Stable anti-ifnar1 formulations

Abstract

The present invention relates to a stable, low viscosity antibody formulation, wherein the formulation comprises a high concentration of an anti-INFAR1 antibody. In some embodiments, the present invention relates generally to a stable antibody formulation comprising about 100 mg / mL to about 200 mg / mL of an antibody or fragment thereof that specifically binds human interferon alpha 1 (INFAR1); about 20 mM to about 80 mM of lysine or a salt thereof; about 0.02% to about 0.06% of a surfactant; an uncharged excipient; and a formulation buffer. In some embodiments, the present invention relates to containers, dosage forms, and / or kits. In some embodiments, the present invention relates to methods of making and using the stable antibody formulation.

Description

[0001] This application is submitted with the sequence list via EFS-Web by reference to a text file named "IFNAR-350WO1_SL.txt", created on August 18, 2016, and having a size of 2,490. Background of the Invention Technical Field

[0003] This invention relates to stable, low-viscosity antibody formulations comprising high concentrations of an antibody or antigen-binding fragment thereof that specifically binds to interferon alpha receptor 1 (IFNAR1). In examples, the antibody formulation comprises anifrolumab or an antigen-binding fragment thereof.

[0004] In some embodiments, the present invention relates to a stable antibody formulation comprising about 100 mg / mL to about 200 mg / mL of an antibody or fragment thereof that specifically binds to IFNAR1, about 25 mM to about 130 mM of lysine or a lysine salt; an uncharged excipient; a surfactant; and a formulation buffer. In some embodiments, the present invention relates to a container, dosage form, and kit. In some embodiments, the present invention relates to a method for preparing and using a stable antibody formulation. Background Technology

[0006] Antibodies have been used to treat a variety of diseases and conditions due to their specificity to their target markers, thereby producing highly selective results when administered systemically. To maintain their efficacy, antibodies must retain their biological activity during their production, purification, transportation, and storage. New production and purification technologies have been developed to allow the production of large quantities of highly purified monoclonal antibodies. However, challenges remain in stabilizing these antibodies for transportation and storage, and even in providing antibodies in dosage forms suitable for administration.

[0007] Denaturation, aggregation, contamination, and particle formation can constitute significant obstacles in antibody formulation and storage. Due to the diversity of antibodies, there is no universal formulation or condition suitable for the storage of all antibodies. The optimal formulation for an antibody is typically specific to that antibody. Furthermore, depending on the antibody concentration and / or the desired physical properties of the antibody formulation (e.g., viscosity), further customization of antibody formulations to suit specific antibodies may be necessary. Antibody storage formulations are often an important part of the commercial antibody research and development process.

[0008] Various methods have been proposed to overcome the challenges associated with antibody stability. For example, in some cases, antibodies are often freeze-dried and then rehydrated shortly before administration. However, rehydration adds an extra step to the administration process and may introduce contaminants into the preparation. Furthermore, rehydrated antibodies may suffer from aggregation and particle formation. Therefore, there is a need to provide stable antibody preparations that overcome the challenges associated with transportation and storage. Summary of the Invention

[0009] This invention relates to stable, low-viscosity antibody formulations comprising high concentrations of an anti-interferon α receptor 1 antibody or an antigen-binding fragment thereof. In some embodiments, the invention generally relates to stable antibody formulations comprising about 100 mg / mL to about 200 mg / mL of an antibody or fragment thereof that specifically binds to IFNAR1, about 25 mM to about 130 mM of lysine or a lysine salt; an uncharged excipient; a surfactant; and a formulation buffer.

[0010] In an embodiment, the present invention relates to an antibody formulation comprising about 100 mg / mL to about 200 mg / mL of anifurumab or its antigen-binding fragment; about 40 mM to about 60 mM of lysine HCl; about 100 mM to about 160 mM of trehalose dihydrate; about 0.02% to about 0.1% of polysorbate 80; and about 15 mM to about 35 mM of histidine / histidine HCl, wherein the formulation is at a pH of about 5.5 to 6.5.

[0011] In another embodiment, the present invention relates to an antibody formulation comprising about 145 mg / mL to about 155 mg / mL of anifurumab or its antigen-binding fragment; about 45 mM to about 55 mM of lysine HCl; about 120 mM to about 140 mM of trehalose dihydrate; about 0.04% to about 0.08% of polysorbate 80; and about 20 mM to about 30 mM of histidine / histidine HCl, wherein the formulation is at a pH of about 5.8 to about 6.1.

[0012] In some embodiments, the present invention relates to an antibody formulation comprising: about 150 mg / mL of anifurumab or its antigen-binding fragment; about 50 mM of lysine HCl; about 130 mM of trehalose dihydrate; about 0.05% of polysorbate 80; and about 25 mM of histidine / histidine HCl, wherein the formulation is at a pH of about 5.9.

[0013] In some embodiments, the present invention relates to an antibody formulation comprising: 150 mg / mL of anifurumab or its antigen-binding fragment; 50 mM of lysine HCl; 130 mM of trehalose dihydrate; 0.05% of polysorbate 80; and 25 mM of histidine / histidine HCl, wherein the formulation is at a pH of about 5.9.

[0014] In another embodiment, the present invention relates to an antibody formulation comprising: 150 mg / mL of anifurumab; 50 mM of lysine HCl; 130 mM of trehalose dihydrate; 0.05% of polysorbate 80; and 25 mM of histidine / histidine HCl, wherein the formulation is at a pH of 5.9.

[0015] In some embodiments, the present invention relates to a pharmaceutical unit dosage form suitable for parenteral administration to humans, the pharmaceutical unit dosage form comprising any of the antibody formulations described herein in a suitable container.

[0016] In some embodiments, the present invention relates to a kit comprising any antibody formulation described herein, a container as described herein, a unit dosage form as described herein, or a pre-filled syringe as described herein.

[0017] In some embodiments, the present invention relates to a method for producing a stable antibody formulation, the method comprising: purifying an antibody to about 100 mg / mL to about 200 mg / mL of an anti-IFNAR antibody or an antigen-binding fragment thereof; placing the isolated antibody in a stabilization formulation to form the stable antibody formulation, wherein the resulting stable antibody formulation comprises: about 100 mg / mL to about 200 mg / mL of antibody; about 25 mM to about 130 mM of lysine or a lysine salt; about 100 mM to about 150 mM of an uncharged excipient; about 0.02% to about 0.1% of a surfactant; and a formulation buffer.

[0018] In some embodiments, the present invention relates to a method of treating type I IFN-mediated diseases or disorders in subjects in need of such treatment, the method comprising administering a therapeutically effective amount of any of the antibody formulations described herein. Attached Figure Description

[0019] For the purpose of illustrating the invention, certain embodiments of the invention are depicted in the accompanying drawings. However, the invention is not limited to the precise arrangement and means of the embodiments depicted in the drawings.

[0020] Figure 1 The viscosity variation with pH is shown in a bead-based high-throughput screening method.

[0021] Figure 2 The viscosity change with varying lysine HCl concentration is shown in a bead-based high-throughput screening method.

[0022] Figure 3 The viscosity changes of the following formulations with varying antibody (anifulumab) concentrations are shown: the formulation contains 25 mM histidine / histidine-HCl, 25 mM lysine, and 130 mM trehalose at pH 6.0 (round); and 25 mM histidine / histidine-HCl, 50 mM lysine, and 130 mM trehalose at pH 6.0 (rhomboid).

[0023] Figure 4 The viscosity changes of the following solutions with varying antibody (anifulumab) concentrations are shown: 0 mM lysine (rhombus); 5 mM lysine (square); 12.5 mM lysine (triangle); 25 mM lysine (x); and 50 mM lysine (asterisk).

[0024] Figure 5 The viscosity changes of the following solutions with varying lysine HCl concentrations are shown: 135 mg / mL anifrucizumab (rhombus); 150 mg / mL anifrucizumab (square); and 180 mg / mL anifrucizumab (triangle). Detailed Implementation

[0025] Definitions

[0026] Before describing the invention in detail, it should be understood that the invention is not limited to specific compositions or method steps, as these compositions or method steps can vary. It must be noted that, 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. The term “a” (or “an”) and the terms “one or more” and “at least one” are used interchangeably herein.

[0027] Furthermore, the term “and / or” as used herein should be understood as a specific disclosure of each of the two specified features or components, with or without the other. Therefore, the term “and / or” as used in phrases such as “A and / or B” herein is intended to include “A and B”, “A or B”, “A” (alone), and “B” (alone). Similarly, the term “and / or” as used in phrases such as “A, B and / or C” is intended to cover the following embodiments: A, B and C; A, B or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0028] Throughout this disclosure, unless otherwise specified, all percentages, ratios, etc., are expressed "by weight". As used herein, "by weight" is synonymous with the term "by mass" and indicates that the ratios or percentages defined herein are expressed based on weight rather than volume, thickness, or some other measure.

[0029] As used herein, the term “approximately” means approximately, in the region of, roughly, or around. When “approximately” is used with a range of values, it modifies that range by extending the upper and lower limits of the listed values. Typically, this article uses the term “approximately” to modify a value by a variation of 10% above and below the specified value.

[0030] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. For example, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd edition, 2002, CRC Press; the Dictionary of Cell and Molecular Biology, 3rd edition, 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, revised edition, 2000, Oxford University Press provide general dictionaries for those skilled in the art of the invention for many of the terms used herein.

[0031] Units, prefixes, and symbols are all represented in their International System of Units (SI) accepted form. Numerical ranges include the numbers defining the range. Unless otherwise specified, amino acid sequences are written from left to right in the direction from amino to carboxyl. The subheadings provided herein are not intended to limit different aspects or embodiments of the invention, which can be obtained by referring to this specification as a whole. Thus, the terms defined herein are defined more fully by referring to the specification in its entirety.

[0032] It should be understood that, in any case where embodiments are described herein with the language “comprising”, other similar embodiments described with “consisting of” and / or “substantially consisting of” are also provided.

[0033] Amino acids are represented in this article by their commonly known three-letter symbols or by the single-letter symbols recommended by the IUPAC-IUB Biochemistry Nomenclature Committee. Similarly, nucleotides are referred to by their universally accepted single-letter codes.

[0034] As used herein, the term "injection force" is the amount of pressure (in Newtons) required to pass the antibody formulation through the injection needle.

[0035] As used herein, the term "autoimmune disease" refers to an impairment, disease state, or symptom associated with the formation of autoantibodies that react with the patient's own cells to form antigen-antibody complexes. The term "autoimmune disease" includes conditions such as, for example, systemic lupus erythematosus (SLE), as well as those triggered by specific external factors, such as acute rheumatic fever. Examples of autoimmune disorders include, but are not limited to: autoimmune hemolytic anemia, autoimmune hepatitis, Beauger's disease, chronic fatigue syndrome, Crohn's disease, dermatomyositis, fibromyalgia, Graves' disease, Hashimoto's thyroiditis, idiopathic thrombocytopenic purpura, lichen planus, multiple sclerosis, myasthenia gravis, psoriasis, rheumatic fever, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic lupus erythematosus, type 1 diabetes mellitus, ulcerative colitis, and vitiligo. In specific contexts, autoimmune diseases include systemic lupus erythematosus (SLE), scleroderma (SSe), myositis, or lupus nephritis.

[0036] The terms “interferon α receptor-1,” “IFNARI,” and “IFNAR” are used interchangeably and include variants, subtypes, species homologs, and analogs of human IFNAR1 that share at least one common epitope with IFNARI. See, for example, de Weerd et al., J. Biol. Chem. 282: 20053-20057 (2007). Thus, in some cases, human antibodies specific to human IFNARIs cross-react with IFNARIs from species other than humans, or with other proteins structurally associated with human IFNAR1 (e.g., human IFNAR1 homologs). In other cases, antibodies may be completely specific to human IFNARIs and do not exhibit species or other types of cross-reactivity. The full-length cDNA sequence of human IFNAR1 has the gene bank accession number NM 000629.

