Anti-interleukin-4 receptor (IL-4R) antibody formulations

Abstract

Pharmaceutical formulations comprising an antibody that specifically binds to human interleukin-4 receptor alpha (hIL-4R alpha) are provided. The formulations can contain, in addition to an anti-IL-4R alpha antibody, one or more buffers, at least one amino acid, at least one sugar, and a surfactant comprising polyethylene glycol or poloxamer. In one aspect, the pharmaceutical formulations do not have significant sub-visible particle formation in the presence of lipase and exhibit a considerable degree of antibody stability during storage and after exposure to heat and other physical stresses.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 337,532 filed on May 2, 2022, the contents of which are incorporated herein by reference.

[0003] Reference to sequence listing

[0004] This application incorporates by reference a computer-readable sequence listing in ST.26 XML format, named 11200WO01_sequence, created on April 24, 2023, and containing 369,229 bytes. Technical Field

[0005] The present disclosure relates to the field of therapeutic antibody preparations. More specifically, the present invention relates to the field of pharmaceutical preparations comprising human antibodies that specifically bind to human interleukin-4 receptor alpha. Background Art

[0006] Interleukin 4 (IL-4) and interleukin 13 (IL-13) are key cytokines that drive allergic and T helper cell type 2 (Th2) polarized inflammatory processes. IL-4 and IL-13 signaling are mediated by heterodimeric receptor complexes, in which IL-4 receptor α (IL-4Rα) is a common receptor subunit for IL-4 and IL-13 signaling. Therefore, IL-4Rα is an attractive therapeutic target because it provides a single target for blocking both IL-4 and IL-13 signaling. Antibodies to hIL-4Rα are described, for example, in U.S. Patents 5,717,072, 7,186,809, and 7,605,237.

[0007] Therapeutic macromolecules (e.g., antibodies) must be formulated in such a way that the molecule is not only suitable for administration to a patient, but also maintains its stability during storage. For example, unless the solution is properly formulated, therapeutic antibodies in liquid solutions are prone to degradation, aggregation, and / or undesirable chemical modifications. The stability of antibodies in liquid formulations depends not only on the type of excipients used in the formulation, but also on the amount and ratio of the excipients relative to each other. Therapeutic formulations may also form particulate matter over time during storage. Particles may be visible or subvisible; subvisible particles are typically less than 150 microns or 100 microns in diameter. Preparations with high protein concentrations (e.g., concentrations of 30 mg / mL or more) are more prone to aggregation and form subvisible particles.

[0008] Polysorbate 20 and polysorbate 80 are commonly used to formulate biomacromolecules (such as antibodies). However, it has been reported that polysorbates (including polysorbate 20 and polysorbate 80) can be degraded in the presence of lipases, forming subvisible particles in the formulation over time. Without wishing to be bound by theory, it is believed that the putative phospholipase B-like 2 (PLBL2) (highly conserved in hamsters, rats, mice, humans and cattle) co-purifies with some classes of proteins in certain processes. One solution to this problem is to use a protein purification process that removes or reduces the activity of lipases. See, for example, US10,342,876. However, there is still a need for alternatives for formulating antibodies (such as anti-hIL-4Rα antibodies) to avoid or minimize the formation of subvisible particles while still maintaining sufficient stability and suitability for administration to patients. Summary of the invention

[0009] Provided herein are stable liquid pharmaceutical formulations comprising an anti-IL-4Rα antibody and one or more excipients, as well as delivery devices, kits, and unit dosage forms comprising such formulations.

[0010] In one aspect, the present disclosure provides a stable liquid pharmaceutical formulation comprising: (i) a human antibody, wherein the antibody specifically binds to human interleukin-4 receptor alpha (hIL-4Rα); (ii) one or more buffers; (iii) a thermal stabilizer; (iv) a viscosity reducer; and (v) a surfactant, wherein the surfactant comprises polyethylene glycol or poloxamer at a concentration of less than 0.2% w / v, or polyethylene glycol at a concentration of less than 1% w / v, wherein the formulation has a pH of 5.7 to 6.1.

[0011] In one aspect, the present disclosure provides a stable liquid pharmaceutical formulation, the stable liquid pharmaceutical formulation comprising: (i) a human antibody, wherein the antibody specifically binds to human interleukin-4 receptor α (hIL-4Rα) and comprises a heavy chain variable region (HCVR), wherein the heavy chain variable region comprises one or more sequences disclosed in Table 1; (ii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) a surfactant, the surfactant comprising polyethylene glycol or poloxamer at a concentration of less than 0.2% w / v, or polyethylene glycol at a concentration of less than 1% w / v, wherein the formulation has a pH of 5.7 to 6.1.

[0012] In some embodiments, the antibody comprises a heavy chain variable region (HCVR) comprising complementary determining regions HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 3, 4 and 5, respectively, and a light chain variable region (LCVR) comprising complementary determining regions LCDR1, LCDR2 and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively. In some embodiments, the antibody comprises a HCVR comprising the amino acid sequence of SEQ ID NO: 1 and a LCVR comprising the amino acid sequence of SEQ ID NO: 2.

[0013] In some embodiments, the antibody has a human IgG heavy chain constant region. In some cases, the heavy chain constant region is of isotype IgG1. In some cases, the heavy chain constant region is of isotype IgG4.

[0014] In some embodiments, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0015] In some embodiments, the surfactant is polyethylene glycol. In some cases, the polyethylene glycol is PEG3350. In some embodiments, the surfactant is present in a concentration of 0.0075% w / v to less than 1% w / v, 0.0075% w / v to 0.75% w / v, 0.01% w / v to 0.5% w / v, or 0.01% w / v to 0.25% w / v. In some embodiments, the surfactant is present in a concentration of 0.01% w / v to 0.19% w / v, for example, 0.01% w / v to 0.15% w / v or 0.05% w / v to 0.15% w / v. In some embodiments, the surfactant is present in a concentration of no more than 0.15% w / v.

[0016] In some embodiments, the surfactant is a poloxamer. In some cases, the poloxamer is poloxamer 188. In some embodiments, the surfactant is present in a concentration of 0.0075% w / v to 0.19% w / v or 0.01% w / v to 0.19% w / v, e.g., 0.01% w / v to 0.15% w / v or 0.05% w / v to 0.15% w / v. In some embodiments, the surfactant is present in a concentration of no greater than 0.15% w / v.

[0017] In some embodiments, the buffer includes acetate buffer and / or histidine buffer. In some embodiments, the buffer includes acetate at a concentration of 10mM to 15mM and / or histidine at a concentration of 15mM to 25mM. In some embodiments, acetate is present at a concentration of 12.5mM ± 1.25mM. In some embodiments, histidine is present at a concentration of 20mM ± 2mM. In some embodiments, the heat stabilizer is sucrose at a concentration of 5% w / v ± 0.5% w / v. In some embodiments, the viscosity reducer is arginine at a concentration of 25mM ± 2.5mM. In some embodiments, arginine is present at a concentration of 50mM ± 2.5mM. In some embodiments, arginine is present at a concentration of 75mM ± 2.5mM.

[0018] In some embodiments, the antibody is present at a concentration of up to 200 mg / mL. In some embodiments, the antibody is present at a concentration of 15 mg / mL to 200 mg / mL. In some embodiments, the antibody is present at a concentration of 100 mg / mL to 200 mg / mL. In some cases, the antibody is present at a concentration of 150 mg / mL ± 15 mg / mL. In some cases, the antibody is present at a concentration of 175 mg / mL ± 15 mg / mL.

[0019] In one aspect, the present disclosure provides a stable liquid pharmaceutical formulation, the stable liquid pharmaceutical formulation comprising: (i) a human antibody at a concentration of 150 mg / mL±10 mg / mL, wherein the antibody specifically binds to human interleukin-4 receptor α (hIL-4Rα) and comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. NO:2 amino acid sequence; (ii) acetate at a concentration of 12.5mM±1.25mM; (iii) histidine at a concentration of 20mM±2mM; (iv) sucrose at a concentration of 5%w / v±0.5%w / v; (v) arginine at a concentration of 25mM±2.5mM; and (vi) a surfactant comprising PEG3350 or poloxamer 188 at a concentration of 0.01%w / v to 0.19%w / v, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2. In some cases, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0020] In one aspect, the present disclosure provides a stable liquid pharmaceutical formulation, the stable liquid pharmaceutical formulation comprising: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human interleukin-4 receptor α (hIL-4Rα) and comprises a heavy chain variable region (HCVR) and a light chain variable region (LCVR), the heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 1, and the light chain variable region comprising the amino acid sequence of SEQ ID NO: 2. NO:2 amino acid sequence; (ii) acetate at a concentration of 12.5mM±1.25mM; (iii) histidine at a concentration of 20mM±2mM; (iv) sucrose at a concentration of 5%w / v±0.5%w / v; (v) arginine at a concentration of 25mM±2.5mM; and (vi) a surfactant comprising PEG3350 or poloxamer 188 at a concentration of 0.01%w / v to 0.19%w / v, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2. In some cases, the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0021] In some embodiments, the formulation comprises a phospholipase. In some embodiments, the phospholipase protein is a phospholipase B-like 2 protein.

[0022] In some embodiments, a stable liquid pharmaceutical formulation as discussed herein contains no more than 4% high molecular weight (HMW) species after stirring at 25° C. for 24 hours as determined by SE-UPLC. In some embodiments, the formulation contains no more than 4% high molecular weight (HMW) species after stirring at 25° C. for 24 hours and (i) storage at 5° C. for 6, 12 or 18 months or (ii) storage at 25° C. for 6 months as determined by SE-UPLC.

[0023] In some embodiments, after vortexing for up to 120 minutes at room temperature, the formulation comprises no more than 3% of high molecular weight (HMW) species as determined by size exclusion-ultra performance liquid chromatography (SE-UPLC). In some cases, after vortexing for up to 120 minutes at room temperature, the formulation comprises no more than 2.5% of high molecular weight (HMW) species as determined by SE-UPLC.

[0024] In some embodiments, the formulation contains no more than 8% high molecular weight (HMW) species after storage at 45° C. for 30 days, as determined by SE-UPLC. In some cases, the formulation contains no more than 9% high molecular weight (HMW) species after storage at 45° C. for 40 days, as determined by SE-UPLC. In some cases, the formulation contains no more than 11% high molecular weight (HMW) species after storage at 45° C. for 50 days, as determined by SE-UPLC.

[0025] In some embodiments, the formulation contains no more than 1000, no more than 500, no more than 300, or no more than 150 particles with a diameter ≥ 10 μm in a volume of 2.25 mL after storage at 5°C for 6 months, as determined by microscopic examination, and wherein the formulation contains a phospholipase protein.

[0026] In some embodiments, the formulation contains no more than 1000, no more than 500, no more than 300, or no more than 150 particles with a diameter ≥ 10 μm in a volume of 2.25 mL after storage at 5°C for 36 months, as determined by microscopic inspection, and wherein the formulation contains a phospholipase protein.

[0027] In some embodiments, the formulation contains no more than 500, no more than 300, no more than 250, or no more than 50 particles with a diameter ≥ 25 μm in a volume of 2.25 mL after storage at 5°C for 6 months, as determined by microscopic examination, and wherein the formulation contains a phospholipase protein.

[0028] In some embodiments, the formulation contains no more than 500, no more than 300, no more than 250, or no more than 50 particles with a diameter ≥ 25 μm in a volume of 2.25 mL after storage at 5°C for 6 months, as determined by microscopic examination, and wherein the formulation contains a phospholipase protein.

[0029] In some embodiments, the formulation does not include an esterase inhibitor.

[0030] In some embodiments, the stable liquid pharmaceutical formulation is contained in a glass vial.

[0031] In some embodiments, the stable liquid drug formulation is contained in a syringe. In some cases, the syringe includes a plunger coated with a fluorocarbon. In some cases, the syringe is a low tungsten syringe. In some cases, the syringe is a prefilled syringe. In some cases, the syringe is a prefilled syringe with a needle.

[0032] In some embodiments, the stable liquid drug formulation is contained in a large volume device or a bolus syringe.

[0033] In one aspect, the present disclosure provides a pen or auto-injector delivery device containing a stable liquid drug formulation as discussed above or herein. In some cases, the delivery device is a disposable pen delivery device. In some cases, the delivery device is a reusable pen delivery device.

