Liquid pharmaceutical formulation of anti-GM-CSF antibody and its use

Abstract

The present disclosure provides liquid pharmaceutical formulations and methods of treating inflammatory or autoimmune diseases or conditions using the liquid pharmaceutical formulations, the liquid pharmaceutical formulations comprising an antibody that specifically binds human GM-CSF and another excipient. In some embodiments, the heavy chain variable region comprises at least (a) a Glu at position 1. In some embodiments, the heavy chain variable region comprises a DYTLT (SEQ ID NO:23) or GYTFT (SEQ ID NO:24) fragment beginning at position 26 according to Kabat numbering.

Description

[Technical Field]

[0001] This invention claims priority to PCT / CN2022 / 135948, filed December 1, 2022, the contents of which are incorporated herein in their entirety. (Technical field)

[0002] The present disclosure relates to liquid pharmaceutical formulations comprising anti-GM-CSF antibodies. [Background technology]

[0003] Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF2), is a monomeric glycoprotein secreted by macrophages, T cells, mast cells, NK cells, endothelial cells, and fibroblasts, where it acts as a cytokine. Naturally occurring drug analogs of GM-CSF are also called sargramostim and molgramostim.

[0004] GM-CSF stimulates stem cells to produce granulocytes (neutrophils, eosinophils, and basophils) and monocytes. Monocytes leave the circulation, migrate to tissues, and mature into macrophages and dendritic cells. As such, it is part of the immune / inflammatory cascade, whereby activation of small numbers of macrophages can rapidly increase their numbers, a critical process in infection control. GM-CSF also exerts several effects on mature cells of the immune system. These include, for example, inhibiting neutrophil migration and altering receptors expressed on the cell surface.

[0005] GM-CSF signals through the signal transduction and transcription activator STAT5. It has been further demonstrated that it signals through STAT3 in macrophages. The cytokine activates macrophages to inhibit fungal survival. It induces the depletion of intracellular free zinc and increases the production of reactive oxygen species, ultimately leading to zinc starvation and toxicity of the fungus. Therefore, GM-CSF contributes to the development of the immune system and promotes defense against infection. GM-CSF also plays a role in embryonic development by acting as an embryonic factor produced by the reproductive tract.

[0006] Inhibiting GM-CSF can be used to treat diseases such as inflammatory and autoimmune disorders, including rheumatoid arthritis (RA), multiple sclerosis (MS), and psoriasis vulgaris. Inhibiting GM-CSF can also be used to treat cancer.

[0007] All references (patent applications, patent publications and UniProtKB / Swiss-Prot accession numbers) cited herein are hereby incorporated by reference in their entirety, as if each individual reference were specifically and individually indicated to be incorporated by reference herein. Summary of the Invention

[0008] In one aspect of the disclosure, a liquid pharmaceutical formulation is provided, comprising: a) 20 mg / ml to 200 mg / ml of an antibody or antigen-binding fragment thereof that specifically binds to human granulocyte-macrophage colony-stimulating factor (GM-CSF) protein, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region CDR1 (HCDR1) of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, a light chain variable region CDR1 (LCDR1) of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5, and an LCDR3 of SEQ ID NO:6; b) a 10 mM to 30 mM pH buffer solution; c) 130 mM to 250 mM of an isotonicity adjuster; d) 0.01 (w / v)% to 0.03 (w / v)% of a surfactant; wherein the formulation has a pH of about 4.5 to about 7.5.

[0009] In some examples, the liquid pharmaceutical formulations herein comprise an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region, the heavy chain variable region being represented by the Kabat numbering system: a) Glu at position 1, b) Arg at position 98; c) Ser at position 72; d) Ala at position 68; e) Leu at position 70; f) Ile at position 48; g) Asp at position 26; h) Leu at position 29; and combinations thereof.

[0010] In some embodiments, the heavy chain variable region comprises at least (a) a Glu at position 1. In some embodiments, the heavy chain variable region comprises a DYTLT (SEQ ID NO:23) or GYTFT (SEQ ID NO:24) fragment beginning at position 26 according to the Kabat numbering system.

[0011] In some examples, the liquid pharmaceutical formulations herein comprise an antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region, the light chain variable region being represented by the Kabat numbering system: a) Ala at position 46; b) Asp at position 60; c) Asp at position 70; d) Ser at position 43; e) Phe at position 87; and combinations thereof.

[0012] In some embodiments, an antibody or antigen-binding fragment thereof provided herein comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8 to 17. In some embodiments, a liquid pharmaceutical formulation provided herein comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19 to 22.

[0013] In some examples, the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO:14 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:22.

[0014] In some embodiments, the antibody or antigen-binding fragment thereof further comprises an Fc region. In some embodiments, the Fc region is an IgG1 Fc region.

[0015] In some embodiments, the pH buffer comprises citric acid, HEPES, histidine, potassium acetate, potassium citrate, potassium phosphate (KH2PO4), sodium acetate, sodium bicarbonate, sodium citrate, sodium phosphate (NaH2PO4), Tris base, and Tris-HCl.

[0016] In some embodiments, the pH buffer comprises 20 mM histidine. In some embodiments, the 20 mM histidine comprises about 6.2 mM histidine and about 13.8 mM histidine hydrochloride monohydrate. In some embodiments, the pH buffer comprises about 20 mM NaAc.

[0017] In some embodiments, the pH is in the range of about 5.5 to about 6.1, hi some embodiments, the pH is about 5.8.

[0018] In some embodiments, the tonicity adjusting agent is one or more selected from the group consisting of sucrose, trehalose, mannitol, arginine, and sodium chloride. In some embodiments, the tonicity adjusting agent comprises 200-220 mM sucrose. In some embodiments, the tonicity adjusting agent comprises about 220 mM sucrose.

[0019] In some embodiments, the liquid pharmaceutical formulation further comprises an antioxidant, a preservative, or a mixture thereof.

[0020] In some embodiments, the liquid pharmaceutical formulation further comprises proline and / or glycine.

[0021] In some embodiments, the surfactant comprises polysorbate 20 or polysorbate 80. In some embodiments, the surfactant comprises about 0.02% (w / v) polysorbate 80.

[0022] In some embodiments, the liquid pharmaceutical formulation comprises between 50 mg / ml and 150 mg / ml of the antibody, hi some embodiments, the liquid pharmaceutical formulation comprises about 100 mg / ml of the antibody.

[0023] In some embodiments, the liquid pharmaceutical formulation comprises 50-150 mg / ml of antibody, 10-20 mM histidine, 200-220 mM sucrose, and 0.01-0.03% (w / v) polysorbate 80, and has a pH of about 5.5 to about 6.1.

[0024] In some embodiments, the liquid pharmaceutical formulation comprises about 100 mg / ml antibody, about 20 mM histidine, about 220 mM sucrose, and about 0.02% (w / v) polysorbate 80, and has a pH of about 5.8.

[0025] In some embodiments, the liquid pharmaceutical formulation is for intravenous (IV) or subcutaneous administration.

[0026] In another aspect of the present disclosure, there is provided a method of treating an inflammatory or autoimmune disease or condition in a patient in need thereof, the method comprising administering to the patient a liquid pharmaceutical formulation according to the present disclosure.

[0027] In some embodiments, the autoimmune disease is selected from the group consisting of alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes mellitus (type 1), celiac disease, autoimmune juvenile idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune myocarditis, multiple sclerosis, pemphigus / pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma / systemic sclerosis, Sjoegren's syndrome, systemic lupus erythematosus, autoimmune thyroiditis, Hashimoto's thyroiditis, autoimmune uveitis, vitiligo, and granulomatosis with polyangiitis (Wegener's granulomatosis).

[0028] In some embodiments, the inflammatory disease is selected from the group consisting of Alzheimer's disease, Addison's disease, atherosclerosis, ankylosing spondylitis, arthritis, osteoarthritis (OA), rheumatoid arthritis (RA), psoriatic arthritis (PA), ankylosing spondylitis, asthma, atherosclerosis, chronic obstructive pulmonary disease (COPD), Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease (PD), vasculitis, ulcerative colitis, and COVID-19. DETAILED DESCRIPTION OF THE INVENTION

[0029] Before describing the present disclosure in detail, it should be understood that the present disclosure is not limited to the particular compositions or biological systems described, as these can, of course, vary. It should be further understood that the terminology used herein is for the purpose of describing particular examples only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms "a / an" and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to a "molecule" optionally includes combinations of two or more such molecules, and the like.

[0030] As used herein, the term "about" refers to a normal error range for the relevant numerical value, which is readily known to one of ordinary skill in the art. As used herein, reference to "about" a value or parameter includes (and describes) examples of the value or parameter itself. In cases of doubt, or in the absence of a commonly accepted understanding in the art of the error range for a value or parameter, "about" means ±1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the value or parameter.

[0031] It should be understood that aspects and embodiments of the present disclosure described herein include "comprising aspects and embodiments," "consisting of aspects and embodiments," and "consisting essentially of aspects and embodiments."

