, methionine, cysteine, glutathione, EDTA, sodium thiosulfate, catalase, or platinum. In some embodiments, the antioxidant is citric acid, uric acid, ascorbic acid, lipoic acid, glutathione, tocopherol, carotene, lycopene, cysteine, or methionine.

[0075] Methionine In currently preferred embodiments, the formulation includes methionine. In some embodiments, the formulation includes L-methionine.

[0076] In some embodiments, the formulation comprises at least about 1 mM, at least about 2 mM, at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 25 mM, at least about 50 mM, or at least about 100 mM methionine. In various embodiments, the formulation comprises about 1 mM to about 100 mM, about 2 mM to about 80 mM, about 5 mM to about 50 mM, or about 10 mM to about 20 mM methionine. In certain embodiments, the formulation comprises about 1 mM, about 2 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 50 mM, or about 100 mM methionine. In some embodiments, the formulation comprises about 1 mM to about 50 mM methionine. In certain embodiments, the formulation comprises about 5 mM to about 15 mM methionine. In a specific embodiment, the formulation comprises about 10 mM methionine.

[0077] In some embodiments, the formulation comprises at least 1 mM, at least 2 mM, at least 5 mM, at least 10 mM, at least 15 mM, at least 20 mM, at least 25 mM, at least 50 mM, or at least 100 mM methionine. In various embodiments, the formulation comprises 1 mM to 100 mM, 2 mM to 80 mM, 5 mM to 50 mM, or 10 mM to 20 mM methionine. In certain embodiments, the formulation comprises 1 mM, 2 mM, 5 mM, 10 mM, 15 mM, 20 mM, 25 mM, 50 mM, or 100 mM methionine. In some embodiments, the formulation comprises 1 mM to 50 mM methionine. In certain embodiments, the formulation comprises 5 mM to 15 mM methionine. In a specific embodiment, the formulation comprises 10 mM methionine.

[0078] Surfactants In some embodiments, the composition includes a surfactant. The surfactant can reduce the surface tension of the liquid. In some embodiments, the surfactant is a non-ionic surfactant. Examples of surfactants include polysorbates (polyoxyethylene sorbitan monolaurate, such as polysorbate 20 and polysorbate 80); TRITON (t-octylphenoxypolyethoxyethanol); sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine; linoleyl-, Examples of surfactants include myristyl or cetyl betaine; lauroamidopropyl, cocamidopropyl, linoleamidopropyl, myristamidopropyl, palmidopropyl, or isostearamidopropyl betaine (e.g., lauroamidopropyl); myristamidopropyl, palmidopropyl, or isostearamidopropyl dimethylamine; sodium methyl cocoyl tartrate or disodium methyl oleyl tartrate; sorbitan monopalmitate; MONAQUAT series (Mona Industries, Inc., Paterson, NJ); polyethyl glycol (PEG), polypropylene glycol (PPG), and copolymers of poloxyethylene and poloxypropylene glycol (e.g., Pluronics / Poloxamer, PF68, etc.). In some of these embodiments, the surfactant is a polysorbate. In certain embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0079] In various embodiments, the composition includes a surfactant at a concentration of about 0.001% to about 1%, e.g., about 0.001% to about 0.1%, about 0.005% to about 0.2%, about 0.01% to about 0.2%, or about 0.05% to about 0.1% (w / v). In various embodiments, the composition includes a surfactant at a concentration of 0.001% to 1%, e.g., 0.001% to 0.1%, 0.005% to 0.2%, 0.01% to 0.2%, or 0.05% to 0.1% (w / v).

[0080] Polysorbate 80 In some embodiments, the formulation comprises polysorbate 80 (PS80).

[0081] In some embodiments, the formulation comprises at least about 0.001%, at least about 0.002%, at least about 0.003%, at least about 0.005%, at least about 0.01%, at least about 0.02%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.5%, or at least about 1% (w / v) polysorbate 80. In some embodiments, the formulation comprises between about 0.001% and about 1%, between about 0.002% and about 0.5%, between about 0.005% and about 0.2%, or between about 0.01% and about 0.1% (w / v) polysorbate 80. In some embodiments, the formulation comprises about 0.001%, about 0.002%, about 0.003%, about 0.005%, about 0.01%, about 0.02%, about 0.05%, about 0.07%, about 0.1%, about 0.2%, about 0.5%, or about 1% (w / v) polysorbate 80. In certain embodiments, the formulation comprises about 0.005% to about 0.5% (w / v) polysorbate 80. In certain embodiments, the formulation comprises about 0.03% to about 0.1% (w / v) polysorbate 80. In certain embodiments, the formulation comprises about 0.05% to about 0.1% (w / v) polysorbate 80. In certain embodiments, the formulation comprises about 0.07% (w / v) polysorbate 80.

[0082] In some embodiments, the formulation comprises at least 0.001%, at least 0.002%, at least 0.003%, at least 0.005%, at least 0.01%, at least 0.02%, at least 0.05%, at least 0.1%, at least 0.2%, at least 0.5%, or at least 1% (w / v) polysorbate 80. In some embodiments, the formulation comprises 0.001% to 1%, 0.002% to 0.5%, 0.005% to 0.2%, or 0.01% to 0.1% (w / v) polysorbate 80. In some embodiments, the formulation comprises 0.001%, 0.002%, 0.003%, 0.005%, 0.01%, 0.02%, 0.05%, 0.07%, 0.1%, 0.2%, 0.5%, or 1% (w / v) polysorbate 80. In certain embodiments, the formulation comprises 0.005% to 0.5% (w / v) polysorbate 80. In certain embodiments, the formulation comprises 0.03% to 0.1% (w / v) polysorbate 80. In certain embodiments, the formulation comprises 0.05% to 0.1% (w / v) polysorbate 80. In certain embodiments, the formulation comprises 0.07% (w / v) polysorbate 80.

[0083] Polysorbate 60 In some embodiments, the formulation comprises polysorbate 60 (PS60).

[0084] In some embodiments, the formulation comprises at least about 0.001%, at least about 0.002%, at least about 0.003%, at least about 0.005%, at least about 0.01%, at least about 0.02%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.5%, or at least about 1% (w / v) polysorbate 60. In some embodiments, the formulation comprises between about 0.001% and about 1%, between about 0.002% and about 0.5%, between about 0.005% and about 0.2%, or between about 0.01% and about 0.1% (w / v) polysorbate 60. In some embodiments, the formulation comprises about 0.001%, about 0.002%, about 0.003%, about 0.005%, about 0.01%, about 0.02%, about 0.05%, about 0.07%, about 0.1%, about 0.2%, about 0.5%, or about 1% (w / v) polysorbate 60. In certain embodiments, the formulation comprises about 0.03% to about 0.1% (w / v) polysorbate 60. In certain embodiments, the formulation comprises about 0.05% to about 0.1% (w / v) polysorbate 60. In certain embodiments, the formulation comprises about 0.07% (w / v) polysorbate 60.

[0085] In some embodiments, the formulation comprises at least 0.001%, at least 0.002%, at least 0.003%, at least 0.005%, at least 0.01%, at least 0.02%, at least 0.05%, at least 0.1%, at least 0.2%, at least 0.5%, or at least 1% (w / v) polysorbate 60. In some embodiments, the formulation comprises 0.001% to 1%, 0.002% to 0.5%, 0.005% to 0.2%, or 0.01% to 0.1% (w / v) polysorbate 60. In some embodiments, the formulation comprises 0.001%, 0.002%, 0.003%, 0.005%, 0.01%, 0.02%, 0.05%, 0.07%, 0.1%, 0.2%, 0.5%, or 1% (w / v) polysorbate 60. In certain embodiments, the formulation comprises 0.03%-0.1% (w / v) polysorbate 60. In certain embodiments, the formulation comprises 0.05%-0.1% (w / v) polysorbate 60. In certain embodiments, the formulation comprises 0.07% (w / v) polysorbate 60.

[0086] Polysorbate 40 In some embodiments, the formulation comprises polysorbate 40 (PS40).

[0087] In some embodiments, the formulation comprises at least about 0.001%, at least about 0.002%, at least about 0.003%, at least about 0.005%, at least about 0.01%, at least about 0.02%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.5%, or at least about 1% (w / v) polysorbate 40. In some embodiments, the formulation comprises between about 0.001% and about 1%, between about 0.002% and about 0.5%, between about 0.005% and about 0.2%, or between about 0.01% and about 0.1% (w / v) polysorbate 40. In some embodiments, the formulation comprises about 0.001%, about 0.002%, about 0.003%, about 0.005%, about 0.01%, about 0.02%, about 0.05%, about 0.07%, about 0.1%, about 0.2%, about 0.5%, or about 1% (w / v) polysorbate 40. In certain embodiments, the formulation comprises about 0.03% to about 0.1% (w / v) polysorbate 40. In certain embodiments, the formulation comprises about 0.05% to about 0.1% (w / v) polysorbate 40. In certain embodiments, the formulation comprises about 0.07% (w / v) polysorbate 40.

[0088] In some embodiments, the formulation comprises at least 0.001%, at least 0.002%, at least 0.003%, at least 0.005%, at least 0.01%, at least 0.02%, at least 0.05%, at least 0.1%, at least 0.2%, at least 0.5%, or at least 1% (w / v) polysorbate 40. In some embodiments, the formulation comprises 0.001% to 1%, 0.002% to 0.5%, 0.005% to 0.2%, or 0.01% to 0.1% (w / v) polysorbate 40. In some embodiments, the formulation comprises 0.001%, 0.002%, 0.003%, 0.005%, 0.01%, 0.02%, 0.05%, 0.07%, 0.1%, 0.2%, 0.5%, or 1% (w / v) polysorbate 40. In certain embodiments, the formulation comprises 0.03%-0.1% (w / v) polysorbate 40. In certain embodiments, the formulation comprises 0.05%-0.1% (w / v) polysorbate 40. In certain embodiments, the formulation comprises 0.07% (w / v) polysorbate 40.

[0089] Polysorbate 20 In some embodiments, the formulation comprises polysorbate 20 (PS20).

