Anti-IL-6 antibody preparation

Abstract

Provided herein are stable aqueous anti-IL-6 antibody formulations that exhibit reduced aggregate formation and oxidation and are suitable for treating IL-6-mediated diseases and disorders.

Description

Technical Field

[0001] 1. Cross - reference to related applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 841,662, filed May 1, 2019, and European Patent Application No. 19181345.0, filed Jun. 19, 2019, both of which are hereby incorporated by reference in their entirety.

[0002] 2. Sequence Listing This application includes a sequence listing submitted via EFS - Web, which is hereby incorporated by reference in its entirety.

Background Art

[0003] 3. Background Art Elevated levels of IL - 6 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 reduce IL - 6 signaling by binding and neutralizing IL - 6 or by binding to the IL - 6 receptor have been approved for the treatment of rheumatoid arthritis and Castleman's disease. More recently, anti - IL6 antibodies have been demonstrated to be useful in the treatment of hepcidin - mediated disorders in genetically selected patients; see US2017 / 0029499A1. For the treatment of diuretic resistance, see WO2018 / 144773. Also, for the treatment of inflammatory cardiovascular diseases, see US2019 / 0241650.

[0004] The therapeutic use of anti - IL - 6 antibodies is facilitated by formulations that maintain the stability of the antibody under various conditions. The therapeutic formulation should allow storage without unacceptable loss of activity of the active antibody, minimize the accumulation of unwanted products such as aggregates or degradation species (e.g., fragmented, oxidized, deamidated, or isomerized species), contain an appropriate concentration of the antibody, and not contain components that are incompatible with therapeutic use.

[0005] In the art, there is a need for a stable aqueous pharmaceutical formulation comprising an anti-IL-6 antibody that is suitable for therapeutic use.

SUMMARY OF THE INVENTION

[0006] 4. Summary We designed, produced, and tested an anti-IL-6 antibody formulation with reduced formation of aggregates, acidic species, and oxidized species. The anti-IL-6 antibody formulation can be used to treat IL-6 mediated diseases.

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

[0008] In some embodiments, the anti-IL-6 antibody comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain. 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. 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 an anti-IL-6 antibody at about 7.5 mg / mL to about 30 mg / mL. In some embodiments, the formulation comprises an anti-IL-6 antibody at about 7.5 mg / mL. In some embodiments, the formulation comprises an anti-IL-6 antibody at about 15 mg / mL. In some embodiments, the formulation comprises an anti-IL-6 antibody at about 30 mg / mL.

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

[0011] In some embodiments, the formulation comprises from about 0.03% to about 0.1% (w / v) polysorbate 80. In some embodiments, the formulation comprises from 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 from about 1% to about 40% (w / v) trehalose. In some embodiments, the formulation comprises about 5% (w / v) trehalose.

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

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

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

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

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

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

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

[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 stirring at 300 rpm for 20 hours as measured by size exclusion high performance liquid chromatography (SEC-HPLC).

[0022] In some embodiments, the formulation has less than 50% acidic species after incubation at 45 °C for 2 weeks as measured by imaging detection capillary isoelectric focusing (icIEF). 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 incubation at 45 °C for 2 weeks as measured by reverse-phase high performance liquid chromatography (RP-HPLC).

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

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

[0026] In some embodiments, the formulation has less than a 50% reduction in potency after storage at 5 ± 3°C for 12 months as measured by IL-6 binding ELISA. In some embodiments, the formulation has less than a 30% reduction in potency after storage at 5 ± 3°C for 12 months as measured by IL-6 binding ELISA. In some embodiments, the formulation has less than a 50% reduction in potency after storage at 5 ± 3°C for 12 months as measured by a HEK Blue cell-based bioassay. In some embodiments, the formulation has less than a 30% reduction in potency after storage at 5 ± 3°C for 12 months as measured by a 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, unit dosage forms comprising the antibody formulation are provided herein. In some embodiments, the unit dosage form comprises about 7.5 mg of anti-IL-6 antibody. In some embodiments, the unit dosage form comprises about 15 mg of anti-IL-6 antibody. In some embodiments, the unit dosage form comprises about 30 mg of anti-IL-6 antibody.

[0029] 5. Brief Description of the Drawings These and other features, aspects, and advantages of the present invention will be better understood with reference to the following description and the accompanying drawings.

Brief Description of the Drawings

[0030]

Figure 1

Figure 2

Figure 3A

Figure 3B

Figure 3C

Figure 4A

Figure 4B

Figure 5A

Figure 5B

Figure 6A

Figure 6B

Figure 7A

Figure 7B

Figure 8A

Figure 8B

Figure 9A

Figure 9B

Figure 10A

Figure 10B

Figure 11A

Figure 11B

Figure 12A

Figure 12B

Figure 13A

Figure 13B

Figure 14A

Figure 14B

Figure 15A

Figure 15B

Figure 16A

Figure 16B

Figure 17A

Figure 17B

Figure 17C

Figure 18A

Figure 18B

Figure 19A

Figure 19B

Figure 20

Figure 21

Figure 22

Figure 23A

Figure 23B

Figure 23C

Figure 24

Figure 25A

Figure 25B

Figure 26

Figure 27

Figure 28

Figure 29A

Figure 29B

Figure 29C

Figure 30

Figure 31

Figure 32A

Figure 32B

Figure 33A

Figure 33B

Figure 33C

Figure 34A

Figure 34B

Mode for Carrying Out the Invention

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

[0032] A "stable" antibody formulation is one in which the antibody substantially retains its physical stability and / or chemical stability and / or its biological activity during 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. "Substantially retains" is intended to mean retention of 85% or more, for example, at least 90% retention or at least 95% retention.

[0033] A protein "retains its physical stability" in a pharmaceutical formulation if it shows no significant physical changes such as aggregation, precipitation, and / or denaturation when examined visually for color and / or clarity, or when measured by ultraviolet light scattering or size exclusion chromatography.

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

[0035] An antibody "retains its biological activity" in the pharmaceutical formulation if the biological activity of the antibody at a given time does not significantly change from the biological activity shown when the pharmaceutical formulation was prepared, as determined, for example, in an antigen binding assay. The "biological activity" of a monoclonal antibody refers to the ability of the antibody to bind to an antigen and elicit a measurable biological response that can be measured in vitro or in vivo. Such activity can be either 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. A histidine buffer or a histidine-HCl buffer has 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, as long as they exhibit the desired biological activity.

[0038] "Antibody fragment" refers to a part of a full-length antibody, generally including its antigen-binding or variable region. Examples of antibody fragments include Fab fragment, Fab' fragment, F(ab')2 fragment, Fv fragment, scFv (sFv) fragment, scFv-Fc fragment, diabody, linear antibody, single-chain antibody molecule, and multispecific antibody formed from antibody fragments.

[0039] "Interleukin 6 (IL-6)" or "IL-6 polypeptide" means a polypeptide or a fragment thereof that has at least about 85% or more amino acid identity to the amino acid sequence provided by NCBI accession number NP_000591 and has IL-6 biological activity. IL-6 is a pleiotropic cytokine with multiple biological functions. Exemplary IL-6 biological activities include immunostimulatory activity and pro-inflammatory activity. "Interleukin 6 (IL-6) nucleic acid" means a polynucleotide encoding interleukin 6 (IL-6) polypeptide. An exemplary interleukin 6 (IL-6) nucleic acid sequence is provided by NCBI accession number 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 in Section 6.2.2.1 below.