[0034] In one aspect, the present disclosure provides a container containing a stable liquid pharmaceutical formulation as discussed above or herein.

[0035] In one aspect, the present disclosure provides a kit comprising (i) a container containing a stable liquid pharmaceutical formulation as discussed above or herein, and (ii) a label for use of the pharmaceutical formulation. In some cases, the label indicates that the pharmaceutical formulation is administered subcutaneously. In some cases, the label indicates that the pharmaceutical formulation is administered intravenously.

[0036] In one aspect, the present disclosure provides a unit dosage form comprising a stable liquid drug formulation as discussed above or herein, wherein the antibody is present in an amount of 1 mg to 500 mg. In some cases, the antibody is present in an amount of about 100 mg. In some cases, the antibody is present in an amount of about 200 mg. In some cases, the antibody is present in an amount of about 300 mg. In some embodiments, the formulation of the unit dosage form is contained in a syringe. In some cases, the syringe is a prefilled syringe. In some embodiments, the formulation of the unit dosage form is contained in a prefilled pen. In some embodiments, the formulation of the unit dosage form is contained in an automatic syringe.

[0037] In one aspect, the present disclosure provides a safety system delivery device containing a stable liquid drug formulation as discussed above or herein. In some cases, the safety system delivery device includes a safety sleeve configured to be extended by manual operation. In some cases, the safety system delivery device includes a safety sleeve configured to automatically extend after injection of the stable liquid drug formulation.

[0038] In various embodiments, any feature or assembly of the embodiment discussed above or herein can be combined, and such combination is contained in the scope of the present disclosure.Any specified value discussed above or herein can be combined with another related value discussed above or herein, to list a scope, and the value represents the upper and lower limits of the scope, and such scope is contained in the scope of the present disclosure.Each value discussed above or herein can be represented by a change of 1%, 5%, 10% or 20%.For example, the concentration of 10mM can be expressed as 10mM ± 0.1mM (1% change), 10mM ± 0.5mM (5% change), 10mM ± 1mM (10% change) or 10mM ± 2mM (20% change).

[0039] Other embodiments will become apparent upon reading the detailed description. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 Shown are the numbers of particles ≥10 μm (upper panel) and ≥25 μm (lower panel) identified by microscopic examination in formulations containing lipase and 150 mg / mL of anti-IL-4R antibody with PEG 3350 or poloxamer 188 (at concentrations of 0.02%, 0.04%, or 0.1% w / v) stored at 5°C for up to 36 months.

[0041] Figure 2A and 2B The PEG3350 concentration is shown ( Figure 2A ) and poloxamer 188 concentration ( Figure 2B ) on the stability (expressed as the percentage of high molecular weight (HMW) species measured by SE-UPLC) of a 150 mg / mL formulation of an anti-IL-4R antibody against stirring stress for periods of 30-120 minutes at room temperature.

[0042] Figure 3 Shown is the effect of polysorbate 20, polysorbate 80, PEG3350, and poloxamer 188 (at varying concentrations) on the stability (expressed as the percentage of high molecular weight (HMW) species measured by SE-UPLC) of a 150 mg / mL formulation of an anti-IL-4R antibody against heat stress (45°C) for up to 56 days. DETAILED DESCRIPTION

[0043] Before describing the present invention, it should be understood that the present invention is not limited to the specific methods and experimental conditions described, because such methods and conditions can vary. It should also be understood that the terminology used herein is only used for the purpose of describing specific embodiments, and is not intended to be limiting, because the scope of the present invention will be limited only by the appended claims.

[0044] 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 the invention belongs. As used herein, the term "about", when used to refer to a particular listed value or range of values, means that the value may differ from the listed value by no more than 1%. For example, as used herein, the expression "about 100" includes 99 and 101 and all values ​​therebetween (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0045] Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, exemplary methods and materials are now described. All patents, applications and non-patent publications mentioned in this specification are incorporated herein by reference in their entirety.

[0046] Pharmaceutical preparations

[0047] As used herein, the expression "pharmaceutical formulation" means a combination of at least one active ingredient (e.g., an anti-IL-4Rα antibody, etc., which is capable of exerting a biological effect in a human or non-human animal) and at least one inactive ingredient, which, when combined with an active ingredient and / or one or more additional inactive ingredients, is suitable for therapeutic administration to a human or non-human animal. Unless otherwise expressly stated, as used herein, the term "formulation" refers to a "pharmaceutical formulation". The present disclosure provides a pharmaceutical formulation comprising at least one therapeutic polypeptide. According to certain embodiments of the present disclosure, the therapeutic polypeptide is an antibody or an antigen-binding fragment thereof that specifically binds to human interleukin-4 receptor α (hIL-4Rα). More specifically, the present disclosure includes a pharmaceutical formulation comprising: (i) a human antibody that specifically binds to hIL-4Rα; (ii) one or more buffers; (iii) a thermal stabilizer; (iv) a surfactant (e.g., an organic cosolvent); and (v) a viscosity modifier. Additional components may be included in the formulation of the present disclosure, provided that such components do not significantly interfere with the viscosity and stability of the formulation. Specific exemplary components and formulations encompassed within the present disclosure are described in detail below.

[0048] In certain embodiments, the pharmaceutical preparations of the present disclosure can be fluid preparations. The expression "fluid preparation" used herein means a mixture of at least two components, which exists mainly in a fluid state at about 2°C to about 45°C. Fluid preparations especially include liquid preparations. Depending on its specific ingredients, fluid preparations can have low, medium or high viscosity.

[0049] Antibodies that specifically bind to human IL-4 receptor alpha

[0050] The pharmaceutical formulations of the present disclosure may comprise a human antibody that specifically binds to human interleukin-4 receptor alpha (IL-4Rα), or an antigen-binding fragment thereof. Reference herein to an IL-4R antibody also refers to a reference to an antibody that binds hIL-4Rα.

[0051] As used herein, the term "antibody" is generally intended to refer to immunoglobulin molecules comprising four polypeptide chains, i.e., two heavy chains (H chains) and two light chains (L chains) interconnected by disulfide bonds, as well as multimers thereof (e.g., IgM); however, immunoglobulin molecules consisting only of heavy chains (i.e., without light chains) are also included in the definition of the term "antibody". Each heavy chain comprises a heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constant region. The heavy chain constant region comprises three domains: CH1, CH2, and CH3. Each light chain comprises a light chain variable region (abbreviated herein as LCVR or VL) and a light chain constant region. The light chain constant region comprises one domain (CL1). The VH and VL regions can also be subdivided into hypervariable regions (referred to as complementary determining regions (CDRs)), with more conserved regions (referred to as framework regions (FRs)) interspersed between the hypervariable regions. Each VH and VL is composed of three CDRs and four FRs arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4.

[0052] In certain embodiments of the present disclosure, the anti-IL-4R antibodies of the present disclosure are human antibodies. As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the present disclosure may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-directed mutagenesis in vitro or by somatic mutations in vivo), for example, in CDRs, particularly CDR3. However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (such as a mouse) have been implanted onto human framework sequences. In various embodiments, the anti-IL-4R antibody is a human IgG antibody. In various embodiments, the anti-IL-4R antibody is a human antibody of isotype IgG1, IgG2, IgG3, or IgG4, or a mixed isotype. In some embodiments, the anti-IL-4R antibody is a human IgG1 antibody. In some embodiments, the anti-IL-4R antibody is a human IgG4 antibody. In any of the embodiments discussed above or herein, the anti-IL-4R antibody may comprise a human kappa light chain. In any of the embodiments discussed above or herein, the anti-IL-4R antibody may comprise a human lambda light chain.

[0053] In some embodiments, the antibodies of the present disclosure may be recombinant human antibodies. As used herein, the term "recombinant human antibody" is intended to include all human antibodies prepared, expressed, produced or isolated by recombinant means, such as antibodies expressed using recombinant expression vectors transfected into host cells, antibodies isolated from recombinant human antibody combinatorial libraries, antibodies isolated from transgenic animals (e.g., mice) relative to human immunoglobulin genes (see, e.g., Taylor et al., (1992) Nucl. Acids Res. 20: 6287-6295) or antibodies prepared, expressed, produced or isolated by any other means involving splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies undergo in vitro mutagenesis (or, when using transgenic animals with respect to human Ig sequences, undergo in vivo somatic cell mutagenesis) and thus the V H and V L Although the amino acid sequence of the region is derived from human germline V H and V L Sequences that are related to but that may not naturally occur within the human antibody germline repertoire in vivo.

[0054] As used herein, the term "antigen-binding portion" or "antigen-binding fragment" of an antibody (or simply "antibody portion" or "antibody fragment") refers to one or more fragments of an antibody that retain the ability to specifically bind to hIL-4Rα.

[0055] As used herein, "isolated antibody" is intended to refer to an antibody that is substantially free of other antibodies having different antigenic specificities (eg, an isolated antibody that specifically binds hlL-4Rα is substantially free of antibodies that specifically bind antigens other than hlL-4Rα).

[0056] The term "specific binding" and the like means that the antibody or antigen-binding fragment thereof forms a relatively stable complex with the antigen under physiological conditions. Specific binding is characterized by at least about 1x10 -6M or greater dissociation constant. Methods for determining whether two molecules specifically bind are well known in the art and include, for example, equilibrium dialysis, surface plasmon resonance, and the like. However, an isolated antibody that specifically binds to hIL-4Rα may have cross-reactivity with other antigens, such as IL-4Rα molecules (orthologs) from other substances. In the context of the present disclosure, a multispecific (e.g., bispecific) antibody that binds to hIL-4Rα and one or more additional antigens is considered to "specifically bind" to hIL-4Rα. In addition, the isolated antibody may be substantially free of other cellular material and / or chemicals. However, in some cases, the isolated antibody may be co-purified with a phospholipase expressed by a mammalian cell line (e.g., CHO cells) from which the anti-IL-4R antibody is produced.

[0057] According to certain embodiments of the present disclosure, the anti-hIL-4R antibody or antigen-binding fragment thereof comprises heavy chain complementary determining regions HCDR1-HCDR2-HCDR3 comprising the amino acid sequences of SEQ ID NOs: 3-4-5, respectively. According to certain embodiments of the present disclosure, the anti-hIL-4R antibody or antigen-binding fragment thereof comprises light chain complementary determining regions LCDR1-LCDR2-LCDR3 comprising the amino acid sequences of SEQ ID NOs: 6-7-8, respectively. In certain embodiments, the anti-hIL-4R antibody or antigen-binding fragment thereof comprises CDRs HCDR1-HCDR2-HCDR3-LCDR1-LCDR2-LCDR3 comprising the amino acid sequences of SEQ ID NOs: 3-4-5-6-7-8, respectively. In some embodiments, the IL-4R antagonist is an anti-IL-4Rα antibody or an antigen-binding fragment thereof, which comprises three HCDRs (HCDR1, HCDR2, and HCDR3) and three LCDRs (LCDR1, LCDR2, and LCDR3), wherein HCDR1 comprises or consists of the amino acid sequence GFTFRDYA (SEQ ID NO:3), HCDR2 comprises or consists of the amino acid sequence ISGSGGNT (SEQ ID NO:4), HCDR3 comprises or consists of the amino acid sequence AKDRLSITIRPRYYGLDV (SEQ ID NO:5), LCDR1 comprises or consists of the amino acid sequence QSLLYSIGYNY (SEQ ID NO:6), LCDR2 comprises or consists of the amino acid sequence LGS (SEQ ID NO:7), and LCDR3 comprises or consists of the amino acid sequence MQALQTPYT (SEQ ID NO:8).

[0058] In certain embodiments, an anti-hIL-4R antibody or antigen-binding fragment thereof comprises heavy chain complementary determining regions HCDR1-HCDR2-HCDR3 comprising the amino acid sequences of SEQ ID NOs: 3-4-5, respectively, and having a heavy chain variable region (HCVR) having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 1. In certain embodiments, an anti-hIL-4R antibody or antigen-binding fragment thereof comprises light chain complementary determining regions LCDR1-LCDR2-LCDR3 comprising the amino acid sequences of SEQ ID NOs: 6-7-8, respectively, and having a light chain variable region (LCVR) having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 2. In certain embodiments, the anti-hIL-4R antibody or antigen-binding fragment thereof comprises: heavy chain complementary determining regions HCDR1-HCDR2-HCDR3 comprising the amino acid sequences of SEQ ID NOs: 3-4-5, respectively, and having a heavy chain variable region (HCVR) having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 1; and light chain complementary determining regions LCDR1-LCDR2-LCDR3 comprising the amino acid sequences of SEQ ID NOs: 6-7-8, respectively, and having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to the amino acid sequence of SEQ ID NO: 2.

