Highly concentrated liquid antibody formulation

Abstract

The present disclosure describes high-concentration liquid formulations of pharmaceutically active antigen-binding proteins, such as monoclonal antibodies. Such formulations comprise, in addition to the antigen-binding protein, at least 80 mM of a buffer and at least 80 mM of a stabilizer. Additionally, the present disclosure relates to pharmaceutical formulations of anti-IL-17C antibodies, and provides methods of making and using such formulations. [Selection diagram] None

Description

[Technical field]

[0001] The present disclosure describes high concentration liquid formulations of pharma- ceutical active antigen binding proteins, such as monoclonal antibodies. Such formulations contain, in addition to the antigen binding protein, at least 80 mM of a buffer and at least 80 mM of a stabilizer. Additionally, the present disclosure relates to pharmaceutical formulations of anti-IL-17C antibodies, and provides methods of making and using such formulations. [Background technology]

[0002] The use of antibodies in medicine has increased in recent years. In many cases, such antibodies are injected via the intravenous (IV) route. Alternative routes of administration are subcutaneous and intramuscular injections, which may offer advantages in terms of patient compliance and ease of administration. However, these injection routes require high protein concentrations in the final solution injected.

[0003] It is therefore desirable to provide a highly concentrated and stable pharmaceutical formulation of a therapeutically effective antigen-binding protein, such as an antibody, for subcutaneous injection. The advantage of subcutaneous injection is that it can be performed by a medical professional with relatively short interaction with the patient. Furthermore, patients can be trained to administer subcutaneous injections themselves. Such self-administration is particularly useful during maintenance administration, as it does not require hospital care (reducing the use of medical resources).

[0004] However, due to the very limited volume for subcutaneous injection, these protein concentrations are now greater than 100 mg / mL, revealing several challenges related to protein stability, protein-protein interactions, and increased viscosity. Viscosity is not only an issue for the biophysical and biochemical properties of therapeutic proteins, but also for the delivery and manufacturing of such highly concentrated protein solutions. The higher the viscosity of the solution, the longer it takes to inject such a viscous solution through a syringe or needle. Thus, the injectability property is affected by viscosity and needs to be considered during the development of highly concentrated liquid formulations. Many of the commercially available autoinjectors are limited to solution viscosities below 20 cP. Thus, in the development of highly concentrated liquid formulations of therapeutic antibodies, viscosity becomes a very important factor with respect to the manufacturing and respective delivery of the product.

[0005] To address these issues, the development of suitable pharmaceutical compositions is of utmost importance.

[0006] However, specific antibodies have properties such as undesirable self-interactions that make them unsuitable for high concentration formulations. This tendency to self-interact can lead to oligomerization, aggregation, and high viscosity at high protein concentrations. Several assays are available to detect and quantify antibody self-interactions, such as self-interaction chromatography and determination of diffusion interaction parameters. For example, Publicover and Vincze (US Pat. No. 7,514,938 B2) describe the use of dielectric relaxation spectroscopy (DRS) to study the interaction and aggregation of micron and submicron scale particles coated with proteins, including antibodies. Holman et al. (US Pat. App. Pub. No. 20070291265 A1) describe a bifurcated fiber optic system that measures light scattering and concentration signals to measure macromolecular aggregation. Obrezanova et al. (mAbs, 7(2):352-363, 2015) describe the systematic measurement of the aggregation tendency of over 500 antibodies using size-exclusion high performance liquid chromatography (SE-HPLC) and an oligomer detection assay, an optical density microtiter plate antibody capture assay. Geoghegan et al. (mAbs, 8(5):941-950, 2016) describe the use of hydrophobic interaction chromatography (HIC) retention time, affinity capture SINS, and dynamic light scattering to measure monoclonal antibody self-interactions, viscosity, and stability. An overview of current methods used to assess colloidal protein interactions is provided by Geng et al. (J Pharm Sci., 103(11):3356-3363, 2014).

[0007] There is therefore a need to develop highly concentrated formulations of antibodies that have a tendency to self-interact. Summary of the Invention

[0008] The present disclosure provides a pharmaceutical formulation for an antigen-binding protein comprising an antigen-binding protein, a buffer, and a stabilizer. More specifically, the present disclosure provides a pharmaceutical formulation for an antigen-binding protein comprising about 100-250 mg / mL of the antigen-binding protein, about 80-120 mM of a buffer providing a pH of about 5.0-7.0, and about 80-120 mM of a stabilizer. In another embodiment, the antigen-binding protein has a tendency to self-interact.

[0009] In one aspect, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising about 100-250 mg / mL, 125-200 mg / mL, 130-180 mg / mL, 140±10 mg / mL, 150±10 mg / mL, 160±10 mg / mL, 170±10 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL of the antigen binding protein.

[0010] In another aspect, the disclosure provides a pharmaceutical formulation for an antigen-binding protein comprising about 100-250 mg / mL of the antigen-binding protein, about 80-120 mM of a buffering agent, and about 80-120 mM of a stabilizer. In another aspect, the concentration of the buffering agent is about 90-110 mM, and the concentration of the stabilizer is about 90-110 mM.

[0011] In another aspect, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising about 100-250 mg / mL of antigen binding protein, about 80-120 mM histidine buffer, and about 80-120 mM stabilizer. In another aspect, the histidine buffer concentration is about 100 mM. In a further aspect, the histidine buffer concentration is 100 mM. In another aspect, the histidine buffer is histidine hydrochloride. In another aspect, the pharmaceutical formulation has a pH of about 5.0 to about 7.0. In another aspect, the pharmaceutical formulation has a pH of 6.0. In another aspect, the antigen binding protein has a tendency to self-interact.

[0012] In one aspect, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising the antigen binding protein, a buffer and a stabilizer. In another aspect, the stabilizer is an amino acid. In a further aspect, the amino acid is arginine.

[0013] In one aspect, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising the antigen binding protein, a buffer and arginine. In another aspect, the arginine concentration is about 100 mM. In a further aspect, the arginine concentration is 100 mM.

[0014] In one aspect, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising an antigen binding protein, a buffer, a stabilizer, and further comprising about 0.005-0.05% (weight / volume) of a non-ionic surfactant. In another aspect, the non-ionic surfactant is polysorbate 20 or polysorbate 80. In a further aspect, the concentration of polysorbate 20 or polysorbate 80 is about 0.02% (weight / volume).

[0015] In one aspect, the disclosure provides pharmaceutical formulations for the antigen binding proteins for subcutaneous or intramuscular administration. In another aspect, the disclosure provides pharmaceutical formulations for the antigen binding proteins in liquid, reconstituted, lyophilized or spray dried form.

[0016] In another embodiment, the antigen binding protein has a tendency to self-interact.

[0017] In another embodiment, the antigen binding protein is a monoclonal antibody.

[0018] In one aspect, the disclosure provides a pharmaceutical formulation for an antigen binding protein, where the antigen binding protein is an antibody. In another aspect, the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody has a tendency to self-interaction.

[0019] WO 2017 / 140831 discloses antibodies that bind to IL-17C and inhibit binding of IL-17C to its receptor across relevant species (e.g., human, mouse, cynomolgus monkeys). Such antibodies have proven effective in various in vivo mouse models for atopic dermatitis and psoriasis.

[0020] In one aspect, the disclosure provides a pharmaceutical formulation for an IL-17C antibody. In one aspect, the IL-17C antibody binds to human IL-17C (SEQ ID NO: 1). In another aspect, the IL-17C antibody comprises heavy and light chain variable regions comprising amino acid sequences 90% identical to SEQ ID NOs: 16 and 17, respectively. In another aspect, the IL-17C antibody comprises heavy and light chain variable regions comprising amino acid sequences according to SEQ ID NOs: 16 and 17, respectively.