[0041] The "percent identity" 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 introducing gaps as necessary to achieve the maximum percent sequence identity. Alignment for the purpose of determining amino acid sequence identity can be achieved in various ways within the skill in the art using, for example, commonly available computer software such as BLAST, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, or MUSCLE software. One of ordinary skill in the art can determine appropriate parameters for aligning the sequences, including any algorithms necessary to achieve a maximum alignment over the full length of the sequences being compared. Unless otherwise specified, percent sequence identity is determined using the BLAST algorithm with default parameters.

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

[0043] "Subject" means a human or non-human mammal including, but not limited to, cows, horses, dogs, sheep, cats, and rodents including mice and rats. "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 delaying or arresting its progression. Of course, treating a disorder or condition is not precluded from, but does not necessarily require, completely eliminating the associated disorder, condition, or symptoms.

[0045] In the present disclosure, the terms "comprises", "comprising", "containing", "having", "includes", "including", and their grammatical variants have the meanings ascribed to them in United States patent law and allow for the presence of additional components beyond those explicitly 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 ±10%, ±5%, or ±1% of the specified value. In certain embodiments, where applicable, the term "about" refers to ± one standard deviation of the specified value. Unless otherwise specified, "about" refers to ±10% of the specified value.

[0047] When ranges are specified, endpoints are included. Further, unless otherwise indicated or not apparent from the context and understanding of one of ordinary skill in the art, values expressed as ranges are assumed to include any and all sub-ranges and specific values within the recited range in different embodiments of the present 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, a sterile and stable aqueous formulation (pharmaceutical composition) containing an antibody is provided herein. 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 buffering 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 buffering component. In presently preferred embodiments, the formulation comprises an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL and methionine at about 5 mM to about 15 mM.

[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 from 5 mg / mL to 300 mg / mL, from 10 mg / mL to 250 mg / mL, from 20 mg / mL to 200 mg / mL, from 30 mg / mL to 150 mg / mL, or from 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. Antibody 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), mouse antibodies, chimeric antibodies, humanized antibodies, human antibodies, and antibodies and antibody fragments isolated from antibody phage libraries.

[0052] 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; anti-CD30 antibodies such as iratumumab; 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 baricitinib; and anti-IL-6 antibodies such as siltuximab, gilteritinib (also known as gilituzumab), and ziltivekimab, but are not limited thereto.

[0053] 6.2.2.1. Anti-IL-6 Antibody In presently preferred embodiments, the antibody formulation comprises an anti-IL-6 antibody.

[0054] In various embodiments, the antibody formulation comprises an anti-IL-6 antibody at about 2 mg / mL to about 200 mg / mL, such as an anti-IL-6 antibody at 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 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 2 mg / mL to 200 mg / mL, such as an anti-IL-6 antibody at 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 200 mg / mL, 10 mg / mL to 30 mg / mL, 10 mg / mL to 60 mg / mL, 10 mg / mL to 120 mg / mL, 10 mg / mL to 200 mg / mL, 30 mg / mL to 60 mg / mL, 30 mg / mL to 120 mg / mL, 30 mg / mL to 200 mg / mL, 60 mg / mL to 120 mg / mL, 60 mg / mL to 200 mg / mL, or 120 mg / mL to 200 mg / mL. In some embodiments, the antibody formulation comprises an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL. In some embodiments, the antibody formulation comprises an anti-IL-6 antibody at 5 mg / mL to 120 mg / mL.

[0055] In typical embodiments, the anti-IL-6 antibody neutralizes the biological activity of IL-6. In some embodiments, the neutralizing antibody prevents the binding of IL-6 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 anti-IL-6 antibodies, each of the multiple having 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, bispecific 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 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 and has non-human V regions and human C region domains. In some embodiments, the antibody is murine.

[0061] In typical embodiments, the anti-IL-6 antibody has a K for binding to human IL-6 of less than 100 nM DIt has. In 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 It has. 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 It has. 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 It has. 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 a elimination half-life after intravenous administration for 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 having at least one amino acid substitution that extends the serum half-life compared to the 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 a substitution with tyrosine, the amino acid substitution at amino acid residue 254 is a substitution with threonine, and the amino acid substitution at amino acid residue 256 is a substitution with glutamic acid (“YTE”). See US 7,083,784, which is 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 elimination half-life of the anti-IL-6 antibody is increased by taking advantage of 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 for IL-6 and one specificity for human serum albumin (Ablynx, WO2006 / 122825 (bispecific nanobody)).

[0066] In some embodiments, the elimination half-life of the anti-IL-6 antibody is increased by PEGylation (Melmed et al., Nature Reviews Drug Discovery 7:641-642 (2008)), by HPMA copolymer conjugation (Lu et al., Nature Biotechnology 17:1101-1104 (1999)), by dextran conjugation (Nuclear Medicine Communications, 16:362-369 (1995)), by conjugation with homoamino acid polymers (HAPs; HAPylation) (Schlapschy et al., Prot Eng Design Sel 20:273-284 (2007)), or by 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 siltuximab and MEDI5117), siltuximab, golimumab, silkumab, 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, golimumab, silkumab, 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 (siltuximab), siltuximab, golimumab, silkumab, 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] 6.2.2.1.1.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 siltuximab and MEDI5117) is described in WO2010 / 088444 and US2012 / 0034212, the disclosures of which are incorporated herein by reference in their entirety. In certain embodiments, the antibody or antigen-binding portion thereof comprises the COR-001 heavy chain V region and the 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) Heavy chain of COR-001 EVQLVESGGGLVQPGGSLRLSCAASGFTISSNYMIWVRQAPGKGLEWVSDLYYYAGDTYY ADSVKGRFTMSRDISKNTVYLQMNSLRAEDTAVYYCARWADDHPPWIDLWGRGTLVTVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGG PSVFLFPPKPKDTLYITREPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYN STYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREE MTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRW QQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 9) Light chain of COR-001 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 with 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 with 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 with SEQ ID NO: 3. In some embodiments, the derivative of COR-001 comprises a VL CDR1 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity with SEQ ID NO: 4. In some embodiments, the derivative of COR-001 comprises a VL CDR2 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity with SEQ ID NO: 5. In some embodiments, the derivative of COR-001 comprises a VL CDR3 having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity with SEQ ID NO: 6.

[0070] In certain embodiments, the derivative of COR-001 comprises a VH domain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity with SEQ ID NO: 7. In certain embodiments, the derivative of COR-001 comprises a VL domain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity with SEQ ID NO: 8. In specific embodiments, the derivative of COR-001 comprises a VH domain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity with SEQ ID NO: 7 and a VL domain having at least about 50%, 75%, 80%, 85%, 90%, 95%, 97%, or 99% identity with 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 a specific embodiment, 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 at a concentration of about 1 mM to about 100 mM, such as, for example, 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 at a concentration of 1 mM to 100 mM, such as, for example, 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 chelating agents, reducing agents, oxygen scavengers, and chain terminators 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] 6.2.3.1. Methionine In a presently preferred embodiment, the formulation contains methionine. In some embodiments, the formulation contains L-methionine.

[0076] In some embodiments, the formulation contains 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 of methionine. In various embodiments, the formulation contains from about 1 mM to about 100 mM, from about 2 mM to about 80 mM, from about 5 mM to about 50 mM, from about 10 mM to about 20 mM of methionine. In certain embodiments, the formulation contains 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 of methionine. In some embodiments, the formulation contains from about 1 mM to about 50 mM of methionine. In specific embodiments, the formulation contains from about 5 mM to about 15 mM of methionine. In a specific embodiment, the formulation contains about 10 mM of methionine.