[0032] The term "pharmaceutical formulation" refers to a formulation that is in a form that allows the biological activity of the active ingredient to be effective and that does not contain other ingredients that are unacceptably toxic to the subject to which the formulation is administered. Such formulations are sterile. Anti-GM-CSF antibody

[0033] The pharmaceutical formulations of the present disclosure may include an antibody or antigen-binding fragment thereof that specifically binds to human GM-CSF. As used herein, the term "GM-CSF" refers to human granulocyte-macrophage colony-stimulating factor. Antibodies against human GM-CSF are described, for example, in WO 2006122797, WO 2015028657, and WO 2018050111.

[0034] As used herein, the term "antibody" generally refers to immunoglobulin molecules and multimers thereof (e.g., IgM) comprising four polypeptide chains (two heavy (H) chains and two light (L) chains linked together by disulfide bonds); however, immunoglobulin molecules consisting only of heavy chains (i.e., lacking light chains) are also included within the definition of the term "antibody." Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains, CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions may be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs, which are arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0035] Unless otherwise specified, as used herein, the term "antibody" should be understood to cover intact antibody molecules and antigen-binding fragments thereof. As used herein, the term "antigen-binding portion" or "antigen-binding fragment" of an antibody (or abbreviated as "antibody portion" or "antibody fragment") refers to one or more fragments of an antibody, e.g., F(ab')2, F(ab)2, Fab', Fab, Fv, scFv, etc., that retain the ability to specifically bind to human GM-CSF or an epitope thereof.

[0036] As used herein, an "isolated antibody" refers to an antibody that is substantially free of other antibodies having different antigen specificities (e.g., an isolated antibody that specifically binds human GM-CSF is substantially free of antibodies that specifically bind to antigens other than human GM-CSF).

[0037] The term "specifically binds" and the like means that an antibody or an antigen-binding fragment thereof and an antigen form a relatively stable complex under physiological conditions. Specific binding is at least about 1 × 10 -8 The specific binding may be characterized by a dissociation constant M or greater. Methods for determining whether two molecules specifically bind are known in the art, and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. However, an isolated antibody that specifically binds human GM-CSF may have cross-reactivity with other antigens, such as GM-CSF (orthologs) from other species. In the context of the present disclosure, a multispecific (e.g., bispecific) antibody that binds human GM-CSF and one or more additional antigens is considered to "specifically bind" human GM-CSF. And, an isolated antibody may be substantially free of other cellular material or chemicals.

[0038] Exemplary anti-human GM-CSF antibodies that can be included in the pharmaceutical formulations of the present disclosure are described in patent application WO 2018050111, the disclosure of which is incorporated herein by reference in its entirety.

[0039] According to some embodiments of the present disclosure, the anti-human GM-CSF antibody or antigen-binding fragment thereof comprises heavy chain complementarity determining region (HCDR) 1 of SEQ ID NO: 1, HCDR2 of SEQ ID NO: 2, and HCDR3 of SEQ ID NO: 3. In some embodiments, the anti-human GM-CSF antibody or antigen-binding fragment thereof comprises the HCDR of SEQ ID NO: 14.

[0040] According to some embodiments of the present disclosure, the anti-human GM-CSF antibody or antigen-binding fragment thereof comprises a light chain complementarity determining region (LCDR) 1 of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5, and an LCDR3 of SEQ ID NO:6. In some embodiments, the anti-human GM-CSF antibody or antigen-binding fragment thereof comprises an LCVR of SEQ ID NO:22.

[0041] According to one embodiment of the present disclosure, there is provided an antibody, the antibody comprising heavy and light chain variable domains having CDR regions defined in SEQ ID NOs: 1-6, as shown below. [Table 1]

[0042] In some embodiments, the anti-GM-CSF antibodies of the disclosure comprise the VH and VL CDRs listed in Table 1 and have one, two, or three additional modifications. Such modifications may be amino acid additions, deletions, or substitutions.

[0043] In some embodiments, the modification is a substitution at most one residue from each CDR. In some embodiments, the modification is a substitution at one, two, or three residues. In one embodiment, the modification is a substitution at one of the residues. In some embodiments, such substitutions are conservative substitutions.

[0044] A "conservative amino acid substitution" is one in which an amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues with similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), β-branched side chains (e.g., threonine, valine, isoleucine), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Therefore, preferably, a non-essential amino acid residue in an immunoglobulin polypeptide is replaced with another amino acid residue from the same side chain family. In another example, the string of amino acids can be replaced with a string of structurally similar amino acids that differ in the order and / or composition of side chain family members.

[0045] In some embodiments, the antibody or fragment thereof includes at most one, at most two, or at most three of the above substitutions.

[0046] In some embodiments, the antibody or fragment thereof has specificity for human GM-CSF protein and comprises HCDR1 of SEQ ID NO:1, HCDR2 of SEQ ID NO:2, HCDR3 of SEQ ID NO:3, LCDR1 of SEQ ID NO:4, LCDR2 of SEQ ID NO:5, and LCDR3 of SEQ ID NO:6. Non-limiting examples of VHs are provided in SEQ ID NOs:7-17, where SEQ ID NO:7 is a murine VH, and SEQ ID NOs:8-17 are humanized VHs, which contain one or more backmutations of the murine variant. Similarly, non-limiting examples of VLs (Vκ) are provided in SEQ ID NOs:18-22. SEQ ID NO:18 is the murine sequence, while SEQ ID NOs:19-22 are humanized sequences, where SEQ ID NOs:20-22 contain one or more backmutations, such as those shown in the examples. The amino acid and nucleotide sequences of several humanized antibody 23F4 are listed in Table 2 below. The combinations of heavy and light chain variable regions are shown in Table 3. [Table 2] [Table 3]

[0047] It has been demonstrated that back mutations can be used to preserve some characteristics of anti-GM-CSF antibodies. Thus, in some embodiments, an anti-GM-CSF antibody (particularly a human or humanized antibody) of the present disclosure includes one or more back mutations. In some embodiments, the VH back mutations (i.e., including amino acids at the designated positions) are one or more selected from (a) Glu (El) at position 1, (b) Arg (R98) at position 98, (c) Ser (S72) at position 72, (d) Ala (A68) at position 68, (e) Leu (L70) at position 70, (f) Ile (I48) at position 48, (g) Asp (D26) at position 26, and (h) Leu (L29) at position 29, and combinations thereof, according to Kabat numbering.

[0048] In some embodiments, the humanized antibody comprises at least the VH backmutation E1. In some embodiments, the humanized antibody comprises at least the VH backmutations E1 and R98. In some embodiments, the humanized antibody comprises at least the VH backmutations E1 and another one of the above listed. In some embodiments, the humanized antibody comprises at least the VH backmutations (E1, R98 and S72), (E1, R98, S72 and A68), (E1, R98, S72, A68, L70 and I48), (E1, R98, S72, A68, L70, I48, D26 and L29), (E1 and S72), (E1, S72 and L70), (E1, S72, L70, I48 and A68), (E1, S72, L70, I48, A68, D26 and L29).

[0049] In some embodiments, the heavy chain variable region comprises a DYTLT (SEQ ID NO:23) or GYTFT (SEQ ID NO:24) fragment N-terminal to CDR1, i.e., starting at position 26 according to Kabat numbering. In one embodiment, the heavy chain variable region comprises DYTLT (SEQ ID NO:23). In one embodiment, the heavy chain variable region comprises GYTFT (SEQ ID NO:24).

[0050] In some embodiments, the humanized antibody comprises one or more backmutations, in some embodiments, the VL backmutations are one or more selected from (a) Ala at position 46 (A46), (b) Asp at position 60 (D60), (c) Asp at position 70 (D70), (d) Ser at position 43 (S43), and (f) Phe at position 87 (F87), and combinations thereof, based on Kabat numbering.

[0051] In some embodiments, the humanized antibody comprises at least two, three, or four of the VL backmutations A46, D60, D70, S43, or F87. In some embodiments, the humanized antibody comprises at least the VL backmutation A46. In some embodiments, the humanized antibody comprises at least the VL backmutations A46 and D60 and another one listed above. In some embodiments, the humanized antibody comprises at least the VL backmutation group (A46, D60, and D70) or (A46, D60, D70, S43, and F87).

[0052] In some embodiments, the humanized antibody contains at least VH backmutations (E1, R98, S72, A68, L70, and I48) and no VL backmutations. In some embodiments, the humanized antibody contains at least VH backmutations (E1, S72, L70, I48, A68, D26, and L29) and no VL backmutations. In some embodiments, the humanized antibody contains at least VH backmutations (E1 and S72) and VL backmutations (A46, D60, D70, S43, and F87).

[0053] In some embodiments, anti-GM-CSF antibodies of the present disclosure include a VH of SEQ ID NOs:8-17 and a VL of SEQ ID NOs:19-22, or their respective biological equivalents. A biological equivalent of a VH or VL is a sequence that contains the specified amino acids and has 80%, 85%, 90%, 95%, 98%, or 99% overall sequence identity. Thus, a biological equivalent of SEQ ID NO:10 may be a VH that has 80%, 85%, 90%, 95%, 98%, or 99% overall sequence identity to SEQ ID NO:10, but retains the CDRs (SEQ ID NOs:1-3 or variants thereof) and, optionally, one, more, or all backmutations.