[0021] In one aspect, the present disclosure provides an injection device comprising a pharmaceutical formulation according to the present disclosure.

[0022] In another aspect, the disclosure provides a method of treating a disease or condition in a subject suitable for treatment with an IL-17C antibody, the method comprising administering to the subject a formulation according to the disclosure in an amount effective to treat the disease or condition. In one aspect, the disease or condition is an inflammatory disease or disorder.

[0023] In another aspect, the disclosure provides a kit comprising one or more vials containing a formulation according to the disclosure and instructions for subcutaneously administering the formulation to a patient.

[0024] In another aspect, the present disclosure provides an injection device comprising a stable anti-IL-17C antibody formulation described herein.

[0025] In another aspect, the present disclosure provides a pharmaceutical formulation according to the present disclosure for therapeutic use, such as for the treatment of inflammatory disorders such as rheumatoid arthritis, psoriasis, pulmonary inflammation, COPD, and / or for the treatment of atopic dermatitis (AD), including moderate to severe AD. [Brief description of the drawings]

[0026] [Figure 1] Summary of the experimental procedure for the BLI-based self-interaction assay: (1) baseline step, (2) loading step with the mAb of interest ([antibody] = 25 nM), (3) quenching step with human Fc fragment (1 μM), and (4) association reaction ([antibody] = 2 μM). The horizontal axis indicates the time course of the assay. [Diagram 2] Overview of the three-step DoE approach leading to a high protein concentration formulation of MAB#1 [Diagram 3] Response contour plot of self-interaction tendency. Formulations contained only histidine-HCl based buffer without surfactant. [Figure 4] Response contour plot of monomer content (right). Formulations contained only histidine-HCl-based buffer without surfactant. [Diagram 5] Enrichment procedure and SEC analysis of the evaluation test performed after the first screening. Enrichment was performed on a laboratory scale by centrifugation at 1500 × g using CentriPrep Ultracel YM-30 (Merck Millipores). [Figure 6] Response contour plots of self-interaction tendency and monomer content (right) of the second experimental design for optimizing a histidine hydrochloride-based formulation. [Figure 7] Response contour plot of monomer content for the second experimental design for optimizing a histidine hydrochloride-based formulation. [Figure 8] Response contour plots of changes in monomer content for the third experimental design for optimizing histidine hydrochloride-based formulations with respect to surfactant and arginine concentrations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Definitions and Further Explanation It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, compositions or biological systems, which can, of course, vary, and the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.

[0028] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a polypeptide" includes a combination of two or more polypeptides, and the like.

[0029] As used herein, "about" when referring to measurable values ​​such as amounts, durations, etc., means to encompass ±20% or ±10% variations from the specified value, including ±5%, ±1%, and ±0.1%, as such variations are appropriate for carrying out the disclosed methods. 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 disclosure pertains. Although any methods and materials similar or equivalent to those described herein can be practically used to test the present disclosure, the preferred materials and methods are described herein, and the following terms will be used in describing and claiming the present disclosure.

[0030] The term "pharmaceutical formulation" or "formulation" refers to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation will be administered. Such a formulation is sterile. A "sterile" formulation is sterile or free of all live microorganisms and their spores.

[0031] The term "viscosity" refers to the internal resistance to flow exhibited by a fluid at a specified temperature and is the ratio of shear stress to shear rate. A liquid has a viscosity of 1 poise if a force of 1 dyne / square centimeter causes two parallel liquid surfaces, each with an area of ​​1 square centimeter and spaced 1 square centimeter apart, to move past each other at a velocity of 1 cm / sec. 1 poise is equal to 100 centipoise. In one embodiment, the viscosity of the formulation, including buffers and stabilizers, is less than about 50 cP, less than about 45 cP, less than about 40 cP, less than about 35 cP, less than about 30 cP, less than about 25 cP, less than about 20 cP, less than about 15 cP, or less than about 10 cP.

[0032] When referring to apparent viscosity, it is understood that the viscosity value depends on the conditions under which the measurement is performed, such as temperature, shear rate, and shear stress used. Apparent viscosity is defined as the ratio of shear stress to the applied shear rate. There are many alternative methods for measuring apparent viscosity. For example, viscosity can be tested by a suitable cone-plate, parallel plate, or other type of viscometer or rheometer.

[0033] A "histidine buffer" is a buffer that contains the amino acid histidine. Examples of histidine buffers include histidine hydrochloride, histidine acetate, histidine phosphate, and histidine sulfate.

[0034] "Isotonic" means that the formulation has essentially the same osmotic pressure as human blood; an isotonic formulation will generally have an osmotic pressure of about 250-350 mOsm. Isotonicity can be measured using a vapor pressure or freezing point depression type osmometer.

[0035] In certain embodiments, the pharmaceutical formulation according to the present disclosure includes a stabilizer. Stabilizers include, but are not limited to, human serum albumin (HSA), bovine serum albumin (BSA), α-casein, globulin, α-lactalbumin, LDH, lysozyme, myoglobin, ovalbumin, and RNAase A. Additionally, stabilizers include amino acids and their metabolites, such as glycine, alanine (α-alanine, β-alanine), arginine, betaine, leucine, lysine, glutamic acid, aspartic acid, proline, 4-hydroxyproline, sarcosine, γ-aminobutyric acid (GABA), opines (alanopine, octopine, strombine), and trimethylamine N-oxide (TMAO). In one embodiment, the stabilizer is an amino acid. In one embodiment, the amino acid is arginine. In one embodiment, the arginine concentration is about 80-120 mM. In one embodiment, the arginine concentration is about 100+ / -20 mM.

[0036] In certain embodiments, the pharmaceutical formulation according to the present disclosure comprises a non-ionic surfactant. Non-ionic surfactants include, but are not limited to, polyoxyethylene sorbitan fatty acid esters (such as polysorbate 20 and polysorbate 80), polyethylene-polypropylene copolymers, polyethylene-polypropylene glycols, polyoxyethylene stearates, polyoxyethylene alkyl ethers such as polyoxyethylene monolauryl ether, alkylphenyl polyoxyethylene ethers (Triton-X), polyoxyethylene-polyoxypropylene copolymers (poloxamers, Piuronic), and sodium dodecyl sulfate (SDS). In one embodiment, the non-ionic surfactant is polysorbate 20 or polysorbate 80. In one embodiment, the concentration of polysorbate 20 or polysorbate 80 is about 0.005-0.04% (weight / volume). In one embodiment, the concentration of polysorbate 20 or polysorbate 80 is about 0.02% (weight / volume). In one embodiment, the non-ionic surfactant is polysorbate 20.

[0037] In certain embodiments, the pharmaceutical formulation according to the present disclosure further comprises a metal chelator. Metal chelators include, but are not limited to, EDTA and EGTA. In one embodiment, the metal chelator is EDTA. In one embodiment, the EDTA concentration is about 0.01 to about 0.02 mM. In one embodiment, the EDTA concentration is about 0.05 mM.