[0059] In certain embodiments, an anti-hIL-4R antibody or antigen-binding fragment thereof comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1. In certain embodiments, an anti-hIL-4R antibody or antigen-binding fragment thereof comprises a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2. In certain embodiments, an anti-hIL-4R antibody or antigen-binding fragment thereof comprises a HCVR / LCVR amino acid sequence pair comprising the amino acid sequences of SEQ ID NO: 1 / 2. In some embodiments, an anti-IL-4R antibody comprises a HCVR / LCVR comprising the amino acid sequences of SEQ ID NO: 1 / 2, respectively, and a human IgG1 heavy chain constant region. In some embodiments, an anti-IL-4R antibody comprises a HCVR / LCVR comprising the amino acid sequences of SEQ ID NO: 1 / 2, respectively, and a human IgG4 heavy chain constant region. In some embodiments, an anti-IL-4R antibody comprises a HCVR / LCVR comprising the amino acid sequences of SEQ ID NO: 1 / 2, respectively, and a human IgG heavy chain constant region. In some embodiments, the anti-IL-4R antibody comprises a HCVR / LCVR comprising the amino acid sequences of SEQ ID NO: 1 / 2, respectively, and a human IgG1 or IgG4 heavy chain constant region. In some embodiments, the anti-IL-4R antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10. In some embodiments, the anti-IL-4R antibody is dupilumab.

[0060] Other anti-IL-4R antibodies that can be used in the context of the methods of the present disclosure include, for example, antibodies known in the art as AMG317 (Corren et al., 2010, Am J Respir Crit Care Med., 181(8):788-796) or MEDI 9314, or as described in U.S. Patents 7,186,809, 7,605,237, 7,638,606, 8,092,804, 8,679,487, 8,877,189, 10,774,141; U.S. Patent Application Publication No. US2021 / 0238294; or International Patent Publications No. WO2019 / 228405, WO2020 / 096381, WO 2020 / 135471, WO2020 / 135710, or WO Any of the anti-IL-4Rα antibodies shown in 2020 / 239134 (the contents of these patents are incorporated herein by reference).

[0061] In some embodiments, the anti-IL-4R antibody comprises one or more of the CDR, HCVR, and / or LCVR sequences shown in Table 1 below.

[0062] The amount of the antibody or its antigen-binding fragment contained in the pharmaceutical preparation of the present disclosure can vary according to the specific properties required for the preparation and the specific circumstances and purposes for which the preparation is intended to be used. In certain embodiments, the pharmaceutical preparation can contain about 1 mg / mL to about 500 mg / mL of antibody; about 5 mg / mL to about 250 mg / mL of antibody; about 5 mg / mL to about 200 mg / mL of antibody; about 15 mg / mL to about 200 mg / mL of antibody; about 25 mg / mL to about 200 mg / mL of antibody; about 50 mg / mL to about 200 mg / mL of antibody; about 100 mg / mL to about 200 mg / mL; about 125 mg / mL to about 175 mg / mL; or about 150 mg / mL to about 200 mg / mL of antibody. For example, a formulation of the present disclosure may be one that comprises about 1 mg / mL; about 2 mg / mL; about 5 mg / mL; about 10 mg / mL; about 15 mg / mL; about 20 mg / mL; about 25 mg / mL; about 30 mg / mL; about 35 mg / mL; about 40 mg / mL; about 45 mg / mL; about 50 mg / mL; about 55 mg / mL; about 60 mg / mL; about 65 mg / mL; about 70 mg / mL; about 75 mg / mL; about 80 mg / mL; about 85 mg / mL; about 90 mg / mL; about 95 mg / mL; about 100 mg / mL; about 105 mg / mL; About 110 mg / mL; about 115 mg / mL; about 120 mg / mL; about 125 mg / mL; about 130 mg / mL; about 135 mg / mL; about 140 mg / mL; about 145 mg / mL; about 150 mg / mL; about 155 mg / mL; about 160 mg / mL; about 165 mg / mL; about 170 mg / mL; about 175 mg / mL; about 180 mg / mL; about 185 mg / mL; about 190 mg / mL; about 195 mg / mL; or about 200 mg / mL of a liquid preparation of an antibody or antigen-binding fragment thereof that specifically binds to hIL-4Rα. In certain embodiments, the pharmaceutical formulation is a liquid formulation that can contain 5±0.5 mg / mL to 200±20 mg / mL of antibody; 15±1.5 mg / mL to 200±20 mg / mL of antibody; 25±2.5 mg / mL to 200±20 mg / mL of antibody; 50±5 mg / mL to 200±20 mg / mL of antibody; 100±10 mg / mL to 200±20 mg / mL of antibody; 150±10 mg / mL of antibody; or 175±10 mg / mL. In some embodiments, the pharmaceutical formulation contains 140±5 mg / mL to 160±5 mg / mL of anti-IL-4R antibody. In some cases, the pharmaceutical formulation contains 165 mg / mL±5 mg / mL to 185 mg / mL±5 mg / mL of anti-IL-4R antibody.In some cases, the pharmaceutical formulation contains 150 mg / mL ± 5 mg / mL of the anti-IL-4R antibody. In some cases, the pharmaceutical formulation contains 175 mg / mL ± 5 mg / mL of the anti-IL-4R antibody.

[0063] Bioequivalent

[0064] The present disclosure encompasses antibodies having amino acid sequences that differ from the exemplary molecules disclosed herein, but that retain the ability to bind hIL-4R. Such variant molecules may contain one or more amino acid additions, deletions or substitutions when compared to the parent sequence, but exhibit biological activity substantially equivalent to that of the antibodies discussed herein.

[0065] The present disclosure includes antigen binding molecules that are bioequivalent to any exemplary antibody described herein. In some embodiments, the antigen binding molecule is a bioequivalent of dupilumab. For example, if two antibodies are drug equivalents or drug substitutes, that is, when administered with the same molar dose (single dose or multiple doses) under similar experimental conditions, their absorption rate and absorption extent do not show significant differences, then they are considered to be bioequivalent. If some antibodies are the same in absorption extent and different in absorption rate, they can be regarded as equivalents or drug substitutes, but can still be considered to be bioequivalent, because this difference in absorption rate is intentional and reflected in the specification, is not necessary for achieving effective in vivo drug concentrations (e.g., in long-term use), and is considered to be medically insignificant for the specific drug product studied.

[0066] In one embodiment, two antibodies are bioequivalent if there are no clinically meaningful differences in safety, purity, and potency.

[0067] In one embodiment, two antibodies are bioequivalent if patients can make one or more switches between the reference product and the biological product without an expected increase in risk of adverse reactions, including clinically significant changes in immunogenicity, or decreased effectiveness, compared to continuous therapy without switching between the reference product and the biological product.

[0068] Bioequivalence can be demonstrated by in vivo and in vitro methods. Bioequivalence metrics include, for example, (a) in vivo tests in humans or other mammals, in which the concentration of the antibody or its metabolites in blood, plasma, serum or other biological fluids over time is measured; (b) in vitro tests that correlate with and can reasonably predict the in vivo bioavailability data in humans; (c) in vivo tests in humans or other mammals, in which the appropriate acute pharmacological effects of the antibody (or its target) are measured over time; and (d) well-controlled clinical trials to establish the safety, efficacy, or bioavailability or bioequivalence of the antigen-binding protein.

[0069] Formulation excipients and pH

[0070] The pharmaceutical formulations of the present disclosure comprise one or more excipients. As used herein, the term "excipient" refers to any non-therapeutic agent added to a formulation to provide a desired consistency, viscosity or stabilizing effect.

[0071] The pharmaceutical formulations of the present disclosure may also include a buffer or a buffer system that is used to maintain a stable pH and help stabilize the anti-IL-4R antibody. In some embodiments, the buffer or buffer system includes at least one buffer whose buffer range completely or partially overlaps with the range of pH 5.5 to 6.3. In various embodiments, the pH of the formulation is 5.5, 5.6, 5.7, 5.8, 5.9, 6.0, 6.1, 6.2 or 6.3. In a certain embodiment, the formulation has a pH of 5.9 ± 0.3. In a certain embodiment, the formulation has a pH of 5.9 ± 0.2. In a certain embodiment, the formulation has a pH of 5.9 ± 0.1. In certain embodiments, the buffer includes a histidine buffer. In certain embodiments, the buffer includes an acetate buffer. In certain embodiments, the buffer (e.g., histidine and / or acetate) is present at a concentration of about 1 mM to about 40 mM, about 5 mM to about 30 mM, about 10 mM to about 15 mM; or about 15 mM to about 25 mM. In some embodiments, the buffer includes a histidine buffer having a concentration of 15mM to 25mM. In some embodiments, the buffer includes a histidine buffer having a concentration of 20mM ± 2mM. In some cases, the histidine buffer is present at a concentration of 15mM, 16mM, 17mM, 18mM, 19mM, 20mM, 21mM, 22mM, 23mM, 24mM or 25mM. In some embodiments, the buffer includes an acetate buffer having a concentration of 10mM to 15mM. In some embodiments, the buffer includes an acetate buffer having a concentration of 12.5mM ± 1.25mM. In some cases, the acetate buffer is present at a concentration of 10mM, 10.5mM, 11mM, 11.5mM, 12mM, 12.5mM, 13mM, 13.5mM, 14mM, 14.5mM or 15mM. In some embodiments, the formulations of the present disclosure include any concentration of histidine and acetate buffer discussed above. In some cases, the formulation contains a histidine buffer at a concentration of 15mM to 25mM, and an acetate buffer at a concentration of 10mM to 15mM. In some cases, the formulation contains a histidine buffer at a concentration of 20mM ± 2mM, and an acetate buffer at a concentration of 12.5mM ± 1.25mM.

[0072] The pharmaceutical formulations of the present disclosure may also include one or more carbohydrates, for example, one or more sugars. Sugars may be reducing sugars or non-reducing sugars. "Reducing sugars" include, for example, sugars with ketone or aldehyde groups, and contain reactive hemiacetal groups, which allow the sugar to act as a reducing agent. Specific examples of reducing sugars include fructose, glucose, glyceraldehyde, lactose, arabinose, mannose, xylose, ribose, rhamnose, galactose, and maltose. Non-reducing sugars may include an anomeric carbon that is an acetal and does not substantially react with amino acids or polypeptides to initiate the Maillard reaction. Specific examples of non-reducing sugars include sucrose, trehalose, sorbose, sucralose, melezitose, and raffinose. Sugar acids include, for example, sugar acids, gluconates, and other polyhydroxy sugars and salts thereof. In some embodiments, the sugar is sucrose. In some cases, sugars (e.g., sucrose) act as thermal stabilizers for anti-IL-4R antibodies.

[0073] The amount of sugar (e.g., sucrose) included in the pharmaceutical preparation of the present disclosure will vary depending on the specific circumstances and the intended purpose of the preparation use. In certain embodiments, the preparation may contain about 0.1% to about 20% sugar; about 0.5% to about 20% sugar; about 1% to about 20% sugar; about 2% to about 15% sugar; about 3% to about 8% sugar; or about 4% to about 6% sugar. For example, the pharmaceutical preparation of the present disclosure may contain about 0.5%; about 1.0%; about 1.5%; about 2.0%; about 2.5%; about 3.0%; about 3.5%; about 4.0%; about 4.5%; about 5.0%; about 5.5%; about 6.0%; about 6.5%; about 7.0%; about 7.5%; about 8.0%; about 8.5%; about 9.0%; about 9.5%; about 10.0%; about 15%; or about 20% sugar (e.g., sucrose). In some embodiments, the formulation contains about 5% sugar (e.g., sucrose). In some embodiments, the formulation contains about 5% ± 0.5% sugar (e.g., sucrose). Each percentage mentioned above corresponds to a weight / volume percentage (w / v).