[0054] In one example, the VH has the amino acid sequence of SEQ ID NO:11, while the VL has the amino acid sequence of SEQ ID NO:19. In one example, the VH has the amino acid sequence of SEQ ID NO:17, while the VL has the amino acid sequence of SEQ ID NO:19. In one example, the VH has the amino acid sequence of SEQ ID NO:11, while the VL has the amino acid sequence of SEQ ID NO:22. It should be noted that each of the listed sequences may be substituted with its biological equivalent.

[0055] As will be further understood by those skilled in the art, the antibodies disclosed herein may be modified to differ in amino acid sequence from the naturally occurring binding polypeptide from which they are derived. For example, a polypeptide or amino acid sequence derived from a designated protein may be similar to the starting sequence, e.g., have a certain percentage identity, e.g., it may have 60%, 70%, 75%, 80%, 85%, 90%, 95%, 98%, or 99% identity to the starting sequence.

[0056] In some embodiments, the antibodies herein further comprise a heavy chain constant region, a light chain constant region, an Fc region, or a combination thereof.

[0057] The Fc region can be engineered to enhance or eliminate effector functions. IgG antibodies can induce direct anti-tumor effects in the form of indirect anti-tumor effects through Fc-mediated effector functions, which involve other immune cells or killer mechanisms. As used herein, "effector function" or "antibody effector function" refers to a biological activity that can be attributed to the binding of the Fc region of an antibody to its effector, such as the C1 complex and an Fc receptor (FcγRIIa or FcγRIIIa). Exemplary effector functions include complement-dependent cytotoxicity (CDC), which is induced by the interaction of an antibody with C1q on the C1 complex; antibody-dependent cell-mediated cytotoxicity (ADCC), which is induced by the binding of the Fc region of an antibody to an Fc receptor on an effector cell; and antibody-dependent cell-mediated phagocytosis (ADCP), in which nonspecific cytotoxic cells expressing Fcγ receptors (FcγRs) recognize bound antibodies on target cells and subsequently trigger phagocytosis of the target cells.

[0058] Of the four IgG subclasses, IgG1 and IgG3 induce the strongest Fc effector functions, however, because IgG1 has the longest half-life and is more stable than IgG3, the majority of therapeutic antibodies with Fc-mediated functions are of the IgG1 isotype.

[0059] IgG2 and IgG4 isotypes have significantly lower binding affinity to FcγRs. Recent evidence has shown that, while the IgG2 isotype is not completely devoid of effector function, the IgG4 isotype can undergo Fab-arm exchange in vivo, generating bispecific antibodies and off-target effects.

[0060] In some embodiments, the isotype of the antibody herein is IgG1. In some embodiments, the isotype of the antibody is human IgG1.

[0061] In some embodiments, the antibodies and fragments of the present disclosure may be monospecific or bispecific antibodies or fragments. For bispecific antibodies, the other specificity may be for a different target epitope of GM-CSF or a different target protein useful for a particular application (e.g., therapeutic application). In one embodiment, the target protein is a cytokine, such as TNF-α, IL-6, IL-1, and IL-17. In another embodiment, the target protein is a chemokine, such as CCL2, CXCL12, and CXCL13. In another embodiment, the target protein is a cell surface protein, such as CD3, CSF-1R, CD20, and CD73.

[0062] In some embodiments, the antibody comprises an amino acid sequence or one or more moieties not typically associated with antibodies. Exemplary modifications are described in more detail below. For example, the antibodies of the present disclosure may comprise a flexible linker sequence or may be modified to attach a functional moiety (e.g., PEG, a drug, a toxin, or a label).

[0063] The antibodies, variants, or derivatives of the present disclosure include modified derivatives, i.e., any type of molecule covalently attached to the antibody so long as the covalent attachment does not interfere with antibody binding to the epitope. For example, the antibody may be modified by, for example, but not limited to, glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization with known protecting / blocking groups, proteolytic cleavage, or linkage to a cellular ligand or other protein. Any one of a number of chemical modifications can be performed by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, and the like. The antibody may also contain one or more non-classical amino acids.

[0064] In some embodiments, the antibody can be conjugated or linked in other ways to another molecule to form a bifunctional molecule. The second molecule can be one of a therapeutic agent, a prodrug, a peptide, a protein, an enzyme, a virus, a lipid, a biological response modifier, a drug, or PEG. Some non-limiting examples are cytokines or other soluble factors, such as IL-10, IL-25, IL-27, IL-33, IL-35, and IL-36. In some embodiments, an antibody-drug conjugate is further provided, which comprises an antibody or fragment of the present disclosure and a small molecule drug.

[0065] The antibody may be conjugated or fused to a therapeutic agent, which may include a detectable label (e.g., a radioactive label), an immunomodulatory agent, a hormone, an enzyme, an oligonucleotide, a photoactivated therapeutic or diagnostic agent, a cytotoxic agent (which may be a drug or a toxin), an ultrasound-enhancing agent, a non-radioactive label, combinations thereof, and other such reagents known in the art. Pharmaceutical preparations

[0066] The formulated antibody is preferably substantially pure and, desirably, substantially homogeneous (e.g., free from contaminating proteins, etc.). A "substantially pure" antibody refers to a composition that comprises at least about 90% antibody by weight, based on the total weight of protein in the composition, and preferably at least about 95% antibody by weight, and a "substantially homogeneous" antibody refers to a composition that comprises at least about 99% antibody by weight, based on the total weight of protein in the composition.

[0067] The term "pharmaceutical formulation" refers to a formulation containing an anti-GM-CSF antibody, which formulation is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0068] The formulation may be liquid. A liquid formulation is an aqueous solution or suspension made in a suitable aqueous solvent, such as water or an aqueous / organic mixture, such as a water-alcohol mixture.

[0069] In some embodiments, the liquid pharmaceutical formulation has a concentration of 20 mg / ml to 200 mg / ml (e.g., 30 mg / ml to 200 mg / ml, 40 mg / ml to 200 mg / ml, 50 mg / ml to 200 mg / ml, 60 mg / ml to 200 mg / ml, 70 mg / ml to 200 mg / ml, 80 mg / ml to 200 mg / ml, 90 mg / ml to 200 mg / ml, 100 mg / ml to 200 mg / ml, 110 mg / ml ~200mg / ml, 120mg / ml~200mg / ml, 130mg / ml~200mg / ml, 140mg / ml~200mg / ml, 150mg / ml~200mg / ml, 160mg / ml~200 mg / ml, 170mg / ml~200mg / ml, 180mg / ml~200mg / ml, 190mg / ml~200mg / ml, 20mg / ml~190mg / ml, 20mg / ml~180mg / ml, 20mg / ml~170mg / ml, 20mg / ml~160mg / ml, 20mg / ml~150mg / ml, 20mg / ml~140mg / ml, 20mg / ml~130mg / ml, 20mg / ml~1 20mg / ml, 20mg / ml~110mg / ml, 20mg / ml~100mg / ml, 20mg / ml~90mg / ml, 20mg / ml~80mg / ml, 20mg / ml~70mg / ml, 20mg / ml~60mg / ml, 20mg / ml~50mg / ml, 20mg / ml~40mg / ml, 30mg / ml~190mg / ml, 40mg / ml~180mg / ml, 50mg / ml~170mg / ml , 60mg / ml~160mg / ml, 70mg / ml~150mg / ml, 80mg / ml~140mg / ml, 90mg / ml~130mg / ml, 100mg / ml~120mg / ml). In some embodiments, the liquid pharmaceutical formulation comprises 20 mg / ml, 30 mg / ml, 40 mg / ml, 50 mg / ml, 60 mg / ml, 70 mg / ml, 80 mg / ml, 90 mg / ml, 100 mg / ml, 110 mg / ml, 120 mg / ml, 130 mg / ml, 140 mg / ml, 150 mg / ml, 160 mg / ml, 170 mg / ml, 180 mg / ml, 190 mg / ml or 200 mg / ml of the antibody.

[0070] In another example, the pharmaceutical formulation further comprises another excipient. As used herein, the term "excipient" refers to an inert substance generally used as a drug diluent, vehicle, preservative, adhesive, or stabilizer, which imparts beneficial physical properties to the formulation, such as increasing protein stability, increasing protein solubility, or reducing viscosity.