[0038] As used herein, the terms "self-interaction" and "self-association" are interchangeable and refer to the non-specific binding of a particular protein to one or more identical proteins. The term non-specific refers to binding by weak forces. Self-association is "non-specific" when two or more identical complete antibodies form reversible or irreversible dimers, trimers, or higher order multimers through electrostatic, van der Waals, or hydrophobic interactions. In a preferred embodiment, the self-association is reversible. An antigen-binding protein, such as an antibody or antibody fragment, is considered to have a tendency to self-interact when the value of kD (diffusion interaction parameter) is less than 0 mL / g. In one embodiment, an antigen-binding protein with a tendency to self-interact has a kD (diffusion interaction parameter) less than 0 mL / g, or less than -5 mL / g, or less than -10 mL / g, or less than -15 mL / g, or less than -20 mL / g. In one embodiment, an antigen-binding protein with a tendency to self-interact has a kD (diffusion interaction parameter) of about -23 mL / g. In one embodiment, the antigen binding protein with a tendency to self-interact has a kD (diffusion interaction parameter) of less than 0 mL / g, or less than -5 mL / g, or less than -10 mL / g, or less than -15 mL / g, or less than -20 mL / g in phosphate buffered saline. In one embodiment, the antigen binding protein with a tendency to self-interact has a kD (diffusion interaction parameter) of about -23 mL / g in phosphate buffered saline. Preferably, the kD (diffusion interaction parameter) is measured in phosphate buffered saline using the dynamic light scattering method described in Connolly et al., 2012, Biophys. J. Vol. 103 or Menzen et al., 2014, J. Pharm. Sci., Vol. 103.

[0039] In one embodiment, the antigen binding protein is a monoclonal antibody or fragment thereof. In one embodiment, the monoclonal antibody or fragment thereof is murine, chimeric, humanized, or fully human. In one embodiment, the monoclonal antibody or fragment thereof binds to IL-17C.

[0040] In one aspect, the pharmaceutical formulations of the present disclosure are stable upon freezing and thawing. A "stable" formulation is one in which all of the proteins therein essentially retain their physical and / or chemical stability and / or biological activity when stored at the intended storage temperature, e.g., 2-8°C. It is desirable for the formulation to essentially retain its physical and chemical stability, as well as its biological activity, upon storage. In general, the storage period is selected based on the intended shelf life of the formulation. In addition, the formulation should be stable after freezing (e.g., at -70°C) and thawing the formulation, e.g., after 1, 2 or 3 cycles of freezing and thawing. A variety of analytical techniques for measuring protein stability are available in the art and are reviewed, for example, in Peptide and Protein Drug Delivery', 247-301, Vincent Lee Ed., Marcel Dekker, Inc., New York, NY, Pubs. (1991) and Jones, A. Adv. Drug Delivery Rev. 10:29-90 (1993). Stability can be measured at a selected temperature for a selected period of time. Stability can be assessed qualitatively and / or quantitatively in a variety of ways, including, for example, assessment of aggregate formation (e.g., using size exclusion chromatography, by measuring turbidity, and / or by visual inspection), assessment of charge heterogeneity using cation exchange chromatography or capillary zone electrophoresis, N- or C-terminal sequence analysis, mass spectrometry, SDS-PAGE analysis to compare reduced and intact antibodies, peptide map (e.g., trypsin or LYS-C) analysis, assessment of antibody biological activity or antigen-binding function, etc.

[0041] In one embodiment, the pharmaceutical formulation of the present disclosure is suitable for subcutaneous or intramuscular administration.

[0042] "IL-17C" refers to the protein known as interleukin 17C (identified by the HUGO Human Genome Nomenclature Committee as ID 5983 and by the Mouse Genome Informatics (MGI) database as ID 2446486). IL-17C has been called CX2 or IL-21 in some older publications. However, it should not be confused with the IL-21 cytokine, which is specifically expressed in activated CD4+ T cells but not in most other tissues (Parrish-Novak et al (2000). Nature 408(6808):57-63). Human IL-21 is located on chromosome 4 and is identified in the HGNC database by ID 6005.

[0043] Human IL-17C is located on chromosome 16 and has the amino acid sequence (UniProt Q9P0M4): MTLLPGLLFLTWLHTCLAHHDPSLRGHPHSHGTPHCYSAEELPLGQAPPHLLARGAKWGQALPVALVSSLEAASHRGRHERPSATTQCPVLRPEEVLEADTHQRSISPWRYRVDTDEDRYPQKLAFAECLCRGCIDARTGRETAALNSVRLLQSLLVLRRRPCSRDGSGLPTPGAFAFHTEFIHVPVGCTCVLPRSV (SEQ ID NO: 1).

[0044] Mouse IL-17C has the amino acid sequence (UniProt Q8K4C5): MSLLLLGWLPTGMTHQDPPSWGKPRSHRTLRCYSAEELSHGQAPPHLLTRSARWEQALPVALVASLEATGHRRQHEGPLAGTQCPVLRPEEVLEADTHERSISPWRYRIDTDENRYPQKLAVAECLCRGCINAKTGRETAALNSVQLLQSLLVLRRQPCSRDGTADPTPGSFAFHTEFIRVPVGCTCVLPRSTQ (sequence number 4).

[0045] Cynomolgus IL-17C has the amino acid sequence (XP_005592825.1): MTLLPGLLFLTWLHACLAHQDPFLRGHPHTHGTPRCYSAEELPLGQAPPHLLARGAKWGQALPVALVSSLEAAGHRRRHDRPSAATQCPVLRPEEVLEADTHQRSISPWRYRVDTDEDRYPQKLAFAECLCRGCIDPRTGRETAALNSVRLLQSLLVLRRRPCSRDGSGLPTPGAFAFHTEFIRVPVGCTCVLPRSV (sequence number 5).

[0046] The term "IL-17RA" refers to a protein known as interleukin-17 receptor A. Human IL-17RA has the amino acid sequence (UniProt Q96F46): (Sequence Number 2).

[0047] The term "IL-17RE" refers to a protein known as interleukin-17 receptor E. Human IL-17RE has the amino acid sequence (UniProt Q8NFR9): (SEQ ID NO:3)

[0048] The mouse IL-17RE has the amino acid sequence (UniProt Q8BH06): (Sequence number 6).

[0049] As used herein, the term "antibody" refers to a protein that includes at least two heavy chains (H) and two light chains (L) that are interconnected by disulfide bonds that interact with an antigen. Each heavy chain is composed of a heavy chain variable region (hereinafter abbreviated as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (hereinafter abbreviated as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL has three CDRs and four FRs arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with an antigen. The constant region of the antibody may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (C1q) of the classical complement system. The term "antibody" includes, for example, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, and chimeric antibodies. Antibodies may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Both the light and heavy chains are divided into regions of structural and functional homology.

[0050] As used herein, the phrase "antibody fragment" refers to one or more portions of an antibody that retain the ability to specifically interact with an antigen (e.g., by binding, steric hindrance, stabilization of spatial distribution). Examples of binding fragments include, but are not limited to, Fab fragments, which are monovalent fragments consisting of the VL, VH, CL and CH1 domains; F(ab)2 fragments, which are bivalent fragments containing two Fab fragments linked by disulfide bridges at the hinge region; Fd fragments consisting of the VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single arm of an antibody; dAb fragments consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity determining regions (CDRs). Furthermore, the two domains VL and VH of the Fv fragment are encoded by separate genes, but can be linked by a synthetic linker that allows these domains to be produced as a single protein chain using recombinant methods. The VL and VH domains pair to form a monovalent molecule known as a single-chain Fv (scFv). See, e.g., Bird et al., (1988) Science 242:423-426 and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879-5883. Such single chain antibodies are also intended to be encompassed within the term "antibody fragment." These antibody fragments can be obtained using conventional techniques known to those of skill in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antibody fragments can also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136).Antibody fragments can be grafted onto polypeptide-based scaffolds such as fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies). Antibody fragments can be incorporated into single-chain molecules that contain a pair of tandem Fv segments (VH-CH1-VH-CH1) that form a pair of antigen-binding sites together with complementary light chain polypeptides (Zapata et al., (1995) Protein Eng. 8:1057-1062 and U.S. Pat. No. 5,641,870).