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

[0078] 6.2.4. Surfactant In some embodiments, the composition includes a surfactant. The surfactant can lower the surface tension of a liquid. In some embodiments, the surfactant is a nonionic surfactant. Examples of surfactants include polysorbates (polyoxyethylene sorbitan monolaurate, e.g., polysorbate 20 and polysorbate 80); TRITON (t-octylphenoxypolyethoxyethanol); sodium dodecyl sulfate (SDS); sodium lauryl sulfate; sodium octyl glucoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine; linoleyl-, 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, N.J.); polyethylene glycol (PEG), polypropylene glycol (PPG), and copolymers of polyoxyethylene and polyoxypropylene 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 comprises a surfactant at a concentration of about 0.001% to about 1%, such as 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 comprises a surfactant at a concentration of 0.001% to 1%, such as 0.001% to 0.1%, 0.005% to 0.2%, 0.01% to 0.2%, or 0.05% to 0.1% (w / v).

[0080] 6.2.4.1. 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) of polysorbate 80. In some embodiments, the formulation comprises about 0.001% to about 1%, about 0.002% to about 0.5%, about 0.005% to about 0.2%, or about 0.01% to about 0.1% (w / v) of 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) of polysorbate 80. In certain embodiments, the formulation comprises about 0.005% to about 0.5% (w / v) of polysorbate 80. In certain embodiments, the formulation comprises about 0.03% to about 0.1% (w / v) of polysorbate 80. In certain embodiments, the formulation comprises about 0.05% to about 0.1% (w / v) of polysorbate 80. In a particular embodiment, the formulation comprises about 0.07% (w / v) of 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) of polysorbate 80. In some embodiments, the formulation comprises 0.001% - 1%, 0.002% - 0.5%, 0.005% - 0.2%, or 0.01% - 0.1% (w / v) of 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) of polysorbate 80. In certain embodiments, the formulation comprises 0.005% - 0.5% (w / v) of polysorbate 80. In certain embodiments, the formulation comprises 0.03% - 0.1% (w / v) of polysorbate 80. In certain embodiments, the formulation comprises 0.05% - 0.1% (w / v) of polysorbate 80. In specific embodiments, the formulation comprises 0.07% (w / v) of polysorbate 80.

[0083] 6.2.4.2. 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) of polysorbate 60. In some embodiments, the formulation comprises from about 0.001% to about 1%, from about 0.002% to about 0.5%, from about 0.005% to about 0.2%, or from about 0.01% to about 0.1% (w / v) of 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) of polysorbate 60. In certain embodiments, the formulation comprises from about 0.03% to about 0.1% (w / v) of polysorbate 60. In certain embodiments, the formulation comprises from about 0.05% to about 0.1% (w / v) of polysorbate 60. In specific embodiments, the formulation comprises about 0.07% (w / v) of 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) of polysorbate 60. In some embodiments, the formulation comprises 0.001% - 1%, 0.002% - 0.5%, 0.005% - 0.2%, or 0.01% - 0.1% (w / v) of 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) of polysorbate 60. In certain embodiments, the formulation comprises 0.03% - 0.1% (w / v) of polysorbate 60. In certain embodiments, the formulation comprises 0.05% - 0.1% (w / v) of polysorbate 60. In specific embodiments, the formulation comprises 0.07% (w / v) of polysorbate 60.

[0086] 6.2.4.3. 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) of polysorbate 40. In some embodiments, the formulation comprises from about 0.001% to about 1%, from about 0.002% to about 0.5%, from about 0.005% to about 0.2%, or from about 0.01% to about 0.1% (w / v) of 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) of polysorbate 40. In certain embodiments, the formulation comprises from about 0.03% to about 0.1% (w / v) of polysorbate 40. In certain embodiments, the formulation comprises from about 0.05% to about 0.1% (w / v) of polysorbate 40. In particular embodiments, the formulation comprises about 0.07% (w / v) of 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) of polysorbate 40. In some embodiments, the formulation comprises 0.001% - 1%, 0.002% - 0.5%, 0.005% - 0.2%, or 0.01% - 0.1% (w / v) of 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) of polysorbate 40. In certain embodiments, the formulation comprises 0.03% - 0.1% (w / v) of polysorbate 40. In certain embodiments, the formulation comprises 0.05% - 0.1% (w / v) of polysorbate 40. In specific embodiments, the formulation comprises 0.07% (w / v) of polysorbate 40.

[0089] 6.2.4.4. 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) of polysorbate 20. In some embodiments, the formulation comprises from about 0.001% to about 1%, from about 0.002% to about 0.5%, from about 0.005% to about 0.2%, or from about 0.01% to about 0.1% (w / v) of 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) of polysorbate 20. In certain embodiments, the formulation comprises from about 0.03% to about 0.1% (w / v) of polysorbate 20. In certain embodiments, the formulation comprises from about 0.05% to about 0.1% (w / v) of polysorbate 20. In specific embodiments, the formulation comprises about 0.07% (w / v) of 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) of polysorbate 20. In some embodiments, the formulation comprises 0.001% - 1%, 0.002% - 0.5%, 0.005% - 0.2%, or 0.01% - 0.1% (w / v) of 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) of polysorbate 20. In certain embodiments, the formulation comprises 0.03% - 0.1% (w / v) of polysorbate 20. In certain embodiments, the formulation comprises 0.05% - 0.1% (w / v) of polysorbate 20. In a particular embodiment, the formulation comprises 0.07% (w / v) of polysorbate 20.

[0092] 6.2.5. Saccharides In some embodiments, the composition comprises saccharides and their derivatives, including monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars, and the like. Examples of saccharides include glucose, mannose, sucrose, trehalose, lactose, fructose, maltose, dextran, dextrin, erythritol, glycerol, arabitol, xylitol, sorbitol, mannitol, melibiose, melezitose, raffinose, mannotriose, stachyose, maltulose, lactulose, glucitol, maltitol, lactitol, isomaltulose, and the like. In some embodiments, the saccharide is a disaccharide. In certain embodiments, the disaccharide is trehalose or sucrose. In various embodiments, the disaccharide is at a concentration of about 1% - about 40%, about 2% - about 20%, or about 2% - about 10% (w / v). In various embodiments, the disaccharide is at a concentration of 1% - 40%, 2% - 20%, or 2% - 10% (w / v).

[0093] 6.2.5.1. Trehalose In some embodiments, the formulation comprises trehalose.

[0094] In various embodiments, the formulation comprises from 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 from about 1% to about 40%, from about 2% to about 30%, from about 3% to about 20%, from about 5% to about 15%, or from 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 a specific embodiment, the formulation comprises 5% (w / v) trehalose.

[0096] 6.2.5.2. Sucrose In some embodiments, the formulation comprises sucrose.

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

[0098] 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) sucrose. In some embodiments, the formulation comprises from 1% to 40%, from 2% to 30%, from 3% to 20%, from 5% to 15%, or from 5% to 10% (w / v) sucrose. In certain embodiments, the formulation comprises 1%, 2%, 3%, 5%, 10%, 15%, 20%, 30%, or 40% (w / v) sucrose. In a specific embodiment, the formulation comprises 5% (w / v) sucrose.

[0099] 6.2.6. 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 acid can be of the L-form, D-form, or a mixture of these forms.