[0071] "Excipients" include, for example, stabilizers such as human serum albumin (HSA), bovine serum albumin (BSA), α-casein, globulin, α-lactalbumin, LDH, lysozyme, myoglobin, ovalbumin, and RNAse A; buffers such as citric acid, HEPES, PBS, histidine, potassium acetate, potassium citrate, potassium phosphate (KH2PO4), sodium acetate, sodium bicarbonate, sodium citrate, sodium phosphate (NaH2PO4), Tris base, and Tris-HCl; and buffers such as glycine, alanine (α-alanine, β-alanine), arginine, betaine, leucine, lysine, glutamic acid, aspartic acid, histidine, proline, 4-hydroxyproline, sarcosine, γ-aminobutyric acid (GABA), and opioids. amino acids / metabolites such as amines (alanopine, octopine, strombine) and trimethylamine N-oxide (TMAO); surfactants such as polysorbate 20 and polysorbate 80 and poloxamer 407; lipid molecules such as phosphatidylcholine, ethanolamine and acetyltryptophan esters; polymers such as polyethylene glycol (PEG) and polyvinylpyrrolidone (PVP) 10, 24, 40;Low molecular weight excipients such as 4-pentanediol, octulose, propylene glycol, raffinose, ribose, sucrose, trehalose, xylitol and xylose, and other excipients such as cellulose, β-cyclodextrin, dextran (10 kd), dextran (40 kd), dextran (70 kd), ficoll, gelatin, hydroxypropylmethylcellulose, hydroxyethyl starch, maltodextrin, methylcellulose, PEG (6 kd), polydextrose, polyvinylpyrrolidone (PVP) kl5 (10 kd), PVP (40 kd), PVP k30 (40 kd), PVP High molecular weight excipients such as k90 (1000 kd), Sephadex G-200 and starch, antioxidants such as ascorbic acid, cysteine ​​hydrochloride, thioglycerol, thioglycolic acid, thiosorbitol and glutathione, reducing agents such as cysteine ​​hydrochloride, dithiothreitol and other thiols or thiophenes, chelating agents such as EDTA, EGTA, glutamic acid and aspartic acid, e.g. Ca, 2 +, Ni 2 +, Mg 2 +, Mn 2 Excipients include, but are not limited to, inorganic salts / metals such as Na2SO4, (NH4)2SO4, Na2HPO4 / NaH2PO4, K2HPO4 / KH2PO4, MgSO4, and NaF; organic salts such as sodium acetate, sodium polyethylene, sodium caprylate / octanoate, proprionate, lactate, succinate, and citrate; and organic solvents such as acetonitrile, dimethyl sulfoxide (DMSO), and ethanol. For additional information regarding excipients, see Remington's Pharmaceutical Sciences (Joseph P. Remington, 18th ed., Mack Publishing Co., Easton, Pa.), which is incorporated herein in its entirety.

[0072] "Isotonic" means that the formulation has an osmotic pressure approximately equal to that of human blood. Isotonic formulations generally have an osmotic pressure of about 250 to about 350 mOsm (e.g., about 250 to about 340, about 250 to about 330, about 250 to about 320, about 250 to about 310, about 250 to about 300, about 260 to about 350, about 270 to about 350, about 280 to about 350, about 290 to about 350, about 300 to about 350, about 260 to about 340, about 270 to about 330, about 280 to about 320, about 290 to about 310 mOsm). Isotonicity may be measured, for example, by vapor pressure or freeze osmometry. In some embodiments, the isotonicity is about 300 mOsm. In some embodiments, the tonicity adjusting agent may be one or more selected from the group consisting of sucrose, trehalose, mannitol, arginine, and sodium chloride. In some embodiments, the tonicity adjusting agent ranges from about 130 to 250 mM (e.g., about 130 mM to about 240 mM, about 150 mM to about 240 mM, about 180 mM to about 240 mM, about 200 mM to about 240 mM, about 130 mM to about 220 mM, about 150 mM to about 220 mM, about 180 mM to about 220 mM, about 130 mM to about 210 mM, about 150 mM to about 210 mM, about 180 mM to about 210 mM, about 200 mM to about 220 mM, or about 200 to about 210 mM). In some embodiments, the tonicity adjusting agent is about 130 mM, about 140 mM, about 150 mM, about 160 mM, about 170 mM, about 180 mM, about 190 mM, about 200 mM, about 210 mM, about 220 mM, about 230 mM, about 240 mM, or about 250 mM. In some embodiments, the tonicity adjusting agent comprises sucrose or trehalose.

[0073] As used herein, "pH buffer" refers to a buffered solution that resists pH changes by the action of its acid-base conjugate components. Preferably, the buffer of the present disclosure has a pH within the range of about 4.5 to about 7.5 (preferably about 5.0 to about 7.0, e.g., about 5.0 to about 6.9, about 5.2 to about 6.8, about 5.3 to about 6.7, about 5.4 to about 6.6, 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, about 5.5 to about 6.4, about 5.5 to about 6.3, about 5.5 to about 6.2, about 5.5 to about 6.1, or about 5.5 to about 6.0). In some embodiments, the buffer has a pH of about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, or 7.0. In one embodiment, the buffer has a pH of 5.8. The required pH level can be achieved by several methods, including, but not limited to, adding an appropriate buffer.

[0074] In some embodiments, the pH buffer comprises histidine, acetate, citrate, and succinate, hi some embodiments, the pH buffer comprises about 10 to about 30 mM histidine and / or about 10 to about 30 mM acetate, e.g., about 10 to about 25 mM, about 10 to about 20 mM, or about 15 mM to about 20 mM histidine and / or about 10 to about 25 mM, about 10 mM to about 20 mM, or about 15 mM to about 20 mM acetate. In some embodiments, the pH buffer comprises about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM, about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM, about 25 mM, about 26 mM, about 27 mM, about 28 mM, about 29 mM, or about 30 mM histidine or acetate.

[0075] In some embodiments, the pH buffer comprises L-histidine and histidine hydrochloride monohydrate. In some embodiments, the pH buffer comprises 20 mM histidine, the histidine being selected from the group consisting of about 4.4 mM L-histidine and about 15.6 mM histidine hydrochloride monohydrate, about 5.2 mM L-histidine and about 14.8 mM histidine hydrochloride monohydrate, about 6.2 mM L-histidine and about 13.8 mM histidine hydrochloride monohydrate, about 6.8 mM L-histidine and about 13.2 mM histidine hydrochloride monohydrate, about 7.8 mM L-histidine and about 12.2 mM histidine hydrochloride monohydrate, about 8.4 mM L-histidine hydrochloride monohydrate and about 11.6 mM histidine hydrochloride monohydrate, or about 9 mM histidine hydrochloride monohydrate. Contains L-histidine and approximately 11 mM histidine hydrochloride monohydrate.

[0076] As used herein, "surfactant" refers to a surface-active agent, preferably a nonionic surfactant. Examples of surfactants herein include polysorbates (e.g., polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, and polysorbate 85), poloxamers (e.g., poloxamer 188 and poloxamer 407), Triton®, sodium dodecyl sulfate (SDS), sodium lauryl sulfate, sodium octyl glucoside (sodium octyli), and the like. glycoside), lauryl-sulfobetaine, myristyl-sulfobetaine, linoleyl-sulfobetaine or stearyl-sulfobetaine, lauryl-sarcosine, myristyl-sarcosine, linoleyl-sarcosine or stearyl-sarcosine, linoleyl-betaine, myristyl-betaine or cetyl-betaine, lauramidopropyl-betaine, cocamidopropyl-betaine, linoleamidopropyl-betaine, myristamidopropyl-betaine, palmidopropyl-betaine or isostearamidopropyl-betaine (e.g., lauramidopropyl), myristamidopropyl-dimethylamine, palmidopropyl-dimethylamine or isostearamidopropyl-dimethylamine, sodium cocoyl methyl taurate or disodium oleoyl methyl taurate, and the MONAQUAT™ series (Mona Industries, Inc. Industries, Inc., Paterson, NJ, polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., Piuronics, PF68, etc.), and the like.

[0077] The concentration of the surfactant is typically about 0.0001% to about 1.0%, about 0.01% to about 0.5%, e.g., about 0.015% (w / v) to about 0.03% (w / v), about 0.02% (w / v) to about 0.03% (w / v), about 0.025% (w / v) to about 0.03% (w / v), about 0.01% (w / v) to about 0.025% (w / v), about 0.01% (w / v) to about 0.02% (w / v), or about 0.01% (w / v) to about 0.015% (w / v). In one embodiment, the surfactant herein comprises polysorbate 80 or polysorbate 20. In some embodiments, the surfactant comprises about 0.01% (w / v), 0.015% (w / v), 0.02% (w / v), 0.025% (w / v), or 0.03% (w / v) of polysorbate 80 or polysorbate 20. In some embodiments, the surfactant comprises about 0.02% (w / v) of polysorbate 80.

[0078] In some embodiments, the liquid pharmaceutical formulation further comprises an antioxidant, a preservative, or a mixture thereof.

[0079] The term "antioxidant" refers to a reagent that inhibits oxidation of other molecules. Examples of antioxidants include ascorbic acid, citrate, lipoic acid, uric acid, cysteine ​​hydrochloride, monothioglycerol, thioglycerol, thioglycolic acid, thiosorbitol, tocopherol, carotenes, lycopene, and glutathione; reducing agents such as cysteine ​​hydrochloride, dithiothreitol; phosphonate compounds such as etidronic acid, deferoxamine, and malate; and other thiols or thiophenes and methionine. In another embodiment, the antioxidant is a metal chelator. Metal chelators include, but are not limited to, ethylenediaminetetraacetate ("EDTA"), ethylene glycol tetraacetic acid ("EGTA"), thiamine tetrahydrofurfuryl disulfide ("TTFD"), and 2,3-dimercaptosuccinic acid ("DMSA"). In some embodiments, the formulation comprises about 1 mM to about 50 mM of antioxidant, hi one embodiment, the formulation comprises about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, or about 45 mM of antioxidant.

[0080] The term "preservative" refers to a pharmaceutically acceptable excipient that prevents the growth of microorganisms within the composition. More particularly, the present disclosure provides multi-dose liquid compositions containing a preservative, which protects the composition from microbial contamination.