[0074] The pharmaceutical formulations of the present disclosure may also include one or more organic cosolvents of a type and amount that stabilizes the anti-IL-4R antibody under conditions of rough handling or agitation (e.g., orbital oscillation). In some embodiments, the organic cosolvent is a surfactant. As used herein, the term "surfactant" means a substance that reduces the surface tension of a fluid dissolved therein and / or reduces the interfacial tension between oil and water. The surfactant may be ionic or nonionic. Specific nonionic surfactants that may be included in the formulations of the present disclosure include, for example, poloxamers (such as poloxamer 188) and polyethylene glycol (PEG) (such as PEG3350).

[0075] The amount of surfactant included in the pharmaceutical preparation of the present disclosure can vary according to the specific properties required for the preparation and the specific circumstances and purposes of the intended use of the preparation. In certain embodiments, the preparation can contain at least about 0.0075% of a surfactant. In certain embodiments, the preparation can contain at least about 0.01% of a surfactant. In certain embodiments, the preparation can contain about 0.0075% to about 0.5% of a surfactant. In certain embodiments, the preparation can contain less than 0.2% of a surfactant. In certain embodiments, the formulation may contain from about 0.0075% to about 0.19% surfactant; from about 0.01% to about 0.19% surfactant; from about 0.0075% to about 0.15% surfactant; from about 0.01% to about 0.15% surfactant; from about 0.0075% to about 0.12% surfactant; from about 0.01% to about 0.12% surfactant; from about 0.0075% to about 0.11% surfactant; from about 0.01% to about 0.11% surfactant; from about 0.0075% to about 0.1% surfactant; from about 0.01% to about 0.1% surfactant; from about 0.0075% to about 0.1% surfactant; from about 0.01% to about 0.1% surfactant; from about 0.0075% to about 0.09% surfactant; or from about 0.01% to about 0.09% surfactant. For example, the formulations of the present disclosure may include about 0.0075%; about 0.01%; about 0.02%; about 0.03%; about 0.04%; about 0.05%; about 0.06%; about 0.07%; about 0.08%; about 0.09%; about 0.1%; about 0.11%; about 0.12%; about 0.13%; about 0.14%; about 0.15%; about 0.16%; about 0.17%; about 0.18%; or about 0.19% of a surfactant (e.g., poloxamer 188 or PEG3350). In some embodiments, the formulation contains less than 0.2% poloxamer (e.g., poloxamer 188). In some embodiments, the formulation contains about 0.0075% to 0.19% poloxamer 188. In some embodiments, the formulation contains about 0.01% to 0.19% poloxamer 188. In some embodiments, the formulation contains less than 1% polyethylene glycol (e.g., PEG3350). In some embodiments, the formulation contains about 0.0075% to about 0.5% PEG3350. In some embodiments, the formulation contains about 0.01% to 0.19% PEG3350. Each percentage mentioned above corresponds to a weight / volume percentage (w / v).

[0076] In certain embodiments, the pharmaceutical formulations of the present disclosure comprise at least one amino acid. In some embodiments, the amino acid is arginine. In some embodiments, arginine is provided in the form of arginine hydrochloride. In some cases, an amino acid (e.g., arginine) serves as a viscosity modifier for an anti-IL-4R antibody formulation.

[0077] The amount of amino acids included in the pharmaceutical preparations of the present disclosure can vary depending on the specific properties required for the preparation and the specific circumstances and purposes for which the preparation is intended to be used. In certain embodiments, the preparation can contain about 1 mM to about 200 mM of amino acids; about 5 mM to about 150 mM; about 10 mM to about 100 mM of amino acids; about 20 mM to about 80 mM of amino acids; about 20 mM to about 30 mM of amino acids; about 45 mM to about 55 mM of amino acids; or about 70 mM to about 80 mM of amino acids. For example, the pharmaceutical preparation of the present disclosure can include about 5mM; about 10mM; about 15mM; about 20mM; about 25mM; about 30mM; about 35mM; about 40mM; about 45mM; about 50mM; about 55mM; about 60mM; about 65mM; about 70mM; about 75mM; about 80mM; about 85mM; about 90mM; about 95mM; or about 100mM of an amino acid (e.g., arginine). In some embodiments, the preparation contains about 25mM of an amino acid (e.g., arginine). In some embodiments, the preparation contains about 50mM of an amino acid (e.g., arginine). In some embodiments, the preparation contains about 75mM of an amino acid (e.g., arginine).

[0078] Exemplary Formulations

[0079] According to one aspect of the present disclosure, a pharmaceutical formulation comprises: (i) a human antibody that specifically binds to hIL-4R (e.g., an antibody comprising one or more sequences disclosed in Table 1 below); (ii) acetate; (iii) histidine; (iv) sucrose; (v) arginine; and (v) a surfactant comprising polyethylene glycol or a poloxamer.

[0080] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (iii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the formulation has a pH of 5.7 to 6.1.

[0081] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody that specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) a surfactant at a concentration of 0.01% w / v to less than 1% w / v (e.g., 0.01% to 0.75% w / v, or 0.01% to 0.5% w / v), the surfactant comprising polyethylene glycol, wherein the formulation has a pH of 5.7 to 6.1.

[0082] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 15 mg / mL to 200 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises polyethylene glycol or a poloxamer, wherein the formulation has a pH of 5.7 to 6.1.

[0083] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 15 mg / mL to 200 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iiii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, wherein the formulation has a pH of 5.7 to 6.1.

[0084] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 15 mg / mL to 200 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM ± 1.25 mM; (iii) histidine at a concentration of 20 mM ± 2 mM; (iv) sucrose at a concentration of 5% w / v ± 0.5% w / v; (v) arginine at a concentration of 25 mM ± 2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v or a concentration of 0.01% w / v to 0.5% w / v, wherein the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0085] In some cases, a stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 15 mg / mL to 200 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM ± 1.25 mM; (iii) histidine at a concentration of 20 mM ± 2 mM; (iv) sucrose at a concentration of 5% w / v ± 0.5% w / v; (v) arginine at a concentration of 25 mM ± 2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises poloxamer 188, wherein the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0086] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 100 mg / mL to 200 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises polyethylene glycol or a poloxamer, wherein the formulation has a pH of 5.7 to 6.1.

[0087] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 100 mg / mL to 200 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, wherein the formulation has a pH of 5.7 to 6.1.

[0088] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 100 mg / mL to 200 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM ± 1.25 mM; (iii) histidine at a concentration of 20 mM ± 2 mM; (iv) sucrose at a concentration of 5% w / v ± 0.5% w / v; (v) arginine at a concentration of 25 mM ± 2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v or a concentration of 0.01% w / v to 0.5% w / v, wherein the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0089] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 100 mg / mL to 200 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM ± 1.25 mM; (iii) histidine at a concentration of 20 mM ± 2 mM; (iv) sucrose at a concentration of 5% w / v ± 0.5% w / v; (v) arginine at a concentration of 25 mM ± 2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises poloxamer 188, wherein the formulation has a pH of 5.9 ± 0.3 or a pH of 5.9 ± 0.2.

[0090] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 150 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises polyethylene glycol or a poloxamer, wherein the formulation has a pH of 5.7 to 6.1.

[0091] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 150 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, wherein the formulation has a pH of 5.7 to 6.1.

[0092] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 150 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM±1.25 mM; (iii) histidine at a concentration of 20 mM±2 mM; (iv) sucrose at a concentration of 5% w / v±0.5% w / v; (v) arginine at a concentration of 25 mM±2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v or a concentration of 0.01% w / v to 0.5% w / v, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2.

[0093] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 150 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM±1.25 mM; (iii) histidine at a concentration of 20 mM±2 mM; (iv) sucrose at a concentration of 5% w / v±0.5% w / v; (v) arginine at a concentration of 25 mM±2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises poloxamer 188, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2.

[0094] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iiii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises polyethylene glycol or a poloxamer, wherein the formulation has a pH of 5.7 to 6.1.

[0095] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1 and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 10 mM to 15 mM; (iii) histidine at a concentration of 15 mM to 25 mM; (iv) sucrose at a concentration of 2.5% w / v to 7.5% w / v; (v) arginine at a concentration of 20 mM to 80 mM; and (vi) PEG3350 or poloxamer 188 at a concentration of 0.01% w / v to 0.19% w / v, wherein the formulation has a pH of 5.7 to 6.1.

[0096] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM±1.25 mM; (iii) histidine at a concentration of 20 mM±2 mM; (iv) sucrose at a concentration of 5% w / v±0.5% w / v; (v) arginine at a concentration of 25 mM±2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v or a concentration of 0.01% w / v to 0.5% w / v, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2.

[0097] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM±1.25 mM; (iii) histidine at a concentration of 20 mM±2 mM; (iv) sucrose at a concentration of 5% w / v±0.5% w / v; (v) arginine at a concentration of 25 mM±2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises poloxamer 188, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2.

[0098] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM±1.25 mM; (iii) histidine at a concentration of 20 mM±2 mM; (iv) sucrose at a concentration of 5% w / v±0.5% w / v; (v) arginine at a concentration of 50 mM±2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v or a concentration of 0.01% w / v to 0.5% w / v, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2.

[0099] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM±1.25 mM; (iii) histidine at a concentration of 20 mM±2 mM; (iv) sucrose at a concentration of 5% w / v±0.5% w / v; (v) arginine at a concentration of 50 mM±2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises poloxamer 188, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2.

[0100] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM±1.25 mM; (iii) histidine at a concentration of 20 mM±2 mM; (iv) sucrose at a concentration of 5% w / v±0.5% w / v; (v) arginine at a concentration of 75 mM±2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v or a concentration of 0.01% w / v to 0.5% w / v, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2.

[0101] In some cases, the stable liquid pharmaceutical formulation comprises: (i) a human antibody at a concentration of 175 mg / mL±10 mg / mL, wherein the antibody specifically binds to human IL-4Rα and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM±1.25 mM; (iii) histidine at a concentration of 20 mM±2 mM; (iv) sucrose at a concentration of 5% w / v±0.5% w / v; (v) arginine at a concentration of 75 mM±2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, wherein the surfactant comprises poloxamer 188, wherein the formulation has a pH of 5.9±0.3 or a pH of 5.9±0.2.

[0102] In any of the various embodiments of the pharmaceutical formulation discussed above or herein, the human IL-4R antibody may comprise a human IgG1 heavy chain constant region.

[0103] In any of the various embodiments of the pharmaceutical formulation discussed above or herein, the human IL-4R antibody may comprise a human IgG4 heavy chain constant region.

[0104] In some embodiments, the human IL-4R antibody may comprise a heavy chain comprising the amino acid sequence of SEQ ID NO:9 and a light chain comprising the amino acid sequence of SEQ ID NO:10.

[0105] Other non-limiting examples of Pharmaceutical Formulations 1 encompassed by the present disclosure are given elsewhere herein, including the working examples given below.

[0106] Stability of drug formulations

[0107] Pharmaceutical preparations of the present disclosure show high levels of stability. As used herein with reference to the term "stable" used in pharmaceutical preparations, it is meant that the antibody in the pharmaceutical preparation maintains an acceptable degree of structure and / or function and / or biological activity after storage for a defined amount of time. The preparation can be stable, even if the antibody contained therein cannot maintain 100% structure and / or function and / or biological activity after storage for a defined amount of time. In some cases, antibody structure and / or function and / or biological activity after storage for a defined amount of time maintains about 90%, about 95%, about 96%, about 97%, about 98% or about 99% and can be considered as "stable".