[0090] In some embodiments, the formulation comprises at least about 0.001%, at least about 0.002%, at least about 0.003%, at least about 0.005%, at least about 0.01%, at least about 0.02%, at least about 0.05%, at least about 0.1%, at least about 0.2%, at least about 0.5%, or at least about 1% (w / v) polysorbate 20. In some embodiments, the formulation comprises between about 0.001% and about 1%, between about 0.002% and about 0.5%, between about 0.005% and about 0.2%, or between about 0.01% and about 0.1% (w / v) polysorbate 20. In some embodiments, the formulation comprises about 0.001%, about 0.002%, about 0.003%, about 0.005%, about 0.01%, about 0.02%, about 0.05%, about 0.07%, about 0.1%, about 0.2%, about 0.5%, or about 1% (w / v) polysorbate 20. In certain embodiments, the formulation comprises about 0.03% to about 0.1% (w / v) polysorbate 20. In certain embodiments, the formulation comprises about 0.05% to about 0.1% (w / v) polysorbate 20. In certain embodiments, the formulation comprises about 0.07% (w / v) polysorbate 20.

[0091] In some embodiments, the formulation comprises at least 0.001%, at least 0.002%, at least 0.003%, at least 0.005%, at least 0.01%, at least 0.02%, at least 0.05%, at least 0.1%, at least 0.2%, at least 0.5%, or at least 1% (w / v) polysorbate 20. In some embodiments, the formulation comprises 0.001% to 1%, 0.002% to 0.5%, 0.005% to 0.2%, or 0.01% to 0.1% (w / v) polysorbate 20. In some embodiments, the formulation comprises 0.001%, 0.002%, 0.003%, 0.005%, 0.01%, 0.02%, 0.05%, 0.07%, 0.1%, 0.2%, 0.5%, or 1% (w / v) polysorbate 20. In certain embodiments, the formulation comprises 0.03% to 0.1% (w / v) polysorbate 20. In certain embodiments, the formulation comprises 0.05% to 0.1% (w / v) polysorbate 20. In certain embodiments, the formulation comprises 0.07% (w / v) polysorbate 20.

[0092] Sugars In some embodiments, the composition comprises sugars and their derivatives, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, and the like. Examples of sugars include glucose, mannose, sucrose, trehalose, lactose, fructose, maltose, dextran, dextrin, erythritol, glycerol, arabitol, syritol, sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, isomaltulose, and the like. In some embodiments, the sugar is a disaccharide. In certain embodiments, the disaccharide is trehalose or sucrose. In various embodiments, the disaccharides are present at a concentration of about 1% to about 40%, about 2% to about 20%, or about 2% to about 10% (w / v).In various embodiments, the disaccharides are present at a concentration of 1% to 40%, 2% to 20%, or 2% to 10% (w / v).

[0093] Trehalose In some embodiments, the formulation comprises trehalose.

[0094] In various embodiments, the formulation comprises about 1% to about 50% (w / v) trehalose (as trehalose dihydrate). In some embodiments, the formulation comprises at least about 1%, at least about 2%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, or at least about 40% (w / v) trehalose. In some embodiments, the formulation comprises about 1% to about 40%, about 2% to about 30%, about 3% to about 20%, about 5% to about 15%, or about 5% to about 10% (w / v) trehalose. In certain embodiments, the formulation comprises about 1%, about 2%, about 3%, about 5%, about 10%, about 15%, about 20%, about 30%, or about 40% (w / v) trehalose. In a specific embodiment, the formulation comprises about 5% (w / v) trehalose.

[0095] In various embodiments, the formulation comprises 1% to 50% (w / v) trehalose (as trehalose dihydrate). In some embodiments, the formulation comprises at least 1%, at least 2%, at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, or at least 40% (w / v) trehalose. In some embodiments, the formulation comprises 1% to 40%, 2% to 30%, 3% to 20%, 5% to 15%, or 5% to 10% (w / v) trehalose. In certain embodiments, the formulation comprises 1%, 2%, 3%, 5%, 10%, 15%, 20%, 30%, or 40% (w / v) trehalose. In specific embodiments, the formulation comprises 5% (w / v) trehalose.

[0096] Sucrose In some embodiments, the formulation comprises sucrose.

[0097] In some embodiments, the formulation contains at least about 1%, at least about 2%, at least about 3%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 30%, or at least about 40% (w / v) sucrose. In some embodiments, the formulation contains about 1% to about 40%, about 2% to about 30%, about 3% to about 20%, about 5% to about 15%, or about 5% to about 10% (w / v) sucrose. In certain embodiments, the formulation contains about 1%, about 2%, about 3%, about 5%, about 10%, about 15%, about 20%, about 30%, or about 40% (w / v) sucrose. In a specific embodiment, the formulation contains about 5% (w / v) sucrose.

[0098] In some embodiments, the formulation contains at least 1%, at least 2%, at least 3%, at least 5%, at least 10%, at least 15%, at least 20%, at least 30%, or at least 40% (w / v) sucrose. In some embodiments, the formulation contains 1%-40%, 2%-30%, 3%-20%, 5%-15%, or 5%-10% (w / v) sucrose. In certain embodiments, the formulation contains 1%, 2%, 3%, 5%, 10%, 15%, 20%, 30%, or 40% (w / v) sucrose. In specific embodiments, the formulation contains 5% (w / v) sucrose.

[0099] Free Amino Acids In some embodiments, the formulation comprises at least one free amino acid. In some embodiments, the formulation comprises one free amino acid. In some embodiments, the formulation comprises two free amino acids. In some embodiments, the formulation comprises three free amino acids. The free amino acids may be L-, D-, or a mixture of these forms.

[0100] In certain embodiments, the at least one free amino acid is glycine, glutamine, asparagine, histidine, arginine, or lysine. In various embodiments, the free amino acid is at a concentration of about 1 mM to about 400 mM, e.g., about 2 mM to about 300 mM, about 5 mM to about 200 mM, or about 10 mM to about 100 mM. In various embodiments, the free amino acid is at a concentration of 1 mM to 400 mM, e.g., 2 mM to 300 mM, 5 mM to 200 mM, or 10 mM to 100 mM.

[0101] In some embodiments, the formulation comprises methionine and at least one additional free amino acid selected from glycine, glutamine, asparagine, histidine, arginine, and lysine. In certain embodiments, the formulation comprises methionine and arginine. In certain embodiments, the formulation comprises methionine, arginine, and histidine.

[0102] Arginine In some embodiments, the formulation comprises arginine, hi some embodiments, the formulation comprises L-arginine.

[0103] In various embodiments, the formulation contains about 5 mM to about 500 mM arginine (as arginine-HCl). In some embodiments, the formulation contains at least about 5 mM, at least about 10 mM, at least about 20 mM, at least about 30 mM, at least about 50 mM, at least about 70 mM, at least about 80 mM, at least about 100 mM, at least about 150 mM, at least about 200 mM, or at least about 400 mM arginine. In various embodiments, the formulation contains about 5 mM to about 400 mM, about 10 mM to about 200 mM, about 20 mM to about 150 mM, about 30 mM to about 100 mM, or about 50 mM to about 80 mM arginine. In certain embodiments, the formulation comprises about 5 mM, about 10 mM, about 20 mM, about 30 mM, about 50 mM, about 70 mM, about 80 mM, about 100 mM, about 150 mM, about 200 mM, or about 400 mM arginine. In certain embodiments, the formulation comprises about 10 mM to about 200 mM arginine. In a specific embodiment, the formulation comprises about 70 mM arginine.

[0104] In various embodiments, the formulation comprises 5 mM to 500 mM arginine (as arginine-HCl). In some embodiments, the formulation comprises at least 5 mM, at least 10 mM, at least 20 mM, at least 30 mM, at least 50 mM, at least 70 mM, at least 80 mM, at least 100 mM, at least 150 mM, at least 200 mM, or at least 400 mM arginine. In various embodiments, the formulation comprises 5 mM to 400 mM, 10 mM to 200 mM, 20 mM to 150 mM, 30 mM to 100 mM, or 50 mM to 80 mM arginine. In certain embodiments, the formulation contains 5 mM, 10 mM, 20 mM, 30 mM, 50 mM, 70 mM, 80 mM, 100 mM, 150 mM, 200 mM, or 400 mM arginine. In certain embodiments, the formulation contains 10 mM to 200 mM arginine. In a specific embodiment, the formulation contains 70 mM arginine.

[0105] 6.2.7. Buffers In some embodiments, the formulation comprises at least one buffering agent (buffering component). Typically, when present, the buffering agent is used to adjust the pH of the formulation to about 4.0 to about 8.0, about 4.5 to about 7.5, about 5.0 to about 7.0, about 5.5 to about 6.5, about 5.7 to about 6.3, about 5.9 to about 6.1, or about 6.0.

[0106] In various embodiments, at least one buffering agent is selected from acetate, succinate, gluconate, histidine, citrate, phosphate, maleate, cacodylate, 2-[N-morpholino]ethanesulfonic acid (MES), bis(2-hydroxyethyl)iminotris[hydroxymethyl]methane (Bis-Tris), N-[2-acetamido]-2-iminodiacetic acid (ADA), glycylglycine, and other organic acid buffers. In some of these embodiments, the buffering agent is histidine, citrate, phosphate, glycine, or acetate. In various embodiments, the buffering components are at a concentration of about 1 mM to about 200 mM, about 1 mM to about 50 mM, or about 5 mM to about 20 mM. In various embodiments, the buffering components are at a concentration of 1 mM to about 200 mM, about 1 mM to about 50 mM, or about 5 mM to about 20 mM. In certain embodiments, the buffer components are at a concentration of about 10 mM, about 15 mM, about 20 mM, or about 25 mM. In certain embodiments, the buffer components are at a concentration of 10 mM, 15 mM, 20 mM, or 25 mM.

[0107] Histidine In some embodiments, the formulation comprises histidine. In some embodiments, the formulation comprises L-histidine.

[0108] In some embodiments, the composition comprises at least about 1 mM, at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 30 mM, at least about 50 mM, at least about 100 mM, at least about 150 mM, or at least about 200 mM histidine. In various embodiments, the composition comprises about 1 mM to about 200 mM, about 5 mM to about 150 mM, about 10 mM to about 100 mM, about 15 mM to about 50 mM, or about 20 mM to about 30 mM histidine. In certain embodiments, the composition comprises about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 30 mM, about 50 mM, about 100 mM, about 150 mM, or about 200 mM histidine. In certain embodiments, the formulation comprises about 10 mM to about 100 mM histidine, hi a specific embodiment, the formulation comprises about 20 mM histidine.