[0051] As used herein, "human antibodies" or "human antibody fragments" include antibodies and antibody fragments having variable regions in which both the framework and CDR regions are derived from sequences of human origin. Human antibodies can also be isolated from synthetic libraries or transgenic mice (e.g., xenomouse), provided that the respective system produces antibodies in the form of antibodies having variable regions in which both the framework and CDR regions are equivalent to sequences of human origin.

[0052] Furthermore, if the antibody contains a constant region, the constant region is also derived from such sequences, including, for example, antibodies that contain human germline sequences, or variants of human germline sequences, or consensus framework sequences derived from the analysis of human framework sequences, for example, as described in Knappik et al., (2000) J Mol Biol 296:57-86.

[0053] The structure and location of immunoglobulin variable domains, e.g., CDRs, can be defined using well-known numbering schemes, such as the Kabat numbering scheme, the Chothia numbering scheme, or a combination of Kabat and Chothia (e.g., Sequences of Proteins of Immunological Interest, USDepartment of Health and Human Services (1991), eds. Kabat et al.; Lazikani et al., (1997) J. Mol. Bio. 273:927-948); Kabat et al., (1991) Sequences of Proteins of Immunological Interest, 5th edit., NIH Publication no. 91-3242 USDepartment of Health and Human Services; Chothia et al., (1987) J. Mol. Biol. 196:901-917; Chothia et al., (1989) Nature 106:111-115; 342:877-883, and Al-Lazikani et al., (1997) J. Mol. Biol. 273:927-948).

[0054] A "humanized antibody" or "humanized antibody fragment" is defined herein as an antibody molecule having constant antibody regions derived from sequences of human origin, and only the variable antibody regions or parts thereof, or the CDRs, are derived from another species. For example, a humanized antibody can be CDR-grafted, in which the CDRs of the variable domain are of non-human origin, while one or more frameworks of the variable domain are of human origin, and the constant domains (if present) are of human origin.

[0055] The term "chimeric antibody" or "chimeric antibody fragment" is defined herein as an antibody molecule having constant antibody regions derived from or corresponding to sequences found in one species and variable antibody regions derived from another species. Preferably, the constant antibody regions are derived from or correspond to sequences found in humans and the variable antibody regions (e.g. VH, VL, CDR or FR regions) are derived from sequences found in a non-human animal, such as mouse, rat, rabbit or hamster.

[0056] The term "isolated antibody" refers to an antibody or antibody fragment that is substantially free of other antibodies or antibody fragments with different antigen specificity. Furthermore, an isolated antibody or antibody fragment may be substantially free of other cellular material and / or chemicals. Thus, in some aspects, the antibody provided is an isolated antibody separated from antibodies with different specificities. An isolated antibody may be a monoclonal antibody. An isolated antibody may be a recombinant monoclonal antibody. However, an isolated antibody that specifically binds to a target epitope, isoform, or variant may have cross-reactivity to other related antigens, such as antigens from other species (e.g., species homologs).

[0057] As used herein, the term "recombinant antibody" includes all antibodies prepared, expressed, created or isolated by means that are not naturally occurring, such as antibodies isolated from host cells transformed to express the antibody, antibodies selected and isolated from recombinant combinatorial human antibody libraries, and antibodies prepared, expressed, created or isolated by any other means including splicing all or part of a human immunoglobulin gene, sequence to other DNA sequences, or antibodies isolated from animals (e.g., mice) transgenic or transchromosomal for human immunoglobulin genes or hybridomas prepared therefrom. Preferably, such recombinant antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies can be subjected to in vitro mutagenesis (or in vivo somatic mutagenesis, when animals transgenic for human Ig sequences are used) such that the amino acid sequences of the VH and VL regions of the recombinant antibodies, while derived from and related to human germline VH and VL sequences, are sequences that may not naturally exist within the human antibody germline repertoire in vivo. The recombinant antibodies can be monoclonal antibodies. In one embodiment, the antibodies and antibody fragments disclosed herein are isolated from the Ylanthia® antibody library disclosed in U.S. Patent Application No. 13 / 321,564 or U.S. Patent Application No. 13 / 299,367, both of which are incorporated herein by reference.

[0058] As used herein, the term "monoclonal antibody" refers to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a unique binding site having a unique binding specificity and affinity for a particular epitope.

[0059] The terms "antagonist of IL-17C" and "IL-17C antagonist" are used interchangeably herein and refer to any molecule that inhibits the activity or function of IL-17C. The term "IL-17C antagonist" includes, but is not limited to, an antibody or antibody fragment that specifically binds to IL-17C. Preferably, the IL-17C antagonist of the present disclosure is an antibody specific for human IL-17C. Such an antibody may be any type of antibody, such as a mouse antibody, a rat antibody, a chimeric antibody, or a humanized antibody.

[0060] The term "IL-17C-specific antagonist antibody" or "IL-17C-specific antagonist antibodies" refers to an antibody or antibody fragment that specifically binds to IL-17C. More preferably, the IL-17C antagonist is an antibody or antibody fragment, such as a monoclonal antibody, that specifically binds to IL-17C and inhibits binding of IL-17C to its receptors, including IL-17RE and IL-17RA. Such an antibody may be any type of antibody, such as a mouse antibody, a rat antibody, a chimeric antibody, or a humanized antibody.

[0061] As used herein, the terms "binds specifically to", "specifically binds to", "is specific to / for" or "specifically recognize" refer to a measurable and reproducible interaction, such as binding between a target and an antibody, in the presence of a population of different molecules, including biomolecules, that determines the presence of the target. For example, an antibody that specifically binds to a target (which may be an epitope) is an antibody that binds to this target with higher affinity, avidity, more readily, and / or with a longer duration than the antibody binds to other targets. For example, a standard ELISA assay can be performed to determine specific binding. Scoring can be done with standard color development (e.g., secondary antibody with horseradish peroxidase and tetramethylbenzidine using hydrogen peroxide). The reaction of some wells is scored by optical density, for example at 450 nm. A typical background (=negative reaction) can be OD 0.1. A typical positive reaction can be OD 1. This means that the difference between positive / negative can be more than 10-fold. Typically, the determination of binding specificity is performed by using a single reference antigen as well as a set of about three to five unrelated antigens, such as milk powder, BSA, transferrin, etc.

[0062] The "percent identity" between a query amino acid sequence and a subject amino acid sequence is the "identity" value calculated by the BLASTP algorithm when the subject amino acid sequence has 100% query coverage with respect to the query amino acid sequence after performing a pairwise BLASTP alignment, expressed as a percentage. Such pairwise BLASTP alignment between the query amino acid sequence and the subject amino acid sequence is performed using the default settings of the BLASTP algorithm available on the National Center for Biotechnology Institute website, with the filter for low complexity regions turned off. Importantly, the query amino acid sequence may be described by an amino acid sequence identified in one or more claims herein.

[0063] The query sequence may be 100% identical to the subject sequence or may contain up to a certain integer number of amino acid modifications relative to the subject sequence such that the percent identity is less than 100%. For example, the query sequence is at least 50, 60, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to the subject sequence. Such modifications include deletions, substitutions (including conservative and non-conservative substitutions), or insertions of at least one amino acid, said modifications being either individually among the amino acids in the query sequence or interspersed in one or more contiguous groups within the query sequence, at the amino-terminal or earboxy-terminal positions of the query sequence, or anywhere between these terminal positions.

[0064] In one embodiment, the present disclosure is directed to an injection device comprising a stable anti-IL-17C antibody formulation as described herein. For subcutaneous delivery, the formulation can be administered via a suitable device, such as (but not limited to) a syringe, an injection device (e.g., INJECT-EASE™ and GENJECT™ devices), an infusion pump (e.g., Accu-Chek™, etc.), a pen-type injector (e.g., GENPEN™, etc.), a needleless device (e.g., MEDDECTOR™ and BIOJECTOR™).