[0037] As used herein, the term "type I interferon" or "type I IFN" refers to a member of the type I interferon family of molecules that are ligands of IFNAR1 (i.e., members of the type I interferon family of molecules that can bind to IFNAR1). Examples of type I interferon ligands are interferon α1, 2a, 2b, 4, 5, 6, 7, S, 10, 14, 16, 17, 21, interferon β, and interferon ω.

[0038] The term "type I IFN-mediated disease or disorder" refers to any type I IFN or IFN-induced disease, disorder, or condition that exhibits a type I IFN pharmacodynamic ("PD") marker expression profile or genetic marker (type I IFN GS). PD marker expression profiles and genetic markers will be understood as equivalent. These diseases, disorders, or conditions include those with an autoimmune component, such as systemic lupus erythematosus (SLE), scleroderma, lupus nephritis, and myositis. Type I IFN-mediated diseases or disorders can be treated with small molecule or biological agents (e.g., antibodies or their antigen-binding fragments). If the therapeutic agent is a biological agent, it can be an antibody specific to any one or more subtypes of type I IFN or IFNα. For example, the antibody may be specific to any one of IFNα1, IFNα2, IFNα4, IFNα5, IFNα6, IFNα7, IFNα8, IFNα10, IFNα14, IFNα17, IFNα21, IFNβ, or IFNω. Alternatively, the antibody may be specific to any two, three, four, five, six, seven, eight, nine, ten, eleven, or twelve of type I IFN or iFNα subtypes. If an antibody is specific for more than one type I IFN subtype, it can be specific for IFNα1, IFNα2, IFNα4, IFNα5, IFNα8, IFNα10, and IFNα21; or it can be specific for IFNα1, IFNα2, IFNα4, IFNα5, IFNα8, and IFNα10; or it can be specific for IFNα1, IFNα2, IFNα4, IFNα5, IFNα8, and IFNα21; or it can be specific for IFNα1, IFNα2, IFNα4, IFNα5, IFNα10, and IFNα21. Therapeutic agents that modulate IFNα activity can neutralize IFNα activity. Type I IFN-mediated diseases or disorders can also be treated with antibodies specific to type I IFN receptors (e.g., IFNAR1). In some respects, anti-IFNAR1 antibodies can cross-react with IFNAR1 from species other than humans. In other respects, this anti-IFNAR1 antibody may be specific only for IFNAR1 and does not exhibit species or other types of cross-reactivity. In some respects, compared with unmodified antibodies, this anti-IFNAR1 antibody exhibits reduced binding affinity to FC ligands and has reduced or eliminated effector functions (ADCC and / or CDC), reduced or eliminated binding to Fc ligands, or reduced or eliminated toxicity.

[0039] The term “MEDI-546” refers to the Fc-modified version of the anti-IFNAR 9D4 antibody described in U.S. Patent No. 7,662,381. The terms “MEDI-546” and “anifulumab” are used interchangeably herein. The sequence of MEDI-546 is described in US2011-0059078. MEDI-546 comprises a combination of three mutations (L234F, L235E, and P331S) introduced into the lower hinge and CH2 domain of human IgG1, where the numbering is based on the EU index proposed in Kabat. These mutations result in reduced binding to human FcyRI (CD64), FcyRIIA (CD32A), FcyRIII (CD16), and C1q. See, for example, US2011 / 0059078 and Oganesyan et al., Acta Crystallographica D 64:700-704 (2008), which is hereby incorporated by reference in its entirety. The VH and Vκ sequences of MEDI-546 are shown in Table 1.

[0040] Table 1

[0041]

[0042] The term "antibody or antigen-binding fragment thereof that modulates type I IFN activity" in its broadest sense refers to an antibody capable of modulating type I IFN activity in a patient (see below). As used herein, the term "modulation" includes inhibition or suppression of type I IFN activity, as well as induction or enhancement of type I IFN activity. In a specific aspect, the type I IFN activity is IFNα activity. In some aspects, suppression of type I IFN GS is suppression of type I IFN activity. In some aspects, the antibody or antigen-binding fragment thereof is monoclonal. In a specific aspect, the antibody or antigen-binding fragment thereof that modulates type I IFN activity specifically binds to a type I IFN receptor (e.g., IFNAR1). In some specific aspects, the antibody or antigen-binding fragment thereof specifically binds to subunit 1 of IFNAR1.

[0043] The term "antibody" is used herein in its broadest sense and includes, for example, monoclonal antibodies, polyclonal antibodies, multivalent antibodies, multispecific antibodies, chimeric antibodies, and humanized antibodies. The term "antibody" includes intact antibodies. The term "antibody" also refers to a protein, or its antigen-binding portion, comprising at least two immunoglobulin heavy chains (H) and two immunoglobulin light chains (L) linked together by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains (CH1, CH2, and CH3). Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain (CL). The VH and VL regions can 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, arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The constant regions of the antibody mediate the binding of immunoglobulins to host tissues or factors, including different cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.

[0044] The term “antigen-binding fragment” refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., IFNAR). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding fragment” of an antibody include (i) Fab fragments: monovalent fragments consisting of VL, VH, CL, and CHI domains; (ii) F(ab')2 fragments: bivalent fragments containing two Fab fragments linked by disulfide bridging in the hinge region; (iii) Fd fragments consisting of VH and CHI domains; (iv) Fv fragments consisting of the VL and VH domains of a single arm of the antibody; (v) dAb fragments consisting of the VH domain (Ward et al., (1989) Nature 34I: 544-546); and (vi) separated complementarity-determining regions (CDRs). Furthermore, although the two domains (VL and VH) of the Fv fragment are encoded by separate genes, they can be joined together using a recombinant approach via a synthetic linker that allows them to be made into a single protein chain, where the VL and VH regions pair to form a monovalent molecule (referred to as a single-chain Fv (scFv); see, for example, Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883. Such single-chain antibodies are also intended to be encompassed within the term "antigen-binding fragment" of antibody. These antibody fragments are obtained using conventional techniques known to those skilled in the art and are screened for efficacy in the same manner as intact antibodies.

[0045] As used herein, “isolated antibody” is intended to refer to an antibody that is substantially free of other antibodies with different antigen specificities (e.g., an isolated antibody that specifically binds to IFNAR is an antibody that is substantially free of antigens that specifically bind to antigens other than IFNAR). However, isolated antibodies that specifically bind to IFNAR may have cross-reactivity with other antigens (e.g., IFNAR molecules from other species). Furthermore, isolated antibodies may be substantially free of other cellular material and / or chemicals.

[0046] As used herein, the term "monoclonal antibody" refers to the preparation of antibody molecules as a single-molecule composition. Monoclonal antibodies exhibit single-specific binding specificity and affinity for a specific epitope.

[0047] As used herein, the term "human antibody" is intended to include antibodies having variable regions in which both the frame region and the CDR region are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, that constant region is also derived from a human germline immunoglobulin sequence. Human antibodies disclosed herein may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced in vitro by random or site-specific mutagenesis or in vivo by somatic mutagenesis). However, as used herein, the term "human antibody" is not intended to include antibodies in which a germline CDR sequence derived from another mammalian species (e.g., mouse) has been grafted onto a human frame sequence.

[0048] The term "human monoclonal antibody" refers to an antibody exhibiting single-binding specificity, having variable regions, both the framework region and the CDR region, derived from human germline immunoglobulin sequences. In one embodiment, the human monoclonal antibody is produced via a hybridoma comprising B cells obtained from a transgenic nonhuman animal (e.g., a transgenic mouse), the B cells having a genome containing human heavy chain transgenes and light chain transgenes fused to immortalized cells.

[0049] As used herein, the term "recombinant human antibody" includes all human antibodies prepared, expressed, generated, or isolated by recombinant means: for example, (a) antibodies isolated from transgenic or transchromosomal animals (e.g., mice) of the human immunoglobulin gene or from hybridomas prepared therefrom (described further below), (b) antibodies isolated from host cells transformed to express human antibodies (e.g., from transfected tumors), (c) antibodies isolated from recombinant combined human antibody libraries, and (d) antibodies prepared, expressed, generated, or isolated by any other means involving splicing a human immunoglobulin gene sequence into other DNA sequences. Such recombinant human antibodies have variable regions in which both the framework region and the CDR region are derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies may be mutagenized in vitro (or, when using transgenic animals with human Ig sequences, mutagenized in somatic cells), and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, although derived from and associated with human germline VH and VL sequences, may not be naturally present in the germline expression profile of human antibodies in vivo.

[0050] As used herein, the term “antibody” also includes “chimeric” antibodies in which a portion of the heavy and / or light chains are identical or homologous to the sequences corresponding to antibodies derived from a particular species or belonging to a particular antibody type or subclass, while the remainder of these chains are identical or homologous to the sequences corresponding to antibodies derived from another species or belonging to another antibody type or subclass, and fragments of such antibodies, provided they exhibit the desired biological activity (US Patent No. 4,816,567; and Morrison et al., Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences] 81: 6851-6855 (1984)).

[0051] The basic antibody structures in vertebrate systems are relatively easy to understand. See, for example, Harlow et al. (1988) Antibodies: A Laboratory Manual (2nd ed.; Cold Spring Harbor Laboratory Press).

[0052] Where two or more definitions exist for a term used and / or accepted in the art, the definition of the term as used herein is intended to include all such meanings unless the contrary is explicitly stated. A specific example is the use of the term “complementarity-determining region” (“CDR”) to describe a non-continuous antigen combination site found in the variable region of both heavy and light chain polypeptides. This particular region has been described by Kabat et al. (1983) USDept. of Health and Human Services, “Sequences of Proteins of Immunological Interest” and Chothia and Lesk, J. Mol. Biol. 196: 901-917 (1987), which are incorporated herein by reference, wherein the definition includes overlap or subsets of amino acid residues when compared with each other. However, the application of any definition to refer to the CDR of an antibody or its variant is intended to fall within the scope of the terminology as defined and used herein. The appropriate amino acid residues covering the CDR as defined by each of the references cited above are elucidated in Table 2 below for comparison. The precise residue numbering covering a specific CDR will vary depending on the sequence and size of the CDR. Given the amino acid sequence of the variable region of an antibody, those skilled in the art can routinely determine which residues constitute a specific CDR.

[0053] Table 2 CDR Definition 1

[0054] Kabat Chothia VH CDR1 31-35 26-32 VH CDR2 50-65 52-58 VH CDR3 95-102 95-102 VL CDR1 24-34 26-32 VL CDR2 50-56 50-52 VL CDR3 89-97 91-96

[0055] 1 The numbering of all CDR definitions in Table 2 follows the numbering convention described by Kabat et al. (see below).

[0056] Kabat et al. also defined a numbering system for variable domain sequences applicable to any antibody. This “Kabat numbering” system can be readily assigned to any variable domain sequence by those skilled in the art, without relying on any experimental data beyond the sequence itself. As used herein, “Kabat numbering” refers to the numbering system described by Kabat et al. (1983), U.S. Department of Health and Human Services, “Sequences of Proteins of Immunological Interest”. Unless otherwise specified, references to specific amino acid residue positions in the anti-IFNAR antibodies disclosed herein, or their antigen-binding fragments, variants, or derivatives, are based on the Kabat numbering system.

[0057] As used herein, the term "treat" refers to therapeutic treatment and prophylactic or preventative measures aimed at preventing or mitigating undesirable physiological changes or impairments, such as the progression of inflammatory diseases or conditions. Beneficial or desired clinical outcomes include, but are not limited to, symptom relief, reduction in disease severity, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the disease state, and reduction (whether partial or complete), whether detectable or undetectable. The term "treatment" also refers to prolonged survival compared to expected survival without treatment. Those requiring treatment include those who already have a condition or impairment, those who are susceptible to a condition or impairment, or those who intend to prevent a condition or impairment.

[0058] The term "treatment" refers to (1) therapeutic measures that cure, alleviate, reduce, and / or halt the progression of a diagnosed pathological condition or symptom, and (2) preventive or defensive measures that prevent and / or slow the progression of a target pathological condition or symptom. Therefore, those who require treatment include those who already have the condition; those who are predisposed to having the condition; and those among them who require prevention of the condition.