[0109] In some embodiments, the composition comprises at least 1 mM, at least 5 mM, at least 10 mM, at least 15 mM, at least 20 mM, at least 30 mM, at least 50 mM, at least 100 mM, at least 150 mM, or at least 200 mM histidine. In various embodiments, the composition comprises 1 mM to 200 mM, 5 mM to 150 mM, 10 mM to 100 mM, 15 mM to 50 mM, or 20 mM to 30 mM histidine. In certain embodiments, the composition comprises 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 30 mM, 50 mM, 100 mM, 150 mM, or 200 mM histidine. In certain embodiments, the formulation comprises 10 mM to 100 mM histidine. In a specific embodiment, the formulation comprises 20 mM histidine.

[0110] pH In some embodiments, the formulation has a pH of about 4.0 to about 8.0, e.g., about 4.5 to about 7.5, about 5.0 to about 7.0, about 5.5 to about 6.5, about 5.7 to about 6.3, or about 5.9 to about 6.1. In certain embodiments, the formulation has a pH of about 4.0, about 4.5, about 5.0, about 5.5, about 5.7, about 5.9, about 6.0, about 6.1, about 6.3, about 6.5, about 7.0, about 7.5, or about 8.0. In certain embodiments, the formulation has a pH of about 5.0 to about 7.0. In certain embodiments, the formulation has a pH of about 5.5 to about 6.5. In certain embodiments, the formulation has a pH of about 5.7 to about 6.3. In a specific embodiment, the formulation has a pH of about 6.0.

[0111] In some embodiments, the formulation has a pH of 4.0 to 8.0, e.g., 4.5 to 7.5, 5.0 to 7.0, 5.5 to 6.5, 5.7 to 6.3, or 5.9 to 6.1. In certain embodiments, the formulation has a pH of 4.0, 4.5, 5.0, 5.5, 5.7, 5.9, 6.0, 6.1, 6.3, 6.5, 7.0, 7.5, or 8.0. In certain embodiments, the formulation has a pH of 5.0 to 7.0. In certain embodiments, the formulation has a pH of 5.5 to 6.5. In certain embodiments, the formulation has a pH of 5.7 to 6.3. In a specific embodiment, the formulation has a pH of 6.0.

[0112] Preservatives In some embodiments, the formulation further comprises at least one preservative.In various embodiments, the at least one preservative is selected from octadecyldimethylbenzylammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkylbenzyldimethylammonium chlorides, the alkyl group of which is a long-chain compound), and benzethonium chloride.Other types of preservatives include aromatic alcohols such as phenol, butyl, and benzyl alcohol, alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol.

[0113] 6.2.9. CURRENTLY PREFERRED ANTI-IL-6 ANTIBODY FORMULATIONS In various embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody and about 1 mM to about 100 mM methionine, e.g., about 1 mM to about 5 mM methionine, about 1 mM to about 10 mM methionine, about 1 mM to about 15 mM methionine, about 1 mM to about 30 mM methionine, about 1 mM to about 50 mM methionine, about 1 mM to about 100 mM methionine, about 5 mM to about 10 mM methionine, about 5 mM to about 15 mM methionine, about 5 mM to about 30 mM methionine, about 5 ... In some embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody and about 5 mM to about 15 mM methionine. In certain embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody and about 10 mM methionine.

[0114] In various embodiments, the antibody formulation comprises 5 mg / mL to 120 mg / mL of anti-IL-6 antibody and 1 mM to 100 mM methionine, e.g., 1 mM to 5 mM methionine, 1 mM to 10 mM methionine, 1 mM to 15 mM methionine, 1 mM to 30 mM methionine, 1 mM to 50 mM methionine, 1 mM to 100 mM methionine, 5 mM to 10 mM methionine, 5 mM to 15 mM methionine, 5 mM to 30 mM methionine, 5 In some embodiments, the antibody formulation comprises 5 mg / mL to 120 mg / mL of anti-IL-6 antibody and 5 mM to 15 mM methionine. In certain embodiments, the antibody formulation comprises 5 mg / mL to 120 mg / mL of anti-IL-6 antibody and 10 mM methionine.

[0115] In some embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody, about 1 mM to about 50 mM of methionine, and about 0.005% to about 0.5% (w / v) of polysorbate 80. In some embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody, about 5 mM to about 15 mM of methionine, and about 0.03% to about 0.1% (w / v) of polysorbate 80. In some embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody, about 5 mM to about 15 mM of methionine, and about 0.05% to about 0.1% (w / v) of polysorbate 80. In certain embodiments, the antibody formulation comprises about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody, about 10 mM methionine, and about 0.07% (w / v) polysorbate 80.

[0116] In some embodiments, the antibody formulation comprises 5 mg / mL to 120 mg / mL of anti-IL-6 antibody, 1 mM to 50 mM methionine, and 0.005% to 0.5% (w / v) polysorbate 80. In some embodiments, the antibody formulation comprises 5 mg / mL to 120 mg / mL of anti-IL-6 antibody, 5 mM to 15 mM methionine, and 0.03% to 0.1% (w / v) polysorbate 80. In some embodiments, the antibody formulation comprises 5 mg / mL to 120 mg / mL of anti-IL-6 antibody, 5 mM to 15 mM methionine, and 0.05% to 0.1% (w / v) polysorbate 80. In certain embodiments, the antibody formulation comprises 5 mg / mL to 120 mg / mL of anti-IL-6 antibody, 10 mM methionine, and 0.07% (w / v) polysorbate 80.

[0117] In some embodiments, the antibody formulation comprises: a) about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody; b) about 1% to about 40% (w / v) trehalose; c) about 0.005% to about 0.5% (w / v) polysorbate 80; d) about 10 mM to about 200 mM arginine; e) about 1 mM to about 50 mM methionine; and f) about 10 mM to about 100 mM histidine, and the antibody formulation has a pH of about 5.0 to about 7.0. In some embodiments, the antibody formulation comprises a) 5 mg / mL to 120 mg / mL of anti-IL-6 antibody, b) 1% to 40% (w / v) trehalose, c) 0.005% to 0.5% (w / v) polysorbate 80, d) 10 mM to 200 mM arginine, e) 1 mM to 50 mM methionine, and f) 10 mM to 100 mM histidine, and the antibody formulation has a pH of 5.0 to 7.0.

[0118] In some embodiments, the antibody formulation comprises: a) about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody; b) about 1% to about 40% (w / v) trehalose; c) about 0.02% to about 0.1% (w / v) polysorbate 80; d) about 10 mM to about 200 mM arginine; e) about 1 mM to about 100 mM methionine; and f) about 10 mM to about 100 mM histidine, and the antibody formulation has a pH of about 5.0 to about 7.0. In some embodiments, the antibody formulation comprises a) 5 mg / mL to 120 mg / mL of anti-IL-6 antibody, b) 1% to 40% (w / v) trehalose, c) 0.02% to 0.1% (w / v) polysorbate 80, d) 10 mM to 200 mM arginine, e) 1 mM to 100 mM methionine, and f) 10 mM to 100 mM histidine, and the antibody formulation has a pH of 5.0 to 7.0.

[0119] In some embodiments, the antibody formulation comprises: a) about 5 mg / mL to about 120 mg / mL of anti-IL-6 antibody; b) about 1% to about 40% (w / v) trehalose; c) about 0.03% to about 0.1% (w / v) polysorbate 80; d) about 10 mM to about 200 mM arginine; e) about 5 mM to about 15 mM methionine; and f) about 10 mM to about 100 mM histidine, and the antibody formulation has a pH of about 5.0 to about 7.0. In some embodiments, the antibody formulation comprises a) 5 mg / mL to 120 mg / mL anti-IL-6 antibody, b) 1% to 40% (w / v) trehalose, c) 0.03% to 0.1% (w / v) polysorbate 80, d) 10 mM to 200 mM arginine, e) 5 mM to 15 mM methionine, and f) 10 mM to 100 mM histidine, and the antibody formulation has a pH of 5.0 to 7.0.

[0120] In certain embodiments, the anti-IL-6 antibody comprises the VH CDR1 sequence of SEQ ID NO: 1, the VH CDR2 sequence of SEQ ID NO: 2, the VH CDR3 sequence of SEQ ID NO: 3, the VL CDR1 sequence of SEQ ID NO: 4, the VL CDR2 sequence of SEQ ID NO: 5, and the VL CDR3 sequence of SEQ ID NO: 6. In certain embodiments, the anti-IL-6 antibody comprises the VH domain amino acid sequence of SEQ ID NO: 7 and the VL domain amino acid sequence of SEQ ID NO: 8. In certain embodiments, the anti-IL-6 antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10.

[0121] In a specific embodiment, the anti-IL-6 antibody is a full-length COR-001 antibody. In various embodiments, the antibody formulation comprises about 5 mg / mL to about 50 mg / mL of COR-001 antibody, e.g., about 5 mg / mL, about 7.5 mg / mL, about 10 mg / mL, about 15 mg / mL, about 20 mg / mL, about 30 mg / mL, or about 50 mg / mL of COR-001 antibody. In various embodiments, the antibody formulation comprises 5 mg / mL to 50 mg / mL of COR-001 antibody, e.g., 5 mg / mL, 7.5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 30 mg / mL, or 50 mg / mL of COR-001 antibody. In some embodiments, the antibody formulation comprises about 7.5 mg / mL to about 30 mg / mL of COR-001 antibody. In some embodiments, the antibody formulation comprises 7.5 mg / mL to 30 mg / mL of COR-001 antibody. In certain embodiments, the antibody formulation comprises about 7.5 mg / mL of COR-001 antibody. In certain embodiments, the antibody formulation comprises 7.5 mg / mL of COR-001 antibody. In certain embodiments, the antibody formulation comprises about 15 mg / mL of COR-001 antibody. In certain embodiments, the antibody formulation comprises 15 mg / mL of COR-001 antibody. In certain embodiments, the antibody formulation comprises about 30 mg / mL of COR-001 antibody. In certain embodiments, the antibody formulation comprises 30 mg / mL of COR-001 antibody.

[0122] In a specific embodiment, the antibody formulation comprises a) about 5 mg / mL to about 120 mg / mL of COR-001 antibody, b) about 5% (w / v) trehalose, c) about 0.07% (w / v) polysorbate 80, d) about 70 mM arginine, e) about 10 mM methionine, and f) about 20 mM histidine, and the antibody formulation has a pH of about 6.0. In a specific embodiment, the antibody formulation comprises a) 5 mg / mL to 120 mg / mL of COR-001 antibody, b) 5% (w / v) trehalose, c) 0.07% (w / v) polysorbate 80, d) 70 mM arginine, e) 10 mM methionine, and f) 20 mM histidine, and the antibody formulation has a pH of 6.0.