[0081] In one embodiment, the preservative is present in the composition in an amount of 0.001 to 2% (w / v). In one embodiment, the preservative is present in the composition in an amount of 0.002 to 1% (w / v). In one embodiment, the one or more preservatives are selected from phenol, m-cresol, benzyl alcohol, chlorobutanol, ethanol, phenoxyethanol, p-chloro-m-cresol, methylparaben, propylparaben, benzalkonium chloride, thimerosal, or any combination thereof. In one embodiment, the one or more preservatives are selected from phenol, m-cresol, benzyl alcohol, and chlorobutanol.

[0082] The viscosity of anti-GM-CSF antibody formulations may be controlled for subcutaneous, intravenous, or intramuscular administration. Viscosity may be affected by protein concentration and pH. For example, viscosity may increase as protein concentration increases. Increasing pH can reduce the viscosity of anti-GM-CSF antibody formulations. In some protein formulations, sodium chloride is added to reduce the viscosity of the formulation. Other components that can affect the viscosity of anti-GM-CSF antibody formulations are amino acids, such as histidine and arginine.

[0083] The liquid pharmaceutical formulations described herein may have a variety of viscosities. Methods for measuring the viscosity of liquid pharmaceutical formulations are known to those skilled in the art and may include, for example, a rheometer (e.g., an Anton Paar MCR301 Rheometer with a 50 mM, 40 mM, or 20 mM cone accessory). In some embodiments of the present disclosure, the viscosity is reported at the high shear limit of 1000 / sec shear rate. In some embodiments, the liquid pharmaceutical formulation has a viscosity between 1.0 cP ± 10% and 20 cP ± 10%. In some embodiments, the liquid pharmaceutical formulation has a viscosity of less than 20 cP, less than 18 cP, less than 15 cP, less than 13 cP, or less than 11 cP. As will be appreciated by those skilled in the art, viscosity is temperature dependent; therefore, unless otherwise specified, viscosities herein are measured at 25°C. In some embodiments, the viscosity of the liquid pharmaceutical formulation at 25° C. is 1.0 cP±10%, 2.0 cP±10%, 3.0 cP±10%, 3.1 cP±10%, 3.2 cP±10%, 3.5 cP±10%, 3.6 cP±10%, 3.8 cP±10%, 4.0 cP±10%, 5.0 cP±10%, 5.3 cP±10%, 6.0 cP±10%, 6.3 cP±10%, 7.0 cP±10%, 7.0 cP±10%, 8.0 cP±10%, 8.0 cP±10%, 9.0 cP±10%, 9.0 cP±10%, 10 ... P±10%, 6.4cP±10%, 6.8cP±10%, 7.0cP±10%, 7.1cP±10%, 7.4cP±10%, 8.0cP±10%, 9.0cP±10%, 10.0cP±10%, 11.0cP±10%, 12.0cP±10%, 13.0cP±10%, 14.0cP±10%, 15.0cP±10% or 16cP±10%.

[0084] In some embodiments, the liquid pharmaceutical formulation further comprises a viscosity modifier. In one embodiment, the viscosity modifier is an amino acid. In one embodiment, the viscosity modifier is L-proline. In some embodiments, the viscosity modifier has a concentration of 1%±0.2% to 5%±1% w / v. In one embodiment, the viscosity modifier is proline at a concentration of 1.5%±0.3% or about 1.5%. In one embodiment, the viscosity modifier is proline at a concentration of 3%±0.6% or about 3%.

[0085] In a first aspect, the present disclosure provides a novel liquid pharmaceutical formulation, comprising: a) an anti-GM-CSF antibody having a concentration of 20 mg / ml to 200 mg / ml as an antibody; b) acetate or histidine at a concentration of 10 mM to 30 mM as a buffer; c) sucrose or trehalose having a concentration of 130 mM to 250 mM as an isotonicity adjuster; d) containing polysorbate 80 or polysorbate 20 at a concentration of 0.01 (w / v)% to 0.03 (w / v)% as a surfactant, Here, the pH of the formulation is from about 4.5 to about 7.5, preferably from about 5.5 to about 6.1.

[0086] In a further embodiment, the formulation does not include other excipients.

[0087] In a preferred embodiment, the present disclosure provides a novel liquid pharmaceutical formulation, comprising: a) an anti-GM-CSF antibody having a concentration of 50 mg / ml to 150 mg / ml; b) histidine at a concentration of 10 mM to 20 mM; c) sucrose having a concentration of 200 mM to 220 mM; d) polysorbate 80 at a concentration of 0.01 (w / v)% to 0.03 (w / v)%, Here, the formulation has a pH of 5.5 to 6.1.

[0088] In a further embodiment, the formulation does not include other excipients.

[0089] In a more preferred embodiment, the present disclosure provides a novel liquid pharmaceutical formulation, comprising: a) an anti-GM-CSF antibody at a concentration of 100 mg / ml, comprising a heavy chain variable region CDR1 (HCDR1) of SEQ ID NO:1, an HCDR2 of SEQ ID NO:2, an HCDR3 of SEQ ID NO:3, a light chain variable region CDR1 (LCDR1) of SEQ ID NO:4, an LCDR2 of SEQ ID NO:5, and an LCDR3 of SEQ ID NO:6; b) histidine at a concentration of 20 mM; c) sucrose at a concentration of 220 mM; d) Polysorbate 80 at a concentration of 0.02 (w / v)%; Here, the formulation has a pH of 5.8.

[0090] In a further embodiment, the formulation does not include other excipients.

[0091] The pharmaceutical formulations may be administered to a patient parenterally, for example by injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.), or by transdermal, mucosal, nasal, pulmonary, or oral administration. Many reusable pen or automatic syringe delivery devices can be used to subcutaneously deliver the pharmaceutical formulations of the present disclosure. Examples include AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25™ pen, HUMALOG™ pen, HUMALIN 70 / 30™ pen (Eli Lilly and Co., Indianapolis, Ind.), NOVOPEN™ I, II, and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (Becton Dickinson, Franklin Lakes, New Jersey), OPTIPEN™, OPTIPEN PRO™, OPTIPEN STARLET™ and OPTICLIK™ (Sanofi-aventis, Frankfurt, Germany). Examples of disposable pen or autosyringe delivery devices used for subcutaneous delivery of the drug compositions of the present disclosure include, but are not limited to, the SOLOSTAR™ pen (Sanofi-Aventis), FLEXPEN™ (Novo Nordisk), and KWIKPEN™ (Lilly), the SURECLICK™ autosyringe (Amgen, Thousand Oaks, Calif.), PENLET™ (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA™ pen (Abbott Labs, Abbott Park, Ill.).

[0092] The use of microinfusers to deliver pharmaceutical formulations of the present disclosure is also contemplated herein. As used herein, the term "microinfuser" refers to a subcutaneous delivery device designed to slowly administer large volumes (e.g., up to about 2.5 ml or more) of therapeutic formulations over an extended period of time (e.g., about 10, 15, 20, 25, 30 minutes or more). See, e.g., U.S. Pat. No. 6,629,949, U.S. Pat. No. 6,659,982, and Meehan et al., J. Controlled Release 46:107-116 (1996). Microinfusers are particularly applicable to the delivery of large doses of therapeutic proteins contained in high concentrations (e.g., about 100, 125, 150, 175, 200 mg / ml or more) or viscous solutions.

[0093] In some embodiments, the present disclosure provides a pre-filled syringe containing any one of the liquid formulations described herein. In some embodiments, the syringe is a 1 ml or 2.25 ml long glass syringe equipped with a 27 gauge thin-walled needle, a fluorocarbon compound-coated rubber plunger, and a rubber needle protector cap.

[0094] In one aspect, the liquid pharmaceutical formulations of the present disclosure may be stored at room temperature, refrigerated (e.g., 2-8°C), or frozen (e.g., at -20°C or -70°C).

[0095] In some embodiments, the formulation of any one of the above embodiments has an attribute selected from the group consisting of: (i) the formulation is stable when stored for an extended period of time at 50° C., 40° C., 25° C., 5° C., −20° C., −30° C., and −80° C.; (ii) the formulation has a low viscosity (viscosity less than 10 cP); (iv) the formulation is isotonic under physiological conditions; (v) the formulation is stable and compatible with intravenous or subcutaneous delivery devices and procedures; and (vi) the formulation is stable when stored for an extended period of time in a glass vial or a pre-filled syringe.

[0096] In one embodiment, the formulation substantially retains its physical and chemical stability and its biological activity upon storage. The storage period is generally selected based on the expected shelf life of the formulation. Several analytical techniques for measuring protein stability are available in the art and are reviewed, for example, in Peptide and Protein Drug Delivery, pp. 247-301, edited by Vincent Lee, published by Marcel Dekker, Inc., New York, NY (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature over a selected period of time. For example, a liquid formulation remains stable at about 40°C for at least about 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In another embodiment, the liquid formulation remains stable for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, or at least about 36 months at about 5° C. and / or 25° C., and / or remains stable for at least about 1 month, at least about 3 months, at least about 6 months, at least about 9 months, at least about 12 months, at least about 18 months, at least about 24 months, at least about 30 months, at least about 36 months, at least about 42 months, or at least about 48 months at about −20° C. and / or −70° C. Furthermore, in some embodiments, the liquid formulation may remain stable after being frozen (e.g., to −80° C.) and thawed (e.g., after one, two, or three freeze-thaw cycles).