[0059] The terms "effective amount" or "amount effective to" or "therapeutic effective amount" include references to the dosage of a therapeutic agent that is sufficient to produce the desired results.

[0060] "Subject" or "patient" means any subject for diagnosis, prognosis, or treatment, especially mammalian subjects. As used herein, the terms "subject" or "patient" include any human or non-human animal. The term "non-human animal" includes all vertebrates, such as mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cattle, bears, chickens, amphibians, reptiles, etc. As used herein, phrases such as "patient with a type I IFN-mediated disease or disorder" include subjects (e.g., mammalian subjects) who benefit from administration of antibodies or antigen-binding fragments thereof that regulate type I IFN activity for, for example, for detection, imaging, or other diagnostic procedures, and / or who benefit from treatment (i.e., mitigation or prevention) of a disease with such antibodies or antigen-binding fragments thereof.

[0061] Antibody formulation

[0062] In embodiments, the present invention provides stable antibody formulations comprising an anti-IFNAR1 antibody or an antigen-binding fragment thereof. In embodiments, the anti-IFNAR1 antibody is anifrucizumab. In embodiments, the formulations of the present invention comprise both anifrucizumab and its antigen-binding fragment.

[0063] In an embodiment, the antibody formulation of the present invention comprises an antibody or an antigen-binding fragment thereof containing a VH domain sequence comprising 0 to 5 amino acid substitutions from a reference VH having the amino acid sequence SEQ ID NO: 1.

[0064] In embodiments, the antibody formulations of the present invention comprise an antibody or an antigen-binding fragment thereof containing a Vκ domain, the Vκ domain comprising 0-5 amino acid substitutions from a reference Vκ having the amino acid sequence SEQ ID NO: 2.

[0065] In some embodiments, the antibody in the antibody formulation is purified before being added to the antibody formulation. The terms "separation" and "purification" refer to separating the antibody from impurities or other contaminants in the composition in which the antibody is present (e.g., a composition containing host cell proteins). In some embodiments, at least 50%, 70%, 80%, 90%, 95%, 98%, 99%, 99.5%, or 99.9% (w / w) of impurities are purified away from the antibody. For example, in some embodiments, purification of an antibody, such as an anti-IFNAR1 antibody, includes separating the antibody from 99% (w / w) of the host cell proteins initially present in the composition.

[0066] In some embodiments, the terms “separation” and “purification” refer to separating an antibody (e.g., an anti-IFNAR1 antibody) from impurities or other contaminants in the composition to a certain extent in accordance with the guidelines of government organizations (e.g., the World Health Organization or the U.S. Food and Drug Administration).

[0067] Methods for purifying antibodies are known to those skilled in the art. Suitable techniques for carrying out purification include different types of chromatography, such as affinity chromatography, hydrophobic interactions, ion exchange (such as cation exchange chromatography or mixed-mode chromatography), and percolation.

[0068] Affinity chromatography is a separation method that utilizes the specific binding properties of antibodies to bind to their affinity ligands. Functional affinity ligands can be immobilized on a solid or semi-solid support, such that when a composition containing the antibody passes through the ligand and solid support, the antibody with a specific binding affinity for the ligand adsorbs onto the ligand, while one or more other impurities are not adsorbed (or bind with lower affinity) and can be separated from the antibody. Examples of impurities that bind atypically (or poorly) include process-related impurities (e.g., host cell proteins, DNA, culture medium components) and some product-related impurities (e.g., antibody fragments). In some embodiments, the solid support containing the ligand is washed once or multiple times with buffer to remove additional impurities, after which the adsorbed antibody is removed from the ligand and support. After one or more impurities have been removed, the adsorbed antibody can be removed from the ligand and support (eluted), resulting in the separation of the antibody from the original composition. Methods for removing antibodies from ligands and supports depend on the ligands and are known to those skilled in the art, and may include, for example, changes in environmental aspects (e.g., pH), the addition of a dissociative agent or denaturant, or the addition of a commercially available elution buffer. In some embodiments, more than one affinity purification process may be used on the composition. Different affinity ligands are known in the art, including protein A and protein G (and combinations thereof). Immobilization ligands are commercially available. For example, protein A affinity systems include MabSelect, MabSelect SuRe, MabSelect Xtra, MabSelect SuRe LX, Sepaharose CL-4B, ProSep vA, ProSep vA Ultra, and Ceramic HyperD.

[0069] Ion exchange chromatography includes cation exchange chromatography and mixed chromatography. Cation exchange chromatography refers to any method by which antibodies and one or more impurities can be separated based on charge difference using a cation exchange matrix. The cation exchange matrix generally comprises covalently bound negatively charged groups. Weak or strong cation exchange resins can be used. Typically, strong cation exchange resins comprise loaded organic groups containing sulfonic acid or sulfonate groups (depending on pH). Weak cation exchange resins typically comprise loaded organic groups containing carboxylic acid or carboxylic acid ester groups (depending on pH). In some embodiments, multimodal cation exchange resins can be used, which combine additional binding mechanisms with ion interactions, such as one or more of hydrogen bonding and hydrophobic interactions. Examples of suitable cation exchange resins are well known in the art and may include, but are not limited to, Fractogel, carboxymethyl (CM), sulfoethyl (SE), sulfopropyl (SP), phosphate (P), and sulfonate (S), PROPAC WCX-10. TM (Dionex), Capto S, S-crosslinked agarose FF, Fractogel EMDSO3M, Toyopearl MegacapII SP 550C, Poros 50HS, and SP-crosslinked agarose matrix. In some embodiments, more than one cation exchange chromatography process may be used with the composition.

[0070] Mixed-mode chromatography refers to methods that utilize more than one form of interaction between the stationary phase and the analyte to achieve their separation from impurities (e.g., process-related impurities such as host cell proteins, DNA, and / or endogenous or exogenous viruses). Examples of suitable anion exchange matrices are known in the art and may include, but are not limited to, Capto Adhere, Sartobind Q, Natrix Q, Chromasorb Q, and Mustang Q.

[0071] In some embodiments, additional filtration steps may be used to remove impurities. For example, in some embodiments, nanofiltration or ultrafiltration is used. Nanofiltration involves passing a composition through a matrix having pore sizes, for example, less than 75 nm, less than 50 nm, and even less than 15 nm, to separate impurities, such as viruses, from antibodies. Commercially available nanofilters and ultrafilters are manufactured by various suppliers, such as Millipore Corporation (Billelika, Massachusetts, e.g., ViresolvePro and Viresolve Pro+), Pall Corporation (East Hills, NY), GE Healthcare Sciences (Piscataway, NJ), and Sartorius Corporation (Göttingen, Germany).

[0072] In some embodiments, the antibody (e.g., anti-IFNAR, or its antigen-binding fragment) used in the formulations of the present invention comprises the VH sequence defined by Kabat in SEQ ID NO: 1 and the Vκ sequence defined by Kabat in SEQ ID NO: 2, wherein the concentration of the antibody in the formulation is 10 mg / ml to 300 mg / ml, 30 mg / ml to 250 mg / ml, 50 mg / ml to 200 mg / ml, 100 mg / ml to 200 mg / ml, 125 mg / ml to 175 mg / ml, 130 mg / ml to 170 mg / ml, 135 mg / ml to 165 mg / ml, 140 mg / ml to 160 mg / ml, 145 mg / ml to 155mg / mL, 130mg / ml, 135mg / ml, 140mg / ml, 145mg / ml, 146mg / ml, 147mg / ml, 148mg / ml, 149mg / ml, 150mg / ml, 151mg / ml, 152mg / ml, 153mg / ml, 154mg / ml, 155mg / ml, 156mg / ml, 157mg / ml, 158mg / ml, 159mg / ml or 160mg / ml. In some embodiments, the concentration of the antibody is approximately 50 mg / ml, 55 mg / ml, 60 mg / ml, 65 mg / ml, 70 mg / ml, 75 mg / ml, 80 mg / ml, 85 mg / ml, 90 mg / ml, 95 mg / ml, 100 mg / ml, 125 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.

[0073] The antibody formulation of the present invention contains lysine. Lysine is an essential amino acid having the following structure:

[0074]

[0075] As used herein, lysine may include lysine in its free base form, and any and all of its salts. In embodiments, the salt forms of lysine are lysine acetate, lysine monochloride, lysine dichloride, lysine L-aspartate, and lysine L-glutamate. In embodiments, lysine includes its pharmaceutically acceptable salts. For example, lysine will include lysine hydrochloride. As used herein, lysine also includes all enantiomers (e.g., L-lysine and S-lysine), and any combination of enantiomers (e.g., 50% L-lysine and 50% S-lysine; 90%–100% L-lysine and 10%–0% S-lysine, etc.). In some embodiments, the term "lysine" includes greater than 99% L-lysine and less than 1% S-lysine. In some embodiments, the term "lysine" includes enantiomerically pure L-lysine. In some embodiments, lysine is pharmaceutical grade lysine.

[0076] In embodiments, in antibody formulations (e.g., antibody formulations containing 100 mg / mL to 200 mg / mL antibody, or about 150 mg / mL antibody), the antibody formulations of the present invention contain about 10 mM to about 100 mM lysine, about 20 mM to about 90 mM lysine, about 30 mM lysine to about 80 mM lysine, about 40 mM to about 70 mM lysine, about 45 mM to about 65 mM lysine, about 45 mM to about 60 mM lysine, and about 50 mM to about 55 mM lysine. In embodiments, in antibody formulations containing 100 mg / mL to 200 mg / mL antibody, or about 150 mg / mL antibody, uncharged excipients, surfactants, and formulation buffers, the formulations of the present invention contain about 50 mM lysine HCl.

[0077] The antibody formulations of the present invention may comprise uncharged excipients. The term excipient refers to a pharmacologically inactive substance formulated with the antibody described herein. In some embodiments, the excipient may help prevent denaturation or otherwise help stabilize the antibody. Suitable excipients that can be used in pharmaceutical compositions are well known in the art. Examples may be taken, for instance, from the manual: Gennaro, Alfonso R., “Remington’s Pharmaceutical Sciences”, Mack Publishing Company, Easton, PA, 1990. In some embodiments, the excipient is an “uncharged” excipient, meaning the excipient does not carry a positive “+” or negative “-” charge. In some embodiments, the excipient is selected from the group consisting of fructose, glucose, mannose, sorbitol, xylose, lactose, maltose, sucrose, dextran, amylopectin, dextrin, cyclodextrin, soluble starch, trehalose, sorbitol, erythritol, isomaltitol, lactitol, maltitol, xylitol, glycerol, lactitol, hydroxyethyl starch, and water-soluble dextran.

[0078] In some embodiments, in the antibody formulation, the non-charged excipient is about 1 mM to about 1 M, about 2 mM to about 500 mM, about 5 mM to about 400 mM, about 10 mM to about 300 mM, or about 20 mM to about 250 mM. In some embodiments, in antibody formulations (e.g., antibody formulations containing 100 mg / mL to 200 mg / mL of antibody), the uncharged excipient is about 30 mM to about 230 mM, about 40 mM to about 220 mM, about 50 mM to about 210 mM, about 60 mM to about 210 mM, about 70 mM to about 200 mM, about 80 mM to about 190 mM, about 90 mM to about 180 mM, about 100 mM to about 170 mM, about 110 mM to about 160 mM, about 120 mM to about 150 mM, about 125 mM to about 145 mM, about 125 mM to about 140 mM, about 120 mM, about 125 mM, about 130 mM, about 135 mM, about 140 mM, about 150 mM, about 160 mM, or about 170 mM. In one embodiment, the uncharged excipient in the antibody formulation is about 130 mM. In some embodiments, in the antibody formulation (e.g., an antibody formulation containing 100 mg / mL to 200 mg / mL antibody or about 150 mg / mL antibody), the uncharged excipient is about 50 mM to about 500 mM, about 100 mM to about 450 mM, about 110 mM to about 350 mM, about 120 mM, about 125 mM, about 130 mM, about 140 mM, or about 145 mM. In one embodiment, the uncharged excipient in the antibody formulation is about 130 mM.