[0123] In certain embodiments, the antibody formulation comprises a) about 7.5 mg / mL to about 30 mg / mL of COR-001 antibody, b) about 5% (w / v) trehalose, c) about 0.07% (w / v) polysorbate 80, d) about 70 mM arginine, e) about 10 mM methionine, and f) about 20 mM histidine, and the antibody formulation has a pH of about 6.0. In certain embodiments, the antibody formulation comprises a) 7.5 mg / mL to 30 mg / mL of COR-001 antibody, b) 5% (w / v) trehalose, c) 0.07% (w / v) polysorbate 80, d) 70 mM arginine, e) 10 mM methionine, and f) 20 mM histidine, and the antibody formulation has a pH of 6.0.

[0124] 6.2.9.1.Viscosity In some embodiments, the viscosity of the formulation is less than 50 cP at 25° C., e.g., less than 40 cP, less than 30 cP, less than 20 cP, less than 10 cP, or less than 5 cP at 25° C. In specific embodiments, the formulation has a viscosity of less than 10 cP at 25° C. In various embodiments, the viscosity of the formulation is 1 cP, 2 cP, 3 cP, 4 cP, 5 cP, 10 cP, 15 cP, 20 cP, 25 cP, 30 cP, 35 cP, or 40 cP at 25° C.

[0125] 6.2.9.2.Agglutination In some embodiments, the formulation reduces antibody aggregation. In certain embodiments, the formulation reduces the formation of soluble aggregates. In certain embodiments, the formulation reduces the formation of insoluble aggregates. In certain embodiments, the formulation reduces the formation of soluble aggregates compared to formulations low in polysorbate 80, as measured by size-exclusion high performance liquid chromatography (SEC-HPLC). In certain embodiments, the formulation reduces the formation of insoluble aggregates compared to formulations low in polysorbate 80, as measured by visual appearance check. In certain embodiments, the formulation reduces the formation of soluble aggregates compared to formulations without methionine, as measured by SEC-HPLC. In some embodiments, the formulation has less than 15% soluble aggregates after 20 hours of stirring at 300 rpm, as measured by SEC-HPLC. In some embodiments, the formulation has less than 10% soluble aggregates after 20 hours of stirring at 300 rpm, as measured by SEC-HPLC. In some embodiments, the formulation has less than 5% soluble aggregates after 20 hours of stirring at 300 rpm as measured by SEC-HPLC. In some embodiments, the formulation has less than 2% soluble aggregates after 20 hours of stirring at 300 rpm as measured by SEC-HPLC.

[0126] 6.2.9.3. Charge Variants In some embodiments, the formulation reduces the proportion of charge variants, as measured by imaging capillary isoelectric focusing (icIEF) as peaks eluting earlier or later than the major species. In certain embodiments, the formulation reduces the proportion of charge variants, as measured by icIEF, compared to a formulation that does not contain methionine. Charge variants include acidic and basic species.

[0127] In some embodiments, the formulation has less than 60% charge variants as measured by icIEF after 12 months of storage at 5±3° C. In some embodiments, the formulation has less than 50% charge variants as measured by icIEF after 12 months of storage at 5±3° C. In some embodiments, the formulation has less than 60% acidic species as measured by icIEF after 12 months of storage at 5±3° C. In some embodiments, the formulation has less than 50% acidic species as measured by icIEF after 12 months of storage at 5±3° C.

[0128] In some embodiments, the formulation has less than 60% charge variants as measured by icIEF after 6 months of storage at 25±2° C. In some embodiments, the formulation has less than 50% charge variants as measured by icIEF after 6 months of storage at 25±2° C. In some embodiments, the formulation has less than 60% acidic species as measured by icIEF after 6 months of storage at 25±2° C. In some embodiments, the formulation has less than 50% acidic species as measured by icIEF after 6 months of storage at 25±2° C.

[0129] In some embodiments, the formulation has less than 60% charge variants as measured by icIEF after 1 month of storage at 40±2° C. In some embodiments, the formulation has less than 50% charge variants as measured by icIEF after 1 month of storage at 40±2° C. In some embodiments, the formulation has less than 60% acidic species as measured by icIEF after 1 month of storage at 40±2° C. In some embodiments, the formulation has less than 50% acidic species as measured by icIEF after 1 month of storage at 40±2° C.

[0130] In some embodiments, the formulation reduces the proportion of acidic species, as measured by imaged capillary isoelectric focusing (icIEF) as a peak eluting earlier than the major species. In various embodiments, the measured acidic species are generated by deamidation, isomerization, oxidation, or other degradation. In certain embodiments, the formulation reduces the proportion of acidic species, as measured by icIEF, compared to a formulation without methionine. In some embodiments, the formulation has less than 60% acidic species after two weeks of incubation at 45° C., as measured by icIEF. In some embodiments, the formulation has less than 50% acidic species after two weeks of incubation at 45° C., as measured by icIEF. In some embodiments, the formulation has less than 40% acidic species after two weeks of incubation at 45° C., as measured by icIEF. In some embodiments, the formulation has less than 30% acidic species after two weeks of incubation at 45° C., as measured by icIEF.

[0131] Oxidation In some embodiments, the formulation reduces oxidation of the antibody. In some embodiments, the formulation reduces oxidation, including oxidation of residue Met431, compared to a formulation without methionine, as measured by reverse-phase high performance liquid chromatography (RP-HPLC). In some embodiments, the formulation has less than 15% oxidized species after 2 weeks of incubation at 45°C, as measured by RP-HPLC. In some embodiments, the formulation has less than 10% oxidized species after 2 weeks of incubation at 45°C, as measured by RP-HPLC. In some embodiments, the formulation has less than 5% oxidized species after 2 weeks of incubation at 45°C, as measured by RP-HPLC. In some embodiments, the formulation has less than 4% oxidized species after 2 weeks of incubation at 45°C, as measured by RP-HPLC. In some embodiments, the formulation has less than 3% oxidized species after 2 weeks of incubation at 45°C, as measured by RP-HPLC.

[0132] In some embodiments, the formulation has less than 10% oxidized species after 12 months of storage at 5±3° C. as measured by RP-HPLC. In various embodiments, the formulation has less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% oxidized species after 12 months of storage at 5±3° C. as measured by RP-HPLC. In certain embodiments, the formulation has less than 6% oxidized species after 12 months of storage at 5±3° C. as measured by RP-HPLC. In certain embodiments, the formulation has less than 5% oxidized species after 12 months of storage at 5±3° C. as measured by RP-HPLC.

[0133] In some embodiments, the formulation has less than 10% oxidized species as measured by RP-HPLC after 6 months of storage at 25±2° C. In various embodiments, the formulation has less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% oxidized species as measured by RP-HPLC after 6 months of storage at 25±2° C. In certain embodiments, the formulation has less than 6% oxidized species as measured by RP-HPLC after 6 months of storage at 25±2° C. In certain embodiments, the formulation has less than 5% oxidized species as measured by RP-HPLC after 6 months of storage at 25±2° C.

[0134] In some embodiments, the formulation has less than 10% oxidized species as measured by RP-HPLC after 1 month of storage at 40±2° C. In various embodiments, the formulation has less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% oxidized species as measured by RP-HPLC after 1 month of storage at 40±2° C. In certain embodiments, the formulation has less than 6% oxidized species as measured by RP-HPLC after 1 month of storage at 40±2° C. In certain embodiments, the formulation has less than 5% oxidized species as measured by RP-HPLC after 1 month of storage at 40±2° C.

[0135] Effect In some embodiments, the formulation preserves the potency of the antibody. In various embodiments, the potency of the anti-IL-6 antibody is measured by IL-6 binding ELISA or HEK Blue cell-based bioassay.

[0136] In some embodiments, the formulation has less than a 50% reduction in potency after 12 months of storage at 5±3° C. as measured by IL-6 binding ELISA. In various embodiments, the formulation has less than a 50%, less than a 40%, less than a 30%, less than a 20%, or less than a 10% reduction in potency after 12 months of storage at 5±3° C. as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 30% reduction in potency after 12 months of storage at 5±3° C. as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 20% reduction in potency after 12 months of storage at 5±3° C. as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 10% reduction in potency after 12 months of storage at 5±3° C. as measured by IL-6 binding ELISA.

[0137] In some embodiments, the formulation has less than a 50% reduction in potency after 12 months of storage at 5±3° C. as measured by a HEK Blue cell-based bioassay. In various embodiments, the formulation has less than a 50%, less than a 40%, less than a 30%, less than a 20%, or less than a 10% reduction in potency after 12 months of storage at 5±3° C. as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 30% reduction in potency after 12 months of storage at 5±3° C. as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 20% reduction in potency after 12 months of storage at 5±3° C. as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 10% reduction in potency after 12 months of storage at 5±3° C. as measured by a HEK Blue cell-based bioassay.

[0138] In some embodiments, the formulation has less than a 50% reduction in potency after 6 months of storage at 25±2°C as measured by IL-6 binding ELISA. In various embodiments, the formulation has less than a 50%, less than a 40%, less than a 30%, less than a 20%, or less than a 10% reduction in potency after 6 months of storage at 25±2°C as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 30% reduction in potency after 6 months of storage at 25±2°C as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 20% reduction in potency after 6 months of storage at 25±2°C as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 10% reduction in potency after 6 months of storage at 25±2°C as measured by IL-6 binding ELISA.

[0139] In some embodiments, the formulation has less than a 50% reduction in potency after 6 months of storage at 25±2° C. as measured by a HEK Blue cell-based bioassay. In various embodiments, the formulation has less than a 50%, less than a 40%, less than a 30%, less than a 20%, or less than a 10% reduction in potency after 6 months of storage at 25±2° C. as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 30% reduction in potency after 6 months of storage at 25±2° C. as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 20% reduction in potency after 6 months of storage at 25±2° C. as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 10% reduction in potency after 6 months of storage at 25±2° C. as measured by a HEK Blue cell-based bioassay.