[0097] The stability of liquid formulations may be qualitatively and / or quantitatively assessed in several different ways, including assessment of dimer, multimer and / or aggregate formation (e.g., size exclusion chromatography (SEC), matrix-assisted laser desorption / ionization time-of-flight mass spectrometry (MALDI-TOF MS), analytical ultracentrifugation, light scattering (photon correlation spectroscopy, dynamic light scattering (DLS), static light scattering, multi-angle laser light scattering (MALLS)), flow-based microscopic imaging, and the like. imaging), electrical impedance (Coulter) counting, light obscuration or other liquid particle counting systems, by measuring turbidity and / or visual inspection), cation exchange chromatography (CEX), isoelectric focusing (IEF) (e.g., capillary technique (cIEF)) or capillary zone electrophoresis to assess charge heterogeneity, amino- or carboxyl-terminal sequence analysis, mass spectrometry, SDS-PAGE or SEC analysis to compare fragmented, intact and multimeric (i.e., dimers, trimers, etc.) antibodies, peptide map (e.g., trypsin or LYS-C) analysis, assessment of antibody biological activity or antigen-binding function, and similar methods. The stability of solid-state formulations may be assessed qualitatively and / or quantitatively in several different ways, including direct tests such as X-ray powder diffraction (XRPD) to identify crystalline structure, using Fourier transform infrared spectroscopy (FTIR) to assess antibody structure in the solid state, and measuring thermal transitions (e.g., melting, glass transition) in lyophilized solids using differential scanning calorimetry (DSC) and indirect tests (e.g., measuring water content by the Karl Fisher test) to estimate potential chemical instability, e.g., due to hydrolysis.The instability may be related to any one or more of aggregation (e.g., non-covalent soluble aggregation, covalent soluble aggregation (e.g., disulfide bond rearrangement / scrambling), insoluble aggregation), deamidation (e.g., Asn deamidation), oxidation (e.g., Met oxidation), isomerization (e.g., Asp isomerization), shearing / hydrolysis / fragmentation (e.g., hinge region fragmentation), succinimide formation, N-terminal extension, C-terminal processing, differential glycosylation, and the like. Therapeutic uses of pharmaceutical preparations

[0098] It should be understood that references to "treating" or "treatment" include prevention and alleviation of established symptoms of a condition. Thus, "treatment" of a condition, disorder, or condition includes (1) preventing or delaying the appearance of clinical symptoms of the condition, disorder, or condition as it progresses in a person who is susceptible to or susceptible to the condition, disorder, or condition but who has not yet experienced or displayed clinical or subclinical symptoms of the condition, disorder, or condition; (2) inhibiting the condition, disorder, or condition, i.e., preventing, reducing, or delaying the progression of the disease or its recurrence (if treatment is maintained) or at least one clinical or subclinical symptom thereof; or (3) ameliorating or attenuating the disease, i.e., resolving the condition, disorder, or condition or at least one clinical or subclinical symptom thereof.

[0099] In one aspect, the present disclosure provides a method of treating an inflammatory or autoimmune disease or condition in a patient in need thereof, the method comprising administering to the patient a liquid pharmaceutical formulation according to the present disclosure.

[0100] In some embodiments, the inflammatory disease or condition is selected from the group consisting of Alzheimer's disease, Addison's disease, atherosclerosis, ankylosing spondylitis, arthritis, osteoarthritis (OA), rheumatoid arthritis (RA), psoriatic arthritis (PA), ankylosing spondylitis, asthma, atherosclerosis, chronic obstructive pulmonary disease (COPD), Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease (PD), vasculitis, ulcerative colitis, and COVID-19.

[0101] In some embodiments, the autoimmune disease or condition is selected from the group consisting of alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes mellitus (type 1), celiac disease, autoimmune juvenile idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune myocarditis, multiple sclerosis, pemphigus / pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma / systemic sclerosis, Sjogren's syndrome, systemic lupus erythematosus, autoimmune thyroiditis, Hashimoto's thyroiditis, autoimmune uveitis, vitiligo, and granulomatosis with polyangiitis (Wegener's granulomatosis).

[0102] "Subject" or "individual" or "animal" or "patient" or "mammal" refers to any subject in need of diagnosis, prognosis, or therapy, particularly mammalian subjects. Mammalian subjects include humans, domestic, farm, and zoo animals, sport or pet animals, such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cows, cows, etc.

[0103] As used herein, the phrases, for example, "in a patient in need of treatment" or "subject in need of treatment" include subjects, e.g., mammalian subjects, who would benefit from the administration of an antibody or composition of the disclosure, e.g., for detection, diagnostic procedures and / or treatment. example Example 1. Preparation of pH and buffer systems

[0104] 155 ml of purified anti-GM-CSF antibody (also referred to as "protein" in all subsequent experiments, which contains the heavy chain / light chain variable region sequences of SEQ ID NO:14 and SEQ ID NO:22 and has a human IgG1 Fc region) with a concentration of 24.20 mg / ml was taken and divided into five portions: three portions of 17.22 ml and two portions of 49 ml. (2) Each portion was dialyzed against buffer solutions 1 to 5 (see Table 4-1). After dialysis, buffer solution 4 was divided into three equal portions, two of which were adjusted to pH 6.0 and pH 6.5 with 10 mM histidine hydrochloride buffer (pH 8.14), respectively. Buffer solution 5 was divided into three equal portions, two of which were adjusted to pH 7.0 and pH 7.5 with 20 mmol / L sodium dihydrogen phosphate solution (pH 9.44), respectively. Then, 9 parts of the protein solution were concentrated to a final protein concentration of 50 mg / ml, and the concentrated products were prepared into the following samples (see Table 4-2). [Table 4-1] [Table 4-2]

[0105] The samples were dispensed (1 ml / bottle), one sample was used for detection at 0 hours, and the other samples were placed at 40°C ± 2°C and sampled at 1, 2, and 4 weeks for detection. DSC (at 0 hours), visual inspection, protein concentration detection, purity measurement by SEC method, purity measurement by CE-SDS method, and CEX-HPLC (see Table 5-1 and Table 5-2 below) were performed. [Table 5-1]

[0106] As can be seen from the DSC results, the Tm values ​​of the samples in buffer solutions 1 to 9 were acceptable. Comparing the results of samples 1 to 9, the Tm values ​​showed a relative decreasing order of 4>2>1>7>8=9>3>5>6 (> indicates better, = indicates equality). [Table 5-2]

[0107] Comparing the remaining samples 1 to 6, the appearance results showed a relative decreasing order of 4 = 2 = 1 > 5 = 3 > 6 (> indicates superior, = indicates equivalent), and all results were within the acceptable range (≦6 NTU). [Table 5-3]

[0108] No obvious change in protein concentration was observed in samples 1 to 6. [Table 5-4]

[0109] Based on the change in purity by SEC method, the decrease showed an increasing order of 4=2<1<5<3<6 (the final value of sample 6 was less than 95%). [Table 5-5]

[0110] Based on the change in the main peak of the CEX-HPLC method, the decrease rate showed an increasing order of 6<3=4=5=2<1 (all the changes in the results were within the acceptable range). [Table 5-6]

[0111] Based on the change in purity measured by non-reducing CE-SDS, the decrease showed an increasing order of 2=3=5<4<6<1.

[0112] Based on the change in purity measured by reducing CE-SDS, the decrease showed an increasing order of 5<3=6<4<2<1 (values ​​for samples 1 and 2 were less than 95%). [Table 6] Example 2. Screening of excipient composition [Table 7-1]

[0113] 306.68 ml of purified protein with a concentration of 8.627 mg / ml was taken. The protein was dialyzed against Buffer Solution 1 in Table 7-1 and concentrated to 30 ml, resulting in a concentration of 84.34 mg / ml. 10 ml of Buffer Solution 1 was added, and the mixture was divided into nine equal portions, each containing 4.4 ml. 1.1 ml of Buffer Solutions 2, 3, 4, 5, 6, 7, 8, 9, and 10 in Table 7-1 was added to each portion to prepare the following samples in Table 7-2. [Table 7-2]

[0114] The stability of each sample was considered based on the results of DSC (at 0 h), visual inspection, protein concentration detection, purity measurement by SEC method, and purity measurement by CE-SDS method after leaving it at 50°C for 1 week. [Table 8-1] The Tm values ​​of plonmarlimab in excipient solutions 1 to 9 are acceptable. [Table 8-2]

[0115] As can be seen from the appearance observation results, the appearances of formulation samples 1 to 9 after being left at 50°C for one week were all within the acceptable range, and the appearance results showed a relative decreasing order of 1 = 2 = 3 = 4 = 6 = 8 = 9 > 5 > 7. [Table 8-3]

[0116] After being left at 50°C for 1 week, no obvious changes were observed in the protein concentrations of formulations 1 to 9. [Table 8-4]

[0117] After being left at 50°C for 1 week, the purity of formulations 1 to 9 measured by SEC method was >97%, and the change in the results was within the acceptable range. [Table 8-5]

[0118] The purity of formulations 1 to 9 measured by CEX-HPLC at 0 hours varied significantly; the difference between the highest and lowest values ​​was 9%. However, after one week at 50°C, the difference between the highest and lowest values ​​was 4.0%, which is within the acceptable range. Therefore, the results at 0 hours were used as the basis for formula selection. The results at 0 hours followed the order 1 (51.9%) = 7 > 2 = 4 = 6 = 8 > 9 > 3 > 5 (42.9%). [Table 8-6]

[0119] After the sample was left at 50°C for one week, the purity changes by the non-reducing CE-SDS method showed a decreasing order of 1=3=4<2=7=8<5=6=9, and the purity changes by the reducing CE-SDS method showed a decreasing order of 1=5=6=7=2=9=4<3=8, all of which were within the acceptable range.