[0079] In some embodiments, the non-electrolyte is trehalose, as represented by the following chemical formula:

[0080]

[0081] In some embodiments, in the antibody formulation, trehalose is about 1 mM to about 1 M, about 2 mM to about 500 mM, about 5 mM to about 400 mM, about 10 mM to about 300 mM, or about 20 mM to about 250 mM. In some embodiments, in antibody formulations (e.g., antibody formulations containing 100 mg / mL to 200 mg / mL of antibody), trehalose is present in amounts of about 30 mM to about 230 mM, about 40 mM to about 220 mM, about 50 mM to about 210 mM, about 60 mM to about 210 mM, about 70 mM to about 200 mM, about 80 mM to about 190 mM, about 90 mM to about 180 mM, about 100 mM to about 170 mM, about 110 mM to about 160 mM, about 120 mM to about 150 mM, about 125 mM to about 145 mM, about 125 mM to about 140 mM, about 120 mM, about 125 mM, about 130 mM, about 135 mM, about 140 mM, about 150 mM, about 160 mM, or about 170 mM. In one embodiment, the trehalose content in the antibody formulation is about 130 mM. In some embodiments, the trehalose content in the antibody formulation (e.g., an antibody formulation containing 100 mg / mL to 200 mg / mL antibody or about 150 mg / mL antibody) is about 50 mM to about 500 mM, about 100 mM to about 450 mM, about 110 mM to about 350 mM, about 120 mM, about 125 mM, about 130 mM, about 140 mM, or about 145 mM. In one embodiment, the trehalose content in the antibody formulation is about 130 mM.

[0082] Antibody formulations may contain other different components. In some embodiments, antibody formulations may contain buffers (e.g., histidine, acetate, phosphate, or citrate buffers) and / or stabilizers (e.g., human serum albumin). In some embodiments, antibody formulations may contain pharmaceutically acceptable carriers, including, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffering substances (e.g., phosphates), sucrose, glycine, sorbic acid, potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), silica sol, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, polyethylene polyoxypropylene block polymers, and polyethylene glycol.

[0083] In some embodiments, the antibody formulation further comprises a surfactant. In some embodiments, the surfactant is selected from the group consisting of Triton X-100, Tween 80, polysorbate 20, polysorbate 80, nonylbenzene alcohol ether-9, polyoxamer, stearyl alcohol, sodium lauryl sulfate, and sorbitol monostearate.

[0084] In some embodiments, the surfactant is polysorbate 80, namely polyoxyethylene (20) dehydrated sorbitan monooleate, as represented by the following chemical formula:

[0085]

[0086] The sum of w + x + y = 20

[0087] Polysorbate 80 (PS-80) is commercially available from several commercial suppliers, such as... TW 80 Know 80 The applicants have found that, in some cases, controlling the concentration of PS-80 in antibody formulations during prolonged storage increases stability and reduces particle formation.

[0088] In some embodiments, PS-80 is an antibody formulation comprising about 0.01% to about 0.1%, about 0.02% to about 0.09%, about 0.02% to about 0.08%, about 0.03% to about 0.08%, about 0.04% to about 0.07%, about 0.05% to about 0.06%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, or about 0.07% of an antibody formulation, such as an antibody formulation comprising about 100 mg / mL to about 200 mg / mL of antibody, or about 150 mg / mL of antibody. In some embodiments, PS-80 is about 0.05% in the antibody formulation.

[0089] In some embodiments, the antibody formulation further comprises a histidine / histidine HCl buffer. In some embodiments, in the antibody formulation of the present invention (e.g., an antibody formulation comprising 100 mg / mL to 200 mg / mL antibody or about 150 mg / mL antibody), the antibody formulation comprises about 1 mM to about 100 mM, about 5 mM to about 80 mM of histidine / histidine HCl buffer, about 10 mM to about 60 mM of histidine / histidine HCl buffer, about 15 mM to about 50 mM of histidine / histidine HCl buffer, about 15 mM to about 30 mM of histidine / histidine HCl buffer, or about 25 mM of histidine / histidine HCl buffer. In one embodiment, in the antibody formulation, the histidine / histidine HCl buffer is about 25 mM.

[0090] In some embodiments, the present invention relates to an antibody formulation comprising: 150 mg / mL of anifurumab or its antigen-binding fragment; 50 mM of lysine HCl; 130 mM of an uncharged excipient; 0.05% of a surfactant; and 25 mM of a formulation buffer, wherein the formulation is at a pH of about 5.9.

[0091] In some embodiments, the present invention relates to an antibody formulation comprising: 150 mg / mL of anifurumab; 50 mM of lysine HCl; 130 mM of an uncharged excipient; 0.05% of a surfactant; and 25 mM of a formulation buffer, wherein the formulation is at a pH of about 5.9.

[0092] In another embodiment, the present invention relates to an antibody formulation comprising: 150 mg / mL of anifurumab; 50 mM of lysine HCl; 130 mM of trehalose dihydrate; 0.05% of polysorbate 80; and 25 mM of histidine / histidine HCl, wherein the formulation is at a pH of 5.9.

[0093] In some embodiments, the present invention relates to a stable antibody formulation comprising: (a) an antibody or antigen-binding fragment thereof at a concentration of about 100 mg / mL to about 200 mg / mL, wherein the antibody is anifurumab; (b) about 0.02% to about 0.1% of polysorbate-80; (c) about 100 mM to about 160 mM of trehalose; (d) about 40 mM to about 60 mM of L-lysine HCl; and (e) 15-35 mM of histidine / histidine HCl. In the embodiments, the pH of the formulation is about 5.5 to about 6.5.

[0094] In a further embodiment, the present invention relates to a stable antibody formulation comprising: (a) an antibody or antigen-binding fragment thereof at a concentration of about 145 mg / mL to about 155 mg / mL, wherein the antibody is anifurumab; (b) about 0.04% to about 0.08% of polysorbate-80; (c) about 120-140 mM of trehalose dihydrate; (d) about 45-55 mM of L-lysine HCl; and (e) about 20-30 mM of histidine / histidine HCl. In the embodiments, the pH of the formulation is about 5.8 to about 6.1.

[0095] In a further embodiment, the present invention relates to a stable antibody formulation comprising: (a) about 150 mg / mL of an antibody or an antigen-binding fragment thereof, wherein the antibody is anifurumab, (b) about 0.05% polysorbate-80, (c) about 130 mM trehalose dihydrate, (d) about 50 mM L-lysine HCl, and (e) about 25 mM histidine / histidine HCl. In the embodiment, the pH of the formulation is about 5.9.

[0096] In some embodiments, the present invention relates to an antibody formulation comprising: 150 mg / mL of anifurumab or its antigen-binding fragment; 50 mM of lysine HCl; 130 mM of trehalose dihydrate; 0.05% of polysorbate 80; and 25 mM of histidine / histidine HCl, wherein the formulation is at a pH of about 5.9.

[0097] In another embodiment, the present invention relates to an antibody formulation comprising: 150 mg / mL of anifurumab; 50 mM of lysine HCl; 130 mM of trehalose dihydrate; 0.05% of polysorbate 80; and 25 mM of histidine / histidine HCl, wherein the formulation is at a pH of 5.9.

[0098] In some embodiments, different components may be omitted from the antibody formulation, or such components may be "substantially non-existent". As used herein, the term "substantially non-existent" refers to an antibody formulation containing less than 0.01%, less than 0.001%, less than 0.0005%, less than 0.0003%, or less than 0.0001% of a specified component.

[0099] Antibody formulations can have different molar osmolality concentrations. Methods for measuring the molar osmolality concentration of antibody formulations are known to those skilled in the art and may include, for example, an osmometer (e.g., an Advanced Instrument Inc. freezing point depressor). In some embodiments, the formulation has a molar osmolality concentration between 200 and 600 mosm / kg, between 260 and 500 mosm / kg, or between 300 and 450 mosm / kg.

[0100] The antibody formulations of the present invention can have different pH levels. In some embodiments, the pH of the antibody formulation is between 4 and 7, between 4.5 and 6.5, or between 5 and 6. In some embodiments, the pH of the antibody formulation is 5.0. In some embodiments, the pH of the antibody formulation is 6.0. In some embodiments, the pH of the antibody formulation is ≤7.0. The desired pH level can be achieved using various means, including but not limited to adding appropriate buffer solutions.

[0101] The antibody formulations described herein have different viscosities. Methods for measuring the viscosity of antibody formulations are known to those skilled in the art and may include, for example, a rheometer (e.g., an Anton Paar MCR301 rheometer with 50 mm, 40 mm, or 20 mm plate attachments). In some embodiments of the invention, viscosity is reported at a high shear limit of 1000 shear rates per second. In some embodiments, the antibody formulation has a viscosity of less than 20 centipoise (cP), less than 18 cP, less than 15 cP, less than 13 cP, or less than 11 cP. In some embodiments, the antibody formulation has a viscosity of less than 13 cP. Those skilled in the art will understand that viscosity is temperature-dependent, and therefore, unless otherwise stated, the viscosities provided herein were measured at 25°C.

[0102] The injection force is related to the amount of resistance provided by the antibody formulation when it is administered to the subject. The injection force will depend on the size of the injection needle and the temperature. In some embodiments, the antibody formulation has an injection force of less than 15N, 12N, 10N, or 8N when administered through a 27Ga spinal thin-tube (STW) needle. In some embodiments, the antibody formulation has an injection force of less than 15N, 12N, 10N, or 8N when administered through a 29Ga STW needle.

[0103] In another embodiment, the antibody formulation of the present invention is an aqueous solution. In some embodiments, the antibody formulation has not been subjected to freezing temperature and / or has not been frozen, i.e., it remains in a liquid state. In some embodiments, the antibodies in the antibody formulation have not been freeze-dried.

[0104] As used herein, the term "stability" generally refers to maintaining the integrity of a bioactive agent (e.g., a protein, peptide, or another bioactive macromolecule) or minimizing its degradation, denaturation, aggregation, or unfolding. As used herein, "improved stability" generally means, under conditions known to lead to degradation, denaturation, aggregation, or unfolding, greater stability of the protein of interest (e.g., an antibody such as anifurumab), peptide, or other bioactive macromolecule compared to a control protein, peptide, or other bioactive macromolecule.

[0105] In some embodiments, stability refers to an antibody formulation having a particle formation level as low as undetectable. As used herein, the phrase "particle formation level as low as undetectable" means that the sample contains less than 1000 particles / mL, less than 700 particles / mL, less than 650 particles / mL, less than 500 particles / mL, less than 400 particles / mL, less than 200 particles / mL, less than 100 particles / mL, or less than 1 particle / mL (as determined by HIAC analysis or visual analysis), wherein the detected particle size is greater than 10 micrometers after storage at about 40°C for about 18 months. In some embodiments, no particles are detected in the antibody formulation, whether by HIAC analysis or visual analysis.

[0106] In some embodiments, stability refers to reduced antibody fragmentation. In examples, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the fragmentation rate of the antibody (e.g., anifrucizumab) in the formulations of the present invention is approximately 2.0% to 4.0% per month over 12 months. In examples, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the fragmentation rate of the antibody (e.g., anifrucizumab) in the formulations of the present invention is approximately 2.0% to 4.0% per month over 6 months. In examples, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the fragmentation rate of the antibody (e.g., anifrucizumab) in the formulations of the present invention is approximately 2.0% to 4.0% per month over 2 months. In the examples, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the fragmentation rate of the antibody (e.g., anifurumab) in the formulations of the present invention is approximately 3.0% to 4.0% per month over a period of 2 months.