[0108] Stability can be measured by determining the percentage of antibodies forming aggregates in the formulation after storing a defined amount of time at a defined temperature or under stress conditions (e.g., stirring), wherein stability is inversely proportional to the percentage of aggregates formed. The percentage of aggregated antibodies can be determined in particular by size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC] or size exclusion ultra-high performance liquid chromatography [SE-UPLC]). As used herein, the phrase "acceptable degree of stability" means that after storing a defined amount of time at a given temperature or under specified stress conditions, it is possible to detect antibodies in the form of aggregates in the formulation for up to about 15%, 10%, 5%, 4%, 3%, 2.5%, 2%, 1.5%, 1%, 0.5% or 0.1%. The defined amount of time after stability is measured can be at least 2 weeks, at least 28 days, 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 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months or more. When assessing stability, the temperature at which the pharmaceutical formulation can be stored can be any temperature from about -80°C to about 45°C, for example, stored at about -80°C, about -30°C, about -20°C, about 0°C, about 4°C-8°C, about 5°C, about 25°C, about 35°C, about 37°C or about 45°C. The "stress conditions" to which the formulated antibody may be subjected may be agitation stress (e.g., vortexing) for 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, 70 minutes, 80 minutes, 90 minutes, 100 minutes, 110 minutes, 120 minutes, 150 minutes, 180 minutes, or longer periods of time. For example, a pharmaceutical formulation comprising an anti-IL-4R antibody may be considered stable if less than about 2%, 1.75%, 1.5%, 1.25%, 1%, 0.75%, 0.5%, 0.25%, or 0.1% of the antibody is detected in aggregate form after nine months of storage at 5°C. A pharmaceutical formulation may also be considered stable if less than about 12% of the antibody is detected in aggregate form after 56 days of storage at 45°C. A pharmaceutical formulation may also be considered stable if less than about 10% or less than about 9% of the antibody is detected in aggregate form after 42 days of storage at 45°C. The pharmaceutical formulation may also be considered stable if less than about 8%, less than about 7.5%, or less than about 7% of the antibody is detected in aggregate form after storage at 45°C for 28 days. The pharmaceutical formulation may also be considered stable if less than about 6% of the antibody is detected in aggregate form after storage at 45°C for 14 days. The pharmaceutical formulation may also be considered stable if less than about 2%, 1.9%, 1.8%, 1.7%, 1.6%, 1.5%, 1%, 0.5%, or 0.1% of the antibody is detected in aggregate form after storage at -20°C, -30°C, or -80°C for three months.The pharmaceutical formulation may also be considered stable if less than 3% or less than 2.5% of the antibody is detected in aggregated form after stirring (e.g., by vortexing) at room temperature for 120 minutes. In some cases, the pharmaceutical formulation may be considered stable if after stirring at 25°C for 24 hours, the pharmaceutical formulation contains no more than 4% high molecular weight (HMW) species, as determined by SE-UPLC. In some cases, the formulation may be considered stable if after stirring at 25°C for 24 hours and (i) after storage at 5°C for 6, 12, or 18 months or (ii) after storage at 25°C for 6 months, the formulation contains no more than 4% high molecular weight (HMW) species, as determined by SE-UPLC.

[0109] Stability can also be measured, inter alia, by determining the particle formation within the formulation after storage at a defined temperature for a defined amount of time. Particle formation can be determined, for example, by microscopy techniques or by microfluidic imaging techniques.

[0110] It is known that mammalian cell lines routinely used to produce recombinant antibodies may contain enzymes that can be co-purified with the antibody and present in the pharmaceutical preparation of the antibody. In some cases, such enzymes can degrade the excipients of the pharmaceutical preparation over time, resulting in the formation of sub-visible particles (e.g., about 10-25 μm or larger). For example, phospholipases are lipases that hydrolyze phospholipids into fatty acids and other products. Phospholipases are divided into four major categories: phospholipase A (including phospholipase A1 and phospholipase A2), phospholipase B, and phosphodiesterase (phosphodiesterase C and phosphodiesterase D). In addition to typical phospholipases, phospholipase B-like enzymes residing in the lysosomal cavity are also believed to be involved in lipid catalysis. For example, based on sequence homology and subcellular localization, phospholipase B-like 2 (PLBL2) is speculated to have esterase activity (Jensen et al., Biochem. J. 402: 449-458 (2007)). PLBL2 is highly conserved in hamsters, rats, mice, humans, and cattle, and can be co-purified with certain classes of target proteins (e.g., therapeutic antibodies, such as anti-IL-4R antibodies) prepared in mammalian cell lines in certain processes. Although such enzymes can be removed by purification or inhibitors (e.g., esterase inhibitors) can be added to counteract the enzyme activity (as disclosed, for example, in U.S. Pat. No. 10,342,876), it is also of interest to select excipients that prevent particle formation while also stabilizing the antibody in the pharmaceutical formulation. Therefore, in some embodiments, the formulations of the present disclosure contain a detectable amount of a phospholipase (e.g., PLBL2). Methods for detecting and quantifying the presence and activity of phospholipase are known in the art. In some embodiments, the phospholipase is detected by immunoassay (e.g., ELISA). In some embodiments, the phospholipase is detected by liquid chromatography-mass spectrometry (LC-MS).

[0111] Thus, a pharmaceutical formulation (containing a phospholipase) can be considered stable if no more than a specified number of particles (e.g., 3000, 1000, 500, 250, 100, or 50 particles ≥ 10 microns are identified in each container) are identified in a volume of 2.25 mL after storage at a defined temperature (e.g., 5°C) for a period of time (e.g., 6, 12, 18, 24, or 36 months or longer). For example, a pharmaceutical formulation can be considered stable if no more than 1000 particles are identified in a volume of 2.25 mL by microscopic examination after storage at 5°C for 24 months. A pharmaceutical formulation can also be considered stable if no more than 500 particles are identified in a volume of 2.25 mL by microscopic examination after storage at 5°C for 24 months. A pharmaceutical formulation can also be considered stable if no more than 250 particles are identified in a volume of 2.25 mL by microscopic examination after storage at 5°C for 24 months. A pharmaceutical formulation may also be considered stable if no more than 150 particles are identified in a volume of 2.25 mL by microscopic examination after 24 months of storage at 5°C. A pharmaceutical formulation may also be considered stable if no more than 1000 particles are identified in a volume of 2.25 mL by microscopic examination after 36 months of storage at 5°C. A pharmaceutical formulation may also be considered stable if no more than 500 particles are identified in a volume of 2.25 mL by microscopic examination after 36 months of storage at 5°C. A pharmaceutical formulation may also be considered stable if no more than 250 particles are identified in a volume of 2.25 mL by microscopic examination after 36 months of storage at 5°C. A pharmaceutical formulation may also be considered stable if no more than 150 particles are identified in a volume of 2.25 mL by microscopic examination after 36 months of storage at 5°C. A pharmaceutical formulation may also be considered stable if no more than 100 particles are identified in a volume of 2.25 mL by microscopic examination after storage at 5°C for 36 months. A pharmaceutical formulation may also be considered stable if no more than 50 particles are identified in a volume of 2.25 mL by microscopic examination after storage at 5°C for 36 months.

[0112] Stability can also be measured by determining the percentage of natural antibodies retained in the preparation after a defined amount of time is stored at a given temperature. The percentage of natural antibodies can be determined by size exclusion chromatography (e.g., size exclusion high performance liquid chromatography [SE-HPLC]). As used herein, the phrase "acceptable degree of stability" means that after a given amount of time is stored at a given temperature, at least 90% of the natural form of antibodies can be detected in the preparation. In certain embodiments, after a defined amount of time is stored at a given temperature, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% of the natural form of antibodies can be detected in the preparation. The defined amount of time after measuring stability can be 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 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months or longer. When assessing stability, the temperature at which the pharmaceutical formulation can be stored can be any temperature from about -80°C to about 45°C, for example, stored at about -80°C, about -30°C, about -20°C, about 0°C, about 2°C-8°C, 4°C-8°C, about 5°C, about 25°C, about 35°C, about 37°C, or about 45°C.

[0113] Stability can also be measured, inter alia, by determining the percentage of antibody that migrates in a fraction ("acidic form") that is more acidic than the main fraction of the antibody ("mainly charged form") during ion exchange, wherein stability is inversely proportional to the fraction of antibody in acidic form. Although not wishing to be bound by theory, deamidation of an antibody may cause the antibody to be more negatively charged and therefore more acidic relative to an antibody that is not deamidated (see, e.g., Robinson, N., Protein Deamidation, PNAS, April 16, 2002, 99(8):5283-5288). The percentage of "acidified" antibody can be determined by ion exchange chromatography (e.g., cation exchange high performance liquid chromatography [CEX-HPLC] or cation exchange ultra high performance liquid chromatography [CEX-UPLC]). As used herein, the phrase "acceptable degree of stability" means that after storage at a given temperature for a defined amount of time, the acidic form of the antibody can be detected in the formulation to be at most 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4%, 3%, 2%, 1%, 0.5% or 0.1%. The defined amount of time after measuring stability can be at least 2 weeks, at least 28 days, 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 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 18 months, at least 24 months, at least 30 months, at least 36 months or more. When evaluating stability, the temperature at which the pharmaceutical formulation can be stored can be any temperature from about -80°C to about 45°C, for example, stored at about -80°C, about -30°C, about -20°C, about 0°C, about 4°C-8°C, about 5°C, about 25°C, or about 45°C.

[0114] Measuring the binding affinity of an antibody to its target can also be used to assess stability. For example, a formulation of the present disclosure can be considered stable if the anti-IL-4R antibody contained in the formulation binds to hIL-4Rα with an affinity that is at least 80%, 85%, 90%, 95% or more of the binding affinity of the antibody prior to storage after storage for a defined amount of time (e.g., 14 days to 9 months) at, for example, -80°C, -30°C, -20°C, 5°C, 25°C, 37°C, 45°C, etc. Binding affinity can be determined by any method, such as, for example, ELISA or plasmon resonance. Biological activity can be determined, for example, by measuring the downstream activity of the IL-4R system in the presence of the antibody and comparing the activity to the activity of the IL-4R system in the absence of the antibody.

[0115] Reference to the stability of a pharmaceutical formulation "after" a specified period of time is intended to mean that a stability parameter (e.g., % native form, % HMW species, or % acidic form) is measured at or about the end of the specified period of time, and is not intended to mean that the pharmaceutical formulation must maintain the same degree of stability thereafter. For example, reference to a specific stability after 12 months means that stability measurements are taken at the beginning of the study or about 12 months later. Other methods for assessing antibody stability in a formulation are described in the following examples.

[0116] As demonstrated in the following examples, the present disclosure is based in part on the discovery that the combination of the claimed excipients and an anti-IL-4R antibody results in a long-term (e.g., 36 months) storage-stable formulation.

[0117] Container and method of application

[0118] Pharmaceutical preparations of the present disclosure may be included in any container suitable for storing medicines and other therapeutic compositions. For example, pharmaceutical preparations may be included in sealed and sterilized plastic or glass containers with a defined volume, such as vials, ampoules, syringes, cartridges, bottles, or IV bags. Different types of vials may be used to hold preparations of the present disclosure, including, for example, transparent and opaque (e.g., amber) glass or plastic vials. Similarly, any type of syringe may be used to hold and / or administer pharmaceutical preparations of the present disclosure. In some embodiments, pharmaceutical preparations are contained in prefilled syringes. In some embodiments, pharmaceutical preparations are contained in prefilled syringes with needles.

[0119] The pharmaceutical preparations disclosed herein may be contained in a "standard tungsten" syringe or a "low tungsten" syringe. As will be appreciated by those of ordinary skill in the art, the method of making a glass syringe generally includes the use of a hot tungsten rod for piercing the glass, thereby creating a hole from which a liquid can be drawn and discharged from the syringe. This method results in trace amounts of tungsten being deposited on the inner surface of the syringe. Subsequent cleaning and other processing steps may be used to reduce the amount of tungsten in the syringe. As used herein, the term "standard tungsten" refers to a syringe containing greater than 500 parts per billion (ppb) of tungsten. The term "low tungsten" refers to a syringe containing less than 500 ppb of tungsten. For example, according to the present disclosure, a low tungsten syringe may contain less than about 490, 480, 470, 460, 450, 440, 430, 420, 410, 390, 350, 300, 250, 200, 150, 100, 90, 80, 70, 60, 50, 40, 30, 20, 10 ppb or less of tungsten.