[0140] In some embodiments, the formulation has less than a 50% reduction in potency after one month of storage at 40±2°C as measured by IL-6 binding ELISA. In various embodiments, the formulation has less than a 50%, less than a 40%, less than a 30%, less than a 20%, or less than a 10% reduction in potency after one month of storage at 40±2°C as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 30% reduction in potency after one month of storage at 40±2°C as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 20% reduction in potency after one month of storage at 40±2°C as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 10% reduction in potency after one month of storage at 40±2°C as measured by IL-6 binding ELISA.

[0141] In some embodiments, the formulation has less than a 50% reduction in potency after 1 month of storage at 40±2°C as measured by a HEK Blue cell-based bioassay. In various embodiments, the formulation has less than a 50%, less than a 40%, less than a 30%, less than a 20%, or less than a 10% reduction in potency after 1 month of storage at 40±2°C as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 30% reduction in potency after 1 month of storage at 40±2°C as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 20% reduction in potency after 1 month of storage at 40±2°C as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 10% reduction in potency after 1 month of storage at 40±2°C as measured by a HEK Blue cell-based bioassay.

[0142] 6.3. Administration of the formulation Suitable routes of administration of the antibody formulations described herein include, but are not limited to, parenteral (e.g., by subcutaneous, intravenous, intramuscular, intradermal, or intrasternal injection or infusion (e.g., by sterile injectable aqueous or non-aqueous solution or suspension, etc.)) and topical (e.g., in the form of a cream or ointment). In certain embodiments, the formulation is suitable for parenteral injection. In certain embodiments, the formulation is suitable for intravenous injection. In certain embodiments, the formulation is suitable for subcutaneous injection.

[0143] In some embodiments, the formulations are suitable for administration in a single dose or multiple doses.

[0144] Dosage Form In another aspect, provided herein is a dosage form containing one or more unit doses of a pharmaceutical composition comprising an anti-IL-6 antibody.

[0145] In various embodiments, the dosage form is a pre-filled syringe. In various embodiments, the dosage form is an auto-injector pen.

[0146] In various embodiments, the dosage form comprises one or more unit doses of the formulation described in Section 6.2 above. In typical embodiments, the formulation is a liquid formulation. In other embodiments, the formulation is a dry formulation, including, but not limited to, a lyophilized agent. In certain embodiments, the dosage form comprises a dry formulation and a measured amount of an aqueous diluent.

[0147] In some embodiments, the unit dosage form comprises a formulation comprising: a) about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody, b) about 1% to about 40% (w / v) trehalose, c) about 0.03% to about 0.1% (w / v) polysorbate 80, d) about 10 mM to about 200 mM arginine, e) about 5 mM to about 15 mM methionine, and f) about 10 mM to about 100 mM histidine, wherein the formulation has a pH of about 5.0 to about 7.0. In some embodiments, the unit dosage form comprises a formulation comprising a) 5 mg / mL to 120 mg / mL of an anti-IL-6 antibody, b) 1% to 40% (w / v) trehalose, c) 0.03% to 0.1% (w / v) polysorbate 80, d) 10 mM to 200 mM arginine, e) 5 mM to 15 mM methionine, and f) 10 mM to 100 mM histidine, wherein the formulation has a pH of 5.0 to 7.0.

[0148] In some embodiments, the unit dosage form comprises a formulation comprising: a) about 7.5 mg / mL to about 30 mg / mL COR-001, b) about 5% (w / v) trehalose, c) about 0.07% (w / v) polysorbate 80, d) about 70 mM arginine, e) about 10 mM methionine, and f) about 20 mM histidine, wherein the formulation has a pH of about 6.0. In certain embodiments, the unit dosage form comprises about 7.5 mg of COR-001. In certain embodiments, the unit dosage form comprises about 15 mg of COR-001. In certain embodiments, the unit dosage form comprises about 30 mg of COR-001. In some embodiments, the unit dosage form comprises a formulation comprising a) 7.5 mg / mL to 30 mg / mL of COR-001, b) 5% (w / v) trehalose, c) 0.07% (w / v) polysorbate 80, d) 70 mM arginine, e) 10 mM methionine, and f) 20 mM histidine, wherein the formulation has a pH of 6.0.

[0149] In certain embodiments, the dosage form comprises a plurality of 7.5 mg unit doses of COR-001. In certain embodiments, the dosage form comprises a single 7.5 mg unit dose of COR-001. In certain embodiments, the dosage form comprises a plurality of 15 mg unit doses of COR-001. In certain embodiments, the dosage form comprises a single 15 mg unit dose of COR-001. In certain embodiments, the unit dosage form comprises a plurality of 30 mg unit doses of COR-001. In certain embodiments, the unit dosage form comprises a single 30 mg unit dose of COR-001.

[0150] 6.5. Treatment method In another aspect, provided herein is a method for treating a disease or disorder in a patient, comprising administering to the patient an anti-IL-6 antibody formulation described herein.

[0151] In some embodiments, the patient has an IL-6-mediated inflammatory disorder.

[0152] In various embodiments, the patient has elevated pre-treatment levels of C-reactive protein (CRP). In some embodiments, the patient has a pre-treatment CRP level of at least 2 mg / L. In some embodiments, the patient has a pre-treatment CRP level of at least 2 mg / L, 2.5 mg / L, 3 mg / L, 3.5 mg / L, 4 mg / L, 4.5 mg / L, or 5 mg / L. In some embodiments, the patient has a pre-treatment CRP level of at least 7.5 mg / L, 10 mg / L, 12.5 mg / L, or 15 mg / L.

[0153] In some embodiments, the IL-6-mediated inflammatory disorder is a hepcidin-mediated disorder. Hepcidin-mediated disorders are described in US2017 / 0029499 (incorporated herein by reference in its entirety).

[0154] In some embodiments, the IL-6-mediated inflammatory disorder is not a hepcidin-mediated disorder.

[0155] In some embodiments, the patient has a non-autoimmune IL-6-mediated inflammatory disorder. In certain embodiments, the patient has an IL-6-mediated inflammatory disorder other than rheumatoid arthritis, giant cell arteritis, polyarticular juvenile idiopathic arthritis, or systemic juvenile idiopathic arthritis.

[0156] In various embodiments, the patient has kidney disease. In some embodiments, the kidney disease is chronic kidney disease (CKD). In some embodiments, the patient has chronic kidney disease at KDOQI stages 1-5. In some embodiments, the patient has chronic kidney disease at KDOQI stages 3-5. In some embodiments, the patient is on dialysis. In some embodiments, the patient is not on dialysis. In certain embodiments, the patient has chronic kidney disease at KDOQI stages 3-5, and the patient is not on dialysis. In certain embodiments, the patient has chronic kidney disease at KDOQI stages 3-5, and the patient is on dialysis. In some embodiments, the patient has cardiorenal syndrome (CRS). In certain embodiments, the patient has CRS type 4. In some embodiments, the patient is being treated with dialysis.

[0157] In certain embodiments, the patient has chronic kidney disease KDOQI stage 3-5 and a CRP level of 2 mg / L or greater. In certain embodiments, the formulation is administered to reduce the risk of cardiovascular morbidity and mortality in adult chronic kidney disease KDOQI stage 3-5 patients with inflammation.

[0158] In various embodiments, the patient has cardiovascular disease.

[0159] In certain embodiments, the patient has atherosclerosis and has a CRP level of 2 mg / L or more. In certain embodiments, the formulation is administered to reduce the risk of cardiovascular morbidity and mortality in adult patients with atherosclerotic cardiovascular disease and inflammation.

[0160] In some embodiments, the patient has previously suffered a myocardial infarction. In some embodiments, the patient has not previously suffered a myocardial infarction.

[0161] In certain embodiments, the patient has previously suffered a myocardial infarction and has a CRP level of 2 mg / L or greater.

[0162] In some embodiments, the cardiovascular disease is congestive heart failure (CHF). In certain embodiments, the patient has congestive heart failure (CHF) with reduced ejection fraction. In certain embodiments, the patient has congestive heart failure (CHF) with a moderate ejection fraction. In certain embodiments, the patient has congestive heart failure (CHF) with preserved ejection fraction. In some embodiments, the cardiovascular disease is acute coronary syndrome. In certain embodiments, the anti-IL-6 antibody formulation is administered at a dose sufficient to reduce non-fatal myocardial infarction, non-fatal stroke, and / or cardiovascular death. In some embodiments, the anti-IL-6 antibody formulation is administered at a dose sufficient to reduce the risk of heart failure. In some embodiments, the anti-IL-6 antibody formulation is administered at a dose sufficient to increase cardiac function. In some embodiments, the anti-IL-6 antibody formulation is administered at a dose sufficient to reduce fibrosis after acute myocardial infarction. In some embodiments, the anti-IL-6 antibody formulation is administered at a dose sufficient to reduce the risk of cardiovascular morbidity and mortality.

[0163] In some embodiments, the cardiovascular disease is non-diuretic resistant heart failure. In some other embodiments, the cardiovascular disease is diuretic resistant heart failure. Diuretic resistant heart failure is described in WO2018 / 144773, the disclosure of which is incorporated herein by reference in its entirety.

[0164] In various embodiments, the patient has anemia. In some embodiments, the patient has anemia of chronic disease. In some embodiments, the patient has iron-refractory iron deficiency anemia (IRIDA).