[0120] Based on the changes in stability results (see Table 9 below) sustained at 50°C for one week, a comparison was made for the different surfactant cases, and no difference was evident between Polysorbate 80 and Polysorbate 20. A comparison was made for the remaining excipient cases, excluding the CEX-HPLC results, and the results for Samples 1 and 4 were similar and slightly better than the other formulations. [Table 9] Example 3. Study on protein solubility

[0121] The solubility and viscosity of proteins at concentrations of 100 mg / ml and 150 mg / ml in a histidine hydrochloride buffer system (pH 5.8) were investigated to determine whether the protein samples could be formulated into highly concentrated products for subcutaneous injection. 3.73 g of the original protein sample was dialyzed against 20 mmol / L histidine hydrochloride (pH 5.5), and the pH was adjusted to 5.8 with 20 mmol / L histidine hydrochloride (pH 6.5). 84.44 ml, 126.65 ml, and 80 ml of solution were taken and concentrated to produce the following samples: [Table 10-1]

[0122] Each batch contained 2 ml of each tube, and Samples 1 and 2 were each composed of six tubes, of which two were used for detection at 0 h, two were placed at 4°C and sampled at 48 h for detection, and two were placed at 25°C and sampled at 48 h for detection. Sample 3 was dispensed into five tubes, placed at 25°C, and sampled at 48 h for clarity testing. The test items included appearance / color, protein concentration, OD350, viscosity, and clarity (see Tables 10-2 and 10-3). [Table 10-2] [Table 10-3]

[0123] In a 20 mmol / L histidine hydrochloride buffer system (pH 5.8), when the protein concentrations were 100 mg / ml and 150 mg / ml, and the samples were left at 4°C and 25°C for 48 hours, no significant changes were observed in the color, clarity, OD350, protein concentration, or viscosity, with the viscosity being less than 10 cP and the clarity being less than 6 NTU. Therefore, the protein of the present disclosure may be developed into a formulation for high-concentration subcutaneous injection. Example 4. Verification of excipient concentration

[0124] An appropriate sucrose concentration was selected based on viscosity and osmotic pressure, and the concentration of polysorbate 80 in the formulation was determined, taking into consideration durability and stability at pH 5.8 (the working range of pH is 5.5 to 6.1). [Table 11-1]

[0125] Three portions of protein were taken, each portion being 480 μl, and 120 μl of solutions A, B and C were added to each portion to prepare the following samples shown in Table 11-2. The samples were mixed uniformly, and the protein concentration and viscosity were measured respectively. [Table 11-2] [Table 12]

[0126] As shown in Table 12, there was no difference in protein concentration among the three samples a, b, and c, the viscosity of all three samples was acceptable, and the viscosity decreased as the sucrose concentration decreased. Example 5. Experimental study on osmotic pressure [Table 13-1]

[0127] Six portions of protein were taken, each portion being 480 μl, and 120 μl of solutions D, E, F, G, H and I were added to each portion to prepare the following samples in Table 13-2. [Table 13-2]

[0128] After uniform mixing, the protein concentration and osmolality were measured, and the D to I formulation solutions were diluted 5x with 20 mmol / L histidine hydrochloride buffer solution (pH 5.8), and the osmolality was measured. The results are shown in Table 14 below. [Table 14] Example 6. pH and Tween® content verification [Table 15-1]

[0129] 3.6 g of protein was dialyzed against 20 mmol / L histidine hydrochloride buffer solution (pH 5.5) and divided into three portions with volumes of 30.47 ml, 103.45 ml, and 30.41 ml, respectively. The pH was detected and adjusted to 5.5, 5.8, and 6.1, respectively, and concentrated in an ultrafiltration centrifuge tube to a final concentration of 125 mg / ml. The concentrated volumes were 9.04 ml, 33.26 ml, and 7.95 ml, respectively. 9.6 ml of the pH 5.8 protein solution was removed, and another two portions were used. One-quarter volume of buffer solutions 1, 2, and 3 were added to the three portions, respectively, to prepare Samples 1 to 3 (see Table 15-2) for the study of the effects of different pHs.

[0130] The remaining 23.26 ml of protein solution (pH 5.8) in step (1) was divided into three equal parts, each 7.45 ml, and 1.86 ml of buffer solutions 4, 2, and 5 were added to each part to prepare samples 4 to 6 (see Table 15-2) for studying the effects of different concentrations of polysorbate 80. [Table 15-2]

[0131] Aliquots: Each batch contained 2 ml of each tube. For samples 1 to 3, one tube was used for detection at 0 h, and the other was stored at 40°C and sampled at 1, 2, and 4 weeks for detection. For samples 4 to 6, two tubes were used for detection at 0 h, and the other was stored at 50°C and sampled at 1 week for detection. The test items included appearance (Table 16-1), protein concentration (Table 16-2), purity by SEC method (Table 16-3), purity by CE-SDS method (Table 16-4), and purity by CEX-HPLC method (Table 16-5). [Table 16-1] [Table 16-2] [Table 16-3] [Table 16-4] [Table 16-5]

[0132] By comparing the stability after 4 weeks at 40°C, we found that the pH value varied within the range of 5.5 to 6.1, with no obvious changes in appearance and protein concentration, and the changes in purity measured by SEC, CEX-HPLC, and CE-SDS methods were all within acceptable ranges.

[0133] By comparing the stability after 1 week at 50°C, we found that, except for the slightly abnormal CEX-HPLC results when the polysorbate 80 concentration was within the range of 0-0.04% (the purity at a polysorbate 80 concentration of 0.04% decreased more rapidly than at lower polysorbate concentrations), there were no significant differences in the changes in other results for appearance, protein concentration, purity by the SEC method, and purity by the CE-SDS method when the polysorbate 80 content was different. Example 7. Adjustments to formulation buffer solutions

[0134] Considering the convenience and controllability of commercial production, in this disclosure, the ratio of histidine to histidine hydrochloride was adjusted to directly achieve the target pH, and the content of sucrose (osmolality adjuster) was also adjusted. [Table 17]

[0135] The pH of formulation solutions 1 to 6 and the osmolality of formulation solutions 3 and 4 were detected. [Table 18-1] [Table 18-2]

[0136] The osmolality of Formulation 4 is closer to the osmolality of the buffer solutions in Table 18-2. Example 8. Prescription adjustment

[0137] During the development of the 50L process, pH verification and osmolality measurements were performed on the batch raw solution. As a result, it was discovered that the pH value was higher than the theoretical value and the osmolality value was lower than the theoretical value for scale-up production, so adjustments were made to the formulation. 8.1 Adjustment of pH and buffer concentration [Table 19]

[0138] The original protein sample was taken and divided into five equal parts, each of which was dialyzed into the above buffer solution at 10 times the volume. The sample batch numbers were Yu-1, Yu-2, Yu-3, Yu-4, and Yu-5, respectively, and the protein concentration and pH value of the sample were detected. The dialyzed samples were concentrated to 100 mg / ml in ultrafiltration centrifuge tubes with batch numbers 1, 2, 3, 4, and 5, respectively, and the protein concentration and pH value of the sample were detected. [Table 20] 8.2 pH Verification

[0139] By comparing small-scale formulation development with a 50L process, we confirmed the effects on pH and osmolality of fluid exchange using a concentration tube and ultrafiltration system. [Table 21-1]

[0140] 150.21 ml of the protein stock solution was taken and divided into three portions, numbered a, b, and c, which were dialyzed against buffer solutions 1 to 3, respectively, and concentrated to 100 mg / ml in an ultrafiltration centrifuge tube. Another portion of the protein stock solution was taken and numbered d. Two 0.005 ml 2 The solution was dialyzed against buffer solution 2 using a membrane pack (Sartocon Slice Cassette Hydrosart, 30 kd, Sartorius) and concentrated to 100 mg / ml. Measurement parameters included protein concentration, osmolality, pH, and electrical conductivity (see Table 21-2).