[0120] Rubber plungers used in syringes and rubber stoppers for closing vial openings may be coated to prevent contamination of the drug contents of the syringe or vial and / or to maintain their stability. Thus, according to certain embodiments, the drug formulation of the present disclosure may be contained within a syringe comprising a coated plunger, or contained within a vial sealed with a coated rubber stopper. For example, the plunger or stopper may be coated with a fluorocarbon film. Examples of coated stoppers and / or plungers suitable for use with vials and syringes containing the drug formulation of the present disclosure are mentioned, for example, in U.S. Patents 4,997,423; 5,908,686; 6,286,699; 6,645,635; and 7,226,554, the contents of which are incorporated herein by reference in their entirety. Specific exemplary coated rubber stoppers and plungers that may be used in the context of the present disclosure may be marketed under the trade names Commercially available, it can be obtained from West Pharmaceutical Services, Inc. (Lionville, PA). According to certain embodiments of the present disclosure, the drug formulation can be contained in a low tungsten syringe including a fluorocarbon-coated plunger. In some embodiments, the container is a syringe, such as the Ompi EZ-Fill TM Syringe or BD Neopak TM Syringe. In some cases, the syringe is a 1 mL long glass syringe with a 1 mL iWest plunger, a 27G thin-walled needle, and an FM30 needle shield or a BD260 needle shield. In some cases, the syringe is a 2.25 mL glass syringe (e.g., Nuova Ompi). In various embodiments, the syringe is a 0.5 mL, 0.6 mL, 0.7 mL, 0.8 mL, 0.9 mL, 1.0 mL, 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, 2.0 mL, 2.1 mL, 2.2 mL, 2.3 mL, 2.4 mL, 2.5 mL, 2.6 mL, 2.7 mL, 2.8 mL, 2.9 mL, 3.0 mL, 3.5 mL, 4.0 mL, 4.5 mL, 5.0 mL, 5.5 mL, 6.0 mL, 6.5 mL, 7.0 mL, 7.5 mL, 8.0 mL, 8.5 mL, 9.0 mL, 9.5 mL, or a 10 mL syringe (e.g., a glass syringe).

[0121] The pharmaceutical preparations can be administered to the patient by parenteral routes such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or transdermal, mucosal, nasal, pulmonary and / or oral administration. Many reusable pens and / or automatic syringe delivery devices can be used for subcutaneous delivery of the pharmaceutical preparations of the present disclosure. Examples include, but are not limited to, AUTOPEN TM(0wen Mumford, Inc., Woodstock, UK), DISSETRONIC TM Pen (Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75 / 25 TM Pen, HUMALOG TM Pen, HUMALIN 70 / 30 TM Pen (Eli Lilly and Co., Indianapolis, IN), NOVOPEN TM I, II and III (Novo Nordisk, Copenhagen, Denmark), NOVOPEN JUNIOR TM (Novo Nordisk, Copenhagen, Denmark), BD TM Pen (Becton Dickinson, Franklin Lakes, NJ), OPTIPEN TM 、OPTIPEN PRO TM 、OPTIPEN STARLET TM and OPTICLIK TM (sanofi-aventis, Frankfurt, Germany), etc. Examples of disposable pen and / or auto-injector delivery devices that can be used for subcutaneous delivery of the pharmaceutical compositions of the present disclosure include, but are not limited to, SOLOSTAR TM Pen (sanofi-aventis), FLEXPEN TM (Novo Nordisk), and KWIKPEN TM (Eli Lilly), SURECLICK TM Autoinjector (Amgen, Thousand Oaks, CA), PENLET TM (Haselmeier, Stuttgart, Germany), EPIPEN (Dey, LP), and HUMIRA TM In some cases, the drug formulation is contained in a syringe specifically adapted for use with an auto-injector. Subcutaneous injections can be administered using a 20-30 gauge needle or a 25-30 gauge needle. In some cases, subcutaneous injections can be administered using a 25 gauge needle. In some cases, subcutaneous injections can be administered using a 27 gauge needle. In some cases, subcutaneous injections can be administered using a 29 gauge needle.

[0122] Another type of delivery device may include a safety system. Such devices can be relatively cheap, and once the injection is completed, a safety sleeve can be manually or automatically extended to the needle. Examples of safety systems may include the ERIS device of West Pharmaceutical, or the UltraSafe device of Becton Dickinson. In addition, it is also contemplated herein to use a large volume device ("LVD") or a pellet syringe to deliver the pharmaceutical preparation of the present disclosure. In some cases, an LVD or a pellet syringe may be configured to inject the drug into the patient. For example, an LVD or a pellet syringe may be configured to deliver a "large" volume of drug (typically about 2 mL to about 10 mL).

[0123] In some embodiments, a pharmaceutical composition comprising an anti-IL-4R antibody is administered using a drug delivery device that is a needle-based injection system, as described in Table 1 of Section 5.2 of ISO 11608-1:2014(E). As described in ISO 11608-1:2014(E), needle-based injection systems can be broadly divided into multi-dose container systems and single-dose (partially or fully evacuated) container systems. The container can be a replaceable container or an integral non-replaceable container.

[0124] As further described in ISO 11608-1:2014(E), a multi-dose container system may involve a needle-based injection device with a replaceable container. In such a system, each container contains multiple doses, the size of which may be fixed or variable (preset by the user). Another multi-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In such a system, each container contains multiple doses, the size of which may be fixed or variable (preset by the user).

[0125] As further described in ISO 11608-1:2014 (E), a single-dose container system may involve a needle-based injection device with a replaceable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (completely evacuated). In another example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partially evacuated). In addition, as described in ISO 11608-1:2014 (E), a single-dose container system may involve a needle-based injection device with an integrated non-replaceable container. In one example of such a system, each container holds a single dose, thereby discharging the entire deliverable volume (completely evacuated). In another example, each container holds a single dose, thereby discharging a portion of the deliverable volume (partially evacuated).

[0126] An exemplary sleeve-triggered autoinjector with manual needle inserter is described in International Publication WO2015 / 004052. An exemplary audible end-of-dose feedback mechanism is described in International Publications WO2016 / 193346 and WO2016 / 193348. An exemplary needle safety mechanism after use of the autoinjector is described in International Publication WO2016 / 193352. An exemplary needle sheath remover mechanism for a syringe autoinjector is described in International Publication WO2016 / 193353. An exemplary support mechanism for supporting the axial position of the syringe is described in International Publication WO2016 / 193355.

[0127] The pharmaceutical formulations of the present disclosure may also be contained in unit dosage form. As used herein, the term "unit dosage form" refers to physically discrete units suitable as single doses for a patient to be treated, each unit containing a predetermined amount of active compound in combination with a desired pharmaceutical carrier, diluent or excipient calculated to produce the desired therapeutic effect. In various embodiments, the unit dosage form is contained in a container as described herein. The actual dosage level of the active ingredient (e.g., anti-IL-4R antibody) in the formulations of the present disclosure may be varied so as to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without adverse effects on the patient. The selected dosage level will depend on a variety of pharmacokinetic factors, including the activity of the particular composition of the present disclosure used, the route of administration, the time of administration, the excretion rate of the particular compound used, the duration of the treatment, other drugs, compounds and / or materials used in combination with the particular composition used, the age, sex, weight, condition, general health and previous medical history of the patient to be treated, and similar factors well known in the medical arts. As used herein, the term "diluent" refers to a solution suitable for altering or achieving an exemplary or appropriate concentration or the concentrations described herein.

[0128] In various embodiments, the unit dosage form contains an amount of active ingredient (e.g., an anti-IL-4R antibody) intended for single use. In various embodiments, the amount of active ingredient in the unit dosage form is about 0.1 mg to about 5000 mg, about 100 mg to about 1000 mg, about 100 mg to about 500 mg, about 100 mg to about 400 mg, about 100 mg to about 200 mg, about 250 mg to about 350 mg, about 125 mg to about 175 mg, about 275 mg to about 325 mg, or a range or interval thereof. For example, a range of values ​​using a combination of any of the above values ​​(or a value included in the above range) as an upper and / or lower limit is intended to be included. In a specific embodiment, the formulation is generally provided in a liquid form of a unit dosage form. In some embodiments, the unit dosage form contains about 100 mg of active ingredient. In some embodiments, the unit dosage form contains about 150 mg. In some embodiments, the unit dosage form contains about 200 mg. In some embodiments, the unit dosage form contains about 300 mg. In some embodiments, the unit dosage form contains about 350 mg. In some embodiments, the unit dosage form contains about 600 mg. In some embodiments, the unit dosage form according to the present disclosure is suitable for subcutaneous administration to a patient.

[0129] The present disclosure also includes methods of preparing unit dosage forms.In an exemplary embodiment, a method of preparing a pharmaceutical unit dosage form comprises combining any of the formulations of the preceding embodiments in a suitable container, such as those discussed herein.

[0130] Therapeutic use of pharmaceutical preparations

[0131] The pharmaceutical formulations of the present disclosure are particularly useful for treating, preventing and / or ameliorating any disease or disorder associated with IL-4R activity.

[0132] The treatment methods disclosed herein include administering to a subject any formulation comprising an anti-hIL-4R antibody as disclosed herein. The subject to whom the pharmaceutical formulation is administered can be, for example, any human or non-human animal in need of such treatment, prevention and / or improvement, or a human or non-human animal that can benefit from inhibiting or attenuating IL-4R and / or IL-4R-mediated activity. The present disclosure also includes the use of any of the pharmaceutical formulations disclosed herein in the manufacture of a medicament for treating, preventing and / or ameliorating any disease or disorder associated with IL-4R activity.

[0133] In some embodiments, the disease or disorder associated with IL-4R activity is an inflammatory disorder, an allergic disorder, a pulmonary / respiratory condition, a gastrointestinal condition, or a skin condition. In some embodiments, the disease or disorder is a type 2 inflammatory condition. In some embodiments, the disease or disorder is an atopic disease. Non-limiting examples of diseases and disorders associated with IL-4R activity include allergies (e.g., food allergies or environmental allergies), anaphylaxis, allergic bronchopulmonary aspergillosis, alopecia areata, asthma (including mild, moderate or severe asthma, persistent asthma or allergic asthma), arthritis (including septic arthritis), atopic dermatitis (including moderate or severe atopic dermatitis), atopic keratoconjunctivitis, autoimmune hemolytic anemia, autoimmune lymphoproliferative syndrome, autoimmune uveitis, Barrett's esophagus, benign prostatic hyperplasia, bronchiectasis, bullous pemphigoid, Churg-Strauss syndrome, chronic idiopathic urticaria, chronic induced urticaria, cold-induced urticaria, Urticaria, contact dermatitis (e.g., allergic contact dermatitis), COPD, eosinophilic esophagitis, eosinophilic duodenitis, eosinophilic gastroenteritis, Graves' disease, dermatitis herpetiformis, hypertrophic scarring, inflammatory bowel disease, Kawasaki disease, nasal polyposis, kidney disease, Netherton syndrome, preeclampsia, prurigo nodularis, pruritus (e.g., chronic pruritus of unknown cause), rhinitis (e.g., allergic rhinitis), sinusitis (e.g., allergic fungal sinusitis, chronic sinusitis with or without nasal polyps), scleroderma, sickle cell disease, Sjögren's syndrome, tuberculosis, ulcerative colitis, and Whipple's disease.

[0134] In some embodiments, the disclosure provides a kit comprising a pharmaceutical formulation discussed herein (e.g., a container containing a formulation or unit dosage form), and packaging or labeling (e.g., a package insert) having instructions for using the pharmaceutical formulation to treat a disease or disorder discussed herein. In some cases, the instructions provide the use of a unit dosage form as discussed herein for treating a disease or disorder.

[0135] A summary of the sequences cited herein and the corresponding SEQ ID NOs is shown in Table 1 below.

[0136] Table 1: Informal Sequence Listing

[0137]

[0138]

[0139]

[0140]

[0141]

[0142]

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155] Example

[0156] The following examples are provided to provide a person of ordinary skill in the art with a complete disclosure and description of how to prepare and use the methods and compositions of the present invention, and are not intended to limit the scope of what the inventors consider to be their invention. Efforts have been made to ensure the accuracy of the numbers used (e.g., amounts, temperatures, etc.), but certain experimental errors and deviations should be considered. Unless otherwise indicated, parts are parts by weight, molecular weights are average molecular weights, temperatures are in degrees Celsius, and pressures are at or near atmospheric pressure.