[0165] In some embodiments, the patient has diabetes. In some embodiments, the patient has liver disease. In some embodiments, the patient has osteoporosis. In some embodiments, the patient has depression. In some embodiments, the patient has asthma. In some embodiments, the patient has a neuroinflammatory disorder, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis (ALS). In some embodiments, the patient has age-related macular degeneration (AMD). In various embodiments, the patient has cancer, such as a solid tumor, small cell lung cancer, non-small cell lung cancer, blood cancer, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), lymphoma, and Hodgkin's lymphoma. In some embodiments, the patient has a skin disease. In some embodiments, the anti-IL-6 antibody formulation prevents aging in the patient. List of embodiments 1. An antibody formulation comprising: An antibody formulation comprising about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody and about 5 mM to about 15 mM of methionine. 2. The anti-IL-6 antibody comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain; The VH domain is VH CDR1 sequence of SEQ ID NO: 1, the VH CDR2 sequence of SEQ ID NO: 2, and comprising the VH CDR3 sequence of SEQ ID NO: 3, The VL domain is VL CDR1 sequence of SEQ ID NO: 4, the VL CDR2 sequence of SEQ ID NO: 5, and 2. The antibody formulation of embodiment 1, comprising a VL CDR3 sequence of SEQ ID NO:6. 3. The antibody formulation of embodiment 1 or 2, wherein the anti-IL-6 antibody comprises the VH domain amino acid sequence of SEQ ID NO:7 and the VL domain amino acid sequence of SEQ ID NO:8. 4. The antibody formulation of any one of embodiments 1 to 3, wherein the anti-IL-6 antibody comprises the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10. 5. The antibody formulation of any one of the preceding embodiments, wherein the formulation comprises from about 7.5 mg / mL to about 30 mg / mL of anti-IL-6 antibody. 6. The antibody formulation of embodiment 5, wherein the formulation comprises about 7.5 mg / mL of the anti-IL-6 antibody. 7. The antibody formulation of embodiment 5, wherein the formulation comprises about 15 mg / mL of the anti-IL-6 antibody. 8. The antibody formulation of embodiment 5, wherein the formulation comprises about 30 mg / mL of the anti-IL-6 antibody. 9. The antibody formulation of any one of the preceding embodiments, wherein the formulation comprises about 10 mM methionine. 10. The antibody formulation of any one of the preceding embodiments, further comprising about 0.03% to about 0.1% (w / v) polysorbate 80. 11. The antibody formulation of embodiment 10, wherein the formulation comprises about 0.05% to about 0.1% (w / v) polysorbate 80. 12. The antibody formulation of embodiment 11, wherein the formulation comprises about 0.07% (w / v) polysorbate 80. 13. The antibody formulation of any one of the preceding embodiments, further comprising about 1% to about 40% (w / v) trehalose. 14. The antibody formulation of embodiment 13, wherein the formulation comprises about 5% (w / v) trehalose. 15. The antibody formulation of any one of the preceding embodiments, further comprising about 10 mM to about 200 mM arginine. 16. The antibody formulation of embodiment 15, wherein the formulation comprises about 70 mM arginine. 17. The antibody formulation of any one of the preceding embodiments, further comprising about 10 mM to about 100 mM histidine. 18. The antibody formulation of embodiment 17, wherein the formulation comprises about 20 mM histidine. 19. The antibody formulation of any one of the preceding embodiments, wherein the antibody formulation has a pH of about 5.0 to about 7.0. 20. The antibody formulation of embodiment 21, wherein the antibody formulation has a pH of about 6.0. 21. An antibody formulation comprising about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody, about 5 mM to about 15 mM methionine, and about 0.03% to about 0.1% (w / v) polysorbate 80. 22. The antibody formulation of embodiment 21, wherein the anti-IL-6 antibody has a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10. 23. An antibody preparation, a) about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody; b) about 1% to about 40% (w / v) trehalose; c) about 0.03% to about 0.1% (w / v) polysorbate 80; d) about 10 mM to about 200 mM arginine; e) about 5 mM to about 15 mM methionine; f) about 10 mM to about 100 mM histidine; An antibody formulation, wherein the antibody formulation has a pH of about 5.0 to about 7.0. 24. The antibody formulation of embodiment 23, wherein the anti-IL-6 antibody has a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10. 25. An antibody preparation, a) about 5 mg / mL to about 120 mg / mL of an anti-IL-6 antibody, wherein the anti-IL-6 antibody has a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10; b) about 5% (w / v) trehalose; c) about 0.07% (w / v) polysorbate 80; d) about 70 mM arginine; and e) about 10 mM methionine; f) about 20 mM histidine; An antibody formulation, wherein the antibody formulation has a pH of about 6.0. 26. The antibody formulation of embodiment 25, wherein the formulation comprises about 7.5 mg / mL of the anti-IL-6 antibody. 27. The antibody formulation of embodiment 25, wherein the formulation comprises about 15 mg / mL of the anti-IL-6 antibody. 28. The antibody formulation of embodiment 25, wherein the formulation comprises about 30 mg / mL of the anti-IL-6 antibody. 29. The antibody formulation of any one of the preceding embodiments, wherein the formulation has a viscosity of less than 10 cP at 25°C. 30. The antibody formulation of any one of the preceding embodiments, wherein the formulation has less than 5% soluble aggregates after 20 hours of stirring at 300 rpm, as measured by size-exclusion high-performance liquid chromatography (SEC-HPLC). 31. The antibody formulation of any one of the preceding embodiments, wherein the formulation has less than 50% acidic species after 2 weeks of incubation at 45°C, as measured by imaging detection capillary isoelectric focusing (icIEF). 32. The antibody formulation of embodiment 31, wherein the acidic species measured is generated by deamidation, isomerization, oxidation, or degradation. 33. The antibody formulation of any one of the preceding embodiments, wherein the formulation has less than 5% oxidized species after 2 weeks of incubation at 45° C., as measured by reverse-phase high performance liquid chromatography (RP-HPLC). 34. The antibody formulation of any one of the preceding embodiments, having less than 50% charge variants after 12 months of storage at 5±3° C. as measured by imaging-detection capillary isoelectric focusing (icIEF). 35. The antibody formulation of embodiment 34, wherein the formulation has less than 50% acidic species after 12 months of storage at 5±3°C, as measured by imaging detection capillary isoelectric focusing (icIEF). 36. The antibody formulation of any one of the preceding embodiments, wherein the formulation has less than 10% oxidized species after 12 months of storage at 5±3° C., as measured by reverse-phase high-performance liquid chromatography (RP-HPLC). 37. The antibody formulation of embodiment 36, wherein the formulation has less than 6% oxidized species after 12 months of storage at 5±3°C, as measured by reverse-phase high-performance liquid chromatography (RP-HPLC). 38. The antibody formulation of any one of the preceding embodiments, wherein the formulation has less than a 50% reduction in potency after 12 months of storage at 5±3°C, as measured by IL-6 binding ELISA. 39. The antibody formulation of embodiment 38, wherein the formulation has less than a 30% reduction in potency after 12 months of storage at 5±3°C, as measured by IL-6 binding ELISA. 40. The antibody formulation of any one of the preceding embodiments, wherein the formulation has less than a 50% reduction in potency after 12 months of storage at 5±3° C. as measured by a HEK Blue cell-based bioassay. 41. The antibody formulation of embodiment 40, having less than a 30% reduction in potency after 12 months of storage at 5±3°C as measured by a HEK Blue cell-based bioassay. 42. The antibody formulation of any one of the preceding embodiments, wherein the formulation is suitable for parenteral administration. 43. The antibody formulation of embodiment 42, wherein the formulation is suitable for intravenous administration. 44. The antibody formulation of embodiment 42, wherein the formulation is suitable for subcutaneous administration. 45. A unit dosage form comprising the antibody formulation of any one of the preceding embodiments. 46. ​​The unit dosage form of embodiment 45, wherein the unit dosage form comprises about 7.5 mg of anti-IL-6 antibody. 47. The unit dosage form of embodiment 45, wherein the unit dosage form comprises about 15 mg of anti-IL-6 antibody. 48. The unit dosage form of embodiment 45, wherein the unit dosage form comprises about 30 mg of anti-IL-6 antibody. [Example]

[0166] 6.6.Example Below are examples of specific embodiments for carrying out the present invention. These examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0167] The practice of the present invention will employ, unless otherwise indicated, conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology, within the skill of the art, such techniques being fully explained in the literature.

[0168] Example 1: Minimizing viscosity at high protein concentrations The final ultrafiltration / permeation step in the manufacturing process of COR-001 requires a transient excess concentration of greater than 100 mg / mL. A viscosity of less than 10 cP is desirable to minimize the risk of filtration flux decline and membrane fouling.

[0169] Several excipients were evaluated to reduce viscosity, and L-arginine salts (e.g., L-arginine-HCl) were identified as the most effective. As shown in Figure 1, viscosity remained below 10 cP for up to 150 mg / mL of COR-001 in the presence of 70 mM or 200 mM L-arginine-HCl.

[0170] To take advantage of the thermal stabilization imparted by trehalose, a combination of L-arginine-HCl and trehalose dihydrate was chosen that resulted in an isotonic composition (i.e., 5% (w / v) of trehalose dihydrate). As shown in Figure 1, 100 mg / mL of COR-001 in 70 mM L-arginine-HCl and 5% trehalose dihydrate had a viscosity of 4 cP. 70 mM L-arginine-HCl and 5% trehalose dihydrate were selected for the COR-001 liquid formulation.

[0171] Example 2: Minimizing agitation-induced aggregation Proteins in liquid formulations are prone to agitation-induced aggregation during handling and transport. In an attempt to prevent agitation-induced protein aggregation, surfactants (e.g., polysorbates) were evaluated for inclusion in COR-001 formulations.

[0172] A range of polysorbate 80 (PS80) concentrations from 0% to 0.10% (w / v) was evaluated at 5, 50, and 120 mg / mL of COR-001 in 5% trehalose dihydrate, 70 mM arginine-HCl, 10 mM methionine, 20 mM histidine, pH 6.0. These formulations (1.2 mL in 3 mL glass vials) were subjected to extreme shaking stress (ambient conditions, 300 rpm for 20 hours) and then analyzed for appearance, OD340, and soluble aggregates by SEC-HPLC, and for the number of subvisible particles by MFI.

[0173] Without PS80, precipitates were observed in all formulations after stirring. As the PS80 level increased, the product solution became less turbid. When the PS80 level reached 0.05% or higher, no particles or opacity were observed after stirring. This appearance trend correlated well with the OD340 and SEC results. Figure 2 shows the effect of PS80 level on soluble aggregate formation by SEC. The results show that PS80 at 0.03% can reduce soluble aggregates at protein concentrations below 50 mg / mL, while PS80 at 0.05% can reduce soluble aggregates at protein concentrations ranging from 5 to 120 mg / mL under a stress-shaking model. A level of 0.07% was selected for the COR-001 liquid formulation.

[0174] Example 3: Minimizing oxidation over long-term storage To evaluate the long-term storage stability of COR-001 in selected liquid formulations (5% trehalose dihydrate, 70 mM L-arginine-HCl, 0.07% PS80, 20 mM L-histidine, pH 6.0), a range of protein concentrations (20, 50, and 120 mg / mL) were prepared and filled at 1.2 mL into 3 mL type I glass vials closed with 13 mm rubber stoppers. The results of long-term storage at 2-8 °C are summarized in Table 1. [Table 1]

[0175] After 9–12 months, there was minimal change in purity as observed by SE-HPLC and non-reducing CE-SDS. However, a 5–10% decrease in the % major isoform was observed by icIEF, accompanied by an increase in acidic species. A significant increase in oxidation (16–46%) was observed at all three protein concentrations by tryptic map / LC-MS analysis. No clear trend in COR-001 potency was observed by IL-6 binding ELISA, indicating that highly oxidized COR-001 did not affect potency, consistent with the oxidation site being primarily on heavy chain Met431 and not within the CDRs.