[0100] In certain embodiments, 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, such as 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, such as 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] 6.2.6.1. Arginine In some embodiments, the formulation comprises arginine. In some embodiments, the formulation comprises L-arginine.

[0103] In various embodiments, the formulation contains from 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 from about 5 mM to about 400 mM, from about 10 mM to about 200 mM, from about 20 mM to about 150 mM, from about 30 mM to about 100 mM, or from about 50 mM to about 80 mM arginine. In certain embodiments, the formulation contains 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 specific embodiments, the formulation contains from about 10 mM to about 200 mM arginine. In a particular embodiment, the formulation contains about 70 mM arginine.

[0104] In various embodiments, the formulation contains 5 mM to 500 mM arginine (as arginine-HCl). In some embodiments, the formulation contains 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 contains 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 specific embodiments, the formulation contains 10 mM to 200 mM arginine. In a particular embodiment, the formulation contains 70 mM arginine.

[0105] 6.2.7. Buffer In some embodiments, the formulation comprises at least one buffering agent (buffering component). Typically, the buffering agent, if present, 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, the 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-imino diacetic 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 component is 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 component is at a concentration of 1 mM to 200 mM, 1 mM to 50 mM, or 5 mM to 20 mM. In certain embodiments, the buffering component is at a concentration of about 10 mM, about 15 mM, about 20 mM, or about 25 mM. In certain embodiments, the buffering component is at a concentration of 10 mM, 15 mM, 20 mM, or 25 mM.

[0107] 6.2.7.1. 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 of histidine. In various embodiments, the composition comprises from about 1 mM to about 200 mM, from about 5 mM to about 150 mM, from about 10 mM to about 100 mM, from about 15 mM to about 50 mM, or from about 20 mM to about 30 mM of 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 of histidine. In specific embodiments, the formulation comprises from about 10 mM to about 100 mM of histidine. In a particular embodiment, the formulation comprises about 20 mM of 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 of histidine. In various embodiments, the composition comprises from 1 mM to 200 mM, from 5 mM to 150 mM, from 10 mM to 100 mM, from 15 mM to 50 mM, or from 20 mM to 30 mM of 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 of histidine. In specific embodiments, the formulation comprises from 10 mM to 100 mM of histidine. In a particular embodiment, the formulation comprises 20 mM of histidine.

[0110] 6.2.7.2. pH In some embodiments, the formulation has a pH of from about 4.0 to about 8.0, such as from about 4.5 to about 7.5, from about 5.0 to about 7.0, from about 5.5 to about 6.5, from about 5.7 to about 6.3, or from 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 specific embodiments, the formulation has a pH of from about 5.0 to about 7.0. In certain embodiments, the formulation has a pH of from about 5.0 to about 7.0. In certain embodiments, the formulation has a pH of from about 5.5 to about 6.5. In certain embodiments, the formulation has a pH of from 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 from 4.0 to 8.0, such as from 4.5 to 7.5, from 5.0 to 7.0, from 5.5 to 6.5, from 5.7 to 6.3, or from 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 specific embodiments, the formulation has a pH of from 5.0 to 7.0. In certain embodiments, the formulation has a pH of from 5.5 to 6.5. In certain embodiments, the formulation has a pH of from 5.7 to 6.3. In a specific embodiment, the formulation has a pH of 6.0.

[0112] 6.2.8. Preservatives In some embodiments, the formulation further comprises at least one preservative. In various embodiments, the at least one preservative is selected from cetyl dimethyl benzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride (a mixture of alkyl benzyl dimethyl ammonium chlorides where the alkyl group is a long-chain compound), and benzetonium chloride. Other types of preservatives include phenol, butyl, and aromatic alcohols such as 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 an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL, and methionine at about 1 mM to about 100 mM, such as methionine at about 1 mM to about 5 mM, about 1 mM to about 10 mM, about 1 mM to about 15 mM, about 1 mM to about 30 mM, about 1 mM to about 50 mM, about 1 mM to about 100 mM, about 5 mM to about 10 mM, about 5 mM to about 15 mM, about 5 mM to about 30 mM, about 5 mM to about 50 mM, about 5 mM to about 100 mM, about 10 mM to about 15 mM, about 10 mM to about 30 mM, about 10 mM to about 50 mM, about 10 mM to about 100 mM, about 15 mM to about 30 mM, about 15 mM to about 50 mM, about 15 mM to about 100 mM, about 30 mM to about 50 mM, about 30 mM to about 100 mM, or about 50 mM to about 100 mM. In some embodiments, the antibody formulation comprises an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL, and methionine at about 5 mM to about 15 mM. In certain embodiments, the antibody formulation comprises an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL and about 10 mM methionine.

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

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

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

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

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

[0119] In some embodiments, the antibody formulation comprises: a) an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL, b) trehalose at about 1% to about 40% (w / v), c) polysorbate 80 at about 0.03% to about 0.1% (w / v), d) arginine at about 10 mM to about 200 mM, e) methionine at about 5 mM to about 15 mM, and f) histidine at about 10 mM to about 100 mM, and the antibody formulation has a pH of about 5.0 to about 7.0. In some embodiments, the antibody formulation comprises: a) an anti-IL-6 antibody at 5 mg / mL to 120 mg / mL, b) trehalose at 1% to 40% (w / v), c) polysorbate 80 at 0.03% to 0.1% (w / v), d) arginine at 10 mM to 200 mM, e) methionine at 5 mM to 15 mM, and f) histidine at 10 mM to 100 mM, 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 the full-length COR-001 antibody. In various embodiments, the antibody formulation comprises from about 5 mg / mL to about 50 mg / mL of the COR-001 antibody, such as, for example, 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 the COR-001 antibody. In various embodiments, the antibody formulation comprises from 5 mg / mL to 50 mg / mL of the COR-001 antibody, such as, for example, 5 mg / mL, 7.5 mg / mL, 10 mg / mL, 15 mg / mL, 20 mg / mL, 30 mg / mL, or 50 mg / mL of the COR-001 antibody. In some embodiments, the antibody formulation comprises from about 7.5 mg / mL to about 30 mg / mL of the COR-001 antibody. In some embodiments, the antibody formulation comprises from 7.5 mg / mL to 30 mg / mL of the COR-001 antibody. In certain embodiments, the antibody formulation comprises about 7.5 mg / mL of the COR-001 antibody. In certain embodiments, the antibody formulation comprises 7.5 mg / mL of the COR-001 antibody. In certain embodiments, the antibody formulation comprises about 15 mg / mL of the COR-001 antibody. In certain embodiments, the antibody formulation comprises 15 mg / mL of the COR-001 antibody. In certain embodiments, the antibody formulation comprises about 30 mg / mL of the COR-001 antibody. In certain embodiments, the antibody formulation comprises 30 mg / mL of the COR-001 antibody.