[0107] In further embodiments, stability refers to reduced antibody aggregation. In embodiments, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the aggregation rate of the antibody formulations of the present invention (containing, for example, aniforumab) is approximately 0.5% to 2.5% per month over 12 months. In embodiments, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the aggregation rate of the antibody formulations of the present invention (containing, for example, aniforumab) is approximately 0.5% to 2.5% per month over 6 months. In embodiments, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the aggregation rate of the antibody formulations of the present invention (containing, for example, aniforumab) is approximately 0.5% to 2.5% per month over 2 months. In another embodiment, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the aggregation rate of the antibody formulation of the present invention (containing, for example, anifurumab) is about 1% to 2% per month over a period of 2 months.

[0108] In further embodiments, stability refers to reduced purity loss. In embodiments, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the purity loss rate of the antibody formulations of the present invention (containing, for example, aniforumab) is approximately 3% to 5% per month over 12 months. In embodiments, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the purity loss rate of the antibody formulations of the present invention (containing, for example, aniforumab) is approximately 3% to 5% per month over 6 months. In another embodiment, as determined by HP-SEC analysis performed on an Agilent HPLC system using a TSK-Gel G3000 column, the purity loss rate of the antibody formulations of the present invention (containing, for example, aniforumab) is approximately 3.5% to 4.5% per month over 2 months.

[0109] Those skilled in the art will understand that, in addition to the composition of the formulation, the stability of a protein depends on other properties. For example, stability can be affected by external forms of temperature, pressure, humidity, pH, and radiation. Therefore, unless otherwise stated, the stability mentioned herein is considered to be measured at 40°C, one atmosphere, 50% relative humidity, pH 6.0, and a normal background radiation level. The stability of antibodies in antibody formulations can be determined by various means. In some embodiments, antibody stability is determined by size exclusion chromatography (SEC). SEC separates analytes (e.g., macromolecules such as proteins and antibodies) based on the hydrodynamic size, diffusion coefficient, and surface characteristics of the analytes. Thus, for example, SEC can separate antibodies in their native three-dimensional conformation from antibodies in different denatured states and / or degraded antibodies. In SEC, the stationary phase typically consists of inert particles packed into a dense three-dimensional matrix within a glass or steel column. The mobile phase can be pure water, an aqueous buffer, an organic solvent, a mixture of these substances, or other solvents. The stationary phase particles have small pores and / or channels that will allow only substances smaller than a certain size to enter. Therefore, large particles are excluded from these pores and channels, and smaller particles are removed from the flowing mobile phase. The time it takes for particles to become fixed in the stationary phase pores depends in part on the rate at which particles can penetrate into the pores. The removal of particles from the mobile phase causes them to take longer to elute from the column and results in separation between particles based on differences in particle size.

[0110] In some embodiments, SEC is combined with identification techniques to identify or characterize proteins or fragments thereof. Protein identification and characterization can be accomplished using a variety of techniques, including but not limited to chromatographic techniques (e.g., high-performance liquid chromatography (HPLC)), immunoassays, electrophoresis, UV / Vis / IR spectroscopy, Raman spectroscopy, surface-enhanced Raman spectroscopy, mass spectrometry, gas chromatography, static light scattering (SLS), Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD), urea-induced protein unfolding, intrinsic tryptophan fluorescence, differential scanning calorimetry, and / or ANS protein binding.

[0111] In some embodiments, protein identification is achieved by high-performance liquid chromatography (HPLC). Various instruments and apparatus for performing HPLC are known to those skilled in the art. Typically, HPLC involves loading a liquid solvent containing the protein of interest onto a separation column, where separation occurs. The HPLC separation column is packed with solid particles (e.g., silica, polymers, or adsorbents), and the sample mixture separates into multiple compounds upon interaction with the column particles. HPLC separation is affected by the conditions of the liquid solvent (e.g., pressure, temperature), the chemical interactions between the sample mixture and the liquid solvent (e.g., hydrophobicity, protonation, etc.), and the chemical interactions between the sample mixture and the solid particles packed within the separation column (e.g., ligand affinity, ion exchange, etc.).

[0112] In some embodiments, SEC and protein identification occur in the same device or simultaneously. For example, SEC and HPLC can be combined, often referred to as HP-SEC.

[0113] In some embodiments, the antibody formulation comprises about 100 mg / ml to about 200 mg / ml of an antibody or an antigen-binding fragment thereof, wherein the antibody is anifurumab, and wherein the formulation is stable when stored at about 40°C for 1 to 24 months. In some embodiments, the formulation is stable when stored at about 25°C for 1 to 18 months. In some embodiments, the formulation is stable when stored at about 5°C for 1 to 6 months. In some embodiments, the formulation is stable when stored at about 5°C for 1 to 3 months. In some embodiments, the formulation is stable when stored at about 5°C for 1 to 12 months. In some embodiments, the formulation is stable when stored at about 5°C for at least 18 months. In some embodiments, the formulation is stable when stored at about 5°C for at least 24 or 36 months.

[0114] The term "stable" can be relative rather than absolute. Therefore, in some embodiments, an antibody is considered stable if, when stored at 2°C to 8°C for 6 months, it exhibits less than 20%, less than 15%, less than 10%, less than 5%, or less than 2% antibody degradation, denaturation, aggregation, or unfolding as determined by HP-SEC. In some embodiments, an antibody is considered stable if, when stored at 2°C to 8°C for 12 months, it exhibits less than 20%, less than 15%, less than 10%, less than 5%, or less than 2% antibody degradation, denaturation, aggregation, or unfolding as determined by SEC HPLC. In some embodiments, an antibody formulation is considered stable if, when stored at 2°C to 8°C for 18 months, it exhibits less than 20%, less than 15%, less than 10%, less than 5%, or less than 2% antibody degradation, denaturation, aggregation, or unfolding as determined by HP-SEC. In some embodiments, when the antibody in the antibody preparation is stored at 2°C to 8°C for 24 months, the antibody is stable if less than 20%, less than 15%, less than 10%, less than 5%, or less than 2% of the antibody is degraded, denatured, aggregated, or unfolded as determined by SECHPLC.

[0115] In some embodiments, an antibody is stable if, when stored at 23°C to 27°C for 3 months, it exhibits less than 20%, less than 15%, less than 10%, less than 5%, or less than 2% antibody degradation, denaturation, aggregation, or unfolding as determined by HP-SEC. In some embodiments, an antibody is stable if, when stored at 23°C to 27°C for 6 months, it exhibits less than 20%, less than 15%, less than 10%, less than 5%, or less than 2% antibody degradation, denaturation, aggregation, or unfolding as determined by HP-SEC. In some embodiments, an antibody is stable if, when stored at 23°C to 27°C for 12 months, it exhibits less than 20%, less than 15%, less than 10%, less than 5%, or less than 2% antibody degradation, denaturation, aggregation, or unfolding as determined by HP-SEC. In some embodiments, when the antibody is stored at 23°C to 27°C for 24 months, if less than 20%, less than 15%, less than 10%, less than 5%, or less than 2% of the antibody degrades, denatures, aggregates, or unfolds as determined by HP-SEC.

[0116] In some embodiments, when the antibody is stored at 40°C, it is considered stable if the antibody degradation, denaturation, aggregation, or unfolding is less than 6%, less than 4%, less than 3%, less than 2%, or less than 1% per month as determined by HP-SEC. In some embodiments, when the antibody is stored at 5°C, it is considered stable if the antibody degradation, denaturation, aggregation, or unfolding is less than 6%, less than 4%, less than 3%, less than 2%, or less than 1% per month as determined by HP-SEC.

[0117] In the examples, when the antibody is stored at 5°C, the antibody is stable if, as determined by HP-SEC, there is 1%, 2%, 3%, 4%, 5%, or 6% (or about 1% to 6%) of antibody degradation, denaturation, aggregation, or unfolding per month for 1 to 3 months, 1 to 6 months, 1 to 12 months, 1 to 18 months, or 1 to 24 months.

[0118] In some embodiments, the antibody formulations of the present invention are considered stable if, over a period of 8 weeks, 4 months, 6 months, 9 months, 12 months, or 24 months, as measured by an antibody binding assay known to those skilled in the art, such as an ELISA, the antibody shows virtually no loss of binding activity of the antibody (including its antibody fragments) compared to a reference antibody. In some embodiments, antibodies stored at about 40°C for at least 1 month retain at least 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the binding capacity to the INFAR1 receptor peptide compared to a reference antibody that has not been stored. In some embodiments, antibodies stored at about 5°C for at least 6 months retain at least 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, or at least about 99% of the binding capacity to the INFAR1 receptor peptide compared to a reference antibody that has not been stored. In some embodiments, antibodies stored at about 40°C for at least 1 month retain at least 95% of their binding affinity to the INFAR1 receptor peptide compared to a reference antibody that has not been stored. In some embodiments, antibodies stored at about 5°C for at least 6 months retain at least 95% of their binding affinity to the INFAR1 receptor peptide compared to a reference antibody that has not been stored.

[0119] The applicants have found that the antibody formulations provided herein result in a significant reduction in particle formation, as determined by visual inspection, microfluidic imaging (MFI), or size exclusion chromatography (SEC).

[0120] In some embodiments, as determined by visual inspection, the preparation is substantially free of particles when stored at about 40°C for at least 1 month. In some embodiments, as determined by visual inspection, the preparation is substantially free of particles when stored at about 5°C for at least 6 months, at least 9 months, at least 12 months, at least 15 months, at least 18 months, at least 24 months, or at least 36 months.

[0121] In some embodiments, the antibody formulations of the present invention can be used for pharmaceutical purposes. Antibodies used in pharmaceutical applications must be of high purity, especially in respect of contaminants from cell cultures, including cellular protein contaminants, cellular DNA contaminants, viruses, and other infectious agents. See “WHO Requirements for the use of animal cells as in vitro substrates for the production of biologicals: Requirements for Biological Substances No. 50.” No. 878, Annex 1, 1998. In response to concerns about contaminants, the World Health Organization (WHO) has set limits on the levels of various contaminants. For example, the WHO recommends a DNA limit of less than 10 ng per dose for protein products. Similarly, the U.S. Food and Drug Administration (FDA) sets a DNA limit of less than or equal to 0.5 pg / mg protein. Therefore, in some embodiments, the present invention relates to antibodies that meet or exceed contaminant limits set by one or more government agencies such as the U.S. Food and Drug Administration and / or the World Health Organization.

[0122] In some embodiments, the antibody formulations described herein are pharmaceutically acceptable. “Pharmaceutically acceptable” means an antibody formulation suitable for contact with human and animal tissues to the extent of reasonable medical judgment without excessive toxicity or other complications commensurate with a reasonable benefit / risk ratio.

[0123] The purity of the antibody formulation may vary. In some embodiments, the therapeutic antibody of interest (e.g., anti-IFNAR1 antibody) is greater than 90% (wt / wt) of the total peptide present in the antibody formulation. In some embodiments, the therapeutic antibody of interest (e.g., anti-IFNAR1) is greater than 95% (wt / wt), 98% (wt / wt), 99% (wt / wt), 99.5% (wt / wt), or 99.9% (wt / wt) of the total peptide present in the antibody formulation.

[0124] The present invention further provides a method for treating type I IFN-mediated diseases or disorders in subjects in need by administering a therapeutically effective amount of the antibody formulation described herein. In embodiments, the disease or disorder is selected from the group consisting of: systemic lupus erythematosus (SLE), insulin-dependent diabetes mellitus, inflammatory bowel disease, multiple sclerosis, psoriasis, autoimmune thyroiditis, rheumatoid arthritis, glomerulonephritis, scleroderma, myositis, and lupus nephritis. In further embodiments, the disease or disorder is an inflammatory bowel disease, such as Crohn's disease, ulcerative colitis, and celiac disease. In further embodiments, the disease or disorder is a lung disease or disorder, such as systemic lupus erythematosus.

[0125] The antibody formulations of the present invention can be administered to subjects by various means. In some embodiments, the antibody formulations are suitable for parenteral administration, such as via inhalation (e.g., powder or spray), transmucosal administration, intravenous administration, subcutaneous administration, or intramuscular administration. In some embodiments, the formulations are injectable formulations. In some embodiments, the present invention relates to a sealed container comprising any antibody formulation as described herein.