[0176] No apparent loss of potency was observed, but the oxidation products are undesirable.

[0177] To evaluate whether adding a third amino acid, methionine, to a formulation containing the two amino acids arginine and histidine could reduce or prevent oxidation during long-term storage, 10 mg / mL and 50 mg / mL COR-001 samples were spiked with L-methionine ranging from 0 to 15 mM (5% trehalose dihydrate, 70 mM L-arginine-HCl, 0.07% PS80, 20 mM L-histidine, pH 6.0) and then incubated under accelerated conditions at 45°C for 2 weeks. Samples were tested by appearance, SEC, CE-SDS, and icIEF, as well as by oxidation assay (RP-HPLC) to measure oxidized species. No obvious effect of varying L-methionine levels was observed by appearance and CE-SDS testing. However, with increasing L-methionine levels, less change was observed in SEC, icIEF, and oxidation testing. As shown in Figures 3A, 3B, and 3C, after two weeks under accelerated conditions at 45°C, L-methionine reduced aggregation, charge change, and oxidation levels for both 10 mg / mL and 50 mg / mL COR-001 compared to formulations without L-methionine. At 10 mM L-methionine, these change levels essentially plateaued, indicating that 10 mM L-methionine was sufficient to stabilize COR-001 under thermal stress conditions. 10 mM methionine was selected for the COR-001 liquid formulation.

[0178] Example 4: Effect of protein concentration on storage stability To evaluate the effect of protein concentration on COR-001 stability during storage, two different protein concentrations (10 and 50 mg / mL) in a selected liquid formulation (5% trehalose dihydrate, 70 mM L-arginine-HCl, 0.07% PS80, 10 mM L-methionine, 20 mM L-histidine, pH 6.0) were prepared and filled at 1.0 mL into 3 mL type I glass vials closed with 13 mm rubber stoppers. Samples were tested after 3 months of storage at 5 ± 3 °C, 25 ± 2 °C, and 40 ± 2 °C. The results are summarized in Table 2. [Table 2]

[0179] The 50 mg / mL sample was less clear than the 10 mg / mL sample due to its higher protein concentration. No visible particles were observed after 3 months in any storage condition. Compared to the 50 mg / mL sample, the 10 mg / mL sample at accelerated temperatures (25 ± 2°C and 40 ± 2°C) showed fewer changes as tested by SEC and CE-SDS assays, but more changes as tested by icIEF and oxidation assays. However, these differences were considered small given the assay variability of these methods. No obvious changes were observed in the potency assay after 3 months in any storage condition. Overall, the results indicate no obvious differences in the stability of COR-001 between 10 mg / mL and 50 mg / mL.

[0180] Example 5: Stability of different lots of COR-001 To evaluate the long-term storage stability of COR-001 in selected liquid formulations, different lots of COR-001 were formulated in liquid formulation buffer (70 mM L-arginine hydrochloride, 5% w / v trehalose dihydrate, 10 mM L-methionine, 0.07% w / v polysorbate 80, 20 mM L-histidine, pH 6.0) and filled into container closure systems (2R type I glass vials with 13 mm Flurotec®-coated butyl rubber stoppers) at 1.3 mL each. The COR-001 protein concentration of each lot is summarized in Table 3. [Table 3]

[0181] Lot STC-261-P221-S24 was prepared in the development laboratory and is intended for developmental use only. Lot VVRG56 is also intended for developmental use. Lot CMC-M-0060, Lot CMC-M-0061, and Lot CMC-N-0011 are clinical drug lots.

[0182] The study included evaluation under long-term storage conditions of 5 ± 3°C, accelerated conditions of 25 ± 2°C / 60% ± 5% relative humidity (RH), and stress conditions of 40 ± 2°C / 75% ± 5% RH. All stability containers were placed in an inverted orientation to simulate a worst-case scenario of contact with the stopper surface.

[0183] A. Stability results under acceleration and stress conditions The stability of each lot of COR-001 prepared in the formulation stored under accelerated and stress conditions is summarized in Tables 4-13 below, with Tables 4-8 showing results under accelerated conditions for up to 12 months and Tables 9-13 showing results under stress conditions for up to 3 months. [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12] [Table 13]

[0184] There was no obvious change in appearance up to 12 months under accelerated conditions (Tables 4-8) and up to 3 months under stressed conditions (Tables 9-13).

[0185] There was no apparent change in clarity up to 12 months under accelerated conditions (Tables 4-8) or up to 3 months under stressed conditions (Tables 9-13). All results were below the reference IV (turbidity standard per EU legislation) except for development lot STC-261-P221, which was prepared in the development laboratory. Clarity for this lot exceeded the reference IV at 6 months under accelerated conditions (Table 4) and at 3 months under stressed conditions (Table 9).

[0186] Under accelerated conditions, there was no obvious trend in color up to 12 months (Tables 4-8). Under stressed conditions, there was a slight trend toward increased color over 3 months of storage (Tables 9-13), but all results were below the reference BY4.

[0187] There was no apparent change in pH up to 12 months under accelerated conditions and up to 3 months under stressed conditions (Figures 4A and 4B), although development lot STC-261-P221-S24 showed a slight decrease at 3 months, likely due to assay variability.

[0188] Polysorbate 80 levels declined over time in all three clinical lots tested under accelerated and stress conditions (Figures 5A and 5B). Under accelerated conditions, the decline in polysorbate 80 levels reached a plateau of approximately 0.04% at 3 months for all three lots, with no clear correlation between protein concentration and plateau levels (Figure 5A). Similarly, under stress conditions, polysorbate 80 levels reached a plateau of approximately 0.04% at 1 month for all three lots (Figure 5B). Notably, the plateau levels between accelerated and stress conditions were similar, suggesting that the decline in polysorbate 80 is temperature independent.

[0189] There was no apparent change in protein concentration up to 12 months under accelerated conditions or 3 months under stressed conditions, except for development lot STC-261-P221-S24 (Figures 6A and 6B), which was tested by the A280 method with sample dilution and the other lots by Solo VPE without dilution. Therefore, the apparent changes in development lots were likely due to variability in assay dilution.

[0190] The levels of monomer (non-aggregated bivalent full-length IgG antibody), high molecular weight (HMW) species, and low molecular weight (LMW) species were measured by size-exclusion chromatography-ultra-high performance liquid chromatography (SEC-UHPLC). The % monomer decreased over time, primarily due to increases in HMW% and LMW%, with more variation under stress conditions. The kinetics of % monomer appeared linear with some lot-to-lot variability, without any clear trend correlating with protein concentration (Figures 7A and 7B, 8A and 8B, 9A and 9B).

[0191] The levels of immunoglobulin gamma (IgG) and the combination of two heavy chains and one light chain (HHL) were measured by non-reducing CE-SDS. Under accelerated conditions, IgG% decreased over time without any clear trend in HHL% (Figures 10A and 11A), suggesting that the decrease was due to an increase in other fragments. Under stressed conditions, IgG% decreased faster than under accelerated conditions, and HHL% also increased over time (Figures 10B and 11B). The changes in both IgG% and HHL% under stressed conditions appeared linear with some variability between lots. However, no clear trend correlating with protein concentration was observed.

[0192] Heavy chain plus light chain (HC+LC) levels were measured by reduced CE-SDS. Under accelerated conditions, the decrease in HC+LC% appeared to reach a plateau after 3 months for all lots (Figure 12A). Under stressed conditions, the decrease in HC+LC% appeared linear, with some variability between lots. However, no clear trend correlating with protein concentration was observed (Figure 12B).

[0193] The levels of major, acidic, and basic species were measured by imaged capillary isoelectric focusing (icIEF). Under accelerated conditions, the % major peak decreased over time (Figure 13A), primarily due to an increase in acidic species (Figure 14A), as no obvious change in basic species was observed (Figure 15A). Similarly, under stress conditions, the % main peak decreased (Figure 13B), the % acidic species increased (Figure 14B), and there was no apparent change in the basic species (Figure 15B). The changes in the % main and % acidic species appeared to be linear with some lot-to-lot variability, independent of protein concentration (Figures 13A and 13B, Figures 14A and 14B, Figures 15A and 15B).

[0194] Oxidation levels were measured by reverse-phase high-performance liquid chromatography (RP-HPLC). Under accelerated conditions, the % oxidation appeared to plateau at 3 months for all lots (Figure 16A). Similarly, under stressed conditions, the % oxidation levels appeared to plateau at 1 month for all lots (Figure 16B). The plateau levels for accelerated and stressed conditions appeared to be 5-6%. Overall, this indicates a maximum oxidation of 5-6%.

[0195] There was no apparent change in the number of subvisible particles tested by high-precision fluid particle counting (HIAC) for all three clinical lots after 1 month under accelerated conditions (Tables 6-8). There was a change in the number of subvisible particles tested by microflow imaging (MFI) for the three clinical lots over 6 months under accelerated conditions (Figures 17A, 17B, and 17C). However, these changes did not correlate with protein concentration. Because similar subvisible particle levels were observed in the placebo lot (CMC-M-0062) at 3-6 months, some of these subvisible particles could be attributed to the nature of the formulation buffer components.

[0196] Up to 12 months under accelerated conditions and 3 months under stressed conditions, there was no apparent change in potency, as tested by both IL-6 binding ELISA and HEK Blue cell-based bioassay (Figures 18A and 18B, Figures 19A and 19B).

[0197] The microbiological quality of the three clinical drug lots was monitored by endotoxin levels and container closure integrity testing (CCIT) in lieu of clinical lot sterility testing. After 1 month under accelerated conditions, the results met all acceptance criteria for long-term storage (Tables 6-8).

[0198] B. Stability Results Under Long-Term Storage Conditions The stability of each lot of COR-001 prepared in formulations stored under long-term storage conditions is summarized below in Tables 14-18, showing results for up to 12 months. Assay acceptance criteria, when available, are listed in each table. [Table 14] [Table 15] [Table 16] [Table 17] [Table 18]

[0199] Under long-term storage conditions, there were no obvious changes in appearance, clarity, and color up to 12 months, and all results met the acceptance criteria (Tables 14-18).