[0157] Example 1: Use of PEG 3350 or Poloxamer 188 to prevent particle formation in lipase-containing formulations

[0158] Without wishing to be bound by theory, it is believed that a putative phospholipase B-like 2 (PLBL2) (highly conserved in hamster, rat, mouse, human, and cattle) co-purifies with some classes of target proteins produced in certain cell lines in certain processes and has esterase activity responsible for hydrolyzing polysorbate 20 and 80. As an alternative to removing the lipase by the purification process (e.g., as described in U.S. Pat. No. 10,342,876), alternative surfactants were used to prepare formulations of IL-4R antibodies and particle formation was measured over time. An anti-IL-4R antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 was formulated at a concentration of 150 mg / mL mAb1 with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, 5% w / v sucrose, and varying concentrations of PEG3350 or poloxamer 188 at pH 5.9. The formulations were stored in syringes at 5°C for up to 36 months and the number of particles (≥10 μm and ≥25 μm) present in the formulations was measured regularly by microscopic examination.

[0159] like Figure 1 As shown, a small number of particles ≥10 μm or ≥25 μm were identified in the formulations during the 36-month observation period. In addition, no significant differences or changes in the number of subvisible particles were observed between different formulations containing PEG3350 or poloxamer 188 during storage. This experiment shows that low concentrations of PEG3350 or poloxamer 188 can prevent particle formulations during long-term storage.

[0160] Example 2: Stirring stress stability of formulations containing PEG 3350 or poloxamer 188

[0161] Stirring stress stability tests were performed on IL-4R antibody formulations containing different concentrations of the surfactant PEG3350 or poloxamer 188. Anti-IL-4R antibodies comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 were formulated at a concentration of 150 mg / mL with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, 5% w / v sucrose, and different concentrations of PEG3350 or poloxamer 188 at pH 5.9. The formulations were stored in glass vials and stirred by vortexing (speed setting = 4) for 30 minutes, 60 minutes, or 120 minutes. The percentage of high molecular weight (HMW) species was then determined by size exclusion ultra-performance liquid chromatography (SE-UPLC).

[0162] like Figure 2AAs shown, antibody formulations containing at least 0.01% (w / v) PEG3350 can prevent the significant increase of HMW species due to stirring (quantified by SE-UHPLC). Smaller amounts of PEG3350 (0.001% or 0.005%) are not sufficient to prevent the formation of HMW. Similarly, Figure 2B As shown, antibody formulations containing at least 0.01% (w / v) poloxamer 188 prevented a significant increase in HMW species, but HMW species were observed with lower amounts of poloxamer 188 (0.001% or 0.005%).

[0163] Example 3: Thermal Stress Stability of Formulations Containing PEG3350 or Poloxamer 188

[0164] The heat stress stability of IL-4R antibody formulations containing PEG3350 or poloxamer 188 was tested and compared to various IL-4R antibody formulations containing polysorbates. Anti-IL-4R antibodies comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 were formulated at a concentration of 150 mg / mL with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, 5% w / v sucrose, and various concentrations of polysorbate 20, polysorbate 80, PEG3350, or poloxamer 188 at pH 5.9. These formulations were subjected to heat stress (45°C) for a period of up to 56 days, and the percentage of high molecular weight (HMW) species was determined by size exclusion ultra-performance liquid chromatography (SE-UPLC) at 7, 14, 28, 42, and 56 days.

[0165] like Figure 3 As shown, antibody formulations containing PEG3350 or poloxamer 188 at a concentration of 0.01% or 0.02% exhibited thermal stability similar to antibody formulations containing lower amounts of polysorbate (up to 0.1% w / v). By 28 days, formulations containing PEG3350 or poloxamer 188 exhibited a lower percentage of HMW species than the control formulation containing 0.2% polysorbate 20.

[0166] Example 4: Thermal Stress Stability of Formulations Containing Different Concentrations of Poloxamer 188 or PEG 3350

[0167] The heat stress stability of IL-4R antibody formulations containing different concentrations of poloxamer 188 or PEG3350 was tested under heat stress conditions (45°C) for up to 3 months. The anti-IL-4R antibody comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 was formulated with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, 5% w / v sucrose and surfactant [0.2% w / v polysorbate 80, 0.01% w / v, 0.1% w / v or 0.5% w / v poloxamer 188, or 0.01% w / v, 0.1% w / v or 0.5% w / v PEG3350] at a concentration of 150 mg / mL at pH 5.9. These formulations were stored in glass vials at 45°C for 1, 2 or 3 months. The percentage of recovered drug product (antibody) was determined by reverse phase ultra-performance liquid chromatography (RP-UPLC). The percentage of high molecular weight (HMW) species was determined by size exclusion ultra-performance liquid chromatography (SE-UPLC). The formation of charge variant species was measured by cation exchange ultra-performance liquid chromatography (CEX-UPLC). Microflow imaging (MFI) was used to measure sub-visible particles.

[0168] Table 2 shows the stability data of formulations containing 0.2% (w / v) polysorbate 80 at 0, 1 and 3 months. Tables 3, 4 and 5 show the stability data of formulations containing 0.01%, 0.1% and 0.5% poloxamer 188, respectively. Tables 6, 7 and 8 show the stability data of formulations containing 0.01%, 0.1% and 0.5% PEG3350, respectively. As shown in Tables 3 and 6, even the lowest tested concentrations of poloxamer 188 and PEG3350 (0.01%) provide a similar degree of protection as 0.2% polysorbate 80. The 0.01% poloxamer 188 formulation exhibits similar stability characteristics to 0.1% and 0.5% poloxamer 188 (see, Tables 3-5). The 0.01% PEG3350 formulation exhibits similar stability characteristics to 0.1% and 0.5% PEG3350 (see, Tables 6-8).

[0169] Table 2: Stability data of formulations containing 0.2% (w / v) polysorbate 80

[0170]

[0171]

[0172] Table 3: Stability data of formulations containing 0.01% (w / v) poloxamer 188

[0173]

[0174] Table 4: Stability data of formulations containing 0.1% (w / v) poloxamer 188

[0175]

[0176] Table 5: Stability data of formulations containing 0.5% (w / v) Poloxamer 188

[0177]

[0178]

[0179] Table 6: Stability data of formulations containing 0.01% (w / v) PEG3350

[0180]

[0181] Table 7: Stability data of formulations containing 0.1% (w / v) PEG3350

[0182]

[0183] Table 8: Stability data of formulations containing 0.5% (w / v) PEG3350

[0184]

[0185]

[0186] Example 5: Stability data of formulations containing different concentrations of poloxamer 188 or PEG 3350 under storage and stress conditions

[0187] The stability of IL-4R antibody formulations with different concentrations of poloxamer 188 or PEG3350 was tested under storage conditions of 5°C for up to 18 months, accelerated conditions (25°C for up to 6 months), heat stress conditions (45°C for up to 2 months), and agitation stress conditions. Anti-IL-4R antibodies comprising the HCVR / LCVR amino acid sequence pair of SEQ ID NO: 1 / 2 were formulated with 20 mM histidine, 12.5 mM sodium acetate, 25 mM arginine-HCl, and 5% w / v sucrose at a concentration of 150 mg / mL in the absence of surfactant or in the presence of 0.02% w / v, 0.04% w / v, or 0.1% w / v of poloxamer 188 or PEG3350, pH 5.9. These formulations were stored in Nuova Ompi 2.25 mL syringes. The percentage of HMW species was determined by SE-UPLC. The formation of charge variant species was measured by CEX-UPLC. Film microscopy and / or MFI is used to measure the number of particles in the container.

[0188] Tables 9-11 show data for formulations without surfactant. Tables 12-14, 15-17 and 18-20 show stability data for formulations containing 0.02%, 0.04% and 0.1% (w / v) poloxamer 188, respectively. Tables 21-23, 24-26 and 27-29 show stability data for formulations containing 0.02%, 0.04% and 0.1% (w / v) PEG3350, respectively. As shown in Tables 12, 15 and 18, formulations containing 0.02%, 0.04% or 0.1% (w / v) poloxamer significantly reduced particles after long-term storage (up to 18 months) at 5°C. Similarly, as shown in Tables 21, 24 and 27, formulations containing 0.02%, 0.04% or 0.1% PEG3350 significantly reduced particles after long-term storage (up to 18 months) at 5°C. Under accelerated conditions at 25°C or heat stress conditions at 45°C, formulations containing 0.02%, 0.04% or 0.1% (w / v) poloxamer 188 or PEG3350 had significantly fewer subvisible particles than formulations without surfactant (see, Tables 10, 13, 16, 19, 22, 25 and 28).

[0189] The formulations were subjected to agitation stress at 25°C for 24 hours and then stored as follows: 6, 12 or 18 months at 5°C, 6 months at 25°C, or 1 or 2 months at 45°C. Compared with formulations without surfactant, formulations containing 0.02%, 0.04% or 0.1% (w / v) poloxamer 188 or PEG3350 significantly reduced the formation of HMW species after stirring at 25°C for 24 hours. In addition, formulations containing 0.02%, 0.04% or 0.1% (w / v) poloxamer 188 or PEG3350 showed less HMW species after stirring for 24 hours and long-term storage at 5°C or 25°C compared to formulations without surfactant, indicating improved stability. See Tables 11, 14, 17, 20, 23, 26 and 29.

[0190] Table 9: Storage stability data of formulations without surfactant (5°C)

[0191]

[0192] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0193] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0194] Table 10: Accelerated Storage and Heat Stress Stability Data for Formulations without Surfactants

[0195]

[0196]

[0197] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0198] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0199] Table 11: Stir stress stability data for formulations without surfactant

[0200]

[0201] * Stir at 25°C for 24 hours and then store at the specified temperature

[0202] HMW = high molecular weight; LMW = low molecular weight

[0203] Table 12: Storage stability data of formulations containing 0.02% (w / v) poloxamer 188 (5°C)

[0204]

[0205]

[0206] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0207] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0208] Table 13: Accelerated Storage and Heat Stress Stability Data for Formulations Containing 0.02% (w / v) Poloxamer 188

[0209]

[0210]

[0211] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0212] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0213] Table 14: Stir stress stability data of formulations containing 0.02% (w / v) Poloxamer 188

[0214]

[0215] * Stir at 25°C for 24 hours and then store at the specified temperature

[0216] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0217] Table 15: Storage stability data of formulations containing 0.04% (w / v) poloxamer 188 (5°C)

[0218]

[0219]

[0220] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0221] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0222] Table 16: Accelerated Storage and Heat Stress Stability Data for Formulations Containing 0.04% (w / v) Poloxamer 188

[0223]

[0224]

[0225] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0226] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0227] Table 17: Stir stress stability data of formulations containing 0.04% (w / v) Poloxamer 188

[0228]

[0229] * Stir at 25°C for 24 hours and then store at the specified temperature

[0230] HMW = high molecular weight; LMW = low molecular weight

[0231] Table 18: Storage stability data of formulations containing 0.1% (w / v) poloxamer 188 (5°C)

[0232]

[0233]

[0234] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0235] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0236] Table 19: Accelerated Storage and Heat Stress Stability Data for Formulations Containing 0.1% (w / v) Poloxamer 188

[0237]

[0238]

[0239] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0240] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0241] Table 20: Stir stress stability data of formulations containing 0.1% (w / v) Poloxamer 188

[0242]

[0243] * Stir at 25°C for 24 hours and then store at the specified temperature

[0244] HMW = high molecular weight; LMW = low molecular weight

[0245] Table 21: Storage stability data of formulations containing 0.02% (w / v) PEG3350 (5°C)

[0246]

[0247]

[0248] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0249] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0250] Table 22: Accelerated storage and heat stress stability data of formulations containing 0.02% (w / v) PEG3350

[0251]

[0252]

[0253] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0254] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0255] Table 23: Stirring stress stability data for formulations containing 0.02% (w / v) PEG3350

[0256]

[0257] * Stir at 25°C for 24 hours and then store at the specified temperature

[0258] HMW = high molecular weight; LMW = low molecular weight

[0259] Table 24: Storage stability data of formulations containing 0.04% (w / v) PEG3350 (5°C)

[0260]

[0261]

[0262] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0263] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0264] Table 25: Accelerated storage and heat stress stability data of formulations containing 0.04% (w / v) PEG3350

[0265]

[0266]

[0267] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0268] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0269] Table 26: Stirring stress stability data for formulations containing 0.04% (w / v) PEG3350

[0270]

[0271] * Stir at 25°C for 24 hours and then store at the specified temperature

[0272] HMW = high molecular weight; LMW = low molecular weight

[0273] Table 27: Storage stability data of formulations containing 0.1% (w / v) PEG3350 (5°C)

[0274]

[0275]

[0276] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0277] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0278] Table 28: Accelerated storage and heat stress stability data of formulations containing 0.1% (w / v) PEG3350

[0279]

[0280] a Microscope inspection USP description: ≥10μm particle size ≤3000 particles / container; ≥25μm particle size ≤300 particles / container

[0281] HMW = high molecular weight; LMW = low molecular weight; N / A = not available

[0282] Table 29: Stirring stress stability data for formulations containing 0.1% (w / v) PEG3350

[0283]

[0284] * Stir at 25°C for 24 hours and then store at the specified temperature

[0285] HMW = high molecular weight; LMW = low molecular weight

[0286] The scope of the present invention is not limited by the specific embodiments described herein. In fact, various modifications of the present invention, except those described herein, will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0287] Table 30: Sequences excluded from ST.26 format sequence listing

[0288] SEQ ID NO: sequence 7 LGS

[0289] *******

Claims

1. A stable liquid pharmaceutical preparation, comprising: (i) a human antibody that specifically binds to human interleukin-4 receptor α (hIL-4Rα): (ii) one or more buffers; (iii) heat stabilizers; (iv) a viscosity modifier; and (v) a surfactant comprising polyethylene glycol or poloxamer at a concentration of 0.01% w / v to 0.19% w / v, wherein the formulation has a pH of 5.7 to 6.