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

[0123] In certain embodiments, the antibody formulation comprises: a) COR-001 antibody at about 7.5 mg / mL to about 30 mg / mL, b) trehalose at about 5% (w / v), c) polysorbate 80 at about 0.07% (w / v), d) arginine at about 70 mM, e) methionine at about 10 mM, and f) histidine at about 20 mM, and the antibody formulation has a pH of about 6.0. In certain embodiments, the antibody formulation comprises: a) COR-001 antibody at 7.5 mg / mL to 30 mg / mL, b) trehalose at 5% (w / v), c) polysorbate 80 at 0.07% (w / v), d) arginine at 70 mM, e) methionine at 10 mM, and f) histidine at 20 mM, 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, for example, less than 40 cP at 25°C, less than 30 cP, less than 20 cP, less than 10 cP, or less than 5 cP at 25°C. In a specific embodiment, 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. Aggregation 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 as measured by size exclusion high performance liquid chromatography (SEC-HPLC) compared to a formulation with less polysorbate 80. In certain embodiments, the formulation reduces the formation of insoluble aggregates as measured by visual appearance check compared to a formulation with less polysorbate 80. In certain embodiments, the formulation reduces the formation of soluble aggregates as measured by SEC-HPLC compared to a formulation without methionine. In some embodiments, the formulation has less than 15% soluble aggregates after stirring at 300 rpm for 20 hours as measured by SEC-HPLC. In some embodiments, the formulation has less than 10% soluble aggregates after stirring at 300 rpm for 20 hours as measured by SEC-HPLC. In some embodiments, the formulation has less than 5% soluble aggregates after stirring at 300 rpm for 20 hours as measured by SEC-HPLC. In some embodiments, the formulation has less than 2% soluble aggregates after stirring at 300 rpm for 20 hours as measured by SEC-HPLC.

[0126] 6.2.9.3. Charge Variant In some embodiments, the formulation reduces the percentage of charge variants measured as peaks eluting earlier or later than the major species by imaged capillary isoelectric focusing (icIEF). In certain embodiments, the formulation reduces the percentage of charge variants as measured by icIEF compared to a formulation without methionine. Charge variants include acidic and basic species.

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

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

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

[0130] In some embodiments, the formulation reduces the percentage of acidic species measured as peaks eluting earlier than the major species measured by imaged capillary isoelectric focusing (icIEF). In various embodiments, the measured acidic species are produced by deamidation, isomerization, oxidation, or other degradation. In certain embodiments, the formulation reduces the percentage 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 incubation at 45° C. for 2 weeks as measured by icIEF. In some embodiments, the formulation has less than 50% acidic species after incubation at 45° C. for 2 weeks as measured by icIEF. In some embodiments, the formulation has less than 40% acidic species after incubation at 45° C. for 2 weeks as measured by icIEF. In some embodiments, the formulation has less than 30% acidic species after incubation at 45° C. for 2 weeks as measured by icIEF.

[0131] 6.2.9.4. Oxidation In some embodiments, the formulation reduces the oxidation of the antibody. In some embodiments, the formulation reduces the oxidation including oxidation of residue Met431 as 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 incubation at 45° C. for 2 weeks as measured by RP-HPLC. In some embodiments, the formulation has less than 10% oxidized species after incubation at 45° C. for 2 weeks as measured by RP-HPLC. In some embodiments, the formulation has less than 5% oxidized species after incubation at 45° C. for 2 weeks as measured by RP-HPLC. In some embodiments, the formulation has less than 4% oxidized species after incubation at 45° C. for 2 weeks as measured by RP-HPLC. In some embodiments, the formulation has less than 3% oxidized species after incubation at 45° C. for 2 weeks as measured by RP-HPLC.

[0132] In some embodiments, the formulation has less than 10% oxidized species after storage at 5 ± 3°C for 12 months 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 storage at 5 ± 3°C for 12 months as measured by RP-HPLC. In certain embodiments, the formulation has less than 6% oxidized species after storage at 5 ± 3°C for 12 months as measured by RP-HPLC. In certain embodiments, the formulation has less than 5% oxidized species after storage at 5 ± 3°C for 12 months as measured by RP-HPLC.

[0133] In some embodiments, the formulation has less than 10% oxidized species after storage at 25 ± 2°C for 6 months 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 storage at 25 ± 2°C for 6 months as measured by RP-HPLC. In certain embodiments, the formulation has less than 6% oxidized species after storage at 25 ± 2°C for 6 months as measured by RP-HPLC. In certain embodiments, the formulation has less than 5% oxidized species after storage at 25 ± 2°C for 6 months as measured by RP-HPLC.

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

[0135] 6.2.9.5. Efficacy In some embodiments, the formulation retains the efficacy of the antibody. In various embodiments, the efficacy of the anti-IL-6 antibody is measured by an IL-6 binding ELISA or a HEK Blue cell-based bioassay.

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

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

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

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

[0140] In some embodiments, the formulation has less than a 50% reduction in potency after storage at 40 ± 2 °C for 1 month 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 storage at 40 ± 2 °C for 1 month as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 30% reduction in potency after storage at 40 ± 2 °C for 1 month as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 20% reduction in potency after storage at 40 ± 2 °C for 1 month as measured by IL-6 binding ELISA. In certain embodiments, the formulation has less than a 10% reduction in potency after storage at 40 ± 2 °C for 1 month as measured by IL-6 binding ELISA.

[0141] In some embodiments, the formulation has less than a 50% reduction in potency after storage at 40 ± 2 °C for 1 month 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 storage at 40 ± 2 °C for 1 month as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 30% reduction in potency after storage at 40 ± 2 °C for 1 month as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 20% reduction in potency after storage at 40 ± 2 °C for 1 month as measured by a HEK Blue cell-based bioassay. In certain embodiments, the formulation has less than a 10% reduction in potency after storage at 40 ± 2 °C for 1 month 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 parenteral (e.g., by subcutaneous, intravenous, intramuscular, intradermal, or intrasternal injection or infusion (e.g., with a sterile aqueous or non-aqueous solution or suspension, etc.)), and topical (e.g., in the form of a cream or ointment), but are not limited thereto. 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 formulation is suitable for administration as a single dose or multiple doses.

[0144] 6.4. Dosage Form In another aspect, dosage forms containing one or more unit doses of a pharmaceutical composition comprising an anti-IL-6 antibody are provided herein.

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

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

[0149] In certain embodiments, the dosage form comprises multiple 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 multiple 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 multiple 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. Method of Treatment In another aspect, provided herein is a method of 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 an elevation in the pre-treatment level 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, which is 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 a renal disease. In some embodiments, the renal 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 at KDOQI stages 3-5 and has a CRP level of 2 mg / L or higher. In certain embodiments, the formulation is administered to reduce the risk of cardiovascular morbidity and mortality in adult patients with chronic kidney disease at KDOQI stages 3-5 who have inflammation.

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

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

[0160] In some embodiments, the patient has had a prior myocardial infarction. In some embodiments, the patient has not had a prior myocardial infarction.

[0161] In certain embodiments, the patient has had a prior 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 a 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 a preserved ejection fraction. In some embodiments, the cardiovascular disease is acute coronary syndrome. In certain embodiments, the anti-IL-6 antibody formulation is administered in 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 in a dose sufficient to reduce the risk of heart failure. In some embodiments, the anti-IL-6 antibody formulation is administered in a dose sufficient to increase cardiac function. In some embodiments, the anti-IL-6 antibody formulation is administered in a dose sufficient to reduce fibrosis after acute myocardial infarction. In some embodiments, the anti-IL-6 antibody formulation is administered in a dose sufficient to reduce the risk of cardiovascular morbidity and mortality.