[0065] The pharmaceutical formulation of the pharmaceutical active anti-IL-17C antibody according to the present disclosure can be administered as a subcutaneous injection, which is repeated several times at time intervals of 1, 2, 3, or 4 weeks. In one embodiment, the pharmaceutical formulation of the pharmaceutical active anti-IL-17C antibody is administered once a week or once every two weeks. The entire amount of the injection is administered within a time period of 1 to 10 minutes, preferably 2 to 6 minutes, and most preferably 1 to 3 minutes in most cases.

[0066] Embodiment In one embodiment, the disclosure provides a pharmaceutical formulation for an antigen-binding protein comprising the antigen-binding protein, a buffer and a stabilizer. More specifically, the disclosure provides a pharmaceutical formulation for an antigen-binding protein comprising about 100-250 mg / mL of the antigen-binding protein, about 100 mM of a buffer providing a pH of about 5.0 to about 7.0, and about 100 mM of a stabilizer. In another aspect, the antigen-binding protein has a tendency to self-interact.

[0067] In one embodiment, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising about 100-250 mg / mL, 125-200 mg / mL, 130-180 mg / mL, 140±10 mg / mL, 150±10 mg / mL, 160±10 mg / mL, 170±10 mg / mL, 140 mg / mL, 150 mg / mL, 160 mg / mL, 170 mg / mL of antigen binding protein. In a further embodiment, the pharmaceutical formulation comprises the antigen binding protein and comprises 140 mg / mL of antigen binding protein, about 100 mM of buffering agent providing a pH of about 5.0 to about 7.0, and about 100 mM of stabilizer. In a further embodiment, the pharmaceutical formulation comprises the antigen binding protein and comprises 150 mg / mL of antigen binding protein, about 100 mM of buffering agent providing a pH of about 5.0 to about 7.0, and about 100 mM of stabilizer. In a further embodiment, the pharmaceutical formulation comprises the antigen binding protein and comprises 160 mg / mL of antigen binding protein, about 100 mM buffering agent providing a pH of about 5.0 to about 7.0, and about 100 mM stabilizer.

[0068] In another embodiment, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising about 100-250 mg / mL of antigen binding protein, about 100 mM histidine buffer, and about 100 mM stabilizer. In a further embodiment, the histidine buffer concentration is 100 mM. In a further embodiment, the histidine buffer is histidine hydrochloride. In another embodiment, the pharmaceutical formulation has a pH of about 5.0 to about 7.0. In another aspect, the pharmaceutical formulation has a pH of 6.0. In another embodiment, the antigen binding protein has a tendency to self-interact. In another embodiment, the stabilizer is an amino acid. In a further aspect, the amino acid is arginine. In another embodiment, the arginine concentration is about 100 mM. In a further embodiment, the arginine concentration is 100 mM. In one embodiment, the pharmaceutical formulation further comprises about 0.005-0.05% (weight / volume) of a non-ionic surfactant. In another embodiment, the non-ionic surfactant is polysorbate 20 or polysorbate 80. In a further embodiment, the concentration of polysorbate 20 or polysorbate 80 is about 0.02% (weight / volume).

[0069] In another embodiment, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising about 100-250 mg / mL of antigen binding protein, about 100 mM histidine buffer, and about 100 mM arginine. In a further embodiment, the histidine buffer concentration is 100 mM. In a further embodiment, the histidine buffer is histidine hydrochloride. In a further embodiment, the arginine concentration is 100 mM. In another embodiment, the pharmaceutical formulation has a pH of about 5.0 to about 7.0. In another aspect, the pharmaceutical formulation has a pH of 6.0. In another embodiment, the antigen binding protein has a tendency to self-interact. In a further embodiment, the pharmaceutical formulation further comprises about 0.005-0.05% (weight / volume) of a non-ionic surfactant. In another embodiment, the non-ionic surfactant is polysorbate 20 or polysorbate 80. In a further embodiment, the concentration of polysorbate 20 or polysorbate 80 is about 0.02% (weight / volume). In another embodiment, the concentration of polysorbate 20 or polysorbate 80 is 0.02% (weight / volume).

[0070] In one embodiment, the disclosure provides a pharmaceutical formulation for the antigen binding protein for subcutaneous or intramuscular administration.

[0071] In one embodiment, the disclosure provides a pharmaceutical formulation for an antigen binding protein, wherein the antigen binding protein is an antibody or an antibody fragment thereof. In another embodiment, the antibody is a monoclonal antibody or an antibody fragment thereof. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency to self-interact. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency to self-interact characterized by a kD (diffusion interaction parameter) value of less than -5 mL / g, or less than -10 mL / g, or less than -15 mL / g, or less than -20 mL / g. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency to self-interact characterized by a kD (diffusion interaction parameter) value of less than -5 mL / g, or less than -10 mL / g, or less than -15 mL / g, or less than -20 mL / g. wherein the kD values ​​were measured in phosphate buffered saline using dynamic light scattering as described in Connolly et al., 2012, Biophys. J. Vol. 103 or Menzen et al., 2014, J. Pharm. Sci., Vol. 103. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency for self-interaction characterized by a kD (diffusion interaction parameter) value of about -23 mL / g. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency for self-interaction characterized by a kD (diffusion interaction parameter) value of -23 mL / g.

[0072] In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency to self-interact in phosphate buffered saline. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency to self-interact characterized by a kD (diffusion interaction parameter) value of less than -5 mL / g, or less than -10 mL / g, or less than -15 mL / g, or less than -20 mL / g in phosphate buffered saline. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency to self-interact characterized by a kD (diffusion interaction parameter) value of less than -5 mL / g, or less than -10 mL / g, or less than -15 mL / g, or less than -20 mL / g in phosphate buffered saline, where the kD value was measured in phosphate buffered saline using dynamic light scattering as described in Connolly et al., 2012, Biophys. J. Vol. 103 or Menzen et al., 2014, J. Pharm. Sci., Vol. 103. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency to self-interaction characterized by a kD (diffusion interaction parameter) value of about -23 mL / g in phosphate buffered saline. In another embodiment, the monoclonal antibody or antibody fragment thereof has a tendency to self-interaction characterized by a kD (diffusion interaction parameter) value of -23 mL / g in phosphate buffered saline.

[0073] In another embodiment, the antibody or antibody fragment thereof is an isolated antibody or antibody fragment thereof or a recombinant antibody or antibody fragment thereof. In another embodiment, the monoclonal antibody or antibody fragment thereof is a human antibody or antibody fragment, a humanized antibody or antibody fragment, or a chimeric antibody or antibody fragment.

[0074] In one embodiment, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising about 100-250 mg / mL of antigen binding protein, about 100 mM histidine buffer, and about 100 mM arginine, wherein the antigen binding protein is an IL-17C antibody or antibody fragment thereof. In a further embodiment, the histidine buffer is histidine hydrochloride. In one embodiment, the IL-17C antibody or antibody fragment thereof binds to human IL-17C (SEQ ID NO: 1). In another embodiment, the IL-17C antibody or antibody fragment thereof comprises heavy and light chain variable regions comprising amino acid sequences 90% identical to SEQ ID NOs: 16 and 17, respectively. In another aspect, the IL-17C antibody or antibody fragment thereof comprises heavy and light chain variable regions comprising amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chains comprising amino acid sequences 90% identical to SEQ ID NOs: 18 and 19, respectively. In another aspect, the IL-17C antibody comprises a heavy chain and a light chain comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In a further embodiment, the histidine buffer concentration is 100 mM. In a further embodiment, the histidine buffer is histidine hydrochloride. In a further embodiment, the arginine concentration is 100 mM. In another embodiment, the pharmaceutical formulation has a pH of about 5.0 to about 7.0. In another aspect, the pharmaceutical formulation has a pH of 6.0. In a further embodiment, the pharmaceutical formulation further comprises about 0.005 to 0.05% (weight / volume) of a non-ionic surfactant. In another embodiment, the non-ionic surfactant is polysorbate 20 or polysorbate 80. In a further embodiment, the concentration of polysorbate 20 or polysorbate 80 is about 0.02% (weight / volume). In another embodiment, the concentration of polysorbate 20 or polysorbate 80 is 0.02% (weight / volume).