[0126] In some aspects, the present invention relates to various pharmaceutical dosage forms. Various dosage forms can be applied to the formulations provided herein. See, for example, *Pharmaceutical Dosage Form: Parenteral Medications*, Vol. 1, 2nd edition. In one embodiment, the pharmaceutical unit dosage form of the present invention comprises an antibody formulation in a suitable container (e.g., a vial or syringe). In one embodiment, the pharmaceutical unit dosage form of the present invention comprises an antibody formulation delivered intravenously, subcutaneously, or intramuscularly. In another embodiment, the pharmaceutical unit dosage form of the present invention comprises an antibody formulation delivered by aerosol. In a specific embodiment, the pharmaceutical unit dosage form of the present invention comprises an antibody formulation delivered subcutaneously. In another embodiment, the pharmaceutical unit dosage form of the present invention comprises an antibody formulation delivered by aerosol. In yet another embodiment, the pharmaceutical unit dosage form of the present invention comprises an antibody formulation administered intranasally.

[0127] The antibody formulation of the present invention can be prepared as a unit dosage form by preparing vials containing equal portions of an aqueous antibody formulation for single use. For example, each vial may contain 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, or 20 ml of antibody specifically binding to the IFNAR1 receptor at concentrations ranging from about 0.1 mg / ml to about 300 mg / ml. If necessary, these formulations can be adjusted to the desired concentration by adding a sterile diluent to each vial. In a specific embodiment, the aqueous antibody formulation of the present invention is formulated as a sterile liquid in single-dose vials containing about 2 mg / mL to about 20 mg / mL of an antibody or its antigen-binding fragment, wherein the antibody is anifurumab. In another specific embodiment, the aqueous antibody formulation of the present invention is prepared as a sterile liquid in single-dose vials containing: about 100 mg / mL to about 200 mg / mL of an antibody or its antigen-binding fragment (wherein the antibody is anifulumab), about 45 mM to 55 mM of lysine HCl, about 0.04% to about 0.08% of polysorbate 80, about 120 mM to about 140 mM of trehalose, and about 20-30 mM of histidine / histidine HCl. In an embodiment, the pH of the formulation is about 6. In one embodiment, the antibody of the present invention is provided at 140 to 160 mg / mL in a 3 cc USP Type I borosilicate amber vial (West Pharmaceutical Services, part number 6800-0675). In one embodiment, the antibody of the present invention is provided at 150 mg / mL in a 3 cc USP Type I borosilicate amber vial.

[0128] The antibody formulation of the present invention can be prepared as a unit dosage form by preparing a pre-filled syringe containing equal portions of the aqueous antibody formulation for single use. For example, each pre-filled syringe may contain 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.5 ml, 0.6 ml, 0.7 ml, 0.8 ml, 0.9 ml, 1 ml, 2 ml, 3 ml, 4 ml, 5 ml, 6 ml, 7 ml, 8 ml, 9 ml, 10 ml, 15 ml, or 20 ml of a different concentration of an antibody or antigen-binding fragment specifically binding to the IFNAR1 polypeptide, wherein the concentration range of the antibody or antigen-binding fragment is from about 140 mg / ml to about 160 mg / ml. In a specific embodiment, the aqueous antibody formulation of the present invention is prepared as a sterile liquid in a single-dose pre-filled syringe, the sterile liquid containing: about 145 mg / mL to about 155 mg / mL of an antibody or its antigen-binding fragment (wherein the antibody is anifulumab), about 45 mM to 55 mM of lysine HCl, about 0.04% to about 0.08% of polysorbate 80, about 120 mM to about 140 mM of trehalose, and about 20-30 mM of histidine / histidine HCl. In the embodiment, the pH of the formulation is about 6. In a specific embodiment, the aqueous antibody formulation of the present invention is prepared as a sterile liquid in a single-dose pre-filled syringe, the sterile liquid containing: about 145 mg / mL to about 155 mg / mL of an antibody or its antigen-binding fragment (wherein the antibody is anifulumab), about 45 mM to 55 mM of lysine HCl, about 0.04% to about 0.08% of polysorbate 80, about 120 mM to about 140 mM of trehalose, and about 20-30 mM of histidine / histidine HCl. In the embodiment, the pH of the formulation is about 6.

[0129] Different doses can be administered in a single dose. For example, in some embodiments, antibodies can be administered in single doses of 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 12 mg, 14 mg, 16 mg, 18 mg, 20 mg, 30 mg, 40 mg, 50 mg, 70 mg, or 100 mg.

[0130] Various types of syringes can be used. The syringe can be filled with the antibody formulation immediately before administration to the subject, for example, less than 1 week, 1 day, 6 hours, 3 hours, 2 hours, 1 hour, 30 minutes, 20 minutes, or 10 minutes prior to administration. In some embodiments, the syringe can be filled with the antibody formulation at a retail point or through a facility treating the subject. In some embodiments, the syringe can be prefilled, for example, with the antibody formulation, more than 1 day, 2 days, 4 days, 1 week, 2 weeks, 1 month, 2 months, 3 months, 6 months, 12 months, 18 months, 24 months, 3 years, or 4 years prior to administration to the subject. In some embodiments, the prefilled syringe includes an injection needle, such as a 27G standard thin-tube injection needle, a 27G thin-tube injection needle, a 29G standard thin-tube injection needle, or a 29G thin-tube injection needle. In some embodiments, the prefilled syringe includes a 27G spinal thin-tube injection needle.

[0131] In some embodiments, any syringe suitable for administration to a desired subject may be used. In some embodiments, the syringe is a plastic syringe or a glass syringe. In some embodiments, the syringe is made of a material that is substantially free of tungsten. In some embodiments, the syringe is coated with silicone. In some embodiments, the pre-filled syringe includes a plunger with a fluoropolymer resin disc. Examples of syringes may include, but are not limited to, BD Hypak. TM SCF1MLL 27G1 / 2-5B BD260LWL, 0.4mg silicone oil MDN (with 27GSTW injection needle); Hypak TM For Biotech 1ml Long (Becton Dickinson), featuring the Becton Dickinson Hypak 1mL long plunger stopper 4023 Flurotec Daikyo Si1000 (catalog number 47271919); C3 Pin; Hypak TM Biotech 0.8mg silicone oil (Beddy Company); and CZ syringe (West Company, catalog number 19550807).

[0132] The aqueous antibody formulations of this invention can be sterilized by various sterilization methods, including sterile filtration, radiation, etc. In a specific embodiment, the percolated antibody formulations are sterilized by filtration using a pre-sterilized 0.2-micron filter. The sterilized aqueous antibody formulations of this invention can be administered to subjects to prevent, treat, and / or manage immune responses, such as inflammatory responses.

[0133] The present invention further provides a pre-filled syringe comprising the antibody formulation of the present invention. In some embodiments, the pre-filled syringe comprises (a) about 100 mg / mL to about 200 mg / mL of anti-IFNAR1 antibody, about 25 mM to 130 mM of lysine or lysine salt, an uncharged excipient, a surfactant, and a formulation buffer.

[0134] The present invention further provides a pre-filled syringe comprising the antibody formulation of the present invention. In some embodiments, the pre-filled syringe comprises (a) about 100 mg / mL to about 200 mg / mL of anifurumab or its antigen-binding fragment, about 40 mM to 60 mM of lysine HCl, about 100 mM to about 160 mM of trehalose dihydrate, 0.02% to about 0.1% of polysorbate 80, and about 15 mM to about 35 mM of histidine / histidine HCl. In embodiments, the pH of the formulation is about 5.5 to about 6.5.

[0135] The present invention further provides a pre-filled syringe comprising the antibody formulation of the present invention. In some embodiments, the pre-filled syringe comprises (a) about 145 mg / mL to about 155 mg / mL of anifurumab or its antigen-binding fragment, about 45 mM to 55 mM of lysine HCl, about 120 mM to about 140 mM of trehalose dihydrate, 0.04% to about 0.08% of polysorbate 80, and 20 mM to about 30 mM of histidine / histidine HCl. In the embodiments, the pH of the formulation is about 5.8 to 6.1.

[0136] The present invention further provides a pre-filled syringe comprising the antibody formulation of the present invention. In some embodiments, the pre-filled syringe comprises (a) about 150 mg / mL of an antibody or an antigen-binding fragment thereof (wherein the antibody is anifuluzumab), about 50 mM lysine HCl, about 0.05% polysorbate 80, about 130 mM trehalose dihydrate, and about 25 mM histidine / histidine HCl. In an example, the pH of the formulation is about 5.9.

[0137] The present invention further provides a pre-filled syringe comprising the antibody formulation of the present invention. In some embodiments, the pre-filled syringe comprises (a) about 150 mg / mL of anifurumab, about 50 mM of lysine HCl, about 0.05% of polysorbate 80, about 130 mM of trehalose dihydrate, and about 25 mM of histidine / histidine HCl. In an example, the pH of the formulation is about 5.9.

[0138] In a specific embodiment, the antibody formulation of the present invention is prepared as a sterile liquid in a single-dose pre-filled syringe, the sterile liquid containing: about 145 mg / mL to about 155 mg / mL of an antibody or its antigen-binding fragment (wherein the antibody is anifurumab), about 45 mM to 55 mM of lysine HCl, about 0.04% to about 0.08% of polysorbate 80, about 120 mM to about 140 mM of trehalose, and about 20-30 mM of histidine / histidine HCl. In the embodiment, the pH of the formulation is about 6.

[0139] In one embodiment, the present invention relates to a pre-filled syringe comprising the antibody formulation of the present invention, wherein when equipped with a 27-gauge spinal thin-walled (STW) needle, the pre-filled syringe has an average glide force between 1 N and 20 N. In another embodiment, the present invention relates to a pre-filled syringe comprising the antibody formulation of the present invention, wherein when equipped with a 27-gauge spinal thin-walled (STW) needle, the pre-filled syringe has an average glide force between 5 N and 15 N. In yet another embodiment, the present invention relates to a pre-filled syringe comprising the antibody formulation of the present invention, wherein when equipped with a 27-gauge spinal thin-walled (STW) needle, the pre-filled syringe has an average glide force of approximately 8 N.

[0140] In some embodiments, the present invention relates to a kit comprising any one of the antibody formulations described herein, the containers described herein, the unit dosage forms described herein, or the pre-filled syringes described herein.

[0141] In some embodiments, the present invention may also relate to a method for producing a stable antibody formulation comprising an antibody, the method comprising: (a) purifying an antibody or an antigen-binding fragment thereof to about 100 mg / mL to about 200 mg / mL, wherein the antibody is anifulumab; and (b) placing the isolated antibody in a stabilization formulation to form the stable antibody formulation, wherein the resulting stable antibody formulation comprises: (i) an antibody or an antigen-binding fragment thereof at about 100 mg / mL to about 200 mg / mL, wherein the antibody is anifulumab; and (ii) about 25 mM to about 130 mM of lysine or a lysine salt; (iii) about 100 mM to about 150 mM of trehalose; and (iv) about 0.02% to about 0.1% of polysorbate 80.

[0142] In some embodiments, the present invention may also relate to a method for producing a stable antibody formulation comprising an antibody, the method comprising: (a) purifying an antibody or an antigen-binding fragment thereof to about 100 mg / mL to about 200 mg / mL, wherein the antibody is anifulumab; and (b) placing the isolated antibody in a stabilization formulation to form the stable antibody formulation, wherein the resulting stable antibody formulation comprises: an antibody at about 100 mg / mL to about 200 mg / mL; about 45 mM to about 55 mM of lysine HCl or lysine or a lysine salt; about 100 mM to about 150 mM of an uncharged excipient; about 0.02% to about 0.1% of a surfactant; and a formulation buffer.