[0163] In some embodiments, the cardiovascular disease is heart failure that is not diuretic-resistant. In some other embodiments, the cardiovascular disease is heart failure that is diuretic-resistant. 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 solid tumors, small cell lung cancer, non-small cell lung cancer, blood cancer, multiple myeloma, leukemia, chronic lymphocytic leukemia (CLL), chronic myeloid 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 of the patient. List of Embodiments 1. An antibody formulation comprising an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL and methionine at about 5 mM to about 15 mM. 2. The anti-IL-6 antibody comprises a heavy chain variable (VH) domain and a light chain variable (VL) domain, 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, 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, the antibody formulation according to Embodiment 1. 3. 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, the antibody formulation according to Embodiment 1 or 2. 4. 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, the antibody formulation according to any one of Embodiments 1 to 3. 5. The antibody formulation according to any one of the preceding embodiments, wherein the formulation comprises an anti-IL-6 antibody at about 7.5 mg / mL to about 30 mg / mL. 6. The antibody formulation according to embodiment 5, wherein the formulation comprises an anti-IL-6 antibody at about 7.5 mg / mL. 7. The antibody formulation according to embodiment 5, wherein the formulation comprises an anti-IL-6 antibody at about 15 mg / mL. 8. The antibody formulation according to embodiment 5, wherein the formulation comprises an anti-IL-6 antibody at about 30 mg / mL. 9. The antibody formulation according to any one of the preceding embodiments, wherein the formulation comprises about 10 mM of methionine. 10. The antibody formulation according to any one of the preceding embodiments, further comprising about 0.03% to about 0.1% (w / v) of polysorbate 80. 11. The antibody formulation according to embodiment 10, wherein the formulation comprises about 0.05% to about 0.1% (w / v) of polysorbate 80. 12. The antibody formulation according to embodiment 11, wherein the formulation comprises about 0.07% (w / v) of polysorbate 80. 13. The antibody formulation according to any one of the preceding embodiments, further comprising about 1% to about 40% (w / v) of trehalose. 14. The antibody formulation according to embodiment 13, wherein the formulation comprises about 5% (w / v) of trehalose. 15. The antibody formulation according to any one of the preceding embodiments, further comprising about 10 mM to about 200 mM of arginine. 16. The antibody formulation according to embodiment 15, wherein the formulation comprises about 70 mM of arginine. 17. The antibody formulation according to any one of the preceding embodiments, further comprising about 10 mM to about 100 mM of histidine. 18. The antibody formulation according to embodiment 17, wherein the formulation comprises about 20 mM of histidine. 19. The antibody formulation according to 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 according to embodiment 21, wherein the antibody formulation has a pH of about 6.0. 21. An antibody formulation comprising an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL, methionine at about 5 mM to about 15 mM, and polysorbate 80 at about 0.03% to about 0.1% (w / v). 22. The antibody formulation according to embodiment 21, wherein the anti-IL-6 antibody has the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10. 23. An antibody formulation, a) an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL, and b) trehalose at about 1% to about 40% (w / v), and c) polysorbate 80 at about 0.03% to about 0.1% (w / v), and d) arginine at about 10 mM to about 200 mM, and e) methionine at about 5 mM to about 15 mM, and f) histidine at about 10 mM to about 100 mM, and having a pH of about 5.0 to about 7.0. An antibody formulation having a pH of about 5.0 to about 7.0. 24. The antibody formulation according to embodiment 23, wherein the anti-IL-6 antibody has the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10. 25. An antibody formulation, a) an anti-IL-6 antibody at about 5 mg / mL to about 120 mg / mL, wherein the anti-IL-6 antibody has the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10, an anti-IL-6 antibody, and b) trehalose at about 5% (w / v), and c) polysorbate 80 at about 0.07% (w / v), and d) arginine at about 70 mM, and e) methionine at about 10 mM, and f) histidine at about 20 mM, and having a pH of about 6.0. An antibody formulation having a pH of about 6.0. 26. The antibody formulation according to embodiment 25, wherein the formulation comprises an anti-IL-6 antibody at about 7.5 mg / mL. 27. The antibody formulation according to embodiment 25, wherein the formulation comprises an anti-IL-6 antibody at about 15 mg / mL. 28. The antibody formulation according to embodiment 25, wherein the formulation comprises an anti-IL-6 antibody at about 30 mg / mL. 29. The antibody formulation according to any one of the preceding embodiments, wherein the formulation has a viscosity of less than 10 cP at 25°C. 30. The antibody formulation according to any one of the preceding embodiments, which has less than 5% soluble aggregates after stirring at 300 rpm for 20 hours as measured by size exclusion high performance liquid chromatography (SEC-HPLC). 31. The antibody formulation according to any one of the preceding embodiments, which has less than 50% acidic species after incubation at 45°C for 2 weeks as measured by imaging detection capillary isoelectric focusing electrophoresis (icIEF). 32. The antibody formulation according to embodiment 31, wherein the acidic species to be measured are generated by deamidation, isomerization, oxidation, or degradation. 33. The antibody formulation according to any one of the preceding embodiments, which has less than 5% oxidized species after incubation at 45°C for 2 weeks as measured by reverse phase high performance liquid chromatography (RP-HPLC). 34. The antibody formulation according to any one of the preceding embodiments, which has less than 50% charged variants after storage at 5 ± 3°C for 12 months as measured by imaging detection capillary isoelectric focusing electrophoresis (icIEF). 35. The antibody formulation according to embodiment 34, wherein the formulation has less than 50% acidic species after storage at 5 ± 3°C for 12 months as measured by imaging detection capillary isoelectric focusing electrophoresis (icIEF). 36. The antibody formulation according to any one of the preceding embodiments, which has less than 10% oxidized species after storage at 5 ± 3°C for 12 months as measured by reverse phase high performance liquid chromatography (RP-HPLC). 37. The antibody formulation according to embodiment 36, which has less than 6% oxidized species after storage at 5 ± 3°C for 12 months as measured by reverse phase high performance liquid chromatography (RP-HPLC). 38. An antibody formulation according to any one of the preceding embodiments, wherein when measured by IL-6 binding ELISA, the formulation has a reduction in potency of less than 50% after storage at 5 ± 3°C for 12 months. 39. The antibody formulation according to embodiment 38, wherein when measured by IL-6 binding ELISA, the formulation has a reduction in potency of less than 30% after storage at 5 ± 3°C for 12 months. 40. An antibody formulation according to any one of the preceding embodiments, wherein when measured by a HEK Blue cell-based bioassay, the formulation has a reduction in potency of less than 50% after storage at 5 ± 3°C for 12 months. 41. The antibody formulation according to embodiment 40, wherein when measured by a HEK Blue cell-based bioassay, the formulation has a reduction in potency of less than 30% after storage at 5 ± 3°C for 12 months. 42. An antibody formulation according to any one of the preceding embodiments, wherein the formulation is suitable for parenteral administration. 43. The antibody formulation according to embodiment 42, wherein the formulation is suitable for intravenous administration. 44. The antibody formulation according to embodiment 42, wherein the formulation is suitable for subcutaneous administration. 45. A unit dosage form comprising an antibody formulation according to any one of the preceding embodiments. 46. The unit dosage form according to embodiment 45, wherein the unit dosage form comprises about 7.5 mg of an anti-IL-6 antibody. 47. The unit dosage form according to embodiment 45, wherein the unit dosage form comprises about 15 mg of an anti-IL-6 antibody. 48. The unit dosage form according to embodiment 45, wherein the unit dosage form comprises about 30 mg of an anti-IL-6 antibody.

Examples

[0166] 6.6. Examples The following 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. Although efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), some experimental errors and deviations are, of course, to be tolerated.

[0167] The practice of the present invention, unless otherwise indicated, uses conventional methods of protein chemistry, biochemistry, recombinant DNA techniques and pharmacology within the scope of the relevant art. Such techniques are well described in the literature.