[0075] In one embodiment, the disclosure provides a pharmaceutical formulation for an antigen binding protein comprising 100-250 mg / mL of antigen binding protein, 100 mM histidine buffer, and 100 mM arginine, wherein the antigen binding protein is an IL-17C antibody or antibody fragment thereof. In one embodiment, the IL-17C antibody or antibody fragment thereof binds to human IL-17C (SEQ ID NO: 1). In another embodiment, the IL-17C antibody or antibody fragment thereof comprises heavy and light chain variable regions comprising amino acid sequences 90% identical to SEQ ID NOs: 16 and 17, respectively. In another aspect, the IL-17C antibody or antibody fragment thereof comprises heavy and light chain variable regions comprising amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chains comprising amino acid sequences 90% identical to SEQ ID NOs: 18 and 19, respectively. In another aspect, the IL-17C antibody comprises heavy and light chains comprising amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In a further embodiment, the histidine buffer concentration is 100 mM. In a further embodiment, the histidine buffer is histidine hydrochloride. In a further embodiment, the arginine concentration is 100 mM. In another embodiment, the pharmaceutical formulation has a pH of about 5.0 to about 7.0. In another aspect, the pharmaceutical formulation has a pH of 6.0. In a further embodiment, the pharmaceutical formulation further comprises about 0.005 to 0.05% (weight / volume) of a non-ionic surfactant. In another embodiment, the non-ionic surfactant is polysorbate 20 or polysorbate 80. In a further embodiment, the concentration of polysorbate 20 or polysorbate 80 is about 0.02% (weight / volume). In another embodiment, the concentration of polysorbate 20 or polysorbate 80 is 0.02% (weight / volume).

[0076] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody or antibody fragment thereof, wherein the formulation comprises: a) about 100 to 250 mg / mL of an IL-17C antibody or an antibody fragment thereof b) about 100 mM histidine buffer that gives a pH of about 5.0 to about 7.0 c) about 100 mM arginine, and d) Approximately 0.005 to 0.05% (weight / volume) of a nonionic surfactant

[0077] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody or antibody fragment thereof, wherein the formulation comprises: a) about 100 to 250 mg / mL of an IL-17C antibody or an antibody fragment thereof b) about 100 mM histidine buffer that gives a pH of about 5.0 to about 7.0 c) about 100 mM arginine, and d) about 0.02% (weight / volume) of a nonionic surfactant

[0078] In one embodiment, the non-ionic surfactant is polysorbate 20 or polysorbate 80.

[0079] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody or antibody fragment thereof, wherein the formulation comprises: a) 100 to 250 mg / mL of an IL-17C antibody or an antibody fragment thereof b) 100 mM histidine buffer giving a pH of 6.0 ± 0.2 c) 100 mM arginine, and d) 0.005 to 0.05% (weight / volume) of a nonionic surfactant

[0080] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody or antibody fragment thereof, wherein the formulation comprises: a) 100 to 250 mg / mL of an IL-17C antibody or an antibody fragment thereof b) 100 mM histidine buffer giving a pH of 6.0 ± 0.2 c) 100 mM arginine, and d) 0.02% (weight / volume) of a non-ionic surfactant

[0081] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody or antibody fragment thereof, wherein the formulation comprises: a) 100 to 250 mg / mL of an IL-17C antibody or an antibody fragment thereof b) 100 mM histidine buffer giving a pH of 6.0 ± 0.2 c) 100 mM arginine, and d) 0.02% (weight / volume) polysorbate 20

[0082] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody or antibody fragment thereof, wherein the formulation comprises: a) 100 to 250 mg / mL of an IL-17C antibody or an antibody fragment thereof b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine, and d) 0.005 to 0.05% (weight / volume) of a nonionic surfactant

[0083] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody or antibody fragment thereof, wherein the formulation comprises: a) 100 to 250 mg / mL of an IL-17C antibody or an antibody fragment thereof b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine, and d) 0.02% (weight / volume) of a non-ionic surfactant

[0084] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody or antibody fragment thereof, wherein the formulation comprises: a) 100 to 250 mg / mL of an IL-17C antibody or an antibody fragment thereof b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine, and d) 0.02% (weight / volume) polysorbate 20

[0085] In one embodiment, the IL-17C antibody or antibody fragment thereof binds to human IL-17C (SEQ ID NO: 1). In another embodiment, the IL-17C antibody or antibody fragment thereof comprises an HCDR1 region comprising the amino acid sequence of SEQ ID NO: 7, an HCDR2 region comprising the amino acid sequence of SEQ ID NO: 8, an HCDR3 region comprising the amino acid sequence of SEQ ID NO: 9, an LCDR1 region comprising the amino acid sequence of SEQ ID NO: 13, an LCDR2 region comprising the amino acid sequence of SEQ ID NO: 14, and an LCDR3 region comprising the amino acid sequence of SEQ ID NO: 15. In another embodiment, the IL-17C antibody or antibody fragment thereof comprises an HCDR1 region of the amino acid sequence of SEQ ID NO: 7, an HCDR2 region of the amino acid sequence of SEQ ID NO: 8, an HCDR3 region of the amino acid sequence of SEQ ID NO: 9, an LCDR1 region of the amino acid sequence of SEQ ID NO: 13, an LCDR2 region of the amino acid sequence of SEQ ID NO: 14, and an LCDR3 region of the amino acid sequence of SEQ ID NO: 15. In another embodiment, the IL-17C antibody or antibody fragment thereof comprises heavy and light chain variable regions comprising amino acid sequences 90% identical to SEQ ID NOs: 16 and 17, respectively. In another aspect, the IL-17C antibody or antibody fragment thereof comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chains comprising amino acid sequences that are 90% identical to SEQ ID NOs: 18 and 19, respectively. In another aspect, the IL-17C antibody comprises heavy and light chains comprising amino acid sequences according to SEQ ID NOs: 18 and 19, respectively.

[0086] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) 100-250 mg / mL IL-17C antibody b) 100 mM histidine buffer giving a pH of 6.0 ± 0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0087] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 140 mg / mL b) 100 mM histidine buffer giving a pH of 6.0 ± 0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0088] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 150 mg / mL b) 100 mM histidine buffer giving a pH of 6.0 ± 0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0089] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 160 mg / mL b) 100 mM histidine buffer giving a pH of 6.0 ± 0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0090] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) 100-250 mg / mL IL-17C antibody b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0091] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 140 mg / mL b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0092] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 150 mg / mL b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0093] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 160 mg / mL b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0094] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) 100-250 mg / mL IL-17C antibody b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0095] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 140 mg / mL b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0096] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 150 mg / mL b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0097] In one embodiment, the disclosure provides a pharmaceutical formulation for an IL-17C antibody, the formulation comprising: a) IL-17C antibody at 160 mg / mL b) 100 mM histidine hydrochloride buffer giving a pH of 6.0±0.2 c) 100 mM arginine; d) 0.02% (weight / volume) polysorbate 20; wherein the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively. In another embodiment, the IL-17C antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 18 and 19, respectively. In another embodiment, the pharmaceutical formulation has a pH of 6.