1.

2. The stable liquid pharmaceutical formulation of claim 1, wherein the antibody comprises a heavy chain variable region (HCVR) comprising complementary determining regions HCDR1, HCDR2 and HCDR3 comprising the amino acid sequences of SEQ ID NOs: 3, 4 and 5, respectively, and a light chain variable region (LCVR) comprising complementary determining regions LCDR1, LCDR2 and LCDR3 comprising the amino acid sequences of SEQ ID NOs: 6, 7 and 8, respectively.

3. The stable liquid pharmaceutical formulation of claim 2, wherein the antibody comprises a HCVR and a LCVR, the HCVR comprising the amino acid sequence of SEQ ID NO: 1, and the LCVR comprising the amino acid sequence of SEQ ID NO:

2.

4. The stable liquid pharmaceutical formulation of any one of claims 1 to 3, wherein the antibody has a human IgG heavy chain constant region.

5. The stable liquid pharmaceutical formulation of claim 4, wherein the heavy chain constant region is of isotype IgG1.

6. The stable liquid pharmaceutical formulation of claim 4, wherein the heavy chain constant region is of isotype IgG4.

7. The stable liquid pharmaceutical formulation of any one of claims 1 to 3, wherein the antibody comprises a heavy chain and a light chain, the heavy chain comprising the amino acid sequence of SEQ ID NO: 9, and the light chain comprising the amino acid sequence of SEQ ID NO:

10.

8. The stable liquid pharmaceutical formulation of any one of claims 1 to 7, wherein the surfactant is polyethylene glycol.

9. The stable liquid pharmaceutical formulation of claim 8, wherein the polyethylene glycol is PEG3350.

10. The stable liquid pharmaceutical formulation of any one of claims 1 to 7, wherein the surfactant is a poloxamer.

11. The stable liquid pharmaceutical formulation of claim 10, wherein the poloxamer is poloxamer 188.

12. The stable liquid pharmaceutical formulation of any one of claims 1 to 11, wherein the buffer comprises an acetate buffer and / or a histidine buffer.

13. The stable liquid pharmaceutical formulation of claim 12, wherein the buffer comprises acetate at a concentration of 10 mM to 15 mM.

14. The stable liquid pharmaceutical formulation of claim 13, wherein the acetate is present at a concentration of 12.5 mM ± 1.25 mM.

15. The stable liquid pharmaceutical formulation of claim 12, wherein the buffer comprises histidine at a concentration of 15 mM to 25 mM.

16. The stable liquid pharmaceutical formulation of claim 15, wherein the histidine is present at a concentration of 20 mM ± 2 mM.

17. The stable liquid pharmaceutical formulation of any one of claims 1 to 16, wherein the thermal stabilizer is sucrose at a concentration of 2.5% w / v to 7.5% w / v.

18. The stable liquid pharmaceutical formulation of claim 17, wherein the sucrose is present at a concentration of 5% w / v ± 0.5% w / v.

19. The stable liquid pharmaceutical formulation of any one of claims 1 to 18, wherein the viscosity modifier is arginine at a concentration of 20 mM to 80 mM.

20. The stable liquid pharmaceutical formulation of claim 19, wherein the arginine is present at a concentration of 25 mM ± 2.5 mM.

21. The stable liquid pharmaceutical formulation of claim 19, wherein the arginine is present at a concentration of 50 mM ± 2.5 mM.

22. The stable liquid pharmaceutical formulation of claim 19, wherein the arginine is present at a concentration of 75 mM ± 2.5 mM.

23. The stable liquid pharmaceutical formulation of any one of claims 1 to 22, wherein the antibody is present at a concentration of up to 200 mg / mL.

24. The stable liquid pharmaceutical formulation of any one of claims 1 to 23, wherein the antibody is present at a concentration of 100 mg / mL to 200 mg / mL.

25. The stable liquid pharmaceutical formulation of claim 24, wherein the antibody is present at a concentration of 150 mg / mL ± 15 mg / mL.

26. The stable liquid pharmaceutical formulation of claim 24, wherein the antibody is present at a concentration of 175 mg / mL ± 15 mg / mL.

27. A stable liquid pharmaceutical formulation, comprising: (i) a human antibody at a concentration of 150 mg / mL±10 mg / mL, wherein the antibody specifically binds to human interleukin-4 receptor α (hIL-4Rα) and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM ± 1.25 mM; (iii) histidine at a concentration of 20 mM ± 2 mM; (iv) sucrose at a concentration of 5% w / v ± 0.5% w / v; (v) arginine at a concentration of 25 mM ± 2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, the surfactant comprising PEG3350 or poloxamer 188, wherein the formulation has a pH of 5.9±0.

2.

28. A stable liquid pharmaceutical formulation, comprising: (i) a human antibody at a concentration of 175 mg / mL ± 10 mg / mL, wherein the antibody specifically binds to human interleukin-4 receptor α (hIL-4Rα) and comprises a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 1, and a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 2; (ii) acetate at a concentration of 12.5 mM ± 1.25 mM; (iii) histidine at a concentration of 20 mM ± 2 mM; (iv) sucrose at a concentration of 5% w / v ± 0.5% w / v; (v) arginine at a concentration of 25 mM ± 2.5 mM; and (vi) a surfactant at a concentration of 0.01% w / v to 0.19% w / v, the surfactant comprising PEG3350 or poloxamer 188, wherein the formulation has a pH of 5.9±0.

2.

29. The stable liquid pharmaceutical formulation of claim 27 or claim 28, wherein the antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO:

10.

30. The stable liquid pharmaceutical formulation of any one of claims 1 to 29, wherein the formulation contains a phospholipase protein.

31. The stable liquid pharmaceutical formulation of any one of claims 1 to 30, wherein the formulation comprises no more than 3% high molecular weight (HMW) species as determined by size exclusion-ultra performance liquid chromatography (SE-UPLC) after vortexing for up to 120 minutes at room temperature.

32. The stable liquid pharmaceutical formulation of claim 31, wherein the formulation comprises no more than 2.5% high molecular weight (HMW) species as determined by SE-UPLC after vortexing for up to 120 minutes at room temperature.

33. The stable liquid pharmaceutical formulation of any one of claims 1 to 30, wherein the formulation contains no more than 8% high molecular weight (HMW) species after storage at 45°C for 30 days as determined by SE-UPLC.

34. The stable liquid pharmaceutical formulation of any one of claims 1 to 30, wherein the formulation contains no more than 9% high molecular weight (HMW) species after storage at 45°C for 40 days as determined by SE-UPLC.

35. The stable liquid pharmaceutical formulation of any one of claims 1 to 30, wherein the formulation contains no more than 11% high molecular weight (HMW) species after storage at 45°C for 50 days as determined by SE-UPLC.

36. The stable liquid pharmaceutical formulation of any one of claims 1 to 35, wherein the formulation contains no more than 1000, no more than 500, or no more than 150 particles with a diameter ≥ 10 μm in a volume of 2.25 mL after storage at 5°C for 6 months, as determined by microscopic examination, and wherein the formulation contains a phospholipase protein.

37. The stable liquid pharmaceutical formulation of any one of claims 1 to 35, wherein the formulation contains no more than 1000, no more than 500, or no more than 150 particles with a diameter ≥ 10 μm in a volume of 2.25 mL after storage at 5°C for 36 months, as determined by microscopic examination, and wherein the formulation contains a phospholipase protein.

38. The stable liquid pharmaceutical formulation of any one of claims 1 to 35, wherein the formulation contains no more than 500, no more than 250, or no more than 50 particles with a diameter ≥ 25 μm in a volume of 2.25 mL after storage at 5°C for 6 months as determined by microscopic examination, and wherein the formulation contains a phospholipase protein.

39. The stable liquid pharmaceutical formulation of any one of claims 1 to 35, wherein the formulation contains no more than 500, no more than 250, or no more than 50 particles with a diameter ≥ 25 μm in a volume of 2.25 mL after storage at 5°C for 6 months, as determined by microscopic examination, and wherein the formulation contains a phospholipase protein.

40. The stable liquid pharmaceutical formulation of any one of claims 36 to 39, wherein the phospholipase protein is a phospholipase B-like 2 protein.

41. The stable liquid pharmaceutical formulation of any one of claims 1 to 35, wherein the formulation contains no more than 4% high molecular weight (HMW) species after stirring at 25°C for 24 hours as determined by SE-UPLC.

42. The stable liquid pharmaceutical formulation of any one of claims 1 to 35, wherein the formulation contains no more than 4% high molecular weight (HMW) species after stirring at 25°C for 24 hours and (i) storage at 5°C for 6, 12 or 18 months or (ii) storage at 25°C for 6 months as determined by SE-UPLC.

43. The stable liquid pharmaceutical formulation of any one of claims 1 to 42, contained in a glass vial.

44. The stable liquid drug formulation of any one of claims 1 to 42, contained in a syringe.

45. The stable liquid drug formulation of claim 44, wherein the syringe comprises a fluorocarbon coated plunger.

46. ​​The stable liquid pharmaceutical formulation of claim 44, wherein the syringe is a low tungsten syringe.

47. The stable liquid pharmaceutical formulation of any one of claims 44 to 46, which is a pre-filled syringe.

48. The stable liquid pharmaceutical formulation of claim 47, which is a pre-filled syringe with a needle.

49. The stable liquid pharmaceutical formulation of any one of claims 1 to 42, contained in a large volume device or a bolus syringe.

50. A pen or auto-injector delivery device containing the stable liquid drug formulation of any one of claims 1 to 42.

51. The delivery device of claim 50, which is a disposable pen delivery device.

52. The delivery device of claim 50, which is a reusable pen delivery device.

53. A container containing the stable liquid pharmaceutical formulation of any one of claims 1 to 42.

54. A kit comprising (i) a container containing the stable liquid pharmaceutical formulation of any one of claims 1 to 42, and (ii) a label for using the pharmaceutical formulation.

55. The kit of claim 54, wherein the label indicates that the pharmaceutical formulation is to be administered subcutaneously.

56. The kit of claim 54, wherein the label indicates that the pharmaceutical formulation is to be administered intravenously.

57. A unit dosage form comprising the stable liquid pharmaceutical formulation of any one of claims 1 to 42, wherein the antibody is present in an amount of 1 mg to 500 mg.

58. The unit dosage form of claim 57, wherein said antibody is present in an amount of about 300 mg.

59. The unit dosage form of claim 57, wherein said antibody is present in an amount of about 200 mg.

60. The unit dosage form of claim 57, wherein said antibody is present in an amount of about 100 mg.

61. The unit dosage form of any one of claims 57 to 60, wherein said formulation is contained in a syringe.

62. The unit dosage form of claim 61, wherein said syringe is a prefilled syringe.

63. A safe system delivery device comprising the stable liquid drug formulation of any one of claims 1 to 42.

64. The safety system delivery device of claim 63, comprising a safety sleeve configured to be extended by manual manipulation.

65. The safe system delivery device of claim 63, comprising a safety sleeve configured to automatically extend after injection of the stable liquid drug formulation.

Images