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

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

[0170] To utilize the thermal stabilization imparted by trehalose, a combination of L-arginine-HCl and trehalose dihydrate resulting in an isotonic composition (i.e., 5% (w / v) of trehalose dihydrate) was selected. 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. For the COR-001 liquid formulation, 70 mM L-arginine-HCl and 5% trehalose dihydrate were selected.

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

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

[0173] In the absence of PS80, precipitates were observed in all formulations after stirring. As the PS80 level increased, the turbidity of the product solution appeared lower, and when the PS80 level reached 0.05% or higher, no particles or opaqueness were observed after stirring. This appearance trend was also in good correlation with the OD340 and SEC results. Figure 2 shows the effect of PS80 level on the formation of soluble aggregates by SEC. The results indicate that PS80 at 0.03% can reduce soluble aggregates at protein concentrations of 50 mg / mL or less, and PS80 at 0.05% can reduce soluble aggregates at protein concentrations in the range of 5 to 120 mg / mL under the stress shaking model. A level of 0.07% of PS80 was selected for COR-001 in the liquid formulation.

[0174] Example 3: Minimizing Oxidation over Long-Term Storage To evaluate the long-term storage stability of COR-001 in the selected liquid formulation (5% trehalose dihydrate, 70 mM L-arginine-HCl, 0.07% PS80, 20 mM L-histidine, pH 6.0), ranges 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, the purity changes as observed by SE - HPLC and non - reducing CE - SDS were minimal. However, a 5 - 10% decrease in the % major isoform was observed by icIEF, with an accompanying increase in the acidic species. By tryptic map / LC - MS analysis, a significant increase in oxidation (16 - 46%) was observed at all three protein concentrations. No clear trend in the potency of COR - 001 was observed by IL - 6 binding ELISA, indicating that highly oxidized COR - 001 had no effect on potency, consistent with the oxidation site being mainly on heavy - chain Met431 and not within the CDR.

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

[0177] To evaluate whether adding methionine, the third amino acid, to a formulation containing the two amino acids arginine and histidine can reduce or prevent oxidation during long-term storage, 10 mg / mL and 50 mg / mL of COR-001 were each spiked with L-methionine in the range of 0 - 15 mM (5% trehalose dihydrate, 70 mM L-arginine-HCl, 0.07% PS80, 20 mM L-histidine, pH 6.0) and then incubated for 2 weeks under accelerated conditions at 45°C. Samples were tested by appearance, SEC, CE-SDS, and icIEF, as well as an oxidation assay (RP-HPLC) to measure oxidized species. No obvious effects of the various L-methionine levels included were observed by appearance and CE-SDS tests. However, with increasing L-methionine levels, little change was observed in SEC, icIEF, and oxidation tests. As shown in Figures 3A, 3B, and 3C, after 2 weeks under accelerated conditions at 45°C, compared to the formulation without added L-methionine, L-methionine reduced aggregation, charge change, and oxidation levels for both 10 mg / mL and 50 mg / mL of COR-001. At 10 mM L-methionine, these change levels essentially reached a plateau, indicating that 10 mM L-methionine is 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 the stability of COR-001 during storage, two different protein concentrations (10 and 50 mg / mL) in the 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 in 1.0 mL aliquots into 3 mL Type I glass vials closed with 13 mm rubber stoppers. Samples were tested after storage for 3 months at 5 ± 3°C, 25 ± 2°C, and 40 ± 2°C. The results are summarized in Table 2.

Table 2

[0179] Since the protein concentration of 50 mg / mL was high, its clarity was lower than that of 10 mg / mL. No visible particles were observed after 3 months under all storage conditions. Compared with the 50 mg / mL sample, the 10 mg / mL sample at accelerated temperatures (25 ± 2 °C and 40 ± 2 °C) had fewer changes tested by SEC and CE - SDS assays but more changes tested by icIEF and oxidation assays. However, considering the assay variability of these methods, the difference in these changes was considered small. No obvious changes were observed in the potency assay after 3 months under all storage conditions. Overall, the results indicate that there is no obvious difference in the stability of COR - 001 in the concentration range of 10 mg / mL to 50 mg / mL.

[0180] Example 5: Stability of Different Lots of COR - 001 To evaluate the long - term storage stability of COR - 001 in the selected liquid formulation, different lots of COR - 001 were formulated in a 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 equipped with 13 mm Flurotec® - coated butyl rubber stoppers) at 1.3 mL each. The COR - 001 protein concentrations of each lot are summarized in Table 3.

Table 3

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

[0182] The study included evaluations 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 the worst-case scenario of contact with the stopper surface.

[0183] A. Stability Results under Accelerated and Stress Conditions The stability of each lot of COR-001 prepared in the formulations stored under accelerated and stress conditions is summarized in Tables 4 - 13 below. Tables 4 - 8 show the results under accelerated conditions for up to 12 months, and Tables 9 - 13 show the 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] Under the accelerated condition, there was no obvious change in appearance up to 12 months (Tables 4 - 8), and under the stress condition, there was no obvious change up to 3 months (Tables 9 - 13).

[0185] Under the accelerated condition, there was no obvious change in clarity up to 12 months (Tables 4 - 8), and under the stress condition, there was no obvious change up to 3 months (Tables 9 - 13). All results were below the reference IV (turbidity standard per EU law), except for the development lot STC - 261 - P221 prepared in the development laboratory. The clarity of this lot exceeded the reference IV at 6 months under the accelerated condition (Table 4) and at 3 months under the stress condition (Table 9).

[0186] Under the accelerated condition, there was no obvious tendency in color up to 12 months (Tables 4 - 8). Under the stress condition, there was a slight tendency for color increase over 3 months of storage (Tables 9 - 13), but all results were below the reference BY4.

[0187] Under the accelerated condition, there was no obvious change in pH up to 12 months, and under the stress condition, there was no obvious change up to 3 months (Figures 4A and 4B). However, the development lot STC - 261 - P221 - S24 slightly decreased at 3 months, which is likely due to the variation in the assay.

[0188] In all three clinical lots tested under the accelerated and stress conditions, the polysorbate 80 level decreased over time (Figures 5A and 5B). Under the accelerated condition, without an obvious correlation between the protein concentration and the plateau level, for all three lots, the decrease in the polysorbate 80 level reached a plateau of approximately 0.04% at 3 months (Figure 5A). Similarly, under the stress condition, for all three lots, the polysorbate 80 level reached a plateau of approximately 0.04% at 1 month (Figure 5B). Notably, the plateau levels between the accelerated condition and the stress condition were similar, suggesting that the decrease in polysorbate 80 is not temperature - dependent.

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

[0190] The levels of monomer (non-aggregated divalent 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 mainly due to the increase in HMW % and LMW %, and there were more changes under stress conditions. The kinetics of monomer % appeared to be linear with some variability from lot to lot without an obvious trend correlating with protein concentration (Figures 7A and 7B, Figures 8A and 8B, Figures 9A and 9B).

[0191] The levels of immunoglobulin γ (IgG), as well as the combination of two heavy chains and one light chain (HHL), were measured by non-reducing CE-SDS. Under accelerated conditions, in terms of HHL %, IgG % decreased over time without an obvious trend (Figures 10A and 11A), suggesting that the decrease was due to the increase in other fragments. Under stress 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 stress conditions appeared to be linear with some variability from lot to lot. However, no obvious trend correlating with protein concentration was observed.