[0143] In some embodiments, the present invention may also relate to a method for producing a stable antibody formulation comprising an antibody, the method comprising: (a) purifying an antibody or an antigen-binding fragment thereof to about 145 mg / mL to about 155 mg / mL, wherein the antibody is anifurumab; and (b) placing the isolated antibody in a stabilization formulation to form the stable antibody formulation, wherein the resulting stable antibody formulation comprises: about 145 mg / mL to about 155 mg / mL of antibody; about 25 mM to about 130 mM of lysine or a lysine salt; about 120 mM to about 140 mM of trehalose dihydrate; about 0.04% to about 0.08% of polysorbate 80; about 20 mM to about 30 mM of histidine / histidine HCl, wherein the formulation is at a pH of about 5.8 to 6.1.

[0144] In some embodiments, the present invention relates to a method for preparing a stable antibody formulation, the method comprising (a) purifying an antibody or an antigen-binding fragment thereof to about 150 mg / mL, wherein the antibody is anifulumab; and (b) placing the isolated antibody in a stabilization formulation to form the stable antibody formulation, wherein the resulting stable antibody formulation comprises: (i) about 150 mg / mL of an antibody or an antigen-binding fragment thereof, wherein the antibody is anifulumab; and (ii) about 50 mM of lysine HCl; (iii) about 130 mM of trehalose; and (iv) about 0.05% of polysorbate 80.

[0145] While many aspects of the invention relate to aqueous formulations, it should be noted that, for equivalent purposes, the antibodies or antibody formulations of the invention may be lyophilized, if desired. Therefore, the invention covers lyophilized formulations of the invention, or lyophilized antibodies, which are subsequently rehydrated to an aqueous form. In some embodiments, the invention relates to a method for producing a formulation of an antibody or antigen-binding fragment thereof comprising anifulumab, the method comprising: (a) purifying an antibody from a cell culture; (b) lyophilizing the isolated antibody; and (c) adding the lyophilized antibody to an aqueous solution to form a rehydrated antibody formulation, wherein the rehydrated antibody formulation comprises: (i) an antibody or antigen-binding fragment thereof at a concentration of about 100 mg / mL to about 200 mg / mL, wherein the antibody is anifulumab; and (ii) about 45 mM to about 55 mM of lysine HCl.

[0146] In some embodiments, the present invention relates to antibody formulations comprising an antibody or an antigen-binding fragment thereof, wherein the antibody is anifurumab, and wherein the antibody formulation is substantially free of particles. In some embodiments, the term "substantially free of particles" means that no visible particles are present when observed under a light box. In some embodiments, the term "substantially free of particles" is synonymous with the previously described phrase "low to undetectable particle formation levels." In some embodiments, substantially free of particles means that the sample contains less than 30 particles / mL, less than 20 particles / mL, less than 20 particles / mL, less than 15 particles / mL, less than 10 particles / mL, less than 5 particles / mL, less than 2 particles / mL, or less than 1 particle / mL, wherein the particles are larger than 25 μm and the particle count is determined by HIAC analysis or visual analysis. In some embodiments, substantially free of particles means that the sample contains 1 to 50 particles / mL, 2 to 40 particles / mL, 3 to 30 particles / mL, 4 to 25 particles / mL, or 5 to 20 particles / mL, wherein the particles are larger than 25 μm and the particle count is determined by HIAC analysis or visual analysis. In some embodiments, the term "visible particle" refers to a particle larger than 25 μm.

[0147] In some embodiments, "substantially particle-free" means that the sample contains 1 to 200 particles / mL, 10 to 150 particles / mL, about 30 particles / mL to about 100 particles / mL, or 40 to 80 particles / mL, wherein the particles are larger than 5 μm and the particle count is determined by HIAC analysis or visual analysis. In some embodiments, the term "visible particles" refers to particles larger than 5 μm. In some embodiments, no particles were detected in the antibody formulation, whether by HIAC analysis or visual analysis.

[0148] In some embodiments, the present invention relates to antibody formulations comprising an antibody or an antigen-binding fragment thereof, wherein the antibody is anifurumab, and wherein the antibody formulation is substantially free of particles when stored at 38°C to 42°C for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, or at least 18 months. In some embodiments, the present invention relates to antibody formulations comprising an antibody or an antigen-binding fragment thereof, wherein the antibody is anifurumab, and wherein the antibody formulation is substantially free of particles when stored at 2-6°C for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 8 months, at least 10 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months, or at least 48 months.

[0149] In some embodiments, the present invention relates to a method for purifying an antibody or an antigen-binding fragment thereof, wherein the antibody is anifulumab, the method comprising (i) obtaining a cell culture containing the antibody, (ii) performing affinity chromatography on the antibody, (iv) performing cation exchange on the antibody, and (v) performing mixed-mode chromatography on the antibody.

[0150] In some embodiments, the present invention relates to a method for purifying an antibody or an antigen-binding fragment thereof, wherein the antibody is anifurumab, the method comprising (i) obtaining a cell culture containing the antibody, (ii) binding the antibody to a protein A column, (iii) eluting the antibody from the protein A column, (iv) performing cation exchange on the antibody, and (v) performing mixed-mode chromatography on the antibody. In some embodiments, the method for purifying the antibody further comprises a virus inactivation process. In some embodiments, the virus inactivation step is performed by lowering the pH to less than 4.0. In some embodiments, the method further comprises a percolation process. In some embodiments, the method further comprises a filtration process. In some embodiments, the filtration process is sufficient to remove live viral particles.

[0151] In some embodiments, the present invention relates to methods of treating a patient. In some embodiments, the invention includes administering to a subject in need of the antibody formulation described herein, the container described herein, the unit dosage form described herein, or the pre-filled syringe described herein.

[0152] In some embodiments, the present invention is adapted to treat lung diseases or disorders by administering the antibody formulation described herein. In some embodiments, the present invention relates to a method of treating a patient suffering from eosinophilic disease or disorder by administering the antibody formulation described herein. In some embodiments, the present invention relates to a method of treating a lung disease or disorder in a subject, the method comprising administering the antibody formulation described herein. In some embodiments, the present invention relates to a method of treating a subject with eosinophilic disease or disorder, the method comprising administering the antibody formulation described herein. In some embodiments, the present invention relates to treating the following lung diseases or disorders in subjects: for example, asthma, COPD, eosinophilic asthma, eosinophilic and neutrophilic combined asthma, aspirin-sensitive asthma, allergic bronchopulmonary aspergillosis, acute and chronic eosinophilic bronchitis, acute and chronic eosinophilic pneumonia, Qiu Shier syndrome, hypereosinophilic syndrome, drug-, irritant-, and radiation-induced pulmonary eosinophilia, infection-induced pulmonary eosinophilia (fungal, tuberculosis, parasite), autoimmune-related pulmonary eosinophilia, eosinophilic esophagitis, or Crohn's disease or combinations thereof, the method comprising administering the antibody formulation described herein. In some embodiments, the present invention relates to treating asthma in subjects, the method comprising administering the antibody formulation described herein. In some embodiments, the present invention relates to treating COPD in subjects, the method comprising administering the antibody formulation described herein.

[0153] In some embodiments, a therapeutically effective amount of the antibody formulation described herein is administered to treat a condition. As used herein, the term "therapeutically effective amount" refers to an amount of therapy (e.g., an antibody that specifically binds to an IFNAR1 receptor peptide) sufficient to reduce the severity of a disease or disorder (e.g., a disease or disorder characterized by aberrant expression and / or activity of an IFNAR1 peptide, a disease or disorder characterized by aberrant expression and / or activity of an IFNAR1 receptor or one or more subunits thereof, an autoimmune disease, an inflammatory disease, a proliferative disease, or an infection or one or more symptoms thereof), reduce the duration of the condition, alleviate one or more symptoms of such a disease or disorder, prevent the progression of such a disease or disorder, cause the remission of such a disease or disorder, or enhance or improve the therapeutic effect of another therapy. In some embodiments, the therapeutically effective amount cannot be specified in advance and may be determined by a caregiver (e.g., by a physician or other healthcare provider) using various methods (e.g., dose adjustment). An appropriate therapeutically effective amount may also be determined by routine experimental use, for example, animal models.

[0154] The terms "therapies" and "therapy" can refer to any one or more regimens, methods, and / or agents that can be used to prevent, treat, manage, or alleviate a disease or disorder (e.g., a disease or disorder characterized by aberrant expression and / or activity of an IFNAR1 peptide, a disease or disorder characterized by aberrant expression and / or activity of an IFNAR1 receptor or one or more subunits thereof, an autoimmune disease, an inflammatory disease, a proliferative disease, or an infection (preferably a respiratory infection) or one or more symptoms thereof). In some embodiments, the terms "therapies" and "therapy" refer to biological therapies, supportive therapies, and / or other therapies known to a skilled medical person that can be used to treat, manage, prevent, or alleviate such a disease or disorder or one or more symptoms.

[0155] As used herein, the term "treatment regimen" refers to a plan for arranging the dosage and timing of administering one or more therapeutic agents (e.g., therapeutic agents) that have a therapeutic effect.

[0156] The antibody formulation of the present invention can be administered via, for example, oral, parenteral, inhalation, or topical administration. As used herein, parenteral administration includes, for example, intravenous, intra-arterial, intraperitoneal, intramuscular, subcutaneous, rectal, or vaginal administration. In some embodiments, the antibody is an anti-IFNAR1 antibody, and the route of administration is intramuscular injection. While all these forms of administration are clearly conceivable to be within the scope of the invention, in some embodiments, the antibody formulation is suitable for administration by injection, particularly via intravenous or intra-arterial injection or infusion.

[0157] In some embodiments, the compositions and methods of the present invention enable manufacturers to produce antibody formulations suitable for human administration in a more efficient manner, or by reducing costs, reducing process steps, reducing the chance of errors, reducing the chance of introducing unsafe or inappropriate additives, reducing waste, increasing shelf life, and so on.

[0158] Example

[0159] The invention will now be described with reference to the following examples. These examples are merely illustrative, and the invention should in no way be construed as limited to these examples, but rather as encompassing any and all variations that become apparent as a result of the teachings provided herein.

[0160] Example 1

[0161] Materials and methods

[0162] Material

[0163] All materials used were USP or multicompendial grade. All solutions and buffers were prepared using USP or HPLC-grade water and filtered before further use. Samples for stability studies were prepared under aseptic conditions in a biosafety cabinet (BSC). Bulk materials were stored at 2–8°C. Stability studies were conducted using the supplies listed in Table 3.

[0164] Table 3

[0165]

[0166] Protein concentration determination

[0167] Protein concentration was determined by measuring absorbance at 280 nm using an Agilent UV-Vis spectrophotometer using a procedure adapted from SOP DV-6233. The measured extinction coefficient was 1.39 (mg / mL) - cm⁻¹. For the sample, a density correction factor was applied for sugar- or non-sugar formulations according to TD-0025.

[0168] Cone and plate viscosity measurement

[0169] Viscosity was measured using an Anton Paar MCR301 rheometer with cone and plate attachments. To minimize the required volume, a single, repeated measurement was performed using a 20 mm cone for screening purposes. Results were recorded at the high shear limit at a shear rate of 1000 rpm.

[0170] Purity was determined by size exclusion chromatography (HPSEC).

[0171] SEC analysis was performed on an Agilent HPLC system equipped with a TSK-Gel G3000 according to the current Formulation Sciences guidelines.

[0172] Visual appearance

[0173] Visual inspection of samples is performed by using particle standards and guidelines adapted from the standard operating procedure: Visual Appearance Evaluation of Protein Drug Substance and Drug Product, to detect the particles, color, and clarity of samples in their respective containers.