[0200] Under long-term storage conditions, there was no obvious change in pH up to 12 months, and all results met the acceptance criteria of 5.7 to 6.3 (Figure 20).

[0201] Polysorbate 80 levels in three clinical lots were monitored under long-term storage conditions. Figure 21 shows that there was a small decline from 0.07% to 0.05-0.06% over 6-9 months. Based on accelerated and stress conditions, the decline in polysorbate 80 under long-term storage conditions may also reach a plateau of 0.04-0.05% (w / v), which, based on formulation development studies, is sufficient to protect the protein from shaking or agitation.

[0202] Under long-term storage conditions, there was no apparent change in protein concentration up to 12 months, and all results met the acceptance criteria (Figure 22). The slight variability observed for development lot STC-261-P221-S24 was likely due to assay variability, as this lot was tested by a different method (A280 method with sample dilution) than the other lots.

[0203] Similar to the accelerated and stressed conditions, there were changes in monomer %, HMW %, and LMW % for all lots under long-term storage conditions. Monomer % decreased over time, primarily due to increases in HMW % and LMW % (Figures 23A, 23B, and 23C). By linear kinetic prediction with 95% confidence, both monomer % and HMW % for all lots would meet the acceptance criteria at 24 months (Figures 23A and 23B). An overlay of the chromatographic profile for lot CMC-M-0061 comparing the changes under long-term storage conditions with those under accelerated (25°C) and stressed (40°C) conditions at 3 months is presented in Figure 24.

[0204] Similar to the accelerated and stressed conditions, IgG% decreased under long-term storage conditions for all lots except lot VVRG56 (Figure 25A). Linear kinetic predictions with 95% confidence indicated that IgG% levels for all lots would meet the acceptance criteria at 24 months (Figure 25A). There was no clear trend in the change in HHL% over time (Figure 25B), suggesting that the decrease in IgG% was due to an increase in other fragments. An overlay of the electrophoretic profile of lot CMC-M-0061, comparing the change under long-term storage conditions (5°C) with the change under accelerated (25°C) and stressed (40°C) conditions at 3 months, is presented in Figure 26, showing the elution locations and potential identities of these fragments.

[0205] Similar to the accelerated and stressed conditions, HC+LC% decreased over time for all lots due to increased fragmentation under long-term storage conditions (Figure 27). Figure 28 presents an overlay of electrophoretic profiles for lot CMC-M-0061, comparing the change under long-term storage conditions (5°C) with the change under accelerated (25°C) and stressed (40°C) conditions at 3 months. By linear kinetic prediction with 95% confidence, the HC+LC% levels for all lots would meet the acceptance criteria at 24 months, except for lots CMC-M-0061 and CMC-N-0011. Based on limited data and the relatively high variability of the data for these two lots, the 95% confidence predictions for the levels at 24 months were overestimated compared to the other lots. Furthermore, the results under accelerated conditions (Figure 12A) show that the decrease in HC+LC% reached a plateau (96%-97%) at 3 months, with no apparent change from 3 to 12 months. Therefore, it is reasonable to expect that the HC+LC% levels of lots CMC-M-0061 and CMC-N-0011 will meet the acceptance criteria at 24 months when stored under long-term storage conditions.

[0206] Similar to the accelerated and stressed conditions, under long-term storage conditions, there was a decrease in the % major species (Figure 29A) and an increase in the % acidic species (Figure 29B) for all lots, with no apparent change in the % basic species (Figure 29C). Figure 30 presents an overlay of electrophoretic profiles for lot CMC-M-0061, comparing the change under long-term storage conditions (5°C) with the change under accelerated (25°C) and stressed (40°C) conditions at 3 months. With decreasing protein concentration, the rate of decline in the % major species appeared to increase, which was not observed under accelerated or stressed conditions. The predicted % major species could decrease to approximately 37% at 24 months for the lot with the fastest kinetics (Figure 29A). The predicted levels of % major species at 24 months under long-term storage conditions are not expected to have any impact on the potency of COR-001.

[0207] Similar to the accelerated and stressed conditions, there was an increase in oxidation levels over time for all lots under long-term storage conditions, which appeared to plateau at 6 months (Figure 31), similar to the plateau level of 5-6% under accelerated and stressed conditions (Figures 16A and 16B). Therefore, it is reasonable to predict that for long-term storage conditions, the maximum oxidation level will remain at 5-6% at 24 months. No effect on potency is expected on the predicted oxidation levels under long-term storage conditions for 24 months.

[0208] Under long-term storage conditions, there was no apparent change in the number of subvisible particles up to 12 months, and all results met the acceptance criteria. Linear kinetic predictions with 95% confidence indicated that the number of subvisible particles ≥10 microns and ≥25 microns in size would meet the acceptance criteria at 24 months (Figures 32A and 32B).

[0209] There was a change in the number of subvisible particles examined by microflow imaging (MFI) under long-term storage conditions (Figures 33A, 33B, and 33C). At 6 months, the number of particles 2 microns or larger was similar to that under accelerated conditions (Figure 17A), suggesting that the increase in these particles was independent of storage temperature. Similar levels were observed in the placebo lot (CMC-M-0062). Therefore, some of these subvisible particulates could be attributed to the nature of the formulation buffer components.

[0210] Similar to accelerated and stress conditions, there was no apparent change in potency of all lots tested by IL-6 binding ELISA and HEK Blue bioassay under long-term storage conditions for up to 12 months, and all results met the acceptance criteria (Figures 34A and 34B).

[0211] The microbiological quality of the three clinical drug lots was monitored by endotoxin levels and container closure integrity testing (CCIT) in lieu of sterility testing, and no changes are expected over long-term storage (Tables 14-18).

[0212] 7. Equivalents and Scope Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above specification, but rather is set forth in the appended claims.

[0213] All cited documents, e.g., references, publications, databases, database entries, and art cited herein, are incorporated by reference into this application, even if not explicitly stated in the cited documents. In the event of a conflict between the statements of the cited documents and this application, the statements of this application shall control.

[0214] Section and table headings are not intended to be limiting.

Claims

1. 1. An antibody formulation comprising: a) 5 mg / mL to 120 mg / mL, for example 10 mg / mL to 50 mg / mL, of an anti-IL-6 antibody comprising a heavy chain amino acid sequence of SEQ ID NO: 9 and a light chain amino acid sequence of SEQ ID NO: 10, and 5 mM to 15 mM methionine; b) a sugar or a derivative thereof; c) a surfactant; and d) free amino acids, The antibody formulation has a pH of 5.0 to 7.

0.

2. The antibody formulation of claim 1 , further comprising a buffer.

3. 3. The antibody formulation of claim 1, wherein the antibody formulation has a pH of 5.7 to 6.

3.

4. The antibody formulation according to any one of claims 1 to 3, wherein the sugar or a derivative thereof is selected from monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, and the like, such as glucose, mannose, sucrose, trehalose, lactose, fructose, maltose, dextran, dextrin, erythritol, glycerol, arabitol, sciritol, sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, isomaltulose, trehalose, and sucrose.

5. 5. The antibody formulation of claim 1, wherein the sugar or derivative thereof is at a concentration of 1% to 40%, 2% to 20%, or 2% to 10% (w / v).

6. The surfactant may be a polysorbate, such as polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80; TRITON (t-octylphenoxypolyethoxyethanol); sodium dodecyl sulfate (SDS); sodium laurel sulfate; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauroamidopropyl-, cocamidopropyl-, linoleyl-, or stearyl-sarcosine; The antibody formulation of any one of claims 1 to 5, wherein the surfactant is selected from the group consisting of noreamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine; myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine; sodium methyl cocoyl tartrate or disodium methyl oleyl tartrate; sorbitan monopalmitate; the MONAQUAT series; polyethyl glycol (PEG), polypropylene glycol (PPG), and a copolymer of poloxyethylene and poloxypropylene glycol.

7. 7. The antibody formulation of claim 1, wherein the surfactant is at a concentration of 0.001% to 1%, e.g., 0.001% to 0.1%, 0.005% to 0.2%, 0.01% to 0.2%, or 0.05% to 0.1% (w / v).

8. The antibody formulation of any one of claims 1 to 7, wherein the free amino acid is selected from glycine, glutamine, asparagine, histidine, arginine, or lysine.

9. 9. The antibody formulation of claim 1, wherein the free amino acid is at a concentration of 1 mM to 400 mM, e.g., 2 mM to 300 mM, 5 mM to 200 mM, or 10 mM to 100 mM.

10. The antibody formulation of any one of claims 2 to 9, wherein the buffering agent is selected from acetate, succinate, gluconate, histidine, citrate, phosphate, maleate, cacodylate, 2-[N-morpholino]ethanesulfonic acid (MES), bis(2-hydroxyethyl)iminotris[hydroxymethyl]methane (Bis-Tris), N-[2-acetamido]-2-iminodiacetic acid (ADA), glycylglycine, and other organic acid buffers.

11. The antibody formulation of any one of claims 2 to 9, wherein the buffer is histidine, citrate, phosphate, glycine, or acetate.

12. The antibody formulation of any one of claims 2 to 11, wherein the buffering agent is at a concentration of 1 mM to 200 mM, such as 1 mM to 50 mM, or 5 mM to 20 mM.

13. a) 7.5 mg / mL to 50 mg / mL of an anti-IL-6 antibody and 5 mM to 15 mM methionine; b) a sugar or a derivative thereof at a concentration of 1% to 40%, 2% to 20%, or 2% to 10% (w / v); c) a surfactant at a concentration of 0.001% to 1%, e.g., 0.001% to 0.1%, 0.005% to 0.2%, 0.01% to 0.2%, or 0.05% to 0.1% (w / v); d) a free amino acid at a concentration of 1 mM to 400 mM, for example, 2 mM to 300 mM, 5 mM to 200 mM, or 10 mM to 100 mM; e) a buffering agent at a concentration of 1 mM to 200 mM, e.g., 1 mM to 50 mM, or 5 mM to 20 mM; The antibody formulation of any one of claims 1 to 12, wherein the antibody formulation has a pH of 5.7 to 6.

3.

14. The antibody formulation of any one of claims 1 to 13, comprising 15 mg / mL or 30 mg / mL of anti-IL-6 antibody.

15. The antibody formulation of any one of claims 1 to 14, in the form of a unit dosage form.

16. 16. The antibody formulation of claim 15, wherein the unit dosage form comprises 15 mg / mL or 30 mg / mL of anti-IL-6 antibody.

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