[0141] The buffer concentration and sucrose concentration of Formulation 2 were the same as those of the confirmed batch for process development. The ultrafiltration centrifuge tube was used to concentrate the sample to 100 mg / ml, and the osmolality of the sample was higher than that of the confirmed batch sample. In contrast, the membrane pack was used to concentrate the sample to 100 mg / ml, and the osmolality of the sample was similar to that of the confirmed batch sample and lower than 300 mOsmol / kg. In other words, the concentration method used in the manufacturing process of the protein sample of the present disclosure had an effect on the osmolality of the concentrated sample. Therefore, in subsequent experiments, the sucrose concentration was adjusted to 0.005 m 2 The membrane pack was used to prepare samples and study the osmotic pressure. [Table 21-2]

[0142] In addition, the pH detection results showed that the method for concentrating the samples did not affect the pH, and the pH of samples a to d was all within the range of pH 5.5 to pH 6.1. Example 9. Verification of sucrose concentration

[0143] A buffer solution containing 6.2 mmol / L histidine and 13.8 mmol / L histidine hydrochloride was used. By comparing different sucrose concentrations, the sucrose concentration in the formulation at an osmolality of 300 mOsmol / kg was confirmed, and the formulation was confirmed. A stock solution was prepared and tested against the density of the dialysis buffer solution and the density of the protein stock solution of the present disclosure. [Table 22]

[0144] The protein solution was dialyzed against buffer solution 1 and concentrated to 100 mg / ml to obtain a stock solution with batch number Protein Stock Solution 1, which was subjected to protein concentration, osmolality, and pH measurement. 8.99 g of the protein solution was dialyzed against buffer solution 2 to produce a stock solution with batch number Protein Stock Solution 2, which was subjected to protein concentration, osmolality, and pH measurement. The protein concentration and the concentration of the corresponding dialysis buffer solution were also measured. The results are shown in Tables 23-1 and 23-2 below. [Table 23-1] [Table 23-2]

Claims

1. 1. A liquid pharmaceutical formulation comprising: (a) 20 mg / ml to 200 mg / ml of an antibody or antigen-binding fragment thereof that specifically binds to human granulocyte-macrophage colony-stimulating factor (GM-CSF) protein, the antibody or antigen-binding fragment thereof comprising a heavy chain variable region CDR1 (HCDR1) of SEQ ID NO: 1, a HCDR2 of SEQ ID NO: 2, a HCDR3 of SEQ ID NO: 3, a light chain variable region CDR1 (LCDR1) of SEQ ID NO: 4, a LCDR2 of SEQ ID NO: 5, and a LCDR3 of SEQ ID NO: 6; (b) a pH buffering agent of 10 mM to 30 mM; (c) 130 mM to 250 mM of a tonicity adjuster; (d) 0.01% (w / v) to 0.03% (w / v) of a surfactant; A liquid pharmaceutical formulation, wherein the formulation has a pH of 4.5 to 7.

5.

2. The antibody or antigen-binding fragment thereof comprises a heavy chain variable region, and the heavy chain variable region is (a) Glu at position 1; (b) Arg at position 98; (c) Ser at position 72; (d) Ala at position 68; (e) Leu at position 70; (f) Ile at position 48; (g) Asp at position 26; (h) Leu at position 29; 10. The liquid pharmaceutical formulation of claim 1, comprising one or more amino acid residues selected from the group consisting of:

3. 3. The liquid pharmaceutical formulation of claim 2, wherein the heavy chain variable region comprises at least (a) a Glu at position 1.

4. 3. The liquid pharmaceutical formulation of claim 2, wherein the heavy chain variable region comprises a DYTLT (SEQ ID NO: 23) or GYTFT (SEQ ID NO: 24) fragment beginning at position 26 according to the Kabat numbering system.

5. The antibody or antigen-binding fragment thereof comprises a light chain variable region, and the light chain variable region is (a) Ala at position 46; (b) Asp at position 60; (c) Asp at position 70; (d) Ser at position 43; (e) Phe at position 87; 5. The liquid pharmaceutical formulation of claim 1, comprising one or more amino acid residues selected from the group consisting of:

6. 6. The liquid pharmaceutical formulation of any one of claims 1 to 5, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 8 to 17.

7. 7. The liquid pharmaceutical formulation of any one of claims 1 to 6, wherein the antibody or antigen-binding fragment thereof comprises a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 19-22.

8. 8. The liquid pharmaceutical formulation of claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 14 and the light chain variable region comprises the amino acid sequence of SEQ ID NO:

22.

9. The liquid pharmaceutical formulation of claim 1 , wherein the antibody or antigen-binding fragment thereof further comprises an Fc region.

10. 10. The liquid pharmaceutical formulation of claim 9, wherein the Fc region is an IgG1 Fc region.

11. The pH buffering agent may be citric acid, HEPES, PBS, histidine, potassium acetate, potassium citrate, potassium phosphate (KH ２ P.O. ４ ), sodium acetate, sodium bicarbonate, sodium citrate, sodium phosphate (NaH ２ P.O. ４ ), Tris base and Tris-HCl.

12. 12. The liquid pharmaceutical formulation of claim 11, wherein the pH buffering agent comprises about 20 mM histidine.

13. 13. The liquid pharmaceutical formulation of claim 12, wherein the 20 mM histidine comprises about 6.2 mM histidine and about 13.8 mM histidine hydrochloride monohydrate.

14. 14. The liquid pharmaceutical formulation of claim 13, wherein the pH buffering agent comprises about 20 mM NaAc.

15. 15. The liquid pharmaceutical formulation of any one of claims 1 to 14, wherein the pH range is from about 5.5 to about 6.

1.

16. 16. The liquid pharmaceutical formulation of claim 15, wherein the pH is about 5.

8.

17. 17. The liquid pharmaceutical formulation of any one of claims 1 to 16, wherein the tonicity adjusting agent is one or more selected from the group consisting of sucrose, trehalose, mannitol, arginine and sodium chloride.

18. 18. The liquid pharmaceutical formulation of claim 17, wherein the tonicity adjusting agent comprises about 200 mM to about 220 mM sucrose.

19. 20. The liquid pharmaceutical formulation of claim 18, wherein the tonicity adjusting agent comprises about 220 mM sucrose.

20. 20. The liquid pharmaceutical formulation of any one of claims 1 to 19, wherein the liquid pharmaceutical formulation further comprises an antioxidant, a preservative, or a mixture thereof.

21. 20. The liquid pharmaceutical formulation of any one of claims 1 to 19, wherein the liquid pharmaceutical formulation further comprises proline and / or glycine.

22. 22. The liquid pharmaceutical formulation of any one of claims 1 to 21, wherein the surfactant comprises polysorbate 20 or polysorbate 80.

23. 23. The liquid pharmaceutical formulation of claim 22, wherein the surfactant comprises 0.02% (w / v) polysorbate 80.

24. 24. The liquid pharmaceutical formulation of any one of claims 1 to 23, wherein the liquid pharmaceutical formulation comprises 50 to 150 mg / ml of the antibody.

25. 25. The liquid pharmaceutical formulation of claim 24, wherein the liquid pharmaceutical formulation comprises 100 mg / ml of the antibody.

26. 26. The liquid pharmaceutical formulation of any one of claims 1 to 25, comprising 50 to 150 mg / ml of the antibody, 10 to 20 mM histidine, 200 to 220 mM sucrose, and 0.01 to 0.03% (w / v) polysorbate 80, and having a pH of about 5.5 to about 6.

1.

27. 27. The liquid pharmaceutical formulation of claim 26, wherein the liquid pharmaceutical formulation comprises about 100 mg / ml of the antibody, about 20 mM histidine, about 220 mM sucrose, and about 0.02% (w / v) polysorbate 80, and has a pH of about 5.

8.

28. 28. The liquid pharmaceutical formulation of any one of claims 1 to 27, wherein the liquid pharmaceutical formulation is for intravenous (IV) or subcutaneous administration.

29. 30. A method of treating an inflammatory or autoimmune disease or condition in a patient in need thereof, comprising administering to the patient a liquid pharmaceutical formulation of any one of claims 1 to 28.

30. 30. The method of claim 29, wherein the autoimmune disease is selected from the group consisting of alopecia areata, autoimmune hemolytic anemia, autoimmune hepatitis, dermatomyositis, diabetes mellitus (type 1), celiac disease, autoimmune juvenile idiopathic arthritis, glomerulonephritis, Graves' disease, Guillain-Barre syndrome, idiopathic thrombocytopenic purpura, myasthenia gravis, autoimmune myocarditis, multiple sclerosis, pemphigus / pemphigoid, pernicious anemia, polyarteritis nodosa, polymyositis, primary biliary cirrhosis, psoriasis, rheumatoid arthritis, scleroderma / systemic sclerosis, Sjogren's syndrome, systemic lupus erythematosus, autoimmune thyroiditis, Hashimoto's thyroiditis, autoimmune uveitis, vitiligo, and granulomatosis with polyangiitis (Wegener's granulomatosis).

31. 30. The method of claim 29, wherein the inflammatory disease is selected from the group consisting of Alzheimer's disease, Addison's disease, atherosclerosis, ankylosing spondylitis, arthritis, osteoarthritis (OA), rheumatoid arthritis (RA), psoriatic arthritis (PA), ankylosing spondylitis, asthma, atherosclerosis, chronic obstructive pulmonary disease (COPD), Crohn's disease, colitis, dermatitis, diverticulitis, fibromyalgia, hepatitis, irritable bowel syndrome (IBS), systemic lupus erythematosus (SLE), nephritis, Parkinson's disease (PD), vasculitis, ulcerative colitis, and COVID-19.

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