[0192] The levels of heavy chain + light chain (HC+LC) were measured by reducing CE-SDS. Under accelerated conditions, the decrease in HC+LC % appeared to reach a plateau after 3 months for all lots (Figure 12A). Under stress conditions, the decrease in HC+LC % appeared to be linear with some variability from lot to lot. However, no obvious trend correlating with protein concentration was observed (Figure 12B).

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

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

[0195] For all three clinical lots after 1 month under accelerated conditions, there was no obvious change in the number of visually invisible particles tested by high-precision fluid particle counting (HIAC) (Tables 6 - 8). For three clinical lots over 6 months under accelerated conditions, there were changes in the number of visually invisible particles tested by microflow imaging (MFI) (Figures 17A, 17B, and 17C). However, these changes were not correlated with the protein concentration. Since similar levels of visually invisible particles were observed in the placebo lot (CMC-M-0062) at 3 - 6 months, some of these visually invisible particles may have been due to the nature of the formulation buffer components.

[0196] There was no obvious change in the potency tested by both IL-6 binding ELISA and HEK Blue cell-based bioassay for up to 12 months under accelerated conditions and up to 3 months under stress conditions (Figures 18A and 18B, Figures 19A and 19B).

[0197] The microbiological quality of three clinical drug lots was monitored by the level of endotoxin and the container closure integrity test (CCIT) instead of the sterility test of the clinical lot. After 1 month under accelerated conditions, the results met all the 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 the formulation stored under long-term storage conditions is summarized in Tables 14 - 18 below, showing the results for up to 12 months. If available, the acceptance criteria for the assay 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 were no obvious changes in pH up to 12 months, and all results met the acceptance criteria of 5.7 - 6.3 (Figure 20).

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

[0202] There were no obvious changes in the protein concentration up to 12 months under long-term storage conditions, and all results met the acceptance criteria (Figure 22). The slight variation observed for the development lot STC-261-P221-S24 may have been due to assay variability as this lot was tested by a different method (A280 method by sample dilution) than the other lots.

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

[0204] Similar to the acceleration and stress conditions, IgG% decreased under long-term storage conditions for all lots except lot VVRG56 (Figure 25A). By linear kinetic prediction at 95% confidence level, the IgG% levels of all lots will meet the acceptance criteria at 24 months (Figure 25A). There was no obvious trend in the change of HHL% over time (Figure 25B), suggesting that the decrease in IgG% was due to the increase of other fragments. An overlay of the electrophoretic profiles of lot CMC-M-0061 comparing the changes under long-term storage conditions (5°C) with those under acceleration conditions (25°C) and stress conditions (40°C) at 3 months is presented in Figure 26, showing the elution positions and potential identities of these fragments.

[0205] Similar to the acceleration and stress conditions, HC+LC% decreased over time in all lots due to the increase of fragments under long-term storage conditions (Figure 27). An overlay of the electrophoretic profiles of lot CMC-M-0061 comparing the changes under long-term storage conditions (5°C) with those under acceleration conditions (25°C) and stress conditions (40°C) at 3 months is presented in Figure 28. By linear kinetic prediction at 95% confidence level, the HC+LC% levels of all lots will meet the acceptance criteria at 24 months, except for lots CMC-M-0061 and CMC-N-0011. Based on the limited data and the relatively high variability of the data for these two lots, the levels at 24 months from the 95% confidence prediction were overestimated compared to other lots. Furthermore, the results under acceleration conditions (Figure 12A) show that the decrease in HC+LC% reached a plateau (96% - 97%) at 3 months and there was no obvious change from 3 months to 12 months. Therefore, it is reasonable to predict 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 acceleration and stress conditions, under long-term storage conditions, there was a decrease in the percentage of the main species (Figure 29A) and an increase in the percentage of acidic species (Figure 29B) for all lots, and no obvious change in the percentage of basic species (Figure 29C). Figure 30 presents an overlay of the electrophoresis profiles of lot CMC-M-0061 comparing the changes under long-term storage conditions (5°C) with the changes under acceleration conditions (25°C) and stress conditions (40°C) over three months. Although the rate of decrease in the percentage of the main species seemed to increase with the decrease in protein concentration, this was not observed under acceleration or stress conditions. The predicted percentage of the main species could potentially decrease to approximately 37% in 24 months for the lot with the fastest kinetics (Figure 29A). The predicted level of the percentage of the main species at 24 months in the long-term storage state is not expected to have any impact on the potency of COR-001.

[0207] Similar to the acceleration and stress conditions, there was a time-dependent increase in the oxidation level in all lots under long-term storage conditions, and it appeared to reach a plateau at six months (Figure 31), which is similar to the plateau level of 5 - 6% under acceleration and stress conditions (Figures 16A and 16B). Therefore, it is reasonable to predict that the maximum oxidation level will remain at 5 - 6% at 24 months under long-term storage conditions. The predicted oxidation level under long-term storage conditions for 24 months is not expected to affect the potency.

[0208] Under long-term storage conditions, there was no obvious change in the number of non-visible particles until 12 months, and all results met the acceptance criteria. By linear kinetics prediction with 95% confidence, the number of non-visible particles with sizes of 10 microns or more and 25 microns or more will meet the acceptance criteria at 24 months (Figures 32A and 32B).

[0209] There was a change in the number of invisible particles tested by microflow imaging (MFI) under long-term storage conditions (Figures 33A, 33B, and 33C). At the 6-month time point, the number of particles 2 microns or larger was similar to the number under accelerated conditions (Figure 17A), suggesting that the increase in these particles is independent of storage temperature. Similar levels were observed in the placebo lot (CMC-M-0062). Thus, some of these invisible microparticles may have been due to the nature of the formulation buffer components.

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

[0211] The microbiological quality of three clinical drug lots was monitored by the level of endotoxin and the container closure integrity test (CCIT) instead of the sterility test. No changes were expected over long-term storage (Tables 14 - 18).

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

[0213] Even if not explicitly recited in the references, all references, such as references, publications, databases, database entries, and techniques cited herein are hereby incorporated by reference into this application. In the event of a conflict between the cited source and the description of this application, the description of this application shall control.

[0214] The headings of sections and tables are not intended to be limiting.

Claims

**Claim 1** An antibody preparation comprising: a) an anti-IL-6 antibody at a concentration of 10 mg / mL to 50 mg / mL, the anti-IL-6 antibody having the heavy chain amino acid sequence of SEQ ID NO: 9 and the light chain amino acid sequence of SEQ ID NO: 10, and 5 mM to 15 mM of methionine; b) 5% (w / v) of trehalose; c) 0.07% (w / v) of polysorbate 80; d) 70 mM of arginine; and e) 20 mM of histidine and having a pH of 5.0 to 7.

0. **Claim 2** The antibody preparation according to claim 1, wherein the preparation comprises the anti-IL-6 antibody at a concentration of 10 mg / mL to 30 mg / mL or 15 mg / mL to 30 mg / mL. **Claim 3** The antibody preparation according to claim 2, wherein the preparation comprises the anti-IL-6 antibody at a concentration of 15 mg / mL. **Claim 4** The antibody preparation according to claim 2, wherein the preparation comprises the anti-IL-6 antibody at a concentration of 30 mg / mL. **Claim 5** The antibody preparation according to any one of claims 1 to 4, wherein the preparation comprises 10 mM of methionine. **Claim 6** The antibody preparation according to any one of claims 1 to 5, wherein the preparation has a pH of 6.0.

Images