[0098] In one embodiment, a pharmaceutical formulation according to the present disclosure is stable upon freezing and thawing.

[0099] In one embodiment, the pharmaceutical formulation according to the present disclosure is for subcutaneous or intramuscular administration.

[0100] In one embodiment, the pharmaceutical formulation according to the present disclosure is in liquid or reconstituted form.

[0101] In one embodiment, the present disclosure provides an injection device comprising a pharmaceutical formulation according to the present disclosure.

[0102] In another embodiment, the present disclosure provides a pharmaceutical formulation as disclosed herein for use in treating a disease or condition suitable for treatment with an IL-17C antibody or antibody fragment thereof in a subject, comprising administering to the subject a formulation according to the disclosure in an amount effective to treat the disease or condition. In one embodiment, the disease or condition is an inflammatory disease or disorder. In another embodiment, the disease or condition is treatment of rheumatoid arthritis, psoriasis, pulmonary inflammation, COPD and / or atopic dermatitis (AD), including moderate to severe AD.

[0103] In another embodiment, the present disclosure provides a method of treating a disease or condition in a subject suitable for treatment with an IL-17C antibody or antibody fragment thereof, the method comprising administering to the subject a formulation according to the present disclosure in an amount effective to treat the disease or condition. In one embodiment, the disease or condition is an inflammatory disease or disorder. In another embodiment, the disease or condition is treatment of rheumatoid arthritis, psoriasis, pulmonary inflammation, COPD and / or atopic dermatitis (AD), including moderate to severe AD.

[0104] In another embodiment, the present disclosure provides a kit comprising one or more vials containing a formulation according to the present disclosure and instructions for subcutaneously administering the formulation to a patient.

[0105] In another embodiment, the present disclosure provides an injection device comprising a stable pharmaceutical formulation as described herein. In another embodiment, the present disclosure provides a kit comprising one or more vials containing a formulation as described herein and instructions for administering the formulation subcutaneously to a patient. In another embodiment, the kit further comprises an injection device for administering the formulation subcutaneously to a patient.

[0106] In another embodiment, the present disclosure provides a pharmaceutical formulation according to the present disclosure for therapeutic use, such as for the treatment of inflammatory disorders such as rheumatoid arthritis, psoriasis, pulmonary inflammation, COPD, and / or for the treatment of atopic dermatitis (AD), including moderate to severe AD.

[0107] In another embodiment, the present disclosure provides a method of treating a disease or condition in a subject suitable for treatment with an anti-IL-17C antibody or antibody fragment thereof, the method comprising administering to the subject a formulation according to the present disclosure in an amount effective to treat said disease or condition, in another embodiment, the disease or condition is an inflammatory disorder, such as, for example, treatment of rheumatoid arthritis, psoriasis, pulmonary inflammation, COPD and / or atopic dermatitis (AD), including moderate to severe AD.

[0108] TIFF0007608173000001.tif144170TIFF0007608173000002.tif246170TIFF0007608173000003.tif81170 EXAMPLES

[0109] Example 1: Determining the self-interaction propensity of IL-17C antibodies The increase in viscosity of highly concentrated liquid formulations of monoclonal antibodies can be explained by intermolecular interactions (Binabaji et al., 2015, Pharm Res. Vol. 32). Such interactions are called self-association or self-interaction. The protein concentration dependence of the self-interaction process can be detected by light scattering techniques, for example dynamic light scattering. This assay principle is well established in science (e.g. Connolly et al., 2012, Biophys. J. Vol. 103; Menzen et al., 2014, J. Pharm. Sci., Vol. 103) and leads to revealing the mutual diffusion coefficient of the molecules. By fitting the molecular mutual diffusion coefficient to the antibody concentration with a linear equation, the parameter kD (diffusion interaction parameter) can be calculated. This parameter is related to the second virial coefficient, and antibodies with a tendency to self-interaction have a kD value less than 0.

[0110] For MAB#1, the kD was -23.6±0.9 mL / g as measured in phosphate buffered saline using the dynamic light scattering method described above, indicating an attractive interaction between antibody molecules, referred to as the antibody-self interaction.

[0111] To find a suitable formulation at high protein concentration for antibodies with a tendency to self-interact (such as MAB#1), a high-throughput method based on biolayer interferometry was established based on the paper by Sun et al. (2013, mAbs, Vol. 5). The method includes a capture step in which the antibody of interest is bound to the sensor surface (e.g., anti-human Fc biosensor) by non-covalent interactions. Then, a suitable saturating agent, such as human Fc protein, saturates the sensor surface. The association reaction is observed for at least 1200 seconds to ensure that equilibrium has been established. A detailed description is shown in Figure 1.

[0112] A high signal intensity at equilibrium indicates a high tendency for self-interaction. relThe parameter was introduced as the ratio of the signal at the association equilibrium and the amount of captured antibody. The results of this assay correlated with those obtained by dynamic light scattering and viscometry (see Table 2).

[0113] TIFF0007608173000004.tif82170

[0114] Example 2: Identification of highly concentrated formulations of antibodies with self-interaction tendencies To find a suitable formulation composition, a three-stage screening approach was devised based on a design of experiments (DoE). In this approach, several buffer substances such as histidine hydrochloride, succinate hydrochloride, sodium phosphate or sodium citrate were tested in combination with excipients such as sodium chloride, trehalose, sucrose, arginine, methionine, mannitol or sorbitol. A theoretical maximum osmolality of 300 mOsm was chosen. Surfactants such as polysorbate 20 and polysorbate 80 were also included in the study at several concentrations. The experimental design is outlined in Figure 2.

[0115] Each experimental design was tested in an accelerated stability study (2 weeks at 40°C, [protein] = 1 mg / mL). The assay setup consisted of high performance size exclusion chromatography and the BLI-based self-interaction assay described above. Using the DoE software MODDE Pro (Umetrics™), the responses "change in monomer fraction" and "self-interaction propensity" were optimized for each DoE setup. The goal was to calculate the buffer composition to minimize both the self-interaction propensity and the change in monomer fraction, ideally revealing a high concentration formulation suitable for subcutaneous administration.

[0116] In the first round of screening, several buffers with different pH values, various salt / sugar ratios and the presence or absence of stabilizers and surfactants were part of the investigation. The results for the histidine-HCl based formulations are shown in Figures 3 and 4.

[0117] Analysis of the monomeric portion of MAB#1 (Figure 4) showed that the sugar chemistry along with the pH range had the strongest effect on the antibody. More acidic pH and sugar alcohols stabilized the antibody. Sorbitol in combination with arginine showed destabilizing properties, while the combination of arginine and trehalose had no effect on the protein.

[0118] A high salt to sugar ratio, along with a high concentration of arginine, appeared to be effective in minimizing the self-interaction tendency of MAB#1 (Figure 3). The pH value was not critical as long as it met the above criteria, since minimal self-interaction was predicted in the pH range of 5.5-7. A A pH value of 6.0 was chosen because it has the highest buffering capacity according to the pH. Furthermore, the presence of detergents reduced the response that occurred in the BLI-based assay. The reason for the curves in Figure 3 was the presence of quadratic and interaction terms in the model. Therefore, other buffer combinations were possible to minimize self-interactions.

[0119] After the first screening round, an evaluation study was performed. The antibodies were formulated at low protein concentrations in at least four buffer compositions containing either histidine hydrochloride, succinate chloride, sodium phosphate or sodium citrate as buffer substances. The protein solutions were then concentrated to at least 100 mg / mL and stored at 5±3° C. for 10 days. The concentration procedure and size exclusion chromatography analysis are shown in FIG. 5.