[0174] Studies evaluating the effects of excipient levels on stability and viscosity

[0175] To investigate the effects of concentration, trehalose level, and lysine HCl level (factors) on stability and viscosity (response), an experimental design approach was used. Box-Behnken designs were prepared using JMP 9.1 software (SAS, Inc., Cary, NATRO). The designs included the following factors: concentration (from 100 mg / mL to 200 mg / mL); trehalose level (from 0 to 211 mM); and lysine HCl level (from 25 mM to 130 mM). Based on previous formulation stability data from the first cycle of the formulation, the pH was set at 6.0. The polysorbate level was set at 0.02%. Based on preliminary high-throughput viscosity screening studies, a low lysine level was defined as 25 mM, where a significant decrease in viscosity was observed in the 0–25 mM lysine HCl range at high concentrations (see Example 2). Stability was evaluated by accelerated stability studies at 40 °C and by visual appearance and purity assessment using HP-SEC (monomer loss, aggregation, fragmentation) as readings. The subvisible particle count was also measured at 5°C after 1.8 months, but no further analysis was performed because no meaningful differences were observed between the samples.

[0176] Robustness of lysine HCl levels and its effect on viscosity spectra

[0177] A stock solution of approximately 200 mg / mL MEDI-546 was prepared in 25 mM histidine / histidine HCl, 25 mM lysine HCl (note: this is the low lysine HCl range), and 130 mM trehalose dihydrate (pH 6.0), and used to prepare a series of dilutions with 0.02% polysorbate 80. Concentrations and viscosities were measured and plotted. The nominal formulation conditions (50 mM lysine HCl) were also prepared and measured. A 0.5 M lysine HCl stock solution was prepared to spike the MEDI-546 stock solution to the nominal 50 mM lysine level. The same dilution and formulation were performed, and viscosities and concentrations were measured.

[0178] Evaluation of the functionality of the lead formulation in a 27Ga STW prefilled syringe

[0179] Pre-filled syringe (“PFS”) (BD Hypak SCF 1MLL 27G1 / 2-SB); 0.4 mg of silicone oil MDN (with a 27G STW thin-tube injection needle) was filled with 150 mg / mL MEDI-546 in 25 mM histidine / histidine HCl, 50 mM lysine HCl, 130 mM trehalose dihydrate, and 0.05% polysorbate 80 (pH 5.9). The viscosity of this batch was measured to be 9.4 mPas, and the concentration was 150.7 mg / mL. The BD Hypak SCF 1MLL 4023 FLUR Daikyo SI1000 stopper was a vacuum stopper. The slippage performance was measured to be 260 mm / min using an Instron 5542 (Norwood, MA 02062). In addition, three analysts assessed injection time with or without the use of arthritis simulation gloves (arthritis gloves from Georgia Tech Research Institute and injection trainers from Limbs & Things in the UK).

[0180] Example 2

[0181] Summary of High-Throughput Viscosity Screening Results

[0182] High-throughput viscosity screening using nanoparticles. In short, nanoparticles of known size are measured in water (known viscosity) and a sample (unknown viscosity), and the ratio is used to determine the unknown viscosity of the sample. This data is collected for screening and trending purposes, not for absolute viscosity determination.

[0183] Figure 1 The HTS screening results for viscosity versus pH are shown. The results indicate that viscosity increases with increasing pH. Based on the effect of pH on viscosity and possible Dorman-type effects during TFF, we determined that the formulation pH should be selected at 5.9. Further robustness testing is needed around pH effects for PFS development. Viscosity versus lysine HCl HTS screening results ( Figure 2 The results showed a significant decrease in viscosity from 0 to 25 mM lysine HCl. Hands-on laboratory observations of sample preparation also indicated that samples without lysine were more viscous and harder to handle at higher concentrations. Therefore, the experiment was started with 25 mM lysine HCl as a low level.

[0184] Example 3

[0185] Overall assessment of the stability and viscosity results of the formulation

[0186] Table 4 summarizes the viscosity and accelerated stability results of the antibody formulations. Table 5 summarizes the subvisible particle results (by HIAC) of the formulations after 1.8 months at 5°C. Overall, the purity loss at 40°C was acceptable, ranging from 3.8% to 4.8% per month. Fragmentation rates ranged from 2.8% to 3.4% per month, and aggregation rates ranged from 0.7% to 2.0% per month. Visual inspection after 1 month at 40°C indicated similar properties for all formulations (particle size standard 1 for all formulations, clarity <III or II, color Y6). Subvisible particle (HIAC) data showed that all samples had less than 670 particles / mL, with particle sizes greater than 10 μm. Viscosities ranged from 2.8 to 39.7 mPas for all formulations. Several 150 mg / mL formulations showed acceptable viscosity values.

[0187] Further analysis of the data in the following examples shows how to use and interpret this data to select appropriate and robust formulations that maximize stability while providing acceptable viscosity.

[0188]

[0189] Table 4 - Summary of viscosity and accelerated stability results of the formulation

[0190]

[0191] Table 5 - Summary of subvisible particle results of the formulation after 1.8 months at 5°C

[0192] Example 4

[0193] Analysis of Results

[0194] Table 6 summarizes the interpretations and conclusions drawn from the data:

[0195] Table 6 - Output of the significance of factors in the measurement response

[0196]

[0197] Based on the analytical results, the formulation with 150 mg / mL MEDI-546 was further evaluated in 25 mM histidine / histidine HCl, 50 mM lysine HCl, 130 mM trehalose dehydrate, 0.05% polysorbate 80, and pH 5.9.

[0198] Example 6

[0199] Confirmation of antibody formulation viscosity and syringe functionality

[0200] Ideally, the slip force of a pre-filled syringe should be as low as possible to ensure functionality. In this work, our target is a viscosity less than 20 mPas and a slip force less than 15 N. Previous experience has shown that acceptable slip performance is achieved for formulations with a nominal viscosity less than 15 mPas when equipped with a 27 Ga thin-tube injection needle. Up to 20 mPas is feasible in 27 Ga STWPFS. Robustness should be included in both the formulation and the slip force to account for variability in the syringe and the formulation.

[0201] In this section, we present additional data demonstrating the robustness of the formulation viscosity versus concentration profile compared to the low-range (25 mM) lysine HCl formulation. The glide slope performance and injection time feasibility of the nominal formulation in 27Ga STW PFS are also evaluated in this section.

[0202] Robustness of lysine HCl levels and its effect on viscosity spectra

[0203] A series of dilutions of MEDI-546 from 100 mg / mL to 200 mg / mL were prepared in two formulations. These contained MEDI-546 in 25 mM histidine / histidine HCl, 130 mM trehalose dehydrate, and 0.02% polysorbate 80 (pH 6.0), as well as 25 mM or 50 mM lysine HCl. Viscosity profiles are shown below. Figure 3 As shown. The results showed that the viscosity of formulations with low (25 mM) and nominal (50 mM) lysine levels was acceptable at 150 mg / mL (<15 mPas), and both were below approximately 20 mPas at 165 mg / mL. Therefore, the results confirm that, in terms of viscosity properties, the nominal level of 50 mM lysine HCl is appropriately within the 25 mM lower limit range. Based on the effect of pH on viscosity and possible Dorman-type effects during TFF, the pH of the antibody formulation was chosen to be 5.9.

[0204] Functional assessment of antibody formulations in pre-filled syringes

[0205] Table 7 presents the results of the functional evaluation of the formulation containing 150 mg / mL MEDI-546 in 25 mM histidine / histidine HCl, 50 mM lysine HCl, 130 mM trehalose dehydrate, and 0.05% polysorbate 80 (pH 5.9).

[0206] The force required to inject the MEDI-546 drug product was within acceptable limits. Table 8 presents the results of user injection assessments (laboratory analysts). Users reported 'injection force was easy'; 'arthritis gloves made APFS difficult to handle'; 'SSI device worked'. Some variability in injection speed was noted based on new users using the injection trainer and gloves (note: injection force was not considered an issue). These results indicate that the formulation is suitable for PFS with a 27Ga STW injection needle. These studies did not identify any issues regarding the viscosity of the antibody formulation.

[0207] Table 7 - Functional Evaluation of Antibody Formulations

[0208] Repeat Release force (N) Average glide force (N) Maximum glide force (N) Absolute maximum force (N) 1 8.0 7.3 8.0 8.5 2 7.0 8.7 9.1 9.1 3 7.8 7.7 8.2 8.5

[0209] Table 8 - User Injection Time Assessment

[0210]

[0211] Example 7

[0212] The effect of lysine and protein on viscosity

[0213] As shown in Table 9 and Figure 4 As shown, the viscosity changes of lysine solutions at different concentrations as the protein (anifulumab) concentration varied were measured.

[0214] Table 9

[0215]

[0216] As shown in Table 10 and Figure 5 As shown, the viscosity changes of antibody (anifulumab) solutions at different concentrations were measured as the protein concentration varied.

[0217] Table 10

[0218]

[0219] The examples shown above illustrate various aspects of the invention and the practice of the inventive method. These examples are not intended to provide an exhaustive description of the many different embodiments of the invention. Therefore, although the invention has been described in considerable detail by means of description and examples for the purpose of clarity, those skilled in the art will readily recognize that many variations and modifications can be made without departing from the spirit or scope of the appended claims.

[0220] All publications, patents and patent applications mentioned in this specification are incorporated herein by reference as if each individual publication, patent or patent application were specifically and individually indicated to be incorporated herein by reference. <110> DEPAZ, ROBERTO DEJESUS, NATALIE BEE, JARED <120> Stable anti-IFNAR1 formulations <130> IFNAR-350WO1 <140> 62 / 207,164 <141> 08 / 19 / 2015 <160> 2 <170> PatentIn version 3.5 <210> 1 <211> 117 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthetic peptides <400> 1 Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Glu 1 5 10 15 Ser Leu Lys Ile Ser Cys Lys Gly Ser Gly Tyr Ile Phe Thr Asn Tyr 20 25 30 Trp Ile Ala Trp Val Arg Gln Met Pro Gly Lys Cys Leu Glu Ser Met 35 40 45 Gly Ile Ile Tyr Pro Gly Asp Ser Asp Ile Arg Tyr Ser Pro Ser Phe 50 55 60 Gln Gly Gln Val Thr Ile Ser Ala Asp Lys Ser Ile Thr Thr Ala Tyr 65 70 75 80 Leu Gln Trp Ser Ser Leu Lys Ala Ser Asp Thr Ala Met Tyr Tyr Cys 85 90 95 Ala Arg His Asp Ile Glu Gly Phe Asp Tyr Trp Gly Arg Gly Thr Leu 100 105 110 Val Thr Val Ser Ser 115 <210> 2 <211> 108 <212> PRT <213> Artificial sequence <220> <223> Description of artificial sequences: Synthetic peptides <400> 2 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Phe Phe Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Leu Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Thr Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asp Ser Ser Ala 85 90 95 Ile Thr Phe Gly Gln Gly Thr Arg Leu Glu Ile Lys 100 105

Claims

1. An antibody formulation comprising: a) Anifrucizumab at concentrations of 145 mg / mL to 155 mg / mL; b) 45 mM to 55 mM lysine HCl; c) 120 mM to 140 mM trehalose dihydrate; d) 0.04% to 0.08% of polysorbate 80; e) 20mM to 30mM histidine / histidine HCl The preparation is at a pH ranging from 5.8 to 6.

1.

2. An antibody formulation comprising: a) 150 mg / mL anifurumab; b) 50 mM lysine HCl; c) 130 mM trehalose dihydrate; d) 0.05% polysorbate 80; e) 25mM histidine / histidine HCl The preparation is at a pH of 5.

9.

3. The antibody formulation as described in claim 1 or 2, wherein the formulation is suitable for intravenous, subcutaneous or intramuscular administration.

4. A sealed container containing an antibody preparation as described in any one of claims 1 to 3.

5. A pharmaceutical unit dosage form suitable for parenteral administration to humans, the pharmaceutical unit dosage form comprising an antibody formulation as described in any one of claims 1 to 3 in a suitable container.

6. The drug unit dosage form of claim 5, wherein the antibody formulation is suitable for intravenous, subcutaneous or intramuscular administration.

7. The drug unit dosage form of claim 5, wherein the suitable container is a pre-filled syringe.

8. Use of the antibody formulation as described in claim 1 or 2 in the preparation of a medicament for the treatment of systemic lupus erythematosus or lupus nephritis in subjects in need of it.

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