[0120] Histidine hydrochloride provides monomeric stability (approximately 95% relative area in SEC experiments) and a viscosity of 20 mPa at a protein concentration of 150 mg / mL. *s, it was chosen as the buffer for further investigation. Furthermore, only limited effort was required to concentrate the proteins in the selected histidine hydrochloride formulations on a laboratory scale. The following buffer was used for the next DoE-based screening round: 50 mM histidine-HCl pH 6.0, 50 mM arginine, 75 mM NaCl and 0.02% Tween 20.

[0121] In the second screening round (DoE2), the selected formulations were further optimized by varying excipient types and concentrations.

[0122] When screening for improved conditions to reduce the protein's self-interaction tendency, the absence of either Tween 20 or Tween 80 showed a significant impact on the response (Figure 6). However, the presence of methionine or arginine as stabilizers affected the self-interaction. As shown in the figure, lower response values ​​could be achieved by using 50 mM arginine instead of 50 mM methionine. The effect was not dependent on the buffer concentration or pH. For these two parameters, improved ranges could also be obtained. The lowest response of the antibody's self-interaction was observed at high histidine concentrations at pH values ​​close to the pKa of 6.0.

[0123] In the development of the formulation, the stabilizing effect on the protein with respect to the monomeric portion is a very important criterion. Therefore, as a secondary criterion, it was decided to choose a buffer system that would maintain a high content of monomers while lowering self-interactions. Thus, Figure 7 shows the results of the formulation improvement with respect to the monomeric content. The model suggested a destabilizing effect of polysorbate 80 compared to polysorbate 20. This effect could be attenuated in the presence of methionine in the composition. This finding indicates the stabilizing effect of methionine on the antibody monomer. As expected in the first screening round, more acidic pH values ​​maintained more monomers than neutral pH values. A high concentration of histidine hydrochloride is preferred to maintain monomeric proteins, as it did to reduce self-interactions. In the second screening round, a formulation containing 100 mM histidine hydrochloride, pH 6.0, 50 mM arginine and 0.02% polysorbate 20 was obtained. 25 mM sodium chloride was added to meet the required theoretical osmolality of approximately 300 mOsm.

[0124] In the third screening round (DoE3), we further optimized the concentrations of detergents and stabilizers. DoE3 led to the conclusion that using the highest possible concentration of arginine with a low concentration of polysorbate 20 minimized the reduction in monomeric moieties (Figure 8). The response contour plot suggested that the optimum for stabilization by arginine was not reached at 100 mM, and that even higher concentrations could achieve higher stability of the molecule. Interestingly, a valid model could not be made to reduce the self-interaction tendency of MAB#1, as there was no significant effect. This result suggests that the presence of arginine or even detergents helps to reduce the tendency of the antibody to self-associate. Thus, a low self-interaction tendency is robust within the tested range of arginine (<100 mM) and polysorbate 20 concentrations (0.001–0.1% (vol / vol)).

[0125] The result of the third optimization round was a formulation based on 100 mM histidine hydrochloride, 100 mM arginine and 0.001% (vol / vol) polysorbate 20.

[0126] Since mechanical stress was not included in the DoE-based formulation development, a shaking stress study was then initiated. The results of this study were that a higher polysorbate concentration was beneficial to maintain the monomer content of the antibody upon shaking (horizontal shaking, 400 rpm). Thus, the final MAB#1 high protein liquid formulation has 160 mg / mL ± 10 mg / mL of MAB#1 in 100 mM histidine hydrochloride, 100 mM arginine, 0.02% polysorbate 20 at pH 6.0.

[0127] Example 3: Stability studies and shelf life evaluation Stability studies were performed to evaluate colloidal (UHP-SEC-MALS, CE-SDS) and chemical stability (HP-CEX) using scientifically based analytical methods under non-GMP. Additionally, protein concentration was measured by UV-Vis spectroscopy and the concentration of active antibody content was analyzed by SPR. Dynamic viscosity was included as a parameter in this stability study to confirm suitability for subcutaneous administration. Samples are stored in an inverted state for 24 months at the intended storage conditions (5°C ± 3°C) and for 6 months at accelerated storage conditions (25°C ± 3°C).

[0128] TIFF0007608173000005.tif198170

[0129] The 12-month stability data showed a slight trend towards a decrease in monomer (0.8% over 12 months) with a slight increase in aggregates (+0.5%) and fragments (+0.3%) over this period for UHP-SEC, while no changes were observed in the cGE profile, CIEX charge pattern, and binding activity over the 12-month period (Table 3).

[0130] The 24-month stability data showed a slight trend towards a decrease in monomer (1.3% over 24 months) with a slight increase in aggregates (+0.9%) and fragments (+0.4%) over this period for UHP-SEC, while no changes were observed in the cGE profile, CIEX charge pattern, and binding activity over the 24-month period (Table 3).

[0131] These observations were confirmed by data obtained from samples stored under accelerated conditions (25°C ± 3°C), which showed a 2.9% decrease in monomer content with a 1.2% increase in aggregates and a 1.7% increase in fragments within 6 months in UHP-SEC. The relative areas of the main charge variants measured by CIEX decreased by 7% with a 6% increase in acidic species and a 2% increase in basic species. The relative binding activity of MAB#1 decreased by 9% compared to t0 (Table 4).

[0132] TIFF0007608173000006.tif177170

[0133] Furthermore, viscosity measurement experiments were performed to determine the flow behavior of the MAB#1 formulation. Dynamic viscosity was measured on a Kinexus Ultra Plus cone-plate rheometer (Malvern) at a fixed temperature of 25 °C. The rheometer was equipped with a measurement cone with an angle of 1° and a diameter of 40 mm. Experiments were performed with a measurement gap of 0.03 mm using approximately 80 μl of sample. Shear-ramp experiments were performed from 10 to 1,000 s -1 The shear range was 20 mPa. * A constant dynamic viscosity of less than s was observed over the shear range tested, suggesting that the samples resembled a Newtonian system.

Claims

1. a) 100-250 mg / mL of an antigen-binding protein; b) a 100 mM buffer providing a pH of 5.0 to 7.0, the buffer being histidine hydrochloride; c) 100 mM stabilizer, the stabilizer being arginine; and d) 0.005 to 0.05% (weight / volume) polysorbate 20 1. A pharmaceutical formulation for an antigen binding protein comprising: The pharmaceutical formulation, wherein said antigen binding protein is a monoclonal IgG antibody that specifically binds to human IL-17C (SEQ ID NO:1).

2. 2. The pharmaceutical formulation of claim 1, wherein the concentration of polysorbate 20 is 0.02% (weight / volume).

3. 3. The pharmaceutical formulation of claim 1 or 2, wherein the buffering agent provides a pH of 6.0±0.

2.

4. The pharmaceutical formulation according to any one of claims 1 to 3, for subcutaneous or intramuscular administration.

5. The pharmaceutical formulation according to any one of claims 1 to 4, wherein the antigen-binding protein has a tendency to self-interact.

6. The pharmaceutical formulation of any one of claims 1 to 5, wherein the monoclonal IgG antibody comprises heavy and light chain variable regions comprising amino acid sequences that are at least 90% identical to SEQ ID NOs: 16 and 17, respectively.

7. 7. The pharmaceutical formulation of claim 6, wherein the monoclonal IgG antibody comprises heavy and light chain variable regions comprising the amino acid sequences according to SEQ ID NOs: 16 and 17, respectively.

8. An injection device comprising a pharmaceutical formulation according to any one of claims 1 to